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A M E R I C A N D I A B E T E S A S S O C I AT I O N
STANDARDS OF
MEDICAL CARE
IN DIABETES—2018
ISSN 0149-5992
January 2018 Volume 41, Supplement 1
[T]he simple word Care may suffice to express [the journal’s] philosophical
mission. The new journal is designed to promote better patient care by serving
the expanded needs of all health professionals committed to the care
of patients with diabetes. As such, the American Diabetes Association views
Diabetes Care as a reaffirmation of Francis Weld Peabody’s contention that
“the secret of the care of the patient is in caring for the patient.”
—Norbert Freinkel, Diabetes Care, January-February 1978
EDITOR IN CHIEF
Matthew C. Riddle, MD
Keep up with the latest information for Diabetes Care and other ADA titles via Facebook (/ADAJournals) and Twitter (@ADA_Journals).
Diabetes Care Volume 41, Supplement 1, January 2018 S3
The Professional Practice Committee (see pp. S154–S155). The ADA funds CPsychol; Jane Reusch, MD; and
(PPC) of the American Diabetes Asso- de-velopment of the Standards of Care Sharon Solomon, MD.
ciation (ADA) is responsible for the out of its general revenues and does not
“Standards of Medical Care in Diabetes” use in-dustry support for this purpose. MEMBERS OF THE PPC
position statement, referred to as the For the current revision, PPC members
Rita R. Kalyani, MD, MHS, FACP (Chair)
Standards of Care. The PPC is a multidis- systematically searched MEDLINE for hu-
ciplinary expert committee comprised of man studies related to each section and Christopher P. Cannon, MD
physicians, diabetes educators, regis-tered published since 1 January 2017. Recom-
Andrea L. Cherrington, MD,
MPH* Donald R. Coustan, MD
dietitians, and others who have expertise mendations were revised based on new
in a range of areas, including adult and evidence or, in some cases, to clarify the Ian H. de Boer, MD, MS*
pediatric endocrinology, epi-demiology, prior recommendation or match the
Hope Feldman, CRNP,
public health, lipid research, hypertension,
FNP-BC Judith Fradkin, MD
strength of the wording to the strength of
David Maahs, MD, PhD
preconception planning, and pregnancy the evidence. A table linking the changes in
care. Appointment to the PPC is based on recommendations to new ev-idence can be
Melinda Maryniuk, MEd, RD,
CDE Medha N. Munshi, MD*
excellence in clinical practice and reviewed at professional
Joshua J. Neumiller, PharmD, CDE,
research. Although the pri-mary role of the .diabetes.org/SOC. The Standards of
FASCP Guillermo E. Umpierrez, MD,
PPC is to review and update the Care was approved by ADA’s Board of
CDE, FACE, FACP* *Subgroup leaders
Standards of Care, it may also be involved Directors, which includes health care
in ADA statements, re-ports, and reviews. professionals, scientists, and lay people.
Feedback from the larger clinical com- AMERICAN COLLEGE OF
The ADA adheres to the National munity was valuable for the 2017 CARDIOLOGY—DESIGNATED
Academy of Medicine Standards for De- revision of the Standards of Care. REPRESENTATIVES (SECTION 9)
veloping Trustworthy Clinical Practice Readers who wish to comment on the Sandeep Das, MD, MPH, FACC
Guidelines. All members of the PPC are 2018 Standards of Care are invited to do Mikhail Kosiborod, MD, FACC
required to disclose potential con-flicts so at professional .diabetes.org/SOC.
of interest with industry and/or other The PPC would like to thank the follow-
relevant organizations. These dis- ing individuals who provided their exper- ADA STAFF
closures are discussed at the onset of tise in reviewing and/or consulting with the Erika Gebel Berg, PhD
each Standards of Care revision meet- committee: Pamela Allweiss, MD, MPH; (Corresponding author: eberg@diabetes.org)
ing. Members of the committee, their David D’Alessio, MD; Thomas Gardner, Tamara Darsow, PhD
employers, and their disclosed conflicts MD, MS; William H. Herman, MD, MPH; Matthew P. Petersen
of interest are listed in the “Professional Felicia Hill-Briggs, PhD; Nisa Maruthur, Sacha Uelmen, RDN, CDE
Practice Committee Disclosures” table MD, MHS; Alicia McAuliffe-Fogarty, PhD, William T. Cefalu, MD
© 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational
and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
Diabetes Care Volume 41, Supplement 1, January 2018 S1
INTRODUCTION
Introduction: Standards of Medical
Care in Diabetesd2018
Diabetes Care 2018;41(Suppl. 1):S1–S2 | https://doi.org/10.2337/dc18-SINT01
Diabetes is a complex, chronic illness re- continue to rely on them as the most au- current position. The Standards of Care
quiring continuous medical care with mul- thoritative and current guidelines for dia- receives annual review and approval by
tifactorial risk-reduction strategies beyond betes care. Readers who wish to comment the ADA Board of Directors.
glycemic control. Ongoing patient self- on the 2018 Standards of Care are invited
management education and support are to do so at professional.diabetes.org/SOC. ADA Statement
critical to preventing acute complications An ADA statement is an official ADA point
and reducing the risk of long-term compli- ADA STANDARDS, STATEMENTS, of view or belief that does not contain clin-
cations. Significant evidence exists that REPORTS, and REVIEWS ical practice recommendations and may be
supports a range of interventions to im- The ADA has been actively involved in the issued on advocacy, policy, economic, or
prove diabetes outcomes. development and dissemination of diabe- medical issues related to diabetes. ADA
The American Diabetes Association’s tes care standards, guidelines, and related statements undergo a formal review pro-
(ADA’s) “Standards of Medical Care in documents for over 25 years. The ADA’s cess, including a review by the appropriate
Diabetes,” referred to as the Standards of clinical practice recommendations are national committee, ADA mission staff, and
Care, is intended to provide clinicians, viewed as important resources for health the Board of Directors.
patients, researchers, payers, and other care professionals who care for people with
interested individuals with the compo-nents diabetes. Consensus Report
of diabetes care, general treatment goals, An expert consensus report of a particu-lar
Standards of Care topic contains a comprehensive ex-
and tools to evaluate the quality of care.
This document is an official ADA position,
The Standards of Care recommen-dations amination and is authored by an expert
is authored by the ADA, and provides all of
are not intended to preclude clin-ical panel (i.e., consensus panel) and repre-
the ADA’s current clinical practice rec-
judgment and must be applied in the sents the panel’s collective analysis, eval-
ommendations. To update the Standards of
context of excellent clinical care, with uation, and opinion. The need for an expert
Care, the ADA’s Professional Practice
adjustments for individual preferences, consensus report arises when clini-cians,
Committee (PPC) performs an extensive
comorbidities, and other patient factors. scientists, regulators, and/or policy makers
clinical diabetes literature search, supple-
For more detailed information about desire guidance and/or clarity on a medical
mented with input from ADA staff and the
management of diabetes, please refer to or scientific issue related to diabetes for
medical community at large. The PPC up-
Medical Management of Type 1 Diabetes which the evidence is contradictory,
dates the Standards of Care annually, or
᠘㺲ᷬ䅓 more frequently online should the PPC emerging, or incomplete. Expert
粘ㄼ 륌冞 determine that new evidence or regula-tory consensus reports may also high-light
#밀㓟$쌢ᾞchanges (e.g., drug approvals, label gaps in evidence and propose areas of
'㗔14+ and Medical Management changes) merit immediate incorporation. future research to address these gaps. An
of Type 2 Diabetes (2). The Standards of Care supersedes all pre- expert consensus report is not an ADA
The recommendations include screen- vious ADA position statementsdand the position and represents expert opinion only
ing, diagnostic, and therapeutic actions recommendations thereindon clinical topics but is produced under the auspices of the
that are known or believed to favorably within the purview of the Stand-ards of Association by invited experts. An expert
affect health outcomes of patients with di- Care; ADA position statements, while still consensus report may be devel-oped after
abetes. Many of these interventions have containing valuable analyses, should not an ADA Clinical Conference or Research
also been shown to be cost-effective (3). be considered the ADA’s Symposium.
The ADA strives to improve and update
the Standards of Care to ensure that clini-
cians, health plans, and policy makers can
GENERAL CHANGES A new recommendation was added The immunization section was updated
The field of diabetes care is rapidly changing about using reliable data metrics to for clarity to more closely align with rec-
as new research, technology, and treat-ments assess and improve the quality of ommendations from the Centers for Dis-
that can improve the health and well-being of diabetes care and reduce costs. ease Control and Prevention.
people with diabetes continue to emerge. Additional discussion was included Text was added about the
With annual updates since 1989, the on the social determinants of health. importance of language choice in
American Diabetes Association’s (ADA’s) Text was added describing the emerg- patient-centered communication.
“Standards of Medical Care in Diabetes” ing use of telemedicine in diabetes care. Pancreatitis was added to the section
(Standards of Care) has long been a leader in on comorbidities, including a new recom-
Section 2. Classification and Diagnosis mendation about the consideration of islet
producing guidelines that capture the most
of Diabetes
current state of the field. Starting in 2018, the autotransplantation to prevent post-
As a result of recent evidence describing
ADA will update the Standards of Care even surgical diabetes in patients with medi-
potential limitations in A1C measure-
more frequently online should the cally refractory chronic pancreatitis who
ments due to hemoglobin variants,
Professional Practice Committee de-termine require total pancreatectomy.
assay interference, and conditions
that new evidence or regulatory changes A recommendation was added to
associated with red blood cell turnover,
merit immediate incorporation into the consider checking serum testosterone
additional recommendations were added
Standards of Care. In addition, the Standards in men with diabetes and signs and
to clarify the appropriate use of the A1C
of Care will now become the ADA’s sole symp-toms of hypogonadism.
test gener-ally and in the diagnosis of
source of clinical practice recommendations,
diabetes in these special cases. Section 4. Lifestyle Management
superseding all prior position and scientific
The recommendation for testing for A recommendation was modified to in-
statements. The change is intended to clarify
prediabetes and type 2 diabetes in clude individual and group settings as
the Associa-tion’s current positions by
children and adolescents was changed, well as technology-based platforms for
consolidating all clinical practice
suggesting testing for youth who are the delivery of effective diabetes self-
recommendations into the Standards of Care.
overweight or obese and have one or management education and support.
For further informa-tion on changes to the
more additional risk factors (Table 2.5). Additional explanation was added to the
classification and definitions of ADA
0 clarification was added that, nutrition section to clarify the ADA’s
Standards of Care, statements, reports, and
while generally not recommended, recommendations that there is no univer-
reviews, see the Introduction.
commu-nity screening may be sal ideal macronutrient distribution and that
considered in specific situations eating plans should be individualized.
Although levels of evidence for several
where an adequate referral system Text was added to address the
recommendations have been updated, for positive tests is established.
these changes are not addressed below as
role of low-carbohydrate diets in
Additional detail was added regarding people with diabetes.
the clinical recommendations have re- current research on antihyperglycemic
mained the same. Changes in evidence treatment in people with posttransplan- Section 5. Prevention or Delay of
level from, for example, E to C are not tation diabetes mellitus. Type 2 Diabetes
noted below. The 2018 Standards of Care The recommendation regarding the use of
con-tains, in addition to many minor Section 3. Comprehensive Medical metformin in the prevention of prediabe-tes
changes that clarify recommendations or Evaluation and Assessment of was reworded to better reflect the data
reflect new evidence, the following more Comorbidities from the Diabetes Prevention Program.
substan-tive revisions. The table describing the components of
a comprehensive medical evaluation Section 6. Glycemic Targets
SECTION CHANGES (Table 3.1) was substantially redesigned Based on new data, the recommendation
Section 1. Improving Care and and re-organized, incorporating for the use of continuous glucose monitor-
Promoting Health in Populations information about the recommended ing (CGM) in adults with type 1 diabetes is
This section was renamed to better capture its frequency of the compo-nents of care at no longer limited to those ages 25 and
subject matter and was reorganized for clarity. both initial and follow-up visits. above but has been expanded to all adults
© 2017 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational
and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.
care.diabetesjournals.org Summary of Revisions
S5
(18 and above) who are not meeting Section 9. Cardiovascular Disease that combines information on staging
glyce-mic targets. and Risk Management chronic kidney disease and the appro-
Additional text was added about a new A new recommendation was added that all priate kidney-related care for each stage.
intermittent or “flash” CGM device that was hypertensive patients with diabetes should A new Table 10.2 was included
recently approved for adult use. monitor their blood pressure at home to help describ-ing the complications of
Details were added about new identify masked or white coat hypertension, as chronic kidney disease and related
CGM de-vices that no longer require well as to improve medication-taking behavior. medical and labora-tory evaluations.
confirmatory self-monitoring of blood A new figure (Fig. 9.1) was added to A new section on acute kidney
glucose for treat-ment decisions. illustrate the recommended antihyper- injury was included.
As in Section 2, this section now tensive treatment approach for adults The effect of specific glucose-lowering
includes an expanded discussion of the with diabetes and hypertension. medications on the delay and progression of
limitations of A1C in certain populations A new table (Table 9.1) was added sum- kidney disease was discussed, with ref-
based on the presence of hemoglobin marizing studies of intensive versus stan- erence to recent CVOT trials that examined
variants, differ-ences in red blood cell dard hypertension treatment strategies. kidney effects as secondary outcomes.
turnover rates, eth-nicity, and age. A recommendation was added to consider A new recommendation was added on
To clarify the classification of mineralocorticoid receptor antagonist ther-apy the noninferiority of the anti–vascular
hypogly-cemia, level 1 hypoglycemia in patients with resistant hypertension. endo-thelial growth factor treatment
was renamed “hypoglycemia alert The lipid management recommendations ranibizumab in reducing the risk of vision
value” from “glucose alert value.” were modified to stratify risk based on two loss in patients with proliferative diabetic
broad categories: those with documented retinopathy when compared with the
Section 7. Obesity Management
ASCVD and those without. traditional stan-dard treatment, panretinal
for the Treatment of Type 2 Diabetes
Owing to studies suggesting similar ben- laser photoco-agulation therapy.
To provide a second set of cost informa-
efits in older versus middle-aged adults, A new section was added
tion, the table of medications for the
recom-mendations were consolidated for describing the mixed evidence on the
treatment of obesity (Table 7.2) was up-
patients with diabetes 40–75 years and .75 use of hyper-baric oxygen therapy in
dated to include National Average Drug
years of age without ASCVD to use people with dia-betic foot ulcers.
Acquisition Cost (NADAC) prices.
moderate-intensity statin.
Section 8. Pharmacologic Approaches Table 9.2 (“Recommendations for sta- Section 11. Older Adults
to Glycemic Treatment tin and combination treatment in adults Three new recommendations were added to
New recommendations for antihyperglyce- with diabetes”) was updated based on highlight the importance of individualiz-ing
mic therapy for adults with type 2 diabetes the new risk stratification approach and pharmacologic therapy in older adults to
have been added to reflect recent cardio- consolidated age-groups. reduce the risk of hypoglycemia, avoid over-
vascular outcomes trial (CVOT) data, indi- To accommodate recent data on new treatment, and simplify complex regimens if
cating that people with atherosclerotic classes of lipid-lowering medications, a possible while maintaining the A1C target.
cardiovascular disease (ASCVD) should re-commendation was modified to
be-gin with lifestyle management and provide additional guidance on adding Section 12. Children and Adolescents
metfor-min and subsequently incorporate nonstatin LDL-lowering therapies for To make the section more comprehensive
an agent proven to reduce major adverse patients with diabetes and ASCVD who and to reflect emerging data on diabetes
cardiovascular events and/or cardiovascu- have LDL choles-terol $70 mg/dL technologies, additional recommendations
lar mortality after considering drug-specific despite maximally toler-ated statin dose. were added on the treatment of type 1
and patient factors. The same recommendations were added diabetes in children and adolescents
The algorithm for antihyperglycemic here as in Section 8 that people with type 2 regard-ing intensive insulin regimens, self-
treatment (Fig. 8.1) was updated to incor- diabetes and ASCVD should begin with life- monitoring of blood glucose, CGM, and
porate the new ASCVD recommendation. style management and metformin and sub- automated insulin delivery systems.
A new table was added (Table 8.1) to sequently incorporate an agent proven to The recommended risk-based timing of
summarize drug-specific and patient fac- reduce major adverse cardiovascular events celiac disease screenings for youth and ad-
tors of antihyperglycemic agents. Figure and/or cardiovascular mortality after con- olescents with type 1 diabetes was defined.
8.1 and Table 8.1 are meant to be used sidering drug-specific and patient factors. 0 recommendation regarding esti-
together to guide the choice of antihy- The text was substantially modified to mating glomerular filtration rate was re-
perglycemic agents as part of patient– describe CVOT data on new diabetes moved because of the poor performance of
provider shared decision-making. agents and outcomes in people with type the estimating equation in youth.
Table 8.2 was modified to focus 2 diabe-tes, providing support for the The type 2 diabetes in children
on the pharmacology and new ASCVD recommendations. section was substantially expanded,
mechanisms of avail-able glucose- A new Table 9.4 was added to with several new recommendations,
lowering medicines in the U.S. summa-rize the CVOT studies. based on a re-cent ADA review.
To provide a second set of cost infor-
mation for antihyperglycemic agents, Section 10. Microvascular Section 13. Management of Diabetes
NADAC data was added to the average Complications and Foot Care in Pregnancy
wholesale prices information in Table A new table was added (Table 10.1), re- A recommendation was added to empha-
8.3 and Table 8.4. placing previous tables 10.1 and 10.2, size that insulin is the preferred agent for
S6 Summary of Revisions Diabetes Care Volume 41, Supplement 1, January 2018
the management of type 1 and type type 1 and type 2 diabetes to take Section 14. Diabetes Care in the Hospital
2 di-abetes in pregnancy. low-dose aspirin starting at the end Insulin degludec was added to the
Based on new evidence, a recom- of the first trimester to lower the risk insulin dosing for enteral/parenteral
mendation was added for women with of preeclampsia. feedings (Table 14.1).
Diabetes Care Volume 41, Supplement 1, January 2018 S7
Recommendations
0 Ensure treatment decisions are timely, rely on evidence-based
guidelines, and are made collaboratively with patients based on
individual preferences, prognoses, and comorbidities. B
0 Align approaches to diabetes management with the Chronic Care Model, em-
phasizing productive interactions between a prepared proactive care team and
an informed activated patient. A
0 Care systems should facilitate team-based care, patient registries, decision sup-
port tools, and community involvement to meet patient needs. B
0 Efforts to assess the quality of diabetes care and create quality improvement
strategies should incorporate reliable data metrics, to promote improved processes
of care and health outcomes, with simultaneous emphasis on costs. E
practice recommendations, whether based these factors into consideration and is psychosocial issues (25,26); and identify-
on evidence or expert opinion, are an effective framework for improving ing, developing, and engaging community
intended to guide an overall ap-proach to the quality of diabetes care (8). resources and public policies that support
care. The science and art of medicine healthy lifestyles (27). The National Diabe-
The CCM includes six
Six Core Elements.
come together when the clini-cian is faced tes Education Program maintains an on-
core elements to optimize the care of
with making treatment rec-ommendations pa-tients with chronic disease: line resource (www.betterdiabetescare
for a patient who may not meet the .nih.gov) to help health care
eligibility criteria used in the studies on 5888 Delivery system design (moving professionals design and implement
which guidelines are based. Recognizing from a reactive to a proactive care more effective health care delivery
that one size does not fit all, the standards delivery system where planned visits systems for those with diabetes.
presented here provide guidance for when are coordi-nated through a team-based The care team, which includes the pa-
and how to adapt recom-mendations for an approach) tient, should prioritize timely and appro-
individual. 5889 Self-management support priate intensification of lifestyle and/or
5890 Decision support (basing care on pharmacologic therapy for patients who
evidence-based, effective care guidelines) have not achieved the recommended
Care Delivery Systems
Over the past 10 years, the proportion of 5891 Clinical information systems metabolic targets (28–30). Strategies
patients with diabetes who achieve recom- (using regis-tries that can provide shown to improve care team behavior and
mended A1C, blood pressure, and LDL cho- patient-specific and population- thereby catalyze reductions in A1C, blood
lesterol levels has increased (3). The mean based support to the care team) pressure, and/or LDL cholesterol include
A1C nationally among people with diabe-tes 5892 Community resources and engaging in explicit and collabo-rative goal
has declined from 7.6% (60 mmol/mol) in policies (identifying or developing setting with patients (31,32); identifying
1999–2002 to 7.2% (55 mmol/mol) in 2007– resources to support healthy and addressing language, numeracy, or
2010 based on the National Health and lifestyles) cultural barriers to care (33–35);
Nutrition Examination Survey (NHANES), with 5893 Health systems (to create a integrating evidence-based guidelines and
younger adults less likely to meet treatment quality-oriented culture) clinical information tools into the process of
targets than older adults (3). This has been care (16,36,37); solic-iting performance
Redefining the roles of the health care
accompanied by improve-ments in feedback, setting re-minders, and
delivery team and empowering patient
cardiovascular outcomes and has led to providing structured care (e.g., guidelines,
self-management are fundamental to the
substantial reductions in end-stage formal case manage-ment, and patient
successful implementation of the CCM
microvascular complications. education resources)
(9). Collaborative, multidisciplinary
Nevertheless, 33–49% of patients still (7); and incorporating care management
teams are best suited to provide care for
do not meet targets for glycemic, blood teams including nurses, dietitians, pharma-
people with chronic conditions such as
pressure, or cholesterol control, and only cists, and other providers (17,38).
diabetes and to facilitate patients’ self-
14% meet targets for all three measures Initiatives such as the Patient-Centered
management (10–12).
while also avoiding smoking (3). Evidence Medical Home show promise for improving
suggests that progress in cardiovascular Strategies for System-Level Improvement health outcomes by fostering
risk factor control (particularly tobacco use) Optimal diabetes management requires an comprehensive primary care and offering
may be slowing (3,4). Certain seg-ments of organized, systematic approach and the new opportuni-ties for team-based chronic
the population, such as young adults and involvement of a coordinated team of disease man-agement (39).
patients with complex comor-bidities, dedicated health care professionals For rural populations or those with lim-
financial or other social hard-ships, and/or working in an environment where patient- ited physical access to health care, teleme-
limited English proficiency, face particular centered high-quality care is a priority dicine is an approach with a growing body
challenges to goal-based care (5–7). Even (7,13,14). While many diabetes processes of evidence for its effectiveness, particu-
after adjusting for these patient factors, the of care have improved nationally in the larly with regards to glycemic control as
persistent variability in the quality of past decade, the overall quality of care for measured by A1C (40,41). Telemedicine is
diabetes care across pro-viders and patients with diabetes remains subopti-mal defined as the use of telecommunica-tions
practice settings indicates that substantial (15). Efforts to increase the quality of to facilitate remote delivery of health-
system-level improvements are still diabetes care include providing care that is related services and clinical information
needed. concordant with evidence-based guidelines (42). Interactive strategies that facilitate
(16); expanding the role of teams to communication between providers and
Chronic Care Model implement more intensive dis-ease patients, including the use of web-based
Numerous interventions to improve ad- management strategies (7,17,18); tracking portal or text messaging and those that
herence to the recommended standards medication-taking behavior at a systems incorporate medication adjustment ap-pear
have been implemented. However, a ma- level (19); redesigning the orga-nization of more effective. There is limited data
jor barrier to optimal care is a delivery care process (20); implement-ing electronic available on the cost-effectiveness of these
system that is often fragmented, lacks health record tools (21,22); empowering strategies.
clinical information capabilities, dupli-cates and educating patients (23,24); removing Successful diabetes care also requires a
services, and is poorly designed for the financial barriers and reducing patient out- systematic approach to supporting patients’
coordinated delivery of chronic care. The of-pocket costs for diabetes education, eye behavior change efforts. High-quality di-
Chronic Care Model (CCM) takes exams, self-monitoring of blood glucose, abetes self-management education and
and necessary medications (7); assessing
and addressing
care.diabetesjournals.org Improving Care and Promoting Health
S9
support (DSMES) has been shown to im- quality (48,49). Using patient registries and can be drawn upon to inform systems-level
prove patient self-management, satisfac- electronic health records, health sys-tems strategies in diabetes. For example, the
tion, and glucose outcomes. National can evaluate the quality of diabetes care National Academy of Medicine has
DSMES standards call for an integrated being delivered and perform inter-vention published a framework for educating health
approach that includes clinical content and cycles as part of quality improve-ment care professionals on the impor-tance of
skills, behavioral strategies (goal set-ting, strategies (50). Critical to these efforts is social determinants of health. Fur-
problem solving), and engagement with provider adherence to clinical practice thermore, there are resources available for
psychosocial concerns (26). For more recommendations and accurate, reliable the inclusion of standardized sociodemo-
information on DSMES, see Section 4 data metrics that include socio- graphic variables in electronic medical re-
“Lifestyle Management.” demographic variables to examine health cords to facilitate the measurement of
In devising approaches to support dis- equity within and across populations (51). health inequities as well as the impact of
ease self-management, it is notable that in In addition to quality improvement interventions designed to reduce those in-
23% of cases, uncontrolled A1C, blood efforts, other strategies that simulta- equities (61–63).
pressure, or lipids was associated with neously improve the quality of care and Social determinants of health are not
poor medication-taking behaviors (19). At a could potentially reduce costs are gaining always recognized and often go undis-
system level, “adequate” medication taking momentum and include reimbursement cussed in the clinical encounter (57). A
is defined as 80% (calculated as the structures that, in contrast to visit-based study by Piette et al. (64) found that among
number of pills taken by the patient in a billing, reward the provision of appropriate patients with chronic illnesses, two-thirds
given time period divided by the number of and high-quality care to achieve metabolic of those who reported not taking medi-
pills prescribed by the physician in that goals (52) and incentives that accommo- cations as prescribed due to cost never
same time period) (19). If medication tak- date personalized care goals (7,53). shared this with their physician. In a more
ing is 80% or above and treatment goals recent study using data from the National
are not met, then treatment intensifica-tion Health Interview Survey (NHIS), Patel et
should be considered (e.g., uptitra-tion). TAILORING TREATMENT al. (57) found that half of adults with
Barriers to medication taking may include
FOR SOCIAL CONTEXT
diabetes reported financial stress and one-
patient factors (remembering to obtain or Recommendations fifth reported food insecurity (FI). Creating
take medications, fear, depres-sion, or 23 Providers should assess social con- systems-level mechanisms to screen for
health beliefs), medication factors text, including potential food insecu- social determinants of health may help
(complexity, multiple daily dosing, cost, or rity, housing stability, and financial overcome structural bar-riers and
side effects), and system factors (inad- barriers, and apply that information communication gaps between patients and
equate follow-up or support). Success in to treatment decisions. A providers (57). In addition, brief, validated
overcoming barriers to medication taking 5888 Refer patients to local screening tools for some social
may be achieved if the patient and pro- community determinants of health exist and could
vider agree on a targeted approach for a resources when available. B facilitate discussion around factors that
specific barrier (11). 23 Provide patients with self- significantly impact treatment during the
The Affordable Care Act has resulted in management support from lay health clinical encounter. Below is a discussion of
increased access to care for many individ- coaches, navigators, or community assessment and treatment consider-ations
uals with diabetes with an emphasis on health workers when available. A in the context of FI, homelessness, and
health promotion and disease prevention limited English proficiency/low literacy.
(43). As mandated by the Affordable Care Health inequities related to diabetes and its
Act, the Agency for Healthcare Research complications are well documented and are Food Insecurity
and Quality developed a National Quality heavily influenced by social deter-minants FI is the unreliable availability of nutri-tious
Strategy based on the triple aims that of health (54–58). Social determi-nants of food and the inability to consistently obtain
include improving the health of a popula- health are defined as the economic, food without resorting to socially
tion, overall quality and patient experi-ence environmental, political, and social condi- unacceptable practices. Over 14% (or one
of care, and per capita cost (44,45). As tions in which people live and are responsi- of every seven people) of the U.S. popu-
health care systems and practices adapt to ble for a major part of health inequality lation is food insecure. The rate is higher in
the changing landscape of health care, it worldwide (59). The ADA recognizes the some racial/ethnic minority groups, in-
will be important to integrate tra-ditional association between social and environ- cluding African American and Latino pop-
disease-specific metrics with measures of mental factors and the prevention and ulations, in low-income households, and in
patient experience, as well as cost, in treatment of diabetes and has issued a call homes headed by a single mother. The risk
assessing the quality of diabe-tes care for research that seeks to better un- for type 2 diabetes is increased twofold in
(46,47). Information and guid-ance specific derstand how these social determinants those with FI (60). Risk for FI can be as-
to quality improvement and practice influence behaviors and how the relation- sessed with a validated two-item screen-
transformation for diabetes care is ships between these variables might be ing tool (65) that includes the statements:
available from the National Diabe-tes modified for the prevention and manage- 1) “Within the past 12 months we worried
Education Program practice transfor- ment of diabetes (60). While a comprehen- whether our food would run out before we
mation website and the National Institute sive strategy to reduce diabetes-related got money to buy more” and 2) “Within the
for Diabetes and Digestive and Kidney health inequities in populations has not past 12 months the food we bought just
Diseases report on diabetes care and been formally studied, general recommen- didn’t last and we didn’t have
dations from other chronic disease models
S10 Improving Care and Promoting Health Diabetes Care Volume 41, Supplement 1, January 2018
money to get more.” An affirmative re- be familiar with resources or have access in U.S. diabetes care, 1999-2010. N Engl J
sponse to either statement had a sensi- to social workers that can facilitate tem- Med 2013;368:1613–1624
Wang J, Geiss LS, Cheng YJ, et al. Long-term and
tivity of 97% and specificity of 83%. porary housing for their patients as a way
recent progress in blood pressure levels among U.S.
to improve diabetes care. adults with diagnosed diabetes, 1988-2008. Diabetes
Treatment Considerations
Care 2011;34:1579–1581
In those with diabetes and FI, the priority is Language Barriers Kerr EA, Heisler M, Krein SL, et al. Beyond
mitigating the increased risk for uncon- Providers who care for non-English speak- co-morbidity counts: how do comorbidity type
trolled hyperglycemia and severe hypo- ers should develop or offer educational and severity influence diabetes patients’
glycemia. Reasons for the increased risk of programs and materials in multiple lan- treatment priorities and self-management? J
hyperglycemia include the steady guages with the specific goals of prevent- Gen Intern Med 2007;22:1635–1640
Fernandez A, Schillinger D, Warton EM, et al.
consumption of inexpensive carbohydrate- ing diabetes and building diabetes
Language barriers, physician-patient language
rich processed foods, binge eating, finan- awareness in people who cannot easily concordance, and glycemic control among in-
cial constraints to the filling of diabetes read or write in English. The National Stan- sured Latinos with diabetes: the Diabetes Study
medication prescriptions, and anxiety/ dards for Culturally and Linguistically Ap- of Northern California (DISTANCE). J Gen Intern
depression leading to poor diabetes self- propriate Services in Health and Health Med 2011;26:170–176
care behaviors. Hypoglycemia can occur Care provide guidance on how health care TRIAD Study Group. Health systems, patients
factors, and quality of care for diabetes: a
as a result of inadequate or erratic providers can reduce language bar-riers by
synthesis of findings from the TRIAD study.
carbohydrate consumption following the improving their cultural compe-tency, Diabetes Care 2010;33:940–947
administration of sulfonylureas or insulin. addressing health literacy, and ensuring Stellefson M, Dipnarine K, Stopka C. The Chronic
If using a sulfonylurea in patients with communication with language assistance Care Model and diabetes management in US
FI, glipizide may be considered due to its (68). The site offers a number of resources primary care settings: a systematic review. Prev
Chronic Dis 2013;10:E26
relatively short half-life. It can be taken and materials that can be used to improve
Coleman K, Austin BT, Brach C, Wagner EH.
immediately before meals, thus obviating the quality of care deliv-ery to non-English– Evidence on the Chronic Care Model in the new
the need to plan meals to an extent that speaking patients. millennium. Health Aff (Millwood) 2009;28:75–85
may be unreachable for those with FI. Piatt GA, Anderson RM, Brooks MM, et al. 3-year
For those needing insulin, rapid-acting Community Support follow-up of clinical and behavioral improve-
Identification or development of commu-nity ments following a multifaceted diabetes care
insulin analogs, preferably delivered by a
resources to support healthy life-styles is a intervention: results of a randomized controlled
pen, may be used immediately after meal
core element of the CCM (8). Health care trial. Diabetes Educ 2010;36:301–309
consumption, whenever food becomes Katon WJ, Lin EHB, Von Korff M, et al. Collab-orative
community linkages are receiv-ing increasing
available. While such insulin analogs may care for patients with depression and chronic
attention from the American Medical illnesses. N Engl J Med 2010;363:2611–2620
be costly, many pharmaceutical com-
Association, the Agency for Health-care Parchman ML, Zeber JE, Romero RR, Pugh JA.
panies provide access to free medications
Research and Quality, and others as a means Risk of coronary artery disease in type 2
through patient assistance programs. If
of promoting translation of clinical diabetes and the delivery of care consistent with
rapid-acting insulin analogs are not op- the chronic care model in primary care settings: a
recommendations for lifestyle modification in
tions for those with FI who need insulin STARNet study. Med Care 2007;45:1129–1134
real-world settings (69). Community health
therapy, a relatively low dose of an ultra- Tricco AC, Ivers NM, Grimshaw JM, et al. Ef-
long-acting insulin analog may be workers (CHWs) (70), peer sup-porters fectiveness of quality improvement strategies on the
prescribed simply to prevent marked (71,72), and lay leaders (73) may assist in the management of diabetes: a systematic review and
delivery of DSMES services (61), particularly meta-analysis. Lancet 2012;379:2252–2261
hyperglycemia, while recognizing that tight Schmittdiel JA, Gopalan A, Lin MW, Banerjee S,
control may not be possible in such cases. in underserved commu-nities. A CHW is
Chau CV, Adams AS. Population health manage-
Providers should also seek local resources defined by the American Public Health ment for diabetes: health care system-level ap-
that might help patients with diabetes and Association as a “frontline public health proaches for improving quality and addressing
their family members to more regularly worker who is a trusted member of and/or has disparities. Curr Diab Rep 2017;17:31
an unusually close understanding of the Saaddine JB, Cadwell B, Gregg EW, et al. Im-
obtain nutritious food (66).
provements in diabetes processes of care and in-
community served” (74). CHWs can be part of
Homelessness termediate outcomes: United States, 1988-2002.
a cost-effective, evidence-based strategy to
Ann Intern Med 2006;144:465–474
Homelessness often accompanies many improve the management of diabetes and O’Connor PJ, Bodkin NL, Fradkin J, et al. Di-abetes
additional barriers to diabetes self- cardiovas-cular risk factors in underserved performance measures: current status and future
management, including FI, literacy and commu-nities and health care systems (75). directions. Diabetes Care 2011;34:1651–1659
numeracy deficiencies, lack of insurance, Jaffe MG, Lee GA, Young JD, Sidney S,
cognitive dysfunction, and mental health Go AS. Improved blood pressure control
issues. Additionally, patients with diabe-tes associated with a large-scale hypertension
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Diabetes Care Volume 41, Supplement 1, January 2018 S13
CLASSIFICATION
Diabetes can be classified into the following general categories:
Type 1 diabetes (due to autoimmune b-cell destruction, usually leading to
absolute insulin deficiency)
Type 2 diabetes (due to a progressive loss of b-cell insulin secretion
frequently on the background of insulin resistance)
Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third
trimester of pregnancy that was not clearly overt diabetes prior to gestation)
Specific types of diabetes due to other causes, e.g., monogenic diabetes syndromes
(such as neonatal diabetes and maturity-onset diabetes of the young [MODY]),
diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and
drug- or chemical-induced diabetes (such as with glucocorticoid use, in the treat-
ment of HIV/AIDS, or after organ transplantation)
This section reviews most common forms of diabetes but is not comprehensive.
For additional information, see the American Diabetes Association (ADA)
position state-ment “Diagnosis and Classification of Diabetes Mellitus” (1).
Type 1 diabetes and type 2 diabetes are heterogeneous diseases in which clinical
presentation and disease progression may vary considerably. Classification is important
for determining therapy, but some individuals cannot be clearly classified as having type 1
Suggested citation: American Diabetes Associa-
or type 2 diabetes at the time of diagnosis. The traditional paradigms of type 2 diabetes tion. 2. Classification and diagnosis of diabetes:
occurring only in adults and type 1 diabetes only in children are no longer accurate, as Standards of Medical Care in Diabetesd2018.
both diseases occur in both age-groups. Children with type 1 diabe-tes typically present Diabetes Care 2018;41(Suppl. 1):S13–S27
with the hallmark symptoms of polyuria/polydipsia, and approx-imately one-third present © 2017 by the American Diabetes Association.
with diabetic ketoacidosis (DKA) (2). The onset of type 1 diabetes may be more variable Readers may use this article as long as the work
is properly cited, the use is educational and not
in adults, and they may not present with the classic symptoms seen in children.
for profit, and the work is not altered. More infor-
Occasionally, patients with type 2 diabetes may present with DKA, particularly ethnic mation is available at http://www.diabetesjournals
minorities (3). Although difficulties in distinguishing .org/content/license.
S14 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018
diabetes type may occur in all age- defects related to inflammation and met- that compared with FPG and A1C cut
groups at onset, the true diagnosis abolic stress among other contributors, points, the 2-h PG value diagnoses
becomes more obvious over time. including genetic factors. Future classi- more people with diabetes.
In both type 1 and type 2 diabetes, fication schemes for diabetes will likely
various genetic and environmental fac-tors focus on the pathophysiology of the un-
A1C
can result in the progressive loss of b-cell derlying b-cell dysfunction and the stage of
mass and/or function that mani-fests disease as indicated by glucose status Recommendations
clinically as hyperglycemia. Once (normal, impaired, or diabetes) (4). To avoid misdiagnosis or missed
hyperglycemia occurs, patients with all diagnosis, the A1C test should be
forms of diabetes are at risk for devel- DIAGNOSTIC TESTS FOR DIABETES performed using a method that is
oping the same chronic complications, certified by the NGSP and standard-
Diabetes may be diagnosed based on
although rates of progression may differ. ized to the Diabetes Control and
plasma glucose criteria, either the
The identification of individualized thera- Complications Trial (DCCT) assay. B
fasting plasma glucose (FPG) or the 2-h
pies for diabetes in the future will require Marked discordance between mea-
plasma glucose (2-h PG) value during a
better characterization of the many paths sured A1C and plasma glucose
75-g oral glucose tolerance test (OGTT),
to b-cell demise or dysfunction (4). levels should raise the possibility of
or A1C cri-teria (6) (Table 2.2).
Characterization of the underlying A1C assay interference due to
Generally, FPG, 2-h PG during 75-g
pathophysiology is more developed in type hemoglobin variants (i.e., hemoglo-
OGTT, and A1C are equally appropriate
1 diabetes than in type 2 diabetes. It is binopathies) and consideration of
for diagnostic testing. It should be noted
now clear from studies of first-degree using an assay without interference
that the tests do not necessarily detect
relatives of patients with type 1 diabetes or plasma blood glucose criteria to
diabetes in the same individuals. The ef-
that the persistent presence of two or more
ficacy of interventions for primary pre- diagnose diabetes. B
autoantibodies is an almost certain In conditions associated with in-creased
vention of type 2 diabetes (7,8) has
predictor of clinical hyperglycemia and red blood cell turnover, such as
primarily been demonstrated among in-
diabetes. The rate of progression is de- sickle cell disease, pregnancy
dividuals who have impaired glucose tol-
pendent on the age at first detection of (second and third trimesters), hemo-
erance (IGT) with or without elevated
antibody, number of antibodies, antibody dialysis, recent blood loss or transfu-
fasting glucose, not for individuals with
specificity, and antibody titer. Glucose and sion, or erythropoietin therapy, only
isolated impaired fasting glucose (IFG)
A1C levels rise well before the clinical plasma blood glucose criteria should
or for those with prediabetes defined by
onset of diabetes, making diagnosis be used to diagnose diabetes. B
A1C criteria.
feasible well before the onset of DKA.
The same tests may be used to screen
Three distinct stages of type 1 diabetes The A1C test should be performed using a
for and diagnose diabetes and to detect
can be identified (Table 2.1) and serve as method that is certified by the NGSP
individuals with prediabetes. Diabetes may
a framework for future research and regu- (www.ngsp.org) and standardized or
be identified anywhere along the spectrum
latory decision-making (4,5). traceable to the Diabetes Control and
of clinical scenarios: in seem-ingly low-risk
The paths to b-cell demise and dys- Complications Trial (DCCT) reference as-
individuals who happen to have glucose
function are less well defined in type 2 say. Although point-of-care A1C assays
testing, in individuals tested based on
diabetes, but deficient b-cell insulin se- may be NGSP certified, proficiency testing
diabetes risk assessment, and in
cretion, frequently in the setting of insulin is not mandated for performing the test, so
symptomatic patients.
resistance, appears to be the common de- use of point-of-care assays for diagnos-tic
nominator. Characterization of subtypes of Fasting and 2-Hour Plasma Glucose purposes is not recommended but may be
this heterogeneous disorder have been The FPG and 2-h PG may be used to di- considered in the future if pro-ficiency
developed and validated in Scandinavian agnose diabetes (Table 2.2). The concor- testing is performed, documented, and
and Northern European populations but dance between the FPG and 2-h PG tests deemed acceptable.
have not been confirmed in other ethnic is imperfect, as is the concordance be- The A1C has several advantages com-
and racial groups. Type 2 diabetes is pri- tween A1C and either glucose-based test. pared with the FPG and OGTT, including
marily associated with insulin secretory Numerous studies have confirmed greater convenience (fasting not required),
36). Type 2 diabetes frequently goes un- assessment tool, such as the ADA risk test
In patients with diabetes, identify and
diagnosed for many years because hy- (Fig. 2.1) (diabetes.org/socrisktest), is
treat other cardiovascular dis-
perglycemia develops gradually and, at recommended to guide providers on whether
ease risk factors. B
earlier stages, is often not severe enough performing a diagnostic test (Table 2.2) is
Testing for type 2 diabetes should be
for the patient to notice the clas-sic appropriate. Prediabetes and type 2 diabetes
considered in children and ado-
diabetes symptoms. Nevertheless, even meet criteria for con-ditions in which early
lescents who are overweight or
undiagnosed patients are at in-creased risk detection is appro-priate. Both conditions are
obese (BMI .85th percentile for
of developing macrovascular and common and impose significant clinical and
age and sex, weight for height
microvascular complications. public health burdens. There is often a long
.85th percentile, or weight .120%
Whereas patients with type 2 diabetes pre-symptomatic phase before the diagnosis
of ideal for height) and who have
may have insulin levels that appear nor- of type 2 diabetes. Simple tests to detect
additional risk factors for diabetes
mal or elevated, the higher blood glucose preclinical disease are readily available. The
(Table 2.5). E
levels in these patients would be expected duration of glycemic burden is a strong
to result in even higher insulin values had predictor of adverse outcomes. There are
Description their b-cell function been normal. Thus, effective interventions that prevent pro-
Type 2 diabetes, previously referred to insulin secretion is defective in these pa- gression from prediabetes to diabetes (see
as “noninsulin-dependent diabetes” or tients and insufficient to compensate for Section 5 “Prevention or Delay of Type 2
“adult-onset diabetes,” accounts for 90– insulin resistance. Insulin resistance may Diabetes”) and reduce the risk of diabetes
95% of all diabetes. This form encom- improve with weight reduction and/or complications (see Section 9 “Cardiovas-cular
passes individuals who have relative pharmacologic treatment of hyperglyce-mia Disease and Risk Management” and Section
(rather than absolute) insulin deficiency but is seldom restored to normal. 10 “Microvascular Complications and Foot
and have peripheral insulin resistance. The risk of developing type 2 diabe- Care”).
At least initially, and often throughout tes increases with age, obesity, and lack
their lifetime, these individuals may not of physical activity. It occurs more fre- Approximately one-quarter of people
need insulin treatment to survive. quently in women with prior GDM, in with diabetes in the U.S. and nearly half of
There are various causes of type 2 di- those with hypertension or dyslipidemia, Asian and Hispanic Americans with di-
abetes. Although the specific etiologies are and in certain racial/ethnic subgroups abetes are undiagnosed (37,38). Although
not known, autoimmune destruction of b- (African American, American Indian, screening of asymptomatic individuals to
cells does not occur and patients do not Hispanic/Latino, and Asian American). It identify those with prediabetes or diabe-tes
have any of the other known causes of is often associated with a strong genetic might seem reasonable, rigorous clin-ical
diabetes. Most but not all patients with predisposition or family history in first- trials to prove the effectiveness of such
type 2 diabetes are overweight or obese. degree relatives, more so than type 1 di- screening have not been conducted and
Excess weight itself causes some degree abetes. However, the genetics of type 2 are unlikely to occur.
of insulin resistance. Patients who are not diabetes is poorly understood. In adults A large European randomized con-
obese or overweight by traditional weight without traditional risk factors for type 2 trolled trial compared the impact of
criteria may have an increased percent- diabetes and/or younger age, consider screening for diabetes and intensive
age of body fat distributed predominantly antibody testing to exclude the diagnosis multifactorial intervention with that of
in the abdominal region. of type 1 diabetes (i.e., GAD). screening and routine care (39). General
DKA seldom occurs spontaneously in practice patients between the ages of
type 2 diabetes; when seen, it usually Screening and Testing for Type 2 40 and 69 years were screened for diabe-
arises in association with the stress of an- Diabetes and Prediabetes in tes and randomly assigned by practice to
other illness such as infection or with the Asymptomatic Adults intensive treatment of multiple risk fac-
use of certain drugs (e.g., corticosteroids, Screening for prediabetes and type 2 di- tors or routine diabetes care. After 5.3
atypical antipsychotics, and sodium– abetes through an informal assessment years of follow-up, CVD risk factors were
glucose cotransporter 2 inhibitors) (35, of risk factors (Table 2.3) or with an modestly but significantly improved with
intensive treatment compared with rou-
tine care, but the incidence of first CVD
Table 2.5—Risk-based screening for type 2 diabetes or prediabetes in asymptomatic events or mortality was not significantly
children and adolescents in a clinical setting* different between the groups (39). The
Criteria excellent care provided to patients in
c Overweight (BMI .85th percentile for age and sex, weight for height .85th percentile, or the routine care group and the lack of
weight .120% of ideal for height) A an unscreened control arm limited the
Plus one or more additional risk factors based on the strength of their association with authors’ ability to determine whether
diabetes as indicated by evidence grades: screening and early treatment improved
c Maternal history of diabetes or GDM during the child’s gestation A c
outcomes compared with no screening
Family history of type 2 diabetes in first- or second-degree relative A
c Race/ethnicity (Native American, African American, Latino, Asian American, Pacific Islander) A c Signs
and later treatment after clinical diag-
of insulin resistance or conditions associated with insulin resistance (acanthosis nigricans, hypertension, noses. Computer simulation modeling
dyslipidemia, polycystic ovary syndrome, or small-for-gestational-age birth weight) B studies suggest that major benefits are
likely to accrue from the early diagnosis
*Persons aged ,18 years.
and treatment of hyperglycemia and
S20 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018
cardiovascular risk factors in type 2 reduced and individuals with false-negative limited data supporting A1C for diag-nosing
diabetes (40); moreover, screening, tests will be retested before substantial time type 2 diabetes in children and
be-ginning at age 30 or 45 years and elapses and complications develop (47). adolescents. Although A1C is not recom-
indepen-dent of risk factors, may be mended for diagnosis of diabetes in chil-
Community Screening
cost-effective (,$11,000 per quality- dren with cystic fibrosis or symptoms
Ideally, testing should be carried out
adjusted life-year gained) (41). suggestive of acute onset of type 1 diabe-
within a health care setting because of
Additional considerations tes and only A1C assays without interfer-
the need for follow-up and treatment.
regarding testing for type 2 diabetes ence are appropriate for children with
Community screening outside a health
and prediabe-tes in asymptomatic hemoglobinopathies, the ADA continues to
patients include the following. care setting is generally not recom- recommend A1C for diagnosis of type 2
mended because people with positive diabetes in this cohort (54,55).
Age tests may not seek, or have access to,
Age is a major risk factor for diabetes. appropriate follow-up testing and care.
Testing should begin at age 45 years However, in specific situations where an GESTATIONAL DIABETES MELLITUS
for all patients. Screening should be adequate referral system is established Recommendations
consid-ered in overweight or obese beforehand for positive tests, community Test for undiagnosed diabetes at the
adults of any age with one or more screening may be considered. Commu- first prenatal visit in those with risk
risk factors for diabetes. nity testing may also be poorly targeted; factors, using standard di-
BMI and Ethnicity i.e., it may fail to reach the groups most agnostic criteria. B
2
In general, BMI $25 kg/m is a risk factor at risk and inappropriately test those at Test for gestational diabetes melli-tus
for diabetes. However, data suggest that very low risk or even those who have at 24–28 weeks of gestation in
the BMI cut point should be lower for the already been diagnosed (48). pregnant women not previously
Asian American population (42,43). The Screening in Dental Practices known to have diabetes. A
BMI cut points fall consistently be-tween Because periodontal disease is associated Test women with gestational diabe-tes
2
23 and 24 kg/m (sensitivity of 80%) for with diabetes, the utility of screening in a mellitus for persistent diabetes at 4–
nearly all Asian American sub-groups (with dental setting and referral to primary care 12 weeks postpartum, using the oral
levels slightly lower for Jap-anese as a means to improve the diagnosis of glucose tolerance test and clinically
Americans). This makes a rounded cut prediabetes and diabetes has been ex- appropriate nonpregnancy
2
point of 23 kg/m practical. An argu-ment plored (49–51), with one study estimating diagnostic criteria. E
can be made to push the BMI cut point to that 30% of patients $30 years of age seen Women with a history of gesta-tional
2
lower than 23 kg/m in favor of increased in general dental practices had dys- diabetes mellitus should have
sensitivity; however, this would lead to an glycemia (51). Further research is needed lifelong screening for the de-
unacceptably low specificity (13.1%). Data to demonstrate the feasibility, effective- velopment of diabetes or prediabe-
from the WHO also suggest that a BMI of ness, and cost-effectiveness of screening tes at least every 3 years. B
2 in this setting. Women with a history of gesta-tional
$23 kg/m should be used to define
increased risk in Asian Ameri-cans (44).
diabetes mellitus found to have
The finding that half of diabetes in Asian prediabetes should receive in-
Screening and Testing for Type 2
Americans is undiagnosed sug-gests that tensive lifestyle interventions or
Diabetes and Prediabetes in Children
testing is not occurring at lower BMI and Adolescents metformin to prevent diabetes. A
thresholds (37,38). In the last decade, the incidence and prev-
Evidence also suggests that other pop- alence of type 2 diabetes in adolescents Definition
ulations may benefit from lower BMI cut has increased dramatically, especially in For many years, GDM was defined as any
points. For example, in a large multiethnic racial and ethnic minority populations (30). degree of glucose intolerance that was first
cohort study, for an equivalent incidence
See Table 2.5 for recommendations on recognized during pregnancy (23), re-
2
rate of diabetes, a BMI of 30 kg/m in non- risk-based screening for type 2 diabe-tes or gardless of whether the condition may
Hispanic whites was equivalent to a BMI of prediabetes in asymptomatic chil-dren and have predated the pregnancy or persisted
2
26 kg/m in African Americans (45). adolescents in a clinical setting. See after the pregnancy. This definition facili-
Section 12 “Children and Adolescents” for tated a uniform strategy for detection and
Medications
additional information on type 2 diabetes in classification of GDM, but it was limited by
Certain medications, such as glucocorti-
children and adolescents. imprecision.
coids, thiazide diuretics, and atypical an-
Some studies question the validity of The ongoing epidemic of obesity and
tipsychotics (46), are known to increase
A1C in the pediatric population, especially diabetes has led to more type 2 diabetes in
the risk of diabetes and should be consid-
among certain ethnicities, and suggest women of childbearing age, with an in-
ered when deciding whether to screen.
OGTT or FPG as more suitable diagnos-tic crease in the number of pregnant women
Testing Interval tests (52). However, many of these studies with undiagnosed type 2 diabetes (56).
The appropriate interval between screen- do not recognize that diabetes di-agnostic Because of the number of pregnant
ing tests is not known (47). The rationale criteria are based on long-term health women with undiagnosed type 2 diabetes,
for the 3-year interval is that with this in- outcomes, and validations are not currently it is reasonable to test women with risk
terval, the number of false-positive tests available in the pediatric popu-lation (53). factors for type 2 diabetes (Table 2.3) at
that require confirmatory testing will be The ADA acknowledges the their initial prenatal visit, using standard
care.diabetesjournals.org Classification and Diagnosis of Diabetes
S21
diagnostic criteria (Table 2.2). Women di- One-Step Strategy Two-Step Strategy
agnosed with diabetes by standard diag- The IADPSG defined diagnostic cut points In 2013, the National Institutes of Health
nostic criteria in the first trimester should be for GDM as the average fasting, 1-h, and (NIH) convened a consensus develop-
classified as having preexisting preges- 2-h PG values during a 75-g OGTT in ment conference to consider diagnostic
tational diabetes (type 2 diabetes or, very women at 24–28 weeks of gestation who criteria for diagnosing GDM (68). The 15-
rarely, type 1 diabetes or monogenic dia- participated in the HAPO study at which member panel had representatives from
betes). GDM is diabetes that is first diag- odds for adverse outcomes reached 1.75 obstetrics/gynecology, maternal-fetal
nosed in the second or third trimester of times the estimated odds of these medicine, pediatrics, diabetes re-search,
pregnancy that is not clearly either preex- outcomes at the mean fasting, 1-h, and 2-h biostatistics, and other related fields. The
isting type 1 or type 2 diabetes (see Section PG levels of the study population. This panel recommended a two-step approach
“Management of Diabetes in Preg- one-step strategy was anticipated to to screening that used a 1-h 50-g glucose
nancy”). The International Association of significantly increase the incidence of GDM load test (GLT) followed by a 3-h 100-g
the Diabetes and Pregnancy Study (from 5–6% to 15–20%), primarily because OGTT for those who screened positive.
Groups (IADPSG) GDM diagnostic only one abnormal value, not two, became The American College of Ob-stetricians
criteria for the 75-g OGTT as well as the sufficient to make the di-agnosis (63). The and Gynecologists (ACOG) rec-ommends
GDM screening and diagnostic criteria anticipated increase in the incidence of any of the commonly used thresholds of
used in the two-step approach were not GDM could have a sub-stantial impact on 130, 135, or 140 mg/dL for the 1-h 50-g
derived from data in the first half of costs and medical in-frastructure needs GLT (69). A systematic review for the U.S.
pregnancy, so the diagnosis of GDM in and has the potential to “medicalize” Preventive Services Task Force compared
early pregnancy by either FPG or OGTT pregnancies previously categorized as GLT cutoffs of 130 mg/dL (7.2 mmol/L) and
values is not evi-dence based (57). normal. Nevertheless, the ADA 140 mg/dL (7.8 mmol/L) (70). The higher
Because GDM confers increased risk recommends these diagnostic criteria with cutoff yielded sensitivity of 70–88% and
for the development of type 2 diabetes the intent of optimizing gestational specificity of 69–89%, while the lower
after delivery (58,59) and because effec- outcomes because these cri-teria were the cutoff was 88–99% sensi-tive and 66–77%
tive prevention interventions are avail- only ones based on preg-nancy outcomes specific. Data regarding a cutoff of 135
able (60,61), women diagnosed with rather than end points such as prediction of mg/dL are limited. As for other screening
GDM should receive lifelong screening subsequent mater-nal diabetes. tests, choice of a cutoff is based upon the
for prediabetes and type 2 diabetes. trade-off between sen-sitivity and
The expected benefits to the offspring specificity. The use of A1C at 24–28 weeks
are inferred from intervention trials that of gestation as a screening test for GDM
Diagnosis
focused on women with lower levels of does not function as well as the GLT (71).
GDM carries risks for the mother and ne-
onate. Not all adverse outcomes are of hyperglycemia than identified using older
equal clinical importance. The Hypergly- GDM diagnostic criteria. Those trials found Key factors cited by the NIH panel in their
cemia and Adverse Pregnancy Outcome modest benefits including reduced rates of decision-making process were the lack of
(HAPO) study (62), a large-scale multina- large-for-gestational-age births and clinical trial data demonstrating the benefits of
tional cohort study completed by more preeclampsia (64,65). It is important to the one-step strategy and the potential
than 23,000 pregnant women, demon- note that 80–90% of women being treated negative consequences of identifying a large
strated that risk of adverse maternal, fe-tal, for mild GDM in two randomized controlled group of women with GDM, including
and neonatal outcomes continuously trials could be managed with lifestyle medicalization of pregnancy with increased
increased as a function of maternal glyce- therapy alone. The OGTT glucose cutoffs health care uti-lization and costs. Moreover,
mia at 24–28 weeks of gestation, even in these two trials overlapped with the screening with a 50-g GLT does not require
within ranges previously considered nor- thresholds recommended by the IADPSG, fasting and is therefore easier to accomplish
mal for pregnancy. For most complications, and in one trial (65), the 2-h PG threshold for many women. Treatment of higher-
there was no threshold for risk. These re- (140 mg/dL [7.8 mmol/L]) was lower than threshold maternal hyperglycemia, as
sults have led to careful reconsideration of the cutoff recommended by the IADPSG identified by the two-step approach, reduces
the diagnostic criteria for GDM. GDM di- (153 mg/dL [8.5 mmol/L]). No randomized rates of neona-tal macrosomia, large-for-
agnosis (Table 2.6) can be accomplished controlled trials of identi-fying and treating gestational-age births (72), and shoulder
with either of two strategies: GDM using the IADPSG criteria versus dystocia, without increasing small-for-
older criteria have been published to date. gestational-age births. ACOG currently
“One-step” 75-g OGTT or Data are also lacking on how the treatment supports the two-step ap-proach (69) but
“Two-step” approach with a 50-g (non- of lower levels of hyperglycemia affects a most recently noted that one elevated value,
fasting) screen followed by a 100-g mother’s future risk for the development of as opposed to two, may be used for the
OGTT for those who screen positive type 2 diabe-tes and her offspring’s risk for diagnosis of GDM. If this approach is
implemented, the incidence of GDM by the
obesity, diabetes, and other metabolic
Different diagnostic criteria will identify two-step strategy will likely in-crease
disorders. Additional well-designed clinical
different degrees of maternal studies are needed to determine the markedly. ACOG recommends either of two
hypergly-cemia and maternal/fetal optimal in-tensity of monitoring and
sets of diagnostic thresholds for the 3-h 100-g
risk, leading some experts to debate, treatment of women with GDM diagnosed
OGTT (73,74). Each is based on different
and disagree on, optimal strategies by the one-step strategy (66,67).
mathematical conversions of the original
for the diagnosis of GDM. recommended thresholds,
S22 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018
NDDG, National Diabetes Data Group. *ACOG recently noted that alternatively one elevated value can be used for diagnosis.
which used whole blood and nonenzymatic outcomes with one-step versus two-step
approach further evaluation, treat-
methods for glucose determination. A re- approaches have been inconsistent to date
ment, and genetic counseling. E
cent secondary analysis of data from a (78,79). In addition, pregnancies compli-
ran-domized clinical trial of identification cated by GDM per the IADPSG criteria, but
Monogenic defects that cause b-cell
and treatment of mild GDM (75) demon- not recognized as such, have comparable
dys-function, such as neonatal diabetes
strated that treatment was similarly ben- outcomes to pregnancies diagnosed as
and MODY, represent a small fraction of
eficial in patients meeting only the lower GDM by the more stringent two-step crite-
pa-tients with diabetes (,5%). Table 2.7
thresholds (73) and in those meeting only ria (80,81). There remains strong consen-
describes the most common causes of
the higher thresholds (74). If the two-step sus that establishing a uniform approach to
monogenic diabetes. For a comprehen-
approach is used, it would appear advan- diagnosing GDM will benefit patients,
sive list of causes, see Genetic
tageous to use the lower diagnostic thresh- caregivers, and policy makers. Longer-term
Diagnosis of Endocrine Disorders (82).
olds as shown in step 2 in Table 2.6. outcome studies are currently under way.
sulfonylureas instead of insulin. Insulin (MODY2), HNF1A-MODY (MODY3), therapy for GCK-MODY; sulfonylureas
gene (INS) mutations are the second most and HNF4A-MODY (MODY1). as first-line therapy for HNF1A-MODY
com-mon cause of permanent neonatal Clinically, patients with GCK-MODY ex- and HNF4A-MODY). Additionally,
dia-betes, and, while treatment presently is hibit mild, stable, fasting hyperglycemia diagnosis can lead to identification of
intensive insulin management, there are and do not require antihyperglycemic other affected family members.
important genetic considerations, as most therapy except sometimes during preg- A diagnosis of MODY should be consid-
of the mutations that cause diabetes are nancy. Patients with HNF1A- or HNF4A- ered in individuals who have atypical di-
dominantly inherited. MODY usually respond well to low doses of abetes and multiple family members with
sulfonylureas, which are considered first- diabetes not characteristic of type 1 or type
Maturity-Onset Diabetes of the Young line therapy. Mutations or deletions in 2 diabetes, although admittedly “atyp-
MODY is frequently characterized by on- HNF1B are associated with renal cysts and ical diabetes” is becoming increasingly
set of hyperglycemia at an early age (clas- uterine malformations (renal cysts and di- difficult to precisely define in the absence
sically before age 25 years, although abetes [RCAD] syndrome). Other extremely of a definitive set of tests for either type of
diagnosis may occur at older ages). rare forms of MODY have been reported to diabetes. In most cases, the presence of
MODY is characterized by impaired insu- involve other transcription factor genes in- autoantibodies for type 1 diabetes pre-
lin secretion with minimal or no defects in cluding PDX1 (IPF1) and NEUROD1. cludes further testing for monogenic dia-
insulin action (in the absence of coexis- betes, but the presence of autoantibodies
tent obesity). It is inherited in an autoso- Diagnosis in patients with monogenic diabetes has
mal dominant pattern with abnormalities A diagnosis of one of the three most com- been reported (84). Individuals in whom
in at least 13 genes on different chromo- mon forms of MODY including GCK- monogenic diabetes is suspected should
somes identified to date. The most com- MODY, HNF1A-MODY, and HNF4A-MODY be referred to a specialist for further eval-
monly reported forms are GCK-MODY allows for more cost-effective therapy (no uation if available, and consultation is
S24 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018
available from several centers. Readily Insulin remains the most widely
Patients with cystic fibrosis–related
available commercial genetic testing fol- used therapy for CFRD (94).
diabetes should be treated with in-
lowing the criteria listed below now Additional resources for the clinical
sulin to attain individualized glyce-
enables a cost-effective (85), often cost- management of CFRD can be found in
mic goals. A
saving, genetic diagnosis that is increas- the position statement “Clinical Care
Beginning 5 years after the diagnosis of
ingly supported by health insurance. A Guidelines for Cystic Fibrosis–Related
cystic fibrosis–related diabetes,
biomarker screening pathway such as the Di-abetes: A Position Statement of the
annual monitoring for complications
combination of urinary C-peptide/creatinine American Diabetes Association and a
of diabetes is recommended. E
ratio and antibody screening may aid in Clin-ical Practice Guideline of the Cystic
determining who should get genetic testing Fibro-sis Foundation, Endorsed by the
Cystic fibrosis–related diabetes (CFRD) is
for MODY (86). It is critical to cor-rectly Pediatric Endocrine Society” (95) and in
the most common comorbidity in people
diagnose one of the monogenic forms of the Interna-tional Society for Pediatric
with cystic fibrosis, occurring in about 20%
diabetes because these pa-tients may be and Adoles-cent Diabetes’s 2014 clinical
of adolescents and 40–50% of adults.
incorrectly diagnosed with type 1 or type 2 practice consensus guidelines (96).
Diabetes in this population, compared with
diabetes, leading to suboptimal, even
individuals with type 1 or type 2 di-abetes,
potentially harmful, treat-ment regimens
is associated with worse nutri-tional status, POSTTRANSPLANTATION
and delays in diagnosing other family
more severe inflammatory lung disease, DIABETES MELLITUS
members (87). The correct di-agnosis is
and greater mortality. Insu-lin insufficiency
especially critical for those with GCK- Recommendations
is the primary defect in CFRD. Genetically
MODY mutations where multiple studies Patients should be screened after
have shown that no complications ensue in determined b-cell func-tion and insulin
organ transplantation for hypergly-
the absence of glucose-lowering therapy resistance associated with infection and
cemia, with a formal diagnosis of
(88). Genetic counseling is rec-ommended inflammation may also con-tribute to the
posttransplantation diabetes melli-
to ensure that affected individ-uals development of CFRD. Milder
tus being best made once a patient
understand the patterns of inheritance and abnormalities of glucose tolerance are is stable on an immunosuppressive
the importance of a correct diagnosis. even more common and occur at ear-lier regimen and in the absence of an
ages than CFRD. Whether individuals with acute infection. E
The diagnosis of monogenic diabetes
IGT should be treated with insulin
should be considered in children and The oral glucose tolerance test is the
adults diagnosed with diabetes in early replacement has not currently been de- preferred test to make a diag-nosis
adulthood with the following findings: termined. Although screening for diabe-tes of posttransplantation diabe-
before the age of 10 years can identify risk tes mellitus. B
Diabetes diagnosed within the first 6 for progression to CFRD in those with Immunosuppressive regimens shown to
months of life (with occasional abnormal glucose tolerance, no benefit has provide the best outcomes for pa-tient
cases presenting later, mostly INS been established with respect to weight, and graft survival should be used,
and ABCC8 mutations) (83,89) height, BMI, or lung function. Continuous irrespective of posttransplanta-tion
Diabetes without typical features of type glucose monitoring or HOMA of b-cell diabetes mellitus risk. E
1 or type 2 diabetes (negative di- function (90) may be more sen-sitive than
abetes-associated autoantibodies, OGT T to detect risk for pro-gression to Several terms are used in the literature to
nonobese, lacking other metabolic CFRD; however, evidence linking these describe the presence of diabetes follow-
fea-tures, especially with strong results to long-term out-comes is lacking, ing organ transplantation. “New-onset di-
family history of diabetes) and these tests are not recommended for abetes after transplantation” (NODAT) is
Stable, mild fasting hyperglycemia screening (91). one such designation that describes indi-
(100–150 mg/dL [5.5–8.5 mmol/L]), CFRD mortality has significantly de- viduals who develop new-onset diabetes
stable A1C between 5.6 and 7.6% creased over time, and the gap in mortal-ity following transplant. NODAT excludes pa-
(be-tween 38 and 60 mmol/mol), between cystic fibrosis patients with and tients with pretransplant diabetes that was
espe-cially if nonobese without diabetes has considerably undiagnosed as well as posttrans-plant
narrowed (92). There are limited clinical hyperglycemia that resolves by the time of
CYSTIC FIBROSIS– trial data on therapy for CFRD. The largest discharge (97). Another term,
RELATED DIABETES study compared three regimens: premeal “posttransplantation diabetes mellitus”
insulin aspart, repaglinide, or oral placebo (PTDM) (97,98), describes the presence of
Recommendations
in cystic fibrosis patients with diabetes or diabetes in the posttransplant setting
Annual screening for cystic fibrosis–
abnormal glucose tolerance. Participants irrespective of the timing of diabetes onset.
related diabetes with oral glucose
all had weight loss in the year preced-ing Hyperglycemia is very common
tolerance test should begin by age
treatment; however, in the insulin-treated during the early posttransplant period,
10 years in all patients with cystic fi-
brosis not previously diagnosed with
group, this pattern was reversed, and with ;90% of kidney allograft recipients
patients gained 0.39 (6 0.21) BMI units (P ex-hibiting hyperglycemia in the first few
cystic fibrosis–related diabetes. B
5 0.02). The repaglinide-treated group had weeks following transplant (97–100). In
c A1C is not recommended as a
initial weight gain, but this was not most cases, such stress- or steroid-
screening test for cystic
sustained by 6 months. The placebo group induced hyperglycemia resolves by the
fibrosis– related diabetes. B
continued to lose weight (93). time of discharge (100,101). Although
care.diabetesjournals.org Classification and Diagnosis of Diabetes
S25
the use of immunosuppressive therapies is metformin was safe to use in renal trans- transethnic genome-wide meta-analysis.
a major contributor to the development of plant recipients (108), but its safety has not PLoS Med 2017;14:e1002383
Ziemer DC, Kolm P, Weintraub WS, et al. Glucose-
PTDM, the risks of transplant rejection been determined in other types of organ
independent, black-white differences in hemoglobin
outweigh the risks of PTDM and the role of transplant. Thiazolidinediones have been A1c levels: a cross-sectional analysis of 2 studies.
the diabetes care provider is to treat used successfully in patients with liver and Ann Intern Med 2010;152:770–777
hyperglycemia appropriately regard-less of kidney transplants, but side effects include Kumar PR, Bhansali A, Ravikiran M, et al. Util-ity
the type of immunosuppression (97). Risk fluid retention, heart failure, and osteopenia of glycated hemoglobin in diagnosing type 2
diabetes mellitus: a community-based study. J
factors for PTDM include both general (109,110). Dipep-tidyl peptidase 4 inhibitors
Clin Endocrinol Metab 2010;95:2832–2835
diabetes risks (such as age, fam-ily history do not interact with immunosuppressant Herman WH. Are there clinical implications of racial
of diabetes, etc.) as well as transplant- drugs and have demonstrated safety in differences in HbA1c? Yes, to not consider
specific factors, such as use of small clinical trials (111,112). Well-designed can do great harm! Diabetes Care
immunosuppressant agents (102). intervention tri-als examining the efficacy 2016;39:1458– 1461
Herman WH, Ma Y, Uwaifo G, et al.; Diabetes
Whereas posttransplantation hyperglyce- and safety of these and other Prevention Program Research Group. Differences
mia is an important risk factor for subse- antihyperglycemic agents in patients with in A1C by race and ethnicity among patients with
quent PTDM, a formal diagnosis of PTDM PTDM are needed. impaired glucose tolerance in the Diabetes Pre-
is optimally made once the patient is sta- vention Program. Diabetes Care
ble on maintenance immunosuppression 2007;30:2453– 2457
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sification of Diabetes Mellitus. Report of the
hyperglycemia should continue insulin with Finnish Diabetes Prevention Study Group. Preven-
Expert Committee on the Diagnosis and
frequent home self-monitoring of blood tion of type 2 diabetes mellitus by changes in lifestyle
Classifi-cation of Diabetes Mellitus. Diabetes
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Care 1997; 20:1183–1197
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reductions may be needed and when it Genuth S, Alberti KG, Bennett P, et al.; Expert
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may be appropriate to switch to noninsulin Committee on the Diagnosis and
lence of diabetes and high risk for diabetes using Classification of Diabetes Mellitus. Follow-up
agents. A1C criteria in the U.S. population in 1988–2006. report on the diag-nosis of diabetes mellitus.
No studies to date have established Diabetes Care 2010;33:562–568 Diabetes Care 2003;26: 3160–3167
which noninsulin agents are safest or Nowicka P, Santoro N, Liu H, et al. Utility of American Diabetes Association. Diagnosis and
hemoglobin A1c for diagnosing prediabetes and classification of diabetes mellitus. Diabetes Care
most efficacious in PTDM. The choice of
diabetes in obese children and adolescents. Dia- 2011;34(Suppl. 1):S62–S69
agent is usually made based on the side betes Care 2011;34:1306–1311 Zhang X, Gregg EW, Williamson DF, et al. A1C level
effect profile of the medication and pos- Lacy ME, Wellenius GA, Sumner AE, Correa A, and future risk of diabetes: a systematic re-view.
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munosuppression regimen (102). Drug sickle cell trait with hemoglobin A1c in African Selvin E, Steffes MW, Zhu H, et al. Glycated
Ameri-cans. JAMA 2017;317:507–515 hemoglobin, diabetes, and cardiovascular risk in
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short-term pilot study reported that and diagnosis in ancestrally diverse populations: a
cardiovascular disease using hemoglobin
S26 Classification and Diagnosis of Diabetes Diabetes Care Volume 41, Supplement 1, January 2018
A1c National Health and Nutrition Examination Americans for type 2 diabetes: The UCSD post-gestational diabetes mellitus as defined
Survey 2005-2006. Am J Prev Med 2011;40:11–17 Filipino Health Study and the North Kohala Study by the International Association of Diabetes
Diabetes Prevention Program Research [Ab-stract]. Diabetes 2014;63(Suppl. 1):A20 and Pregnancy Study Groups criteria. Eur J
Group. HbA1c as a predictor of diabetes and Hsu WC, Araneta MRG, Kanaya AM, Chiang JL, Endocrinol 2016;175:287–297
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Program: a randomized clinical trial. Diabetes Asian Americans for type 2 diabetes screening. Gestational diabetes and the incidence of
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Dabelea D, Mayer-Davis EJ, Saydah S, et al.; WHO Expert Consultation. Appropriate Diabetes Care 2002;25:1862– 1868
SEARCH for Diabetes in Youth Study. body-mass index for Asian populations and Ratner RE, Christophi CA, Metzger BE, et al.;
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among children and adolescents from 2001 to strategies. Lancet 2004;363:157–163 Group. Prevention of diabetes in women with
2009. JAMA 2014;311: 1778–1786 Chiu M, Austin PC, Manuel DG, Shah BR, a history of gestational diabetes: effects of
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S28 Diabetes Care Volume 41, Supplement 1, January 2018
Continued on p. S31
care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S31
S32 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 41, Supplement 1, January 2018
may help to prevent hypoglycemia in Conversely, prediabetes and/or diabetes Hearing Impairment
in-dividuals with cognitive dysfunction. has been found to develop in approxi- Hearing impairment, both in high-frequency
mately one-third of patients after an epi- and low/mid-frequency ranges, is more
Nutrition
sode of acute pancreatitis (47), thus the common in people with diabetes than in those
In one study, adherence to the Mediter-
relationship is likely bidirectional. Postpan- without, perhaps due to neuropathy and/or
ranean diet correlated with improved
creatitis diabetes may include either new- vascular disease. In a National Health and
cognitive function (39). However, a
onset disease or previously unrecognized Nutrition Examination Survey (NHANES)
recent Cochrane review found
diabetes (48). Studies of patients treated analysis, hearing impair-ment was about
insufficient ev-idence to recommend any
with incretin-based therapies for diabetes twice as prevalent in peo-ple with diabetes
dietary change for the prevention or
have also reported that pancreatitis may compared with those without, after adjusting
treatment of cogni-tive dysfunction (40).
occur more frequently with these medica- for age and other risk factors for hearing
Statins tions, but results have been mixed (49,50). impairment (61).
A systematic review has reported that data Islet autotransplantation should be con-
do not support an adverse effect of statins HIV
sidered for patients requiring total pancre-
on cognition (41). The U.S. Food and Drug atectomy for medically refractory chronic Recommendation
Administration (FDA) post-marketing pancreatitis to prevent postsurgical diabe- Patients with HIV should be screened for
surveillance databases have also revealed tes. Approximately one-third of patients diabetes and prediabetes with a fasting
a low reporting rate for cog-nitive-related undergoing total pancreatectomy with is-let glucose level every 6–12 months
adverse events, including cognitive autotransplantation are insulin free one before starting antiretrovi-ral therapy
dysfunction or dementia, with statin year postoperatively, and observational and 3 months after starting or changing
therapy, similar to rates seen with other studies from different centers have dem- antiretroviral therapy. If initial screening
commonly prescribed cardiovascular onstrated islet graft function up to a de- results are normal, checking fasting
medications (41). Therefore, fear of cog- cade after the surgery in some patients glu-cose every year is advised. E
nitive decline should not be a barrier to (51–55). Both patient and disease factors
statin use in individuals with diabetes and should be carefully considered when de- Diabetes risk is increased with certain
a high risk for cardiovascular disease. ciding the indications and timing of this protease inhibitors (PIs) and nucleoside
surgery. Surgeries should be performed in reverse transcriptase inhibitors (NRTIs).
Fatty Liver Disease skilled facilities that have demonstrated New-onset diabetes is estimated to oc-cur
Diabetes is associated with the develop-
expertise in islet autotransplantation. in more than 5% of patients infected with
ment of nonalcoholic chronic liver disease
HIV on PIs, whereas more than 15% may
and with hepatocellular carcinoma (42).
Fractures have prediabetes (62). PIs are asso-ciated
Elevations of hepatic transaminase con-
Age-specific hip fracture risk is signifi- with insulin resistance and may also lead
centrations are associated with higher BMI, cantly increased in people with both type 1 to apoptosis of pancreatic b-cells. NRTIs
waist circumference, and triglycer-ide (relative risk 6.3) and type 2 (relative risk also affect fat distribution (both lip-
levels and lower HDL cholesterol lev-els. 1.7) diabetes in both sexes (56). Type 1 ohypertrophy and lipoatrophy), which is
Interventions that improve metabolic diabetes is associated with osteoporosis, associated with insulin resistance.
abnormalities in patients with diabetes but in type 2 diabetes, an increased risk of Individuals with HIV are at higher risk
(weight loss, glycemic control, and treat- hip fracture is seen despite higher bone for developing prediabetes and diabe-
ment with specific drugs for hyperglyce- mineral density (BMD) (57). In three large tes on antiretroviral (ARV) therapies, so
mia or dyslipidemia) are also beneficial for observational studies of older adults, a screening protocol is recommended
fatty liver disease (43,44). femoral neck BMD T score and the World (63). The A1C test underestimates
Health Organization Fracture Risk Assess- glyce-mia in people with HIV and is not
Pancreatitis ment Tool (FRAX) score were associated recom-mended for diagnosis and may
Recommendation with hip and nonspine fractures. Fracture present challenges for monitoring (64).
Islet autotransplantation should be risk was higher in participants with dia- In those with prediabetes, weight loss
considered for patients requiring betes compared with those without dia- through healthy nutrition and physical
total pancreatectomy for medically betes for a given T score and age or for a activity may reduce the progression
refractory chronic pancreatitis to given FRAX score (58). Providers should toward dia-betes. Among patients with
prevent postsurgical diabetes. C assess fracture history and risk factors in HIV and diabetes, preventive health
older patients with diabetes and recom- care using an approach similar to that
Diabetes is linked to diseases of the exo- mend measurement of BMD if appro-priate used in pa-tients without HIV is critical to
crine pancreas such as pancreatitis, which for the patient’s age and sex. Fracture reduce the risks of microvascular and
may disrupt the global architecture or prevention strategies for people with macrovas-cular complications.
physiology of the pancreas, often result-ing diabetes are the same as for the general For patients with HIV and ARV-associated
in both exocrine and endocrine population and include vitamin D hyperglycemia, it may be appropriate to
dysfunction. Up to half of patients with di- supplementation. For patients with type 2 consider discontinuing the problematic ARV
abetes may have impaired exocrine pan- diabetes with fracture risk factors, agents if safe and effective alternatives are
creas function (45). People with diabetes thiazolidinediones (59) and sodium– available (65). Before making ARV sub-
are at an approximately twofold higher risk glucose cotransporter 2 inhibitors (60) stitutions, carefully consider the possible
of developing acute pancreatitis (46). should be used with caution.
S34 Comprehensive Medical Evaluation and Assessment of Comorbidities Diabetes Care Volume 41, Supplement 1, January 2018
effect on HIV virological control and the diabetes than in those without (74,75). The Behavioral Risk Factor Surveillance
potential adverse effects of new ARV Current evidence suggests that periodon- System (BRFSS) estimated the lifetime
agents. In some cases, antihyperglycemic tal disease adversely affects diabetes out- prevalence of generalized anxiety disorder to
agents may still be necessary. comes, although evidence for treatment be 19.5% in people with either type 1 or type
benefits remains controversial (23). 2 diabetes (79). Common diabetes-specific
Low Testosterone in Men concerns include fears related to
Recommendation Psychosocial/Emotional Disorders hypoglycemia (80,81), not meeting blood
In men with diabetes who have Prevalence of clinically significant psycho- glucose targets (78), and insulin injections or
symptoms or signs of hypogonadism pathology diagnoses are considerably infusion (82). Onset of complications presents
such as decreased sexual desire more common in people with diabetes than another critical point when anxiety can occur
(libido) or activity, or erectile dys- in those without the disease (76). (83). People with dia-betes who exhibit
function, consider screening with a Symptoms, both clinical and subclinical, excessive diabetes self-management
morning serum testosterone level. B that interfere with the person’s ability to behaviors well beyond what is prescribed or
carry out daily diabetes self-manage-ment needed to achieve glycemic targets may be
Mean levels of testosterone are lower in men tasks must be addressed. Providers should experiencing symptoms of obsessive-
with diabetes compared with age-matched consider an assessment of symp-toms of compulsive disorder (84).
men without diabetes, but obesity is a major depression, anxiety, and disor-dered General anxiety is a predictor of
confounder (66,67). Treatment in eating, and of cognitive capacities using injection-related anxiety and associated
asymptomatic men is controversial. patient-appropriate standardized/ validated with fear of hypoglycemia (81,85). Fear of
Testosterone replacement in men with tools at the initial visit, at peri-odic intervals, hy-poglycemia and hypoglycemia
symptomatic hypogonadism may have ben- and when there is a change in disease, unaware-ness often co-occur, and
efits including improved sexual function, well treatment, or life circum-stance. Including interventions aimed at treating one often
being, muscle mass and strength, and bone caregivers and family members in this benefit both (86). Fear of hypoglycemia
density. (68). In men with diabetes who have assessment is recom-mended. Diabetes may explain avoidance of behaviors
symptoms or signs of low testos-terone distress is addressed in Section 4 “Lifestyle associated with lowering glucose such as
(hypogonadism), a morning total testosterone Management,” as this state is very increasing in-sulin doses or frequency of
should be measured using an accurate and common and distinct from the monitoring. If fear of hypoglycemia is
reliable assay. Free or bioavail-able psychological disorders dis-cussed below identified and a person does not have
testosterone levels should also be mea-sured (77). symptoms of hypoglycemia, a structured
in men with diabetes who have total program, blood glucose awareness
Anxiety Disorders
testosterone levels close to the lower limit, training, deliv-ered in routine clinical
given expected decreases in sex hormone– Recommendations practice, can im-prove A1C, reduce the
binding globulin with diabetes. Further testing Consider screening for anxiety in rate of severe hypoglycemia, and restore
(such as luteinizing hormone and follicle- people exhibiting anxiety or worries hypoglycemia awareness (87,88).
stimulating hormone levels) may be needed regarding diabetes complications,
to distinguish between pri-mary and insulin injections or infusion, taking Depression
secondary hypogonadism. medications, and/or hypoglycemia
Recommendations
that interfere with self-management
Obstructive Sleep Apnea Providers should consider annual
behaviors and those who express
Age-adjusted rates of obstructive sleep screening of all patients with diabetes,
fear, dread, or irrational thoughts
apnea, a risk factor for cardiovascular especially those with a self-reported
and/or show anxiety symptoms such
disease, are significantly higher (4- to 10- history of depression, for depressive
as avoidance behaviors, exces-sive
fold) with obesity, especially with cen-tral symptoms with age-appropriate de-
repetitive behaviors, or social
obesity (69). The prevalence of ob- pression screening measures, recog-
withdrawal. Refer for treatment if
structive sleep apnea in the population nizing that further evaluation will be
anxiety is present. B necessary for individuals who have a
with type 2 diabetes may be as high as
People with hypoglycemia unaware-
23%, and the prevalence of any sleep dis- positive screen. B
ness, which can co-occur with fear of
ordered breathing may be as high as 58% Beginning at diagnosis of complica-
hypoglycemia, should be treated us-
(70,71). In obese participants enrolled in tions or when there are significant
ing blood glucose awareness training
the Action for Health in Diabetes (Look changes in medical status, consider
(or other evidence-based interven-
AHEAD) trial, it exceeded 80% (72). Sleep assessment for depression. B
tion) to help reestablish awareness
apnea treatment (lifestyle modification, Referrals for treatment of depres-sion
of hypoglycemia and reduce fear of
continuous positive airway pressure, oral should be made to mental health
hypoglycemia. A
appliances, and surgery) significantly providers with experience us-ing
improves quality of life and blood pressure cognitive behavioral therapy,
Anxiety symptoms and diagnosable disor-
control. The evidence for a treatment ef- interpersonal therapy, or other evi-
ders (e.g., generalized anxiety disorder,
fect on glycemic control is mixed (73). dence-based treatment approaches
body dysmorphic disorder, obsessive-
in conjunction with collaborative care
Periodontal Disease compulsive disorder, specific phobias, and
with the patient’s diabetes treatment
Periodontal disease is more severe, and posttraumatic stress disorder) are common
team. A
may be more prevalent, in patients with in people with diabetes (78).
care.diabetesjournals.org Comprehensive Medical Evaluation and Assessment of Comorbidities S35
History of depression, current depression, (98,99); in people with type 2 diabetes, those taking second-generation (atypical)
and antidepressant medication use are risk bingeing (excessive food intake with an antipsychotics such as olanzapine require
factors for the development of type 2 accompanying sense of loss of control) greater monitoring because of an increase
diabetes, especially if the individual has is most commonly reported. For people in risk of type 2 diabetes associated with
other risk factors such as obesity and with type 2 diabetes treated with insulin, this medication (106).
family history of type 2 diabetes (89–91). intentional omission is also frequently re-
Elevated depressive symptoms and ported (100). People with diabetes and
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Diabetes Care Volume 41, Supplement 1, January 2018 S51
For guidelines related to screening for increased risk for type 2 diabetes
(prediabetes), please refer to Section 2 “Classification and Diagnosis of Diabetes.”
Recommendations
At least annual monitoring for the development of diabetes in those with pre-
diabetes is suggested. E
Patients with prediabetes should be referred to an intensive behavioral lifestyle
intervention program modeled on the Diabetes Prevention Program to achieve
and maintain 7% loss of initial body weight and increase moderate-intensity
physical activity (such as brisk walking) to at least 150 min/week. A
Technology-assisted tools including Internet-based social networks, distance
learning, and mobile applications that incorporate bidirectional communi-cation
may be useful elements of effective lifestyle modification to prevent
diabetes. B
Given the cost-effectiveness of diabetes prevention, such intervention
programs should be covered by third-party payers. B
Screening for prediabetes and type 2 diabetes risk through an informal assess-ment
of risk factors (Table 2.3) or with an assessment tool, such as the American Diabetes
Association risk test (Fig. 2.1), is recommended to guide providers on whether Suggested citation: American Diabetes Association.
performing a diagnostic test for prediabetes (Table 2.4) and previ-ously undiagnosed Prevention or delay of type 2 diabetes:
type 2 diabetes (Table 2.2) is appropriate (see Section 2 “Classification and Standards of Medical Care in Diabetesd2018.
Diagnosis of Diabetes”). Those determined to be at high risk for type 2 diabetes, Diabetes Care 2018;41(Suppl. 1):S51–S54
including people with A1C 5.7–6.4% (39–47 mmol/mol), im-paired glucose tolerance, © 2017 by the American Diabetes Association.
or impaired fasting glucose, are ideal candidates for diabetes prevention efforts. Readers may use this article as long as the work
is properly cited, the use is educational and not
Using A1C to screen for prediabetes may be problem-atic in the presence of certain
for profit, and the work is not altered. More infor-
hemoglobinopathies or conditions that affect red blood cell turnover. See Section 2 mation is available at http://www.diabetesjournals
“Classification and Diagnosis of Diabetes” and .org/content/license.
S52 Prevention or Delay of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018
Section 6 “Glycemic Targets” for encouraged to distribute their activity showed beneficial effects in those with pre-
addi-tional details on the throughout the week with a minimum fre- diabetes (1), moderate-intensity physical
appropriate use of the A1C test. quency of three times per week with at least activity has been shown to improve insu-lin
At least annual monitoring for the 10 min per session. A maximum of 75 min of sensitivity and reduce abdominal fat in
de-velopment of diabetes in those strength training could be applied toward the children and young adults (18,19). On the
with pre-diabetes is suggested. total 150 min/week physical activity goal (6). basis of these findings, providers are en-
To implement the weight loss and couraged to promote a DPP-style pro-
physical activity goals, the DPP used an in- gram, including its focus on physical
LIFESTYLE INTERVENTIONS dividual model of treatment rather than a activity, to all individuals who have been
The Diabetes Prevention Program group-based approach. This choice was identified to be at an increased risk of type
The strongest evidence for diabetes preven- based on a desire to intervene before par- 2 diabetes. In addition to aerobic activity,
tion comes from the Diabetes Prevention ticipants had the possibility of developing an exercise regimen designed to prevent
Program (DPP) (1). The DPP demonstrated diabetes or losing interest in the program. diabetes may include resistance training
that an intensive lifestyle intervention could The individual approach also allowed for (6,20). Breaking up prolonged sedentary
reduce the incidence of type 2 di-abetes by tailoring of interventions to reflect the di- time may also be encouraged, as it is
58% over 3 years. Follow-up of three large versity of the population (6). associated with moderately lower
studies of lifestyle interven-tion for diabetes The DPP intervention was administered postprandial glucose levels (21,22). The
prevention has shown sustained reduction in as a structured core curriculum followed by preventative effects of exercise appear to
the rate of conver-sion to type 2 diabetes: a more flexible maintenance program of extend to the prevention of gestational
43% reduction at 20 years in the Da Qing individual sessions, group classes, moti- diabetes mellitus (GDM) (23).
study (2), 43% reduction at 7 years in the vational campaigns, and restart opportuni-
Finnish Diabetes Prevention Study (DPS) (3),
Technology Assistance to Deliver
ties. The 16-session core curriculum was
Lifestyle Interventions
and 34% reduc-tion at 10 years (4) and 27% completed within the first 24 weeks of the
Information technology platforms may
reduction at 15 years (5) in the U.S. Diabetes program and included sections on low-
effectively deliver the core components of
Preven-tion Program Outcomes Study ering calories, increasing physical activity,
the DPP (24–26), lowering weight, reduc-
(DPPOS). self-monitoring, maintaining healthy life-
ing risk for diabetes and cardiovascular
The two major goals of the DPP inten- style behaviors, and psychological, social,
disease, and achieving cost savings
sive, behavioral, lifestyle intervention were and motivational challenges. For further
(27,28). Recent studies support content
to achieve and maintain a minimum of 7% de-tails on the core curriculum sessions,
delivery through virtual small groups
weight loss and 150 min of physical activity refer to ref. 6.
, Internet-driven social networks (30,31),
per week similar in intensity to brisk
Nutrition cell phones, and other mobile de-vices.
walking. The DPP lifestyle interven-tion
Reducing caloric intake is of paramount im- Mobile applications for weight loss and
was a goal-based intervention: all
portance for those at high risk for develop-ing diabetes prevention have been vali-dated
participants were given the same weight
type 2 diabetes, though recent evidence for their ability to reduce A1C in the setting
loss and physical activity goals, but indi-
suggests that the quality of fats consumed in of prediabetes (31). The Cen-ters for
vidualization was permitted in the specific
the diet is more important than the total Disease Control and Prevention (CDC)
methods used to achieve the goals (6).
quantity of dietary fat (7–9). For example, the Diabetes Prevention Recognition Program
The 7% weight loss goal was selected be-
Mediterranean diet, which is relative-ly high in (DPRP) (http://www.cdc.gov/
cause it was feasible to achieve and maintain
monounsaturated fats, may help to prevent diabetes/prevention/recognition/index
and likely to lessen the risk of developing
type 2 diabetes (10–12). .htm) has begun to certify electronic and
diabetes. Participants were encouraged to
Whereas overall healthy low-calorie mobile health-based modalities as effec-
achieve the 7% weight loss during the first 6
eating patterns should be encouraged, tive vehicles for DPP-based interventions
months of the intervention. The recom-
there is also some evidence that particu-lar that may be considered alongside more
mended pace of weight loss was 1–2 lb/week.
dietary components impact diabetes risk. traditional face-to-face and coach-driven
Calorie goals were calculated by estimating
Higher intakes of nuts (13), berries (14), programs. A recent study showed that an
the daily calories needed to maintain the
yogurt (15), coffee, and tea (16) are as- all-mobile approach to administering DPP
participant’s initial weight and subtracting
sociated with reduced diabetes risk. Con- content can be effective as a prevention
500–1,000 calories/day (depending on initial
versely, red meats and sugar-sweetened tool, at least over the short term, in over-
body weight). The initial focus was on
beverages are associated with an in- weight and obese individuals at high risk
reducing total dietary fat. After several weeks,
creased risk of type 2 diabetes (8). for diabetes (32).
the concept of calorie balance and the need
As is the case for those with diabetes,
to restrict calories as well as fat was Cost-effectiveness
individualized medical nutrition therapy
introduced (6). cost-effectiveness model suggested that
(see Section 4 “Lifestyle Management”
The goal for physical activity was selected the lifestyle intervention used in the DPP
for more detailed information) is effective
to approximate at least 700 kcal/week was cost-effective (33). Actual cost data
in lowering A1C in individuals diagnosed
expenditure from physical activity. For ease of from the DPP and DPPOS con-firmed this
with prediabetes (17).
translation, this goal was described as at (34). Group delivery of DPP content in
least 150 min of moderate-intensity physical Physical Activity community or primary care settings has the
activity per week similar in inten-sity to brisk Just as 150 min/week of moderate-intensity potential to reduce over-all program costs
walking. Participants were physical activity, such as brisk walking, while still producing
care.diabetesjournals.org Prevention or Delay of Type 2 Diabetes
S53
weight loss and diabetes risk reduction Metformin was overall less effective to people with prediabetes. Currently, there
(35–37). The use of community health than lifestyle modification in the DPP are significant barriers to the pro-vision of
workers to support DPP efforts has been and DPPOS, though group differences education and support to those with
shown to be effective with cost savings de-clined over time (5) and metformin prediabetes. However, the strate-gies for
(see Section 1 “Improving Care and may be cost-saving over a 10-year supporting successful behavior change
Promoting Health in Populations” for more period (34). It was as effective as and the healthy behaviors recom-mended
information). The CDC helps to coordi-nate lifestyle modification in participants with for people with prediabetes are
the National Diabetes Prevention Program 2 comparable to those for diabetes. Al-
BMI $35 kg/m but not significantly
(National DPP), a resource de-signed to better than placebo in those over 60 though reimbursement remains a barrier,
bring evidence-based lifestyle change years of age (1). In the DPP, for women studies show that providers of diabetes
programs for preventing type 2 diabetes to with history of GDM, metformin and self-management education and support
communities (http://www intensive lifestyle mod-ification led to an are particularly well equipped to assist
.cdc.gov/diabetes/prevention/index.htm). equivalent 50% reduc-tion in diabetes people with prediabetes in developing and
Early results from the CDC’s National DPP risk (46), and both interventions maintaining behaviors that can pre-vent or
during the first 4 years of implementation remained highly effective during a 10- delay the development of diabe-tes
are promising (39). On 7 July 2016, the year follow-up period (47). Metformin (17,50).
Centers for Medicare and Medicaid Ser- should be recommended as an option
vices (CMS) proposed expanded Medi- for high-risk individuals (e.g., those with
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proposed implementation in 2018 (https:// possible defi-ciency (see Section 8 with lifestyle intervention or metformin. N Engl J
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Diabetes Care Volume 41, Supplement 1, January 2018 S55
6. GLYCEMIC TARGETS
includes ADA’s current clinical practice recommendations and is intended to provide
the components of diabetes care, general treatment goals and guidelines, and tools
to evaluate quality of care. Members of the ADA Professional Practice Committee, a
multidisciplinary expert committee, are responsible for updating the Standards of
Care annually, or more frequently as warranted. For a detailed description of ADA
standards, statements, and reports, as well as the evidence-grading system for
ADA’s clinical practice recommendations, please refer to the Standards of Care
Introduction. Readers who wish to comment on the Standards of Care are invited to
do so at professional.diabetes.org/SOC.
Recommendations
Most patients using intensive insulin regimens (multiple-dose insulin or in-sulin
pump therapy) should perform self-monitoring of blood glucose (SMBG) prior
to meals and snacks, at bedtime, occasionally postprandially, prior to exercise,
when they suspect low blood glucose, after treating low blood glucose until
they are normoglycemic, and prior to critical tasks such as
driving. B
When prescribed as part of a broad educational program, SMBG may help to
guide treatment decisions and/or self-management for patients taking less fre-
quent insulin injections B or noninsulin therapies. E
When prescribing SMBG, ensure that patients receive ongoing
instruction and regular evaluation of SMBG technique, SMBG results,
and their ability to use SMBG data to adjust therapy. E Suggested citation: American Diabetes
When used properly, continuous glucose monitoring (CGM) in conjunction with Associa-tion. 6. Glycemic targets: Standards
of Medical Care in Diabetesd2018. Diabetes
intensive insulin regimens is a useful tool to lower A1C in adults with type 1
Care 2018; 41(Suppl. 1):S55–S64
diabetes who are not meeting glycemic targets. A
© 2017 by the American Diabetes Association.
CGM may be a useful tool in those with hypoglycemia unawareness and/or Readers may use this article as long as the work
frequent hypoglycemic episodes. C is properly cited, the use is educational and not
Given the variable adherence to CGM, assess individual readiness for for profit, and the work is not altered. More infor-
continuing CGM use prior to prescribing. E mation is available at http://www.diabetesjournals
.org/content/license.
S56 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018
should be advised against purchasing or most CGM devices include alarms for
When prescribing CGM, robust di-
reselling preowned or secondhand test hypo-and hyperglycemic excursions. The
abetes education, training, and sup-
strips, as these may give incorrect results. inter-mittent or “flash” CGM device, very
port are required for optimal CGM
Only unopened vials of glucose test strips re-cently approved for adult use only (18),
implementation and ongoing use. E
should be used to ensure SMBG accuracy. differs from previous CGM devices. Spe-
People who have been cifically, it does not have alarms, does not
successfully using CGM should For Patients on Intensive Insulin Regimens
Most patients using intensive insulin require calibration with SMBG, and does
have continued access after they
regimens (multiple-dose insulin or insulin not communicate continuously (only on
turn 65 years of age. E
pump therapy) should perform SMBG prior demand). It is reported to have a lower
to meals and snacks, at bedtime, oc- cost than traditional systems. A study in
Self-monitoring of Blood Glucose adults with well-controlled type 1 diabe-tes
Major clinical trials of insulin-treated pa- casionally postprandially, prior to exercise,
when they suspect low blood glucose, af- found that flash CGM users spent less time
tients have included SMBG as part of
ter treating low blood glucose until they are in hypoglycemia than those using SMBG
multifactorial interventions to demon-strate
normoglycemic, and prior to critical tasks (19). However, due to significant
the benefit of intensive glycemic control on
such as driving. For many patients, this will differences between flash CGM and other
diabetes complications. SMBG is thus an
require testing 6–10 (or more) times daily, CGM devices, more discussion is needed
integral component of effective therapy (2).
although individual needs may vary. A on outcomes and regarding specific rec-
SMBG allows patients to eval-uate their
database study of almost 27,000 children ommendations.
individual response to therapy and assess
and adolescents with type 1 diabetes For most CGM systems, confirmatory
whether glycemic targets are being
showed that, after adjust-ment for multiple SMBG is required to make treatment de-
achieved. Integrating SMBG results into
confounders, increased daily frequency of cisions, though a randomized controlled
diabetes management can be a useful tool
SMBG was significantly associated with trial of 226 adults suggested that an en-
for guiding medical nutrition therapy and
lower A1C (–0.2% per ad-ditional test per hanced CGM device could be used safely
physical activity, preventing hypoglycemia,
day) and with fewer acute complications and effectively without regular confirma-
and adjusting medications (particularly
(8). tory SMBG in patients with well-controlled
prandial insulin doses). Among patients
type 1 diabetes at low risk of severe hy-
with type 1 diabetes, there is a correlation
For Patients Using Basal Insulin and/or Oral poglycemia (1). Two CGM devices are now
between greater SMBG fre-quency and
Agents approved by the U.S. Food and Drug Ad-
lower A1C (3). The patient’s specific needs
The evidence is insufficient regarding ministration (FDA) for making treatment
and goals should dictate SMBG frequency
when to prescribe SMBG and how often decisions without SMBG confirmation
and timing.
testing is needed for patients who do not (18,20), including the flash CGM device.
Optimization use intensive insulin regimens, such as Although performed with older gener-
SMBG accuracy is dependent on the those with type 2 diabetes using oral ation CGM devices, a 26-week random-
instru-ment and user, so it is important to agents and/or basal insulin. For patients ized trial of 322 patients with type 1
evalu-ate each patient’s monitoring using basal insulin, assessing fasting diabetes showed that adults aged $25
technique, both initially and at regular glucose with SMBG to inform dose years using intensive insulin therapy and
intervals thereafter. Optimal use of SMBG adjustments to achieve blood glucose CGM experienced a 0.5% reduction in A1C
requires proper review and interpretation targets results in lower A1Cs (9,10). (from ;7.6% to 7.1% [;60 mmol/mol to 54
of the data, by both the patient and the For individuals with type 2 diabetes mmol/mol]) compared with those using
pro-vider. Among patients who check their on less intensive insulin therapy, more intensive insulin therapy with SMBG (21).
blood glucose at least once daily, many fre-quent SMBG (e.g., fasting, The greatest predictor of A1C lower-ing for
report taking no action when results are before/after meals) may be helpful, as all age-groups was frequency of sensor
high or low. In a yearlong study of insulin- increased fre-quency is associated use, which was highest in those aged $25
naive patients with suboptimal initial with meeting A1C targets (11). years and lower in younger age-groups.
glycemic control, a group trained in struc- Several randomized trials have called Two clinical trials in adults with type 1
tured SMBG (a paper tool was used at into question the clinical utility and cost- diabetes not meeting A1C targets and
least quarterly to collect and interpret 7- effectiveness of routine SMBG in noninsu- using multiple daily injections also found
point SMBG profiles taken on 3 consec- lin-treated patients (12–15). Meta-analyses that the use of CGM compared with usual
utive days) reduced their A1C by 0.3 per- have suggested that SMBG can reduce care resulted in lower A1C levels than
centage points more than the control group A1C by 0.25–0.3% at 6 months (16,17), but SMBG over 24–26 weeks (22,23). Other
(4). Patients should be taught how to use the effect was attenuated at 12 months in small, short-term studies have
SMBG data to adjust food in-take, one analysis (16). A key consideration is demonstrated similar A1C reductions us-
exercise, or pharmacologic therapy to that performing SMBG alone does not ing CGM compared with SMBG in adults
achieve specific goals. The ongoing need lower blood glucose levels. To be useful, with A1C levels $7% (53 mmol/mol)
for and frequency of SMBG should be the information must be integrated into (24,25).
reevaluated at each routine visit to avoid clinical and self-management plans. A registry study of 17,317 participants
overuse (5–7). SMBG is especially confirmed that more frequent CGM use is
important for insulin-treated patients to Continuous Glucose Monitoring associated with lower A1C (26), whereas
monitor for and prevent asymptomatic CGM measures interstitial glucose (which another study showed that children with .
hypoglycemia and hyperglycemia. Patients correlates well with plasma glucose), and 70% sensor use (i.e., $5 days per
care.diabetesjournals.org Glycemic Targets S57
week) missed fewer school days (27). A1C TESTING when the A1C result does not correlate
Small randomized controlled trials in adults with the patient’s SMBG levels. Options
Recommendations
and children with baseline A1C ,7.0–7.5% for monitoring include more frequent
Perform the A1C test at least two
(53–58 mmol/mol) have con-firmed and/ or different timing of SMBG or
times a year in patients who are
favorable outcomes including a reduced CGM use. Other measures of average
meeting treatment goals (and who
frequency of hypoglycemia (de-fined as a glycemia such as fructosamine and 1,5-
have stable glycemic control). E
blood glucose level ,70 mg/dL [3.9 anhydroglucitol are available, but their
Perform the A1C test quarterly in
mmol/L]) and maintaining A1C ,7% (53 translation into average glucose levels
patients whose therapy has changed
mmol/mol) during the study period in and their prog-nostic significance are not
or who are not meeting glycemic
groups using CGM, suggesting that CGM as clear as for A1C. Though some
goals. E
may provide further benefit for individu-als variability exists among different
Point-of-care testing for A1C provides
with type 1 diabetes who already have individuals, generally the association
the opportunity for more timely
good glycemic control (28–30). between mean glucose and A1C within
treatment changes. E
meta-analysis suggests that com-pared an individual correlates over time (42).
with SMBG, CGM is associated with short- A1C does not provide a measure of
A1C reflects average glycemia over
term A1C lowering of ;0.26% in insulin- glycemic variability or hypoglycemia. For
approximately 3 months and has strong
treated patients (31). The long-term patients prone to glycemic variability,
predictive value for diabetes complica-tions
effectiveness of CGM needs to be especially patients with type 1 diabetes or
(39,40). Thus, A1C testing should be
determined. This technology may be par- type 2 diabetes with severe insulin de-
performed routinely in all patients with
ticularly useful in insulin-treated patients ficiency, glycemic control is best evalu-ated
diabetesdat initial assessment and as part
with hypoglycemia unawareness and/or by the combination of results from A1C and
of continuing care. Measurement
frequent hypoglycemic episodes, although SMBG or CGM. A1C may also confirm the
approximately every 3 months deter-mines
studies have not shown consistent reduc- accuracy of the patient’s me-ter (or the
whether patients’ glycemic targets have
tions in severe hypoglycemia (31–33). A patient’s reported SMBG re-sults) and the
been reached and maintained. The
CGM device equipped with an automatic adequacy of the SMBG testing schedule.
frequency of A1C testing should depend on
low glucose suspend feature has been
the clinical situation, the treatment
approved by the FDA. The Automation to A1C and Mean Glucose
regimen, and the clinician’s judgment. The
Simulate Pancreatic Insulin Response Table 6.1 shows the correlation between
use of point-of-care A1C testing may
(ASPIRE) trial of 247 patients with type 1 A1C levels and mean glucose levels based
provide an opportunity for more timely
diabetes and documented nocturnal hypo- on two studies: the international A1C-
treatment changes during encounters be-
glycemia showed that sensor-augmented Derived Average Glucose (ADAG) study,
tween patients and providers. Patients with
insulin pump therapy with a low glucose which assessed the correlation between
type 2 diabetes with stable glycemia well
suspend function significantly reduced A1C and frequent SMBG and CGM in
within target may do well with A1C testing
nocturnal hypoglycemia over 3 months adults (83% non-Hispanic whites) with type
only twice per year. Unstable or intensively
without increasing A1C levels (34). These 1, type 2, and no diabetes (43), and an
managed patients (e.g., preg-nant women
devices may offer the opportunity to empirical study of the average blood
with type 1 diabetes) may require testing
reduce hypoglycemia for those with a glucose levels at premeal, post-meal, and
more frequently than every 3 months (41).
history of nocturnal hypoglycemia. The bedtime associated with spec-ified A1C
FDA has also approved the first hybrid levels using data from the ADAG trial (37).
closed-loop system. The safety of hybrid A1C Limitations The American Diabetes Association (ADA)
closed-loop systems has been sup-ported The A1C test is an indirect measure of and the American As-sociation for Clinical
in the literature (35) and may have average glycemia and, as such, is subject Chemistry have de-termined that the
advantages over sensor-augmented pump to limitations. As with any laboratory test, correlation (r 50.92) in the ADAG trial is
therapy in specific populations, such as there is variability in the measurement of strong enough to justify reporting both the
pregnant women with type 1 diabetes (36). A1C. Although such variability is less on an A1C result and the es-timated average
intraindividual basis than that of blood glucose (eAG) result when a clinician
Due to variable adherence, optimal glucose measurements, clinicians should orders the A1C test. Clini-cians should
CGM use requires an assessment of exercise judgment when using A1C as the note that the mean plasma glucose
indi-vidual readiness for the technology sole basis for assessing glycemic control, numbers in the table are based on ;2,700
as well as initial and ongoing education particularly if the result is close to the readings per A1C in the ADAG trial. In a
and support (26,37). Additionally, pro- threshold that might prompt a change in recent report, mean glucose measured
viders need to provide robust diabetes medication therapy. Conditions that affect with CGM versus central labo-ratory–
education, training, and support for opti- red blood cell turnover (hemolytic and other measured A1C in 387 participants in three
mal CGM implementation and ongoing anemias, recent blood transfusion, use of randomized trials demonstrated that A1C
use. As people with type 1 or type 2 drugs that stimulate erythropo-esis, end- may underestimate or overesti-mate mean
diabetes are living longer, healthier stage kidney disease, and pregnancy) may glucose. Thus, as suggested, a patient’s
lives, individuals who have been result in discrepancies between the A1C CGM profile has considerable potential for
successfully using CGM should have result and the pa-tient’s true mean optimizing his or her glyce-mic
continued access to these devices after glycemia. Hemoglobin variants must be management (42).
they turn 65 years of age (38). considered, particularly
S58 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018
–67(53)154(123185)8.(6.810.3)
–911(97)269(217314)14.(12.017.5)
–512(108)298(240347)16.(13.319.3)
Mean bedtime glucose
–8(64)183(147217)10.(8.12.1)21
–10(86)240(193282)13.(10.715.7)4
Data in parentheses represent 95% CI, unless otherwise noted. A calculator for converting A1C results into eAG, in either mg/dL or mmol/L, is available at http://professional.diabetes.org/eAG. *These estimates are;basedonADAGdataof2,700glucosemeasurementsover3monthsperA1Cmeasurementin507adultswithtype1,type2,andnodiabetes.ThecorrelationbetweenA1Candaverageglucosewas0.92(43).
—Table6.1Mean glucose levels for speci ed A1C levels (37,43)fi
–06(42)126(100152)7.(5.58.5)
–7.7.99(5864)167(157177)9.(8.9.8)155(148161)8.(8.8.9)189(180197)10.(10.10.9)175(163188)9.(9.10.4)537625070
mmol/L
–0494284827.7.49(5358)152(143162)8.(7.9.0)152(147157)8.(8.8.7)176(170183)9.(9.10.2)177(166188)9.(9.10.4)
–9(75)212(170249)11.(9.413.9)8
–5.6.49(3747)122(117127)6.(6.7.0)118(115121)6.(6.6.7)144(139148)8.(7.8.2)136(131141)7.(7.7.8)585540753
–6.6.99(4753)142(135150)7.(7.8.3)139(134144)7.(7.8.0)164(159169)9.(8.9.4)153(145161)8.(8.8.9)595741850
–0919348398.8.5(6469)178(164192)9.(9.10.7)179(167191)9.(9.10.6)206(195217)11.(10.12.0)222(197248)12.(10.13.8)
and Children
In the ADAG study, there were no signif-
icant differences among racial and ethnic
groups in the regression lines between
mg/dL
A1C and mean glucose, although the study
was underpowered to detect a difference
and there was a trend toward a difference
between the African/African American and
mmol/L
–
– A1C levels in African Americans than in
–
–
whites at a given mean glucose
–
concentration (44,45). Moreover, African
mmol/L
–
–
–
–
–
–
–
–
–
–
–
–
A1C GOALS
For glycemic goals in children, please refer
–
–
–
–
Diabetes in Pregnancy.”
Recommendations
A reasonable A1C goal for many
nonpregnant adults is ,7% (53
mmol/mol). A
–
–
–
–
curvilinear relationship between A1C and death compared with those previously ran-
can be achieved without significant
microvascular complications. Such anal- domized to the standard arm (62). The
hypoglycemia or other adverse ef-
yses suggest that, on a population level, benefit of intensive glycemic control in this
fects of treatment (i.e., polyphar-
the greatest number of complications will cohort with type 1 diabetes has been
macy). Appropriate patients might
be averted by taking patients from very shown to persist for several decades
include those with short duration of
poor control to fair/good control. These and to be associated with a modest
diabetes, type 2 diabetes treated
analyses also suggest that further lower- reduction in all-cause mortality (64).
with lifestyle or metformin only, long
ing of A1C from 7% to 6% [53 mmol/mol to
life expectancy, or no signifi-cant Cardiovascular Disease and Type 2 Diabetes
42 mmol/mol] is associated with fur-ther
cardiovascular disease. C In type 2 diabetes, there is evidence that
reduction in the risk of microvascular
c Less stringent A1C goals (such as , more intensive treatment of glycemia in
complications, although the absolute risk
8% [64 mmol/mol]) may be ap- newly diagnosed patients may reduce
reductions become much smaller. Given
propriate for patients with a history long-term CVD rates. During the UKPDS,
the substantially increased risk of hypo-
of severe hypoglycemia, limited life there was a 16% reduction in CVD events
glycemia in type 1 diabetes trials and with
expectancy, advanced microvascu- (combined fatal or nonfatal MI and sud-den
polypharmacy in type 2 diabetes, the risks
lar or macrovascular complications, death) in the intensive glycemic con-trol
of lower glycemic targets out-weigh the
extensive comorbid conditions, or arm that did not reach statistical
potential benefits on microvas-cular
long-standing diabetes in whom the significance (P 5 0.052), and there was no
complications.
goal is difficult to achieve de-spite suggestion of benefit on other CVD
diabetes self-management ACCORD, ADVANCE, and VADT outcomes (e.g., stroke). However, after 10
education, appropriate glucose Three landmark trials (Action to Control years of observational follow-up, those
monitoring, and effective doses of Cardiovascular Risk in Diabetes [ACCORD], originally randomized to intensive glyce-
multiple glucose-lowering agents Action in Diabetes and Vascular Disease: mic control had significant long-term re-
including insulin. B Preterax and Diamicron MR Controlled ductions in MI (15% with sulfonylurea or
Evaluation [ADVANCE], and Veterans Af-fairs insulin as initial pharmacotherapy, 33%
A1C and Microvascular Complications Diabetes Trial [VADT]) showed that lower A1C with metformin as initial pharmacother-apy)
Hyperglycemia defines diabetes, and gly- levels were associated with re-duced onset or and in all-cause mortality (13% and 27%,
cemic control is fundamental to diabetes progression of some micro-vascular respectively) (56).
management. The Diabetes Control and complications (58–60). ACCORD, ADVANCE, and VADT sug-
Complications Trial (DCCT) (2), a prospec- The concerning mortality findings in the gested no significant reduction in CVD
tive randomized controlled trial of inten- ACCORD trial (61), discussed below, and outcomes with intensive glycemic control in
sive versus standard glycemic control in the relatively intense efforts required to participants followed for 3.5–5.6 years who
patients with type 1 diabetes, showed de- achieve near-euglycemia should also be had more advanced type 2 diabetes than
finitively that better glycemic control is considered when setting glycemic tar-gets. UKPDS participants. All three trials were
associated with significantly decreased However, on the basis of physician conducted in relatively older partic-ipants
rates of development and progression of judgment and patient preferences, select with longer known duration of di-abetes
microvascular (retinopathy [51], neurop- patients, especially those with little co- (mean duration 8–11 years) and either
athy, and diabetic kidney disease) compli- morbidity and long life expectancy, may CVD or multiple cardiovascular risk factors.
cations. Follow-up of the DCCT cohorts in benefit from adopting more intensive gly- The target A1C among intensive control
the Epidemiology of Diabetes Interven- cemic targets (e.g., A1C target ,6.5% [48 subjects was ,6% (42 mmol/mol) in
tions and Complications (EDIC) study mmol/mol]) as long as significant hy- ACCORD, ,6.5% (48 mmol/mol) in
demonstrated persistence of these poglycemia does not become a barrier. ADVANCE, and a 1.5% reduction in A1C
microvascular benefits despite the fact compared with control subjects in VADT,
that the glycemic separation between A1C and Cardiovascular Disease with achieved A1C of 6.4% vs. 7.5% (46
the treatment groups diminished and Outcomes mmol/mol vs. 58 mmol/mol) in ACCORD,
dis-appeared during follow-up. Cardiovascular Disease and Type 1 Diabetes 6.5% vs. 7.3% (48 mmol/mol vs. 56
The Kumamoto Study (53) and UK Pro- Cardiovascular disease (CVD) is a more mmol/mol) in ADVANCE, and 6.9% vs.
spective Diabetes Study (UKPDS) (54,55) common cause of death than microvascular 8.4% (52 mmol/mol vs. 68 mmol/mol) in
confirmed that intensive glycemic control complications in populations with diabetes. VADT. Details of these studies are re-
significantly decreased rates of microvas- There is evidence for a cardiovascular ben-efit viewed extensively in “Intensive Glycemic
cular complications in patients with type 2 of intensive glycemic control after long-term Control and the Prevention of Cardiovas-
diabetes. Long-term follow-up of the follow-up of cohorts treated early in the course cular Events: Implications of the ACCORD,
UKPDS cohorts showed enduring effects of type 1 diabetes. In the DCCT, there was a ADVANCE, and VA Diabetes Trials” (65).
of early glycemic control on most micro- trend toward lower risk of CVD events with The glycemic control comparison in
vascular complications (56). intensive control. In the 9-year post-DCCT ACCORD was halted early due to an in-
Therefore, achieving A1C targets of ,7% follow-up of the EDIC cohort, participants creased mortality rate in the intensive
(53 mmol/mol) has been shown to reduce previously randomized to the intensive arm compared with the standard treatment arm
microvascular complications of diabetes. had a significant 57% reduc-tion in the risk of (1.41% vs. 1.14% per year; hazard ra-tio
Epidemiological analyses of the DCCT (2) nonfatal myocardial in-farction (MI), stroke, or 1.22 [95% CI 1.01–1.46]), with a similar
and UKPDS (57) demonstrate a cardiovascular increase in cardiovascular deaths. Analysis
S60 Glycemic Targets Diabetes Care Volume 41, Supplement 1, January 2018
A1C and Glycemic Targets Figure 6.1—Depicted are patient and disease factors used to determine optimal A1C targets.
Numerous aspects must be considered Characteristics and predicaments toward the left justify more stringent efforts to lower A1C; those
when setting glycemic targets. The ADA toward the right suggest less stringent efforts. Adapted with permission from Inzucchi et al. (72).
care.diabetesjournals.org Glycemic Targets S61
low blood glucose), exercise management, with hypoglycemia-prone diabetes (fam-ily prone patients also require urine or blood
medication adjustment, glucose monitor- members, roommates, school person-nel, ketone monitoring. If accompa-nied by
ing, and routine clinical surveillance may child care providers, correctional institution ketosis, vomiting, or alteration in the level
improve patient outcomes (76). CGM with staff, or coworkers) should be instructed on of consciousness, marked hyper-glycemia
automated low glucose suspend has been the use of glucagon kits in-cluding where requires temporary adjustment of the
shown to be effective in reducing hypogly- the kit is and when and how to administer treatment regimen and immediate in-
cemia in type 1 diabetes (34). For patients glucagon. An individual does not need to teraction with the diabetes care team. The
with type 1 diabetes with severe hypogly- be a health care pro-fessional to safely patient treated with noninsulin therapies or
cemia and hypoglycemia unawareness administer glucagon. Care should be taken medical nutrition therapy alone may tem-
that persists despite medical treatment, to ensure that glu-cagon kits are not porarily require insulin. Adequate fluid and
human islet transplantation may be an op- expired. caloric intake must be ensured. Infection or
tion, but the approach remains experimen- dehydration is more likely to necessitate
Hypoglycemia Prevention
tal (83,84). hospitalization of the person with diabetes
Hypoglycemia prevention is a critical com-
In 2015, the ADA changed its prepran- than the person without diabetes.
ponent of diabetes management. SMBG
dial glycemic target from 70–130 mg/dL and, for some patients, CGM are essential A physician with expertise in diabetes
(3.9–7.2 mmol/L) to 80–130 mg/dL (4.4– tools to assess therapy and detect incipient management should treat the hospital-ized
7.2 mmol/L). This change reflects the hypoglycemia. Patients should understand patient. For further information on the
results of the ADAG study, which situations that increase their risk of hypo- management of diabetic ketoacidosis and
demonstrated that higher glycemic targets glycemia, such as fasting for tests or pro- the hyperglycemic nonketotic hyper-
corresponded to A1C goals (37). An cedures, delayed meals, during or after osmolar state, please refer to the ADA con-
additional goal of raising the lower range of intense exercise, and during sleep. Hypo- sensus report “Hyperglycemic Crises in
the glycemic target was to limit glycemia may increase the risk of harm to Adult Patients With Diabetes” (87).
overtreatment and provide a safety margin self or others, such as with driving. Teach-
in patients titrat-ing glucose-lowering drugs ing people with diabetes to balance insulin References
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Hypoglycemia Treatment ran-domized trial comparing continuous glucose
always sufficient for prevention.
Providers should continue to counsel mon-itoring with and without routine blood
In type 1 diabetes and severely insulin-
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response. In type 2 diabetes, ingested and hypoglycemia awareness in many
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Diabetes Care Volume 41, Supplement 1, January 2018 S65
There is strong and consistent evidence that obesity management can delay the
progression from prediabetes to type 2 diabetes (1,2) and may be beneficial in the
treatment of type 2 diabetes (3–8). In overweight and obese patients with type 2 diabetes,
modest and sustained weight loss has been shown to improve glycemic control and to
reduce the need for glucose-lowering medications (3–5). Small studies have
demonstrated that in obese patients with type 2 diabetes more extreme dietary energy
restriction with very-low-calorie diets can reduce A1C to ,6.5% (48 mmol/mol) and fasting
glucose to ,126 mg/dL (7.0 mmol/L) in the absence of pharmacologic therapy or ongoing
procedures (7,9,10). Weight loss–induced improvements in glycemia are most likely to
occur early in the natural history of type 2 diabetes when obesity-associated insulin
resistance has caused reversible b-cell dysfunction but insulin secretory capacity re-mains
relatively preserved (5,8,10,11).The goal of this section is to provide evidence-based
recommendations for dietary, pharmacologic, and surgical interventions for obesity
management as treatments for hyperglycemia in type 2 diabetes.
ASSESSMENT
Recommendation
Suggested citation: American Diabetes
At each patient encounter, BMI should be calculated and documented in Associa-tion. 7. Obesity management for the
the medical record. B treatment of type 2 diabetes: Standards of
Medical Care in Diabetesd2018. Diabetes
At each routine patient encounter, BMI should be calculated as weight divided by Care 2018;41(Suppl. 1): S65–S72
2 © 2017 by the American Diabetes Association.
height squared (kg/m ) (12). BMI should be classified to determine the presence of
Readers may use this article as long as the work
overweight or obesity, discussed with the patient, and documented in the patient
is properly cited, the use is educational and not
record. In Asian Americans, the BMI cutoff points to define overweight and obesity for profit, and the work is not altered. More infor-
are lower than in other populations (Table 7.1) (13,14). Providers should advise over- mation is available at http://www.diabetesjournals
weight and obese patients that, in general, higher BMIs increase the risk of .org/content/license.
S66 Obesity Management for the Treatment of Type 2 Diabetes Diabetes Care Volume 41, Supplement 1, January 2018
2
BMI category (kg/m )
25.0–26.9 27.0–29.9 30.0–34.9 35.0–39.9 $40
Treatment (or 23.0–26.9*) (or 27.5–32.4*) (or 32.5–37.4*) (or $37.5*)
Diet, physical activity, and behavioral therapy † † † † †
Pharmacotherapy † † † †
Metabolic surgery † † †
*Cutoff points for Asian American individuals. †Treatment may be indicated for selected motivated patients.
weight loss maintenance programs that promote weight loss or to be weight neu- adhere to low-calorie diets and to rein-force
provide at least monthly contact with a tral. Agents associated with weight loss lifestyle changes including physical activity.
trained interventionist and focus on on- include metformin, a-glucosidase inhibi- Providers should be knowledge-able about
going monitoring of body weight (weekly tors, sodium–glucose cotransporter 2 in- the product label and should balance the
or more frequently), continued hibitors, glucagon-like peptide 1 agonists, potential benefits of success-ful weight loss
consump-tion of a reduced-calorie diet, and amylin mimetics. Dipeptidyl peptidase against the potential risks of the medication
and partic-ipation in high levels of 4 inhibitors appear to be weight neutral. for each patient. These medications are
physical activity (200–300 min/week Unlike these agents, insulin contraindicated in women who are or may
[24]). Some com-mercial and proprietary secretagogues, thiazolidinediones, and become pregnant. Women in their
weight loss pro-grams have shown insulin have often been associated with reproductive years must be cautioned to use
promising weight loss results (25). weight gain (see Section 8. Pharmacologic a reliable method of contraception.
When provided by trained practitioners Approaches to Glycemic Treatment”).
Assessing Efficacy and Safety
in medical care settings with close medical A recent meta-analysis of 227 random-
Efficacy and safety should be assessed
monitoring, short-term (3-month) inter- ized controlled trials of antihyperglycemic
at least monthly for the first 3 months of
ventions that use very-low-calorie diets treatments in type 2 diabetes found that
treatment. If a patient’s response is
(defined as #800 kcal/day) and total meal A1C changes were not associated with
deemed insuffi-cient (weight loss ,5%)
replacements may achieve greater short- baseline BMI, indicating that obese pa-
after 3 months or if there are any safety
term weight loss (10–15%) than in-tensive tients can benefit from the same types of
or tolerability is-sues at any time, the
behavioral lifestyle interventions that treatments for diabetes as normal-weight
medication should be discontinued and
typically achieve 5% weight loss. However, patients (28).
alternative medica-tions or treatment
weight regain following the ces-sation of
approaches should be considered.
very-low-calorie diets is greater than Concomitant Medications In general, pharmacologic treatment of
following intensive behavioral life-style Providers should carefully review the pa-
obesity has been limited by low adherence,
interventions unless a long-term tient’s concomitant medications and,
modest efficacy, adverse effects, and weight
comprehensive weight loss maintenance whenever possible, minimize or provide
regain after medication cessation (30).
program is provided (26,27). alternatives for medications that pro-
mote weight gain. Medications associ-
PHARMACOTHERAPY ated with weight gain include atypical METABOLIC SURGERY
antipsychotics (e.g., clozapine, olanza- Recommendations
Recommendations
pine, risperidone, etc.) and antidepres- Metabolic surgery should be recom-
When choosing glucose-lowering
sants (e.g., tricyclic antidepressants, mended as an option to treat type 2
medications for overweight or obese
selective serotonin reuptake inhibitors, diabetes in appropriate surgical
patients with type 2 diabetes, con-
and monoamine oxidase inhibitors), glu- candidates with BMI $40 kg/m
2
sider their effect on weight. E
cocorticoids, oral contraceptives that 2
Whenever possible, minimize the (BMI $37.5 kg/m in Asian Ameri-
contain progestins, anticonvulsants in- cans), regardless of the level of
medications for comorbid conditions
cluding gabapentin, and a number of an- gly-cemic control or complexity of
that are associated with weight gain. E
tihistamines and anticholinergics. glucose-lowering regimens, and in
Weight loss medications may be ef-fective
2
as adjuncts to diet, physical ac-tivity, adults with BMI 35.0–39.9 kg/m
and behavioral counseling for
Approved Weight Loss Medications 2
(32.5–37.4 kg/m in Asian Ameri-
The U.S. Food and Drug Administration
selected patients with type 2 diabetes cans) when hyperglycemia is inade-
(FDA) has approved medications for both
2
and BMI $27 kg/m . Potential ben-efits quately controlled despite lifestyle
short-term and long-term weight and optimal medical therapy. A
must be weighed against the
management. Phentermine is indicated as
potential risks of the medications. A Metabolic surgery should be con-
short-term (a few weeks) adjunct in
If a patient’s response to weight loss sidered as an option for adults with
conjunction with lifestyle and behavioral
medications is ,5% weight loss af-ter type 2 diabetes and BMI 30.0–
weight loss interventions (29). Five weight 2 2
3 months or if there are any safety or loss medications (or combination 34.9 kg/m (27.5–32.4 kg/m in
tolerability issues at any time, the medications) are FDA-approved for long- Asian Americans) if hyperglycemia
medication should be dis-continued term use (more than a few weeks) by is inadequately controlled despite
and alternative medica-tions or 2 optimal medical control by either
patients with BMI $27 kg/m with one or oral or injectable medications (in-
treatment approaches should be
more obesity-associated comorbid cluding insulin). B
considered. A
conditions (e.g., type 2 diabetes, hyperten-
Metabolic surgery should be per-
sion, and dyslipidemia) and by patients
formed in high-volume centers with
Antihyperglycemic Therapy 2
with BMI $30 kg/m who are motivated to multidisciplinary teams that
When evaluating pharmacologic treat- lose weight (30–34). Medications ap- understand and are experienced in
ments for overweight or obese patients proved by the FDA for the treatment of the management of diabetes and
with type 2 diabetes, providers should obesity and their advantages and disad- gastrointestinal surgery. C
first consider their choice of glucose- vantages are summarized in Table 7.2. The Long-term lifestyle support and rou-
lowering medications. Whenever possi- rationale for weight loss medications is to tine monitoring of micronutrient
ble, medications should be chosen to help patients to more consistently
S68 Obesity Management for the Treatment of Type 2 Diabetes
Table 7.2—Medications approved by the FDA for the treatment of obesity
Generic drug name National Average Drug 1–4
1-Year weight change status
1,5–12
(proprietary name[s]), dosage, Usual adult dosing Average wholesale Acquisition Cost (per Average weight loss % Patients with $5% Adverse effects
13 14 6 6
strength, and form frequency price (per month) month) relative to placebo loss of baseline weight Common Serious
Short-term treatment (a few weeks)
Phentermine (Lomaira) 37.5mg q.d.or8mg t.i.d. $5-$76 (37.5 mg); $3-$60 (37.5 mg); N/A* N/A* Headache, elevated blood Dyspnea, angina pectoris,
$52 (8 mg) Unavailable (8 mg) pressure, elevated syncope, severe
heart rate, insomnia, hypertension
dry mouth,
constipation, anxiety,
palpitations
Long-term treatment (more than a few weeks)
Lipase inhibitor
Orlistat (Alli) 60 mg caps 60 mg or 120 mg t.i.d. $41–82 (60 mg); $42 (60 mg); 2.5 kg (60 mg); 35–73% Abdominal pain/ Liver failure and oxalate
or orlistat (Xenical) (during or up to 1 h $703 (120 mg) $556 (120 mg) 3.4 kg (120 mg) discomfort, oily spotting/ nephropathy
120 mg caps after a low-fat meal) stool, fecal urgency,
flatulence,
malabsorption of fat
soluble vitamins (A, D, E,
K) and medications (e.g.,
cyclosporine, thyroid
hormone replacement,
or anticonvulsants),
potentiation of the
effects of warfarin
Selective serotonin (5-HT) 5-HT2C receptor agonist
Lorcaserin (Belviq) 10 mg 10 mg b.i.d. $289 $230 3.2 kg 38–48% Hypoglycemia, headache, Serotonin syndrome or
tabs fatigue NMS-like reactions,
suicidal ideation, heart
Continued on p. S69
care.diabetesjournals.org
Table 7.2—Continued
Generic drug name National Average Drug 1–4
1-Year weight change status
1,5–12
(proprietary name[s]), dosage, Usual adult dosing Average wholesale Acquisition Cost (per Average weight loss % Patients with $5% Adverse effects
13 14 6 6
strength, and form frequency price (per month) month) relative to placebo loss of baseline weight Common Serious
Opioid antagonist/aminoketone antidepressant combination
Naltrexone/bupropion Maximum dose: two $290 (maximum dose) $231 (maximum dose) 2.0–4.1 kg 36–57% Nausea, constipation, Depression, precipitation of
(Contrave) 8 mg/90 mg tablets of Contrave (32 mg/360 mg) headache, vomiting mania, contraindicated in
tabs b.i.d. for a total daily patients with a seizure
dosage of naltrexone disorder
32 mg/bupropion
360 mg
Glucagon-like peptide 1 receptor agonist
Liraglutide (Saxenda) Maintenance dose: $1,385 $1,105 5.8–5.9 kg 51–73% Hypoglycemia, nausea, Pancreatitis, thyroid C-cell
6 mg/mL prefilled pen 3 mg s.c. q.d. vomiting, diarrhea, tumors in rodents,
constipation, headache contraindicated in
patients with personal/
family history of MTC or
MEN2, acute renal
failure
All medications are contraindicated in women who are or may become pregnant. Women in their reproductive years must be cautioned to use a reliable method of contraception. Caps, capsules; ER,
extended release; MEN2, multiple endocrine neoplasia type 2; MTC, medullary thyroid carcinoma; N/A, not applicable; NMS, neuroleptic malignant syndrome; s.c., subcutaneous; tabs, tablets.
*Phentermine is FDA-approved as a short-term adjunct (a few weeks) in a regimen of weight reduction based on exercise, behavioral modification, and caloric restriction.
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Diabetes Care Volume 41, Supplement 1, January 2018 S73
Insulin Therapy
Insulin is the mainstay of therapy for individuals with type 1 diabetes.
Generally, the starting insulin dose is based on weight, with doses ranging
Suggested citation: American Diabetes
from 0.4 to 1.0 units/kg/day of total insulin with higher amounts required Associ-ation. 8. Pharmacologic approaches to
during puberty. The American Diabetes Association/JDRF Type 1 Diabetes glyce-mic treatment: Standards of Medical
Sourcebook notes 0.5 units/kg/day as a typical starting dose in patients with Care in Diabetesd2018. Diabetes Care
type 1 diabetes who are metabolically stable, with higher weight-based 2018;41(Suppl. 1): S73–S85
dosing required immediately following presentation with ketoacidosis (1), © 2017 by the American Diabetes Association.
and provides detailed information on intensification of therapy to meet Readers may use this article as long as the work
is properly cited, the use is educational and not
individualized needs. The American Diabetes Association (ADA) position
for profit, and the work is not altered. More infor-
statement “Type 1 Diabetes Management Through the Life Span” mation is available at http://www.diabetesjournals
additionally provides a thorough overview of type 1 diabetes treatment (2). .org/content/license.
S74 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018
Education regarding matching prandial compared with U-100 glargine in placebo (23). The Reducing With
insulin dosing to carbohydrate intake, patients with type 1 diabetes (19,20). Metformin Vascular Adverse Lesions in
premeal glucose levels, and anticipated Rapid-acting inhaled insulin used be- Type 1 Diabetes (REMOVAL) trial
activity should be considered, and se- fore meals in patients with type 1 diabe-tes investigated the addition of metformin
lected individuals who have mastered was shown to be noninferior when therapy to titrated insulin therapy in adults
carbohydrate counting should be edu- compared with aspart insulin for A1C low- with type 1 diabetes at increased risk for
cated on fat and protein gram estimation ering, with less hypoglycemia observed cardiovascular disease and found that
(3–5). Although most studies of multiple with inhaled insulin therapy (21). How-ever, metformin did not signifi-cantly improve
daily injections versus continuous subcu- the mean reduction in A1C was greater glycemic control beyond the first 3 months
taneous insulin infusion (CSII) have been with aspart (–0.21% vs. –0.40%, satisfying of treatment and that progression of
small and of short duration, a systematic the noninferiority margin of 0.4%), and atherosclerosis (measured by carotid
review and meta-analysis concluded that more patients in the insulin aspart group artery intima-media thickness) was not
there are minimal differences between the achieved A1C goals of significantly reduced, although other
two forms of intensive insulin therapy in #7.0% (53 mmol/mol) and #6.5% (48 cardiovascular risk factors such as body
A1C (combined mean between-group mmol/mol). Because inhaled insulin car- weight and LDL cholesterol im-proved (24).
difference favoring insulin pump therapy tridges are only available in 4-, 8-, and Metformin is not FDA-approved for use in
–0.30% [95% CI –0.58 to –0.02]) and se- 12-unit doses, limited dosing increments patients with type 1 diabetes.
vere hypoglycemia rates in children and to fine-tune prandial insulin doses in type
Incretin-Based Therapies
adults (6). A 3-month randomized trial in 1 diabetes are a potential limitation.
Due to their potential protection of b-cell mass
patients with type 1 diabetes with noctur- Postprandial glucose excursions may be
and suppression of glucagon release,
nal hypoglycemia reported that sensor- better controlled by adjusting the tim-ing of
glucagon-like peptide 1 (GLP-1) receptor
augmented insulin pump therapy with the prandial (bolus) insulin dose admin-
agonists (25) and dipeptidyl peptidase 4
threshold suspend feature reduced istration. The optimal time to administer
(DPP-4) inhibitors (26) are being studied in
nocturnal hypoglycemia without increas-ing prandial insulin varies, based on the type of
patients with type 1 diabetes but are not
glycated hemoglobin levels (7). The U.S. insulin used (regular, rapid-acting ana-log,
currently FDA-approved for use in pa-tients
Food and Drug Administration (FDA) has inhaled, etc.), measured blood glucose
with type 1 diabetes.
also approved the first hybrid closed-loop level, timing of meals, and carbohydrate
system pump. The safety and effi-cacy of consumption. Recommendations for pran- Sodium–Glucose Cotransporter 2 Inhibitors
hybrid closed-loop systems has been dial insulin dose administration should Sodium–glucose cotransporter 2 (SGLT2)
supported in the literature in ado-lescents therefore be individualized. inhibitors provide insulin-independent
and adults with type 1 diabetes (8,9). glucose lowering by blocking glucose re-
Pramlintide absorption in the proximal renal tubule by
Intensive management using CSII Pramlintide, an amylin analog, is an agent inhibiting SGLT2. These agents provide
and continuous glucose monitoring that delays gastric emptying, blunts pan- modest weight loss and blood pressure
should be encouraged in selected creatic secretion of glucagon, and en- reduction in type 2 diabetes. There are
patients when there is active hances satiety. It is FDA-approved for use three FDA-approved agents for patients
patient/family participa-tion (10–12). in adults with type 1 diabetes. It has been with type 2 diabetes, but none are FDA-
The Diabetes Control and Complica-tions shown to induce weight loss and lower in- approved for the treatment of patients with
Trial (DCCT) clearly showed that in-tensive sulin doses. Concurrent reduction of pran- type 1 diabetes (2). SGLT2 inhibitors may
therapy with multiple daily injections or CSII dial insulin dosing is required to reduce the have glycemic benefits in patients with
delivered by multidisci-plinary teams of risk of severe hypoglycemia. type 1 or type 2 diabetes on insulin therapy
physicians, nurses, dieti-tians, and behavioral (27). The FDA issued a warning about the
scientists improved glycemia and resulted in Investigational Agents risk of ketoacidosis occurring in the
better long-term outcomes (13–15). The study Metformin absence of significant hyperglyce-mia
was carried out with short-acting and Adding metformin to insulin therapy may (euglycemic diabetic ketoacidosis) in
intermediate-acting human insulins. Despite reduce insulin requirements and improve patients with type 1 or type 2 diabe-tes
better mi-crovascular, macrovascular, and all- metabolic control in patients with type 1 treated with SGLT2 inhibitors. Symptoms
cause mortality outcomes, intensive therapy diabetes. In one study, metformin was of ketoacidosis include dysp-nea, nausea,
was associated with a high rate of severe found to reduce insulin requirements (6.6 vomiting, and abdominal pain. Patients
hypoglycemia (61 episodes per 100 patient- units/day, P , 0.001), and led to small should be instructed to stop taking SGLT2
years of therapy). Since the DCCT, a number reductions in weight and total and LDL inhibitors and seek medical attention
of rapid-acting and long-acting insulin an- cholesterol but not to improved gly-cemic immediately if they have symptoms or
alogs have been developed. These analogs control (absolute A1C reduction 0.11%, P 5 signs of ketoacidosis (28).
are associated with less hypoglycemia, less 0.42) (22). A randomized clin-ical trial
weight gain, and lower A1C than human similarly found that, among over-weight
insulins in people with type 1 diabetes (16– adolescents with type 1 diabetes, the SURGICAL TREATMENT
18). Longer-acting basal analogs (U-300 addition of metformin to insulin did not FOR TYPE 1 DIABETES
glargine or degludec) may addi-tionally improve glycemic control and in-creased Pancreas and Islet Transplantation
convey a lower hypoglycemia risk risk for gastrointestinal adverse events Pancreas and islet transplantation have
after 6 months compared with been shown to normalize glucose levels
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment
S75
Figure 8.1—Antihyperglycemic therapy in type 2 diabetes: general recommendations. *If patient does not tolerate or has contraindications to
metformin, consider agents from another class in Table 8.1. #GLP-1 receptor agonists and DPP-4 inhibitors should not be prescribed in
combination. If a patient with ASCVD is not yet on an agent with evidence of cardiovascular risk reduction, consider adding.
inhibitor, SGLT2 inhibitor, GLP-1 receptor second agent with evidence of cardiovas- dual therapy, proceed to a three-drug
agonist, or basal insulin (Fig. 8.1); the choice cular risk reduction after consideration of combination (Fig. 8.1). Again, if A1C target
of which agent to add is based on drug- drug-specific and patient factors (see p. S77 is not achieved after ;3 months of triple
specific effects and patient factors (Table CARDIOVASCULAR OUTCOMES TRIALS). If A1C target therapy, proceed to combination injectable
8.1). For patients with ASCVD, add a is still not achieved after ;3 months of therapy (Fig. 8.2). Drug choice is based
on
Pharmacologic Approaches to Glycemic Treatment S77
Table 8.1—Drug-specific and patient factors to consider when selecting antihyperglycemic treatment in adults with type 2 diabetes
care.diabetesjournals.org
*See ref. 31 for description of efficacy. †FDA approved for CVD benefit. CVD, cardiovascular disease; DKA, diabetic ketoacidosis; DKD, diabetic kidney disease; NASH,
nonalcoholic steatohepatitis; RAs, receptor agonists; SQ, subcutaneous; T2DM, type 2 diabetes.
S78 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018
Figure 8.2—Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; hypo, hypoglycemia. Adapted with
permission from Inzucchi et al. (31).
patient preferences (37), as well as various dual therapy, with continuous Of note, prices listed are average whole-
patient, disease, and drug characteristics, reevalu-ation of patient factors to sale prices (AWP) (39) and National Aver-
with the goal of reducing blood glucose guide treat-ment (Table 8.1). age Drug Acquisition Costs (NADAC) (40)
levels while minimizing side effects, espe- Table 8.2 lists drugs commonly used in and do not account for discounts, re-bates,
cially hypoglycemia. If not already in- the U.S. Cost-effectiveness models of the or other price adjustments often involved in
cluded in the treatment regimen, addition newer agents based on clinical utility and prescription sales that affect the actual
of an agent with evidence of cardiovas- glycemic effect have been reported (38). cost incurred by the patient. While there
cular risk reduction should be consid-ered Table 8.3 provides cost information for are alternative means to esti-mate
in patients with ASCVD beyond currently approved noninsulin therapies. medication prices, AWP and NADAC
care.diabetesjournals.org
Table 8.2—Pharmacology of available glucose-lowering agents in the U.S. for the treatment of type 2 diabetes
Class Compound(s) Cellular mechanism(s) Primary physiological action(s) Renal dosing recommendations (63–66)*
Biguanides c Metformin Activates AMP kinase (? other) ↓ Hepatic glucose production c No dose adjustment if eGFR .45;
do not initiate OR assess risk/benefit if currently on metformin if eGFR 30–45;
discontinue if eGFR ,30
Sulfonylureas (2nd c Glyburide
Closes KATP channels on b-cell ↑ Insulin secretion c Avoid use in patients with renal impairment
generation) c Glipizide plasma membranes c Initiate conservatively at 2.5 mg daily to avoid hypoglycemia
c Glimepiride c Initiate conservatively at 1 mg daily to avoid hypoglycemia
Meglitinides c Repaglinide Closes KATP channels on b-cell ↑ Insulin secretion c Initiate conservatively at 0.5 mg with meals if eGFR ,30
(glinides) c Nateglinide plasma membranes c Initiate conservatively at 60 mg with meals if eGFR ,30
Thiazolidinediones c Pioglitazone Activates the nuclear ↑ Insulin sensitivity c No dose adjustment required
c Rosiglitazone§ transcription factor PPAR-g c No dose adjustment required
a-Glucosidase c Acarbose Inhibits intestinal a-glucosidase Slows intestinal carbohydrate c Avoid if eGFR ,30
inhibitors c Miglitol digestion/absorption c Avoid if eGFR ,25
DPP-4 inhibitors c Sitagliptin Inhibits DPP-4 activity, ↑ Insulin secretion (glucose c 100 mg daily if eGFR .50;
increasing postprandial incretin dependent); 50 mg daily if eGFR 30–50;
(GLP-1, GIP) concentrations ↓ Glucagon secretion (glucose 25 mg daily if eGFR ,30
dependent)
c Saxagliptin c5 mg daily if eGFR .50;
2.5 mg daily if eGFR #50
c Linagliptin c No dose adjustment required
c Alogliptin c 25 mg daily if eGFR .60;
Continued on p. S80
Amylin mim
1, January
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S81
Table 8.3—Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S.
ER and XL, extended release; IR, immediate release. †Calculated for 30-day supply (AWP or NADAC unit price 3 number of doses
required to provide maximum approved daily dose 3 30 days); median AWP or NADAC listed alone when only one product and/or
price. *Utilized to calculate median AWP and NADAC (min, max); generic prices used, if available commercially. ††Not applicable;
data not available. **Administered once weekly. †††AWP and NADAC calculated based on 120 mg three times daily.
were utilized to provide two separate mea- late postprandial hypoglycemia when The empagliflozin and liraglutide trials
sures to allow for a comparison of drug prices taking a sulfonylurea. Other drugs not demonstrated significant reductions in
with the primary goal of highlighting the shown in Table 8.1 (e.g., inhaled insulin, a- cardiovascular death. Exenatide once-
importance of cost considerations when glucosidase inhibitors, colesevelam, bro- weekly did not have statistically sig-nificant
prescribing antihyperglycemic treat-ments. mocriptine, and pramlintide) may be tried in reductions in major adverse cardiovascular
The ongoing Glycemia Reduction Approaches specific situations but considerations events or cardiovascu-lar mortality but did
in Diabetes: A Comparative Ef-fectiveness include modest efficacy in type 2 diabetes, have a significant reduction in all-cause
Study (GRADE) will compare four drug frequency of administration, potential for mortality. In con-trast, other GLP-1
classes (sulfonylurea, DPP-4 in-hibitor, GLP-1 drug interactions, cost, and/or side effects. receptor agonists have not shown similar
receptor agonist, and basal insulin) when reductions in cardiovascular events (Table
added to metformin therapy over 4 years on Cardiovascular Outcomes Trials 9.4). Whether the benefits of GLP-1
glycemic control and other medical, There are now three large randomized receptor agonists are a class effect
psychosocial, and health economic outcomes controlled trials reporting statistically sig- remains to be definitively established. See
(41). nificant reductions in cardiovascular events ANTIHYPERGLYCEMIC THERAPIES AND
CARDIOVASCULAR OUTCOMES in
Rapid-acting secretagogues (meglitinides) for two SGLT2 inhibitors (empagliflozin and
may be used instead of sulfonylureas in canagliflozin) and one GLP-1 receptor Section 9 “Cardiovascular Disease and
patients with sulfa allergies or irregular meal agonist (liraglutide) where the majority, if Risk Management” and Table 9.4 for a de-
schedules or in those who develop not all patients, in the trial had ASCVD. tailed description of these cardiovascular
S82 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 41, Supplement 1, January 2018
Table 8.4—Median cost of insulin products in the U.S. calculated as AWP (39) and NADAC (40) per 1,000 units of specified dosage
form/product
Median AWP Median NADAC
Insulins Compounds Dosage form/product (min, max)* (min, max)*
Rapid-acting c Lispro U-100 vial; $330 $264
analogs U-100 3 mL cartridges; $408 $326
U-100 prefilled pen; U-200 prefilled pen $424 $339
c Aspart U-100 vial; $331 $265
U-100 3 mL cartridges; $410 $330
U-100 prefilled pen $426 $341
c Glulisine U-100 vial; $306 $245
U-100 prefilled pen $394 $315
c Inhaled insulin Inhalation cartridges $725 ($544, $911) N/A†
Short-acting analogs c Human Regular U-100 vial $165 ($165, $178) $135 ($135, $145)
Intermediate-acting analogs c Human NPH U-100 vial; $165 ($165, $178) $135 ($135, $145)
U-100 prefilled pen $377 $305
Concentrated Human c U-500 Human U-500 vial; $178 $143
Regular insulin Regular insulin U-500 prefilled pen $230 $184
Basal analogs c Glargine U-100 vial; U-100 prefilled pen; $298 $239 ($239, $241)
U-300 prefilled pen
c Glargine biosimilar U-100 prefilled pen $253 $203
c Detemir U-100 vial; U-100 prefilled pen $323 $259
c Degludec U-100 prefilled pen; U-200 prefilled pen $355 $285
Premixed insulin products c NPH/Regular 70/30 U-100 vial; $165 ($165, $178) $134 ($134, $146)
U-100 prefilled pen $377 $305
c Lispro 50/50 U-100 vial; $342 $278
U-100 prefilled pen $424 $339
c Lispro 75/25 U-100 vial; $342 $273
U-100 prefilled pen $424 $340
c Aspart 70/30 U-100 vial; $343 $275
U-100 prefilled pen $426 $341
Premixed insulin/GLP-1 c Degludec/Liraglutide 100/3.6 prefilled pen $763 N/A†
receptor agonist products c Glargine/Lixisenatide 100/33 prefilled pen $508 $404
*AWP or NADAC calculated as in Table 8.3; median listed alone when only one product and/or price. †Not applicable; data not available.
outcomes trials. Additional large avoid using insulin as a threat or de- to reduce the risk of symptomatic and noc-
random-ized trials of other agents in scribing it as a sign of personal turnal hypoglycemia (43–48). Longer-
these classes are ongoing. failure or punishment. acting basal analogs (U-300 glargine or
Of note, these studies examined the Equipping patients with an algorithm for degludec) may additionally convey a lower
drugs in combination with metformin (Table self-titration of insulin doses based on self- hypoglycemia risk compared with U-100
9.4) in the great majority of pa-tients for monitoring of blood glucose improves glargine when used in combination with
whom metformin was not con-traindicated glycemic control in patients with type 2 di- oral antihyperglycemic agents (49– 55).
or not tolerated. For patients with type 2 abetes initiating insulin (42). Comprehen- While there is evidence for reduced
diabetes who have ASCVD, on lifestyle sive education regarding self-monitoring of hypoglycemia with newer, longer-acting
and metformin therapy, it is rec-ommended blood glucose, diet, and the avoidance of basal insulin analogs, people without a
to incorporate an agent with strong and appropriate treatment of hypogly- history of hypoglycemia are at decreased
evidence for cardiovascular risk re-duction cemia are critically important in any pa-tient risk and could potentially be switched to
especially those with proven ben-efit on using insulin. human insulin safely. Thus, due to high
both major adverse cardiovascular events costs of analog insulins, use of human in-
and cardiovascular death after con- Basal Insulin sulin may be a practical option for some
sideration of drug-specific patient factors Basal insulin alone is the most convenient patients, and clinicians should be familiar
(Table 8.1). See Fig. 8.1 for additional rec- initial insulin regimen, beginning at 10 units with its use (56). Table 8.4 provides AWP
ommendations on antihyperglycemic per day or 0.1–0.2 units/kg/day, depend-ing and NADAC (40) information (cost per
treatment in adults with type 2 diabetes. on the degree of hyperglycemia. Basal 1,000 units) for currently available in-sulin
insulin is usually prescribed in conjunc-tion and insulin combination products in the
Insulin Therapy with metformin and sometimes one U.S. There have been substantial
Many patients with type 2 diabetes even- additional noninsulin agent. When basal increases in the price of insulin over the
tually require and benefit from insulin therapy. insulin is added to antihyperglycemic past decade and the cost-effectiveness of
The progressive nature of type 2 diabetes agents in patients with type 2 diabetes, different antihyperglycemic agents is an
should be regularly and objectively explained long-acting basal analogs (U-100 glargine important consideration in a patient-
to patients. Providers should or detemir) can be used instead of NPH centered approach to care, along with
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment
S83
efficacy, hypoglycemia risk, weight, pulmonary disease and is not recommended insulin (NPH/Regular 70/30, 70/30 aspart
and other patient and drug-specific in patients who smoke or who recently stop- mix, 75/25 or 50/50 lispro mix) twice daily,
factors (Table 8.1) (57). ped smoking. It requires spirometry (FEV 1) usually before breakfast and before dinner.
testing to identify potential lung disease in all Each approach has its advan-tages and
Bolus Insulin
patients prior to and after starting therapy. disadvantages. For example, providers
Many individuals with type 2 diabetes may
may wish to consider regimen flexibility
require mealtime bolus insulin dos-ing in
Combination Injectable Therapy when devising a plan for the ini-tiation and
addition to basal insulin. Rapid-acting
If basal insulin has been titrated to an ac- adjustment of insulin therapy in people with
analogs are preferred due to their prompt
ceptable fasting blood glucose level (or if type 2 diabetes, with rapid-acting insulin
onset of action after dosing. In September
the dose is .0.5 units/kg/day) and A1C re- offering greater flexibility in terms of meal
2017, the FDA approved a new faster-
mains above target, consider advancing to planning than premixed in-sulin. If one
acting formulation of insulin aspart. The
combination injectable therapy (Fig. 8.2). regimen is not effective (i.e., basal insulin
recommended starting dose of meal-time
When initiating combination inject-able plus GLP-1 receptor agonist), consider
insulin is 4 units, 0.1 units/kg, or 10% of
therapy, metformin therapy should be switching to another regimen to achieve
the basal dose. If A1C is ,8% (64 mmol/
maintained while other oral agents may be A1C targets (i.e., basal insulin plus single
mol) when starting mealtime bolus in-sulin,
discontinued on an individual ba-sis to injection of rapid-acting insulin or pre-
consideration should be given to
avoid unnecessarily complex or costly mixed insulin twice daily) (60,61). Regular
decreasing the basal insulin dose.
regimens (i.e., adding a fourth anti- human insulin and human NPH/Regular
Premixed Insulin premixed formulations (70/30) are less
hyperglycemic agent). In general, GLP-1
Premixed insulin products contain both a
receptor agonists should not be discon- costly alternatives to rapid-acting insulin
basal and prandial component, allowing
tinued with the initiation of basal insulin. analogs and premixed insulin analogs,
coverage of both basal and prandial needs
Sulfonylureas, DPP-4 inhibitors, and GLP-1 respectively, but their pharmacody-namic
with a single injection. NPH/Regular 70/30
receptor agonists are typically stopped profiles may make them less optimal.
insulin, for example, is composed of 70%
once more complex insulin regimens be- Fig. 8.2 outlines these options, as well
NPH insulin and 30% regular insulin. The use
yond basal are used. In patients with sub- as recommendations for further intensifi-
of premixed insulin products has its advan-
optimal blood glucose control, especially cation, if needed, to achieve glycemic
tages and disadvantages, as discussed be-
those requiring large insulin doses, adjunc- goals. If a patient is still above the A1C
low in COMBINATION INJECTABLE THERAPY. tive use of a thiazolidinedione or SGLT2 target on premixed insulin twice daily,
Concentrated Insulin Products inhibitor may help to improve control and consider switching to premixed analog in-
Several concentrated insulin preparations reduce the amount of insulin needed, sulin three times daily (70/30 aspart mix,
are currently available. U-500 regular insu- though potential side effects should be 75/25 or 50/50 lispro mix). In general, three
lin, by definition, is five times as concen- considered. Once an insulin regimen is ini- times daily premixed analog insu-lins have
trated as U-100 regular insulin and has a tiated, dose titration is important with ad- been found to be noninferior to basal-bolus
delayed onset and longer duration of ac- justments made in both mealtime and regimens with similar rates of
tion than U-100 regular, possessing both basal insulins based on the blood glucose hypoglycemia (62). If a patient is still above
prandial and basal properties. U-300 glar- levels and an understanding of the phar- the A1C target on basal insulin plus single
gine and U-200 degludec are three and macodynamic profile of each formulation injection of rapid-acting insulin before the
two times as concentrated as their U-100 (pattern control). largest meal, advance to a basal-bolus
formulations and allow higher doses of Studies have demonstrated the non- regimen with $2 injections of rapid-acting
basal insulin administration per volume inferiority of basal insulin plus a single insulin before meals. Con-sider switching
used. U-300 glargine has a longer duration injection of rapid-acting insulin at the larg- patients from one regimen to another (i.e.,
of ac-tion than U-100 glargine. The FDA est meal relative to basal insulin plus a premixed analog insulin three times daily
has also approved a concentrated GLP-1 receptor agonist relative to two daily to basal-bolus regimen or vice-versa) if
formulation of rapid-acting insulin lispro, U- injections of premixed insulins (Fig. 8.2). A1C targets are not being met and/or
200 (200 units/mL). These concentrated Basal insulin plus GLP-1 recep-tor agonists depending on other patient considerations
preparations may be more comfortable for are associated with less hy-poglycemia (60,61). Metformin should be continued in
the patient and may improve adherence for and with weight loss instead of weight gain patients on combination injectable insulin
patients with insulin resistance who require but may be less tolerable and have a therapy, if not contra-indicated and if
large doses of insulin. While U-500 regular greater cost (58,59). In No-vember 2016, tolerated, for further gly-cemic benefits.
insulin is available in both prefilled pens the FDA approved two dif-ferent once-daily
and vials (a dedicated syringe was FDA fixed-dual combination products containing
approved in July 2016), other concentrated basal insulin plus a GLP-1 receptor
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S86 Diabetes Care Volume 41, Supplement 1, January 2018
Table 9.1—Randomized controlled trials of intensive versus standard hypertension treatment strategies
CVD, cardiovascular disease; T2D, type 2 diabetes. Data from this table can also be found in the ADA position statement “Diabetes and Hypertension” (5).
with the acknowledgment that the ben- adults, such as functional limitations, overweight or obese; a Dietary
efits and risks of intensive blood pres- polypharmacy, and multimorbidity,
Approaches to Stop Hypertension–
sure targets are uncertain and may vary may be best suited for less intensive
style dietary pattern including reduc-
across patients (5). Similar to the factors blood pressure targets. Notably, there
ing sodium and increasing potassium
that influence management of hyper- is an absence of high-quality data
intake; moderation of alcohol intake;
glycemia, factors that influence blood avail-able to guide blood pressure
and increased physical activity. B
pressure treatment targets may include targets in type 1 diabetes.
risks of treatment (e.g., hypotension, Based on current evidence, ADA rec-
Lifestyle management is an important
drug adverse effects), life expectancy, ommends hypertension diagnosis and
component of hypertension treatment
co-morbidities including vascular compli- treatment as outlined, emphasizing individ-
because it lowers blood pressure, enhan-
cations, patient attitude and expected ualization of blood pressure targets. ADA is
ces the effectiveness of some antihyper-
treatment efforts, and resources and aware of hypertension recommendations
tensive medications, promotes other
support system (19). Specific factors to from other organizations (20a). The ADA
aspects of metabolic and vascular health,
consider are the absolute risk of car- Professional Practice Committee continu-
and generally leads to few adverse ef-
diovascular events (15,20), risk of pro- ously reviews and considers all studies,
fects. Lifestyle therapy consists of reduc-
gressive kidney disease as reflected by par-ticularly high-quality trials including
ing excess body weight through caloric
albuminuria, adverse effects, age, and people with diabetes, for potential
restriction, restricting sodium intake (,2,300
overall treatment burden. Patients who incorporation in future recommendations.
have higher risk of cardiovascular mg/day), increasing consump-tion of fruits
events (particularly stroke) or albumin- Treatment Strategies and vegetables (8–10 serv-ings per day)
uria and who are able to attain intensive Lifestyle Intervention and low-fat dairy products (2–3 servings
blood pressure control relatively easily per day), avoiding excessive alcohol
Recommendation consumption (no more than 2 servings per
and without substantial adverse effects
For patients with blood pressure day in men and no more than 1 serving per
may be best suited for intensive blood
.120/80 mmHg, lifestyle inter- day in women) (21), and increasing activity
pressure targets. In contrast, patients
vention consists of weight loss if levels (22).
with conditions more common in older
care.diabetesjournals.org Cardiovascular Disease and Risk Management
S89
These lifestyle interventions are rea- Initial Number of Antihypertensive Medications. analysis of randomized clinical trials found
sonable for individuals with diabetes and Initial treatment for people with diabetes a small benefit of evening versus morning
mildly elevated blood pressure (systolic . depends on the severity of hypertension dosing of antihypertensive medications
120 mmHg or diastolic .80 mmHg) and (Fig. 9.1). Those with blood pressure be- with regard to blood pressure control but
should be initiated along with tween 140/90 mmHg and 159/99 mmHg had no data on clinical effects (35). In two
pharmacologic therapy when hypertension may begin with a single drug. For patients subgroup analyses of a single subsequent
is diagnosed (Fig. 9.1) (22). A lifestyle ther- with blood pressure $160/100 mmHg, initial randomized controlled trial, moving at least
apy plan should be developed in collabo- pharmacologic treatment with two one antihypertensive medication to
ration with the patient and discussed as antihypertensive medications is rec- bedtime significantly reduced cardio-
part of diabetes management. ommended in order to more effectively vascular events, but results were based on
achieve adequate blood pressure control a small number of events (36).
Pharmacologic Interventions (23,24). Single-pill antihypertensive com-
Hyperkalemia and AKI. Treatment with ACE
binations may improve medication ad-
Recommendations inhibitors or ARBs can cause AKI and hyper-
herence in some patients (25).
Patients with confirmed office-based blood kalemia, while diuretics can cause AKI and
Classes of Antihypertensive Medications. Ini-tial
pressure $140/90 mmHg should, in either hypokalemia or hyperkalemia (de-
treatment for hypertension should include
addition to lifestyle ther-apy, have pending on mechanism of action) (37,38).
any of the drug classes demon-strated to
prompt initiation and timely titration of Detection and management of these ab-
reduce cardiovascular events in patients
pharmacologic therapy to achieve
with diabetes: ACE inhibitors (26,27), normalities is important because AKI and
blood pressure goals. A
angiotensin receptor blockers (ARBs) hyperkalemia each increase the risks of
Patients with confirmed office-based cardiovascular events and death (39).
(26,27), thiazide-like diuretics (28), or
blood pressure $160/100 mmHg Therefore, serum creatinine and potassium
dihydropyridine calcium channel blockers
should, in addition to lifestyle ther- should be monitored during treatment with an
(29). For patients with albumin-uria (urine
apy, have prompt initiation and ACE inhibitor, ARB, or diuretic, particu-larly
albumin-to-creatinine ratio [UACR] $30
timely titration of two drugs or a sin- among patients with reduced glomer-ular
mg/g), initial treatment should include an
gle-pill combination of drugs dem- filtration who are at increased risk of
ACE inhibitor or ARB in order to reduce the
onstrated to reduce cardiovascular hyperkalemia and AKI (37,38,40).
risk of progressive kidney disease (5) (Fig.
events in patients with diabetes. A
Treatment for hypertension should include 9.1). In the ab-sence of albuminuria, risk of
Resistant Hypertension
drug classes demonstrated to reduce progressive kidney disease is low, and
cardiovascular events in pa-tients with ACE inhibitors and ARBs have not been Recommendation
diabetes (ACE inhibitors, angiotensin found to afford superior cardioprotection Patients with hypertension who are not
receptor blockers, thiazide-like diuretics, when compared with thiazide-like diuretics meeting blood pressure targets on
or dihydropyridine calcium or dihydro-pyridine calcium channel three classes of antihypertensive
channel blockers). A blockers(30). b-Blockers may be used for medications (including a diuretic)
Multiple-drug therapy is generally the treatment of prior myocardial infarction should be considered for mineralocor-
required to achieve blood pressure (MI), ac-tive angina, or heart failure but ticoid receptor antagonist therapy. B
targets. However, combinations of have not been shown to reduce mortality
ACE inhibitors and angiotensin re- as blood pressure-lowering agents in the Resistant hypertension is defined as
ceptor blockers and combinations of absence of these conditions (11,31). blood pressure $140/90 mmHg despite a
ACE inhibitors or angiotensin re- therapeutic strategy that includes ap-
ceptor blockers with direct renin in- Multiple-drug ther-apy is
Multiple-Drug Therapy. propriate lifestyle management plus a di-
hibitors should not be used. A often required to achieve blood pressure uretic and two other antihypertensive drugs
An ACE inhibitor or angiotensin re- targets (Fig. 9.1), particularly in the setting belonging to different classes at adequate
ceptor blocker, at the maximumly of diabetic kidney disease. However, the doses. Prior to diagnosing resis-tant
tolerated dose indicated for blood use of both ACE inhibitors and ARBs in hypertension, a number of other conditions
pressure treatment, is the recom- combination, or the combina-tion of an should be excluded, including medication
mended first-line treatment for hy- ACE inhibitor or ARB and a direct renin nonadherence, white coat hypertension,
pertension in patients with diabetes inhibitor, is not recommended given the and secondary hyperten-sion. In general,
and urinary albumin-to-creatinine lack of added ASCVD benefit and in- barriers to medication adherence (such as
ratio $300 mg/g creatinine A or 30– creased rate of adverse eventsdnamely, cost and side effects) should be identified
299 mg/g creatinine B. If one class is hyperkalemia, syncope, and acute kidney and addressed (Fig. 9.1). Mineralocorticoid
not tolerated, the other injury (AKI) (32–34). Titration of and/or receptor an-tagonists are effective for
addition of further blood pressure medi- management of resistant hypertension in
should be substituted B.
For patients treated with an ACE in-hibitor, cations should be made in a timely fash-ion patients with type 2 diabetes when added
angiotensin receptor blocker, or to overcome clinical inertia in achieving to existing treatment with a ACE inhibitor or
blood pressure targets. ARB, thiazide-like diuretic, and
diuretic, serum creatinine/estimated
Bedtime Dosing. Growing evidence suggests dihydropyridine calcium channel blocker
glomerular filtration rate and serum
that there is an association between the (41). Miner-alocorticoid receptor
potassium levels should be monitored
absence of nocturnal blood pressure dip- antagonists also reduce albuminuria and
at least annually. B
ping and the incidence of ASCVD. A meta- have
S90 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018
Figure 9.1—Recommendations for the treatment of confirmed hypertension in people with diabetes. *An ACE inhibitor (ACEi) or ARB is suggested to
treat hypertension for patients with UACR 30–299 mg/g creatinine and strongly recommended for patients with UACR $300 mg/g creatinine. **Thiazide-
like diuretic; long-acting agents shown to reduce cardiovascular events, such as chlorthalidone and indapamide, are preferred. ***Dihydropyridine
calcium channel blocker. BP, blood pressure. This figure can also be found in the ADA position statement “Diabetes and Hypertension” (5).
additional cardiovascular benefits (42– monitoring for serum creatinine and po- Pregnancy and Antihypertensive Medications.
45). However, adding a mineralocor- tassium in these patients, and long-term Since there is a lack of randomized con-
ticoid receptor antagonist to a regimen outcome studies are needed to better trolled trials of antihypertensive therapy
including an ACE inhibitor or ARB may evaluate the role of mineralocorticoid re- in pregnant women with diabetes, rec-
increase the risk for hyperkalemia, em- ceptor antagonists in blood pressure ommendations for the management of
phasizing the importance of regular management. hypertension in pregnant women with
care.diabetesjournals.org Cardiovascular Disease and Risk Management
S91
diabetes should be similar to those for all LIPID MANAGEMENT In adults with diabetes, it is reasonable to
pregnant women. The American College of Lifestyle Intervention obtain a lipid profile (total cholesterol, LDL
Obstetricians and Gynecologists (ACOG) has cholesterol, HDL cholesterol, and tri-
recommended that women with mild to Recommendations glycerides) at the time of diagnosis, at the
moderate gestational hypertension (systolic Lifestyle modification focusing on initial medical evaluation, and at least ev-
blood pressure ,160 mmHg or diastolic blood weight loss (if indicated); the reduc- ery 5 years thereafter in patients under the
pressure ,110 mmHg) do not need to be tion of saturated fat, trans fat, and age of 40 years. In younger patients with
treated with antihypertensive med-ications as cholesterol intake; increase of die- longer duration of disease (such as those
there is no benefit identified that clearly tary n-3 fatty acids, viscous fiber, and with youth-onset type 1 diabetes), more
outweighs potential risks of therapy (46). A plant stanols/sterols intake; and frequent lipid profiles may be rea-sonable.
2014 Cochrane systematic review of increased physical activity should be A lipid panel should also be ob-tained
antihypertensive therapy for mild to moderate recommended to im-prove the lipid immediately before initiating statin therapy.
chronic hypertension that included 49 trials profile in patients Once a patient is taking a statin, LDL
and over 4,700 women did not find any with diabetes. A cholesterol levels should be assessed 4–
conclusive evi-dence for or against blood Intensify lifestyle therapy and opti- 12 weeks after initiation of statin therapy,
pressure treat-ment to reduce the risk of mize glycemic control for patients after any change in dose, and on an
preeclampsia for the mother or effects on with elevated triglyceride levels individual basis (e.g., to moni-tor for
perinatal outcomes such as preterm birth, ($150 mg/dL [1.7 mmol/L]) and/ or medication adherence and effi-cacy). In
small-for-gestational-age infants, or fetal low HDL cholesterol (,40 mg/dL cases where patients are adherent but the
death (47). For pregnant women who require [1.0 mmol/L] for men, ,50 mg/dL LDL cholesterol level is not responding,
antihypertensive therapy, systolic blood [1.3 mmol/L] for women). C clinical judgment is rec-ommended to
pressure levels of 120–160 mmHg and di- determine the need for and timing of lipid
astolic blood pressure levels of 80–105 Lifestyle intervention, including weight panels. In individual patients, the highly
mmHg are suggested to optimize mater-nal loss, increased physical activity, and variable LDL choles-terol–lowering
health without risking fetal harm. Lower med-ical nutrition therapy, allows some response seen with statins is poorly
targets (systolic blood pressure 110–119 pa-tients to reduce ASCVD risk factors. understood (50). Clinicians should attempt
mmHg and diastolic blood pres-sure 65–79 Nutrition intervention should be tailored to find a dose or alterna-tive statin that is
mmHg) may contribute to im-proved long- according to each patient’s age, tolerable, if side effects occur. There is
term maternal health; however, they may be diabetes type, pharmacologic treatment, evidence for benefit from even extremely
associated with impaired fetal growth. lipid lev-els, and medical conditions. low, less than daily statin doses (51).
Pregnant women with hypertension and Recommendations should focus on re-
evidence of end-organ damage from ducing saturated fat, cholesterol, and trans
cardiovascular and/or renal disease may be fat intake and increasing plant stanols/ Statin Treatment
considered for lower blood pressure targets to sterols, n-3 fatty acids, and viscous fiber
Recommendations
avoid progression of these con-ditions during (such as in oats, legumes, and citrus) in-
For patients of all ages with diabe-tes
pregnancy. take. Glycemic control may also and atherosclerotic cardiovas-cular
beneficially modify plasma lipid levels, disease, high-intensity statin therapy
During pregnancy, treatment with ACE
particularly in patients with very high should be added to lifestyle
inhibitors, ARBs, and spironolactone are
triglycerides and poor glycemic control. therapy. A
contraindicated as they may cause fetal
See Section 4 “Lifestyle Management” for For patients with diabetes aged ,40
damage. Antihypertensive drugs known to be
additional nutrition information. years with additional athero-sclerotic
effective and safe in pregnancy include
cardiovascular disease risk factors,
methyldopa, labetalol, and long-acting
the patient and provider should
nifedipine, while hydralzine may be consid- Ongoing Therapy and Monitoring With
Lipid Panel consider using moderate-intensity
ered in the acute management of hyperten-
statin in addition to lifestyle
sion in pregnancy or severe preeclampsia
Recommendations therapy. C
(46). Diuretics are not recommended for In adults not taking statins or other lipid- For patients with diabetes aged 40– 75
blood pressure control in pregnancy but may lowering therapy, it is reasonable to years A and .75 years B without
be used during late-stage pregnancy if obtain a lipid profile at the time of atherosclerotic cardiovascular dis-
needed for volume control (46,48). ACOG
diabetes diagnosis, at an initial medi- ease, use moderate-intensity statin
also recommends that postpartum patients
cal evaluation, and every 5 years in addition to lifestyle therapy.
with gestational hypertension, pre-eclampsia,
thereafter if under the age of 40 years, In clinical practice, providers may need
and superimposed preeclampsia have their
or more frequently if indicated. E to adjust the intensity of statin
blood pressures observed for 72 h in the
Obtain a lipid profile at initiation of statins therapy based on individual patient
hospital and for 7–10 days postpar-tum.
or other lipid-lowering ther-apy, 4–12 response to medication (e.g., side
Long-term follow-up is recommended for
weeks after initiation or a change in effects, tolerability, LDL cholesterol
these women as they have increased life-time
dose, and annually thereafter as it may levels, or percent LDL reduction on
cardiovascular risk (49). See Section 13
help to monitor the response to therapy statin therapy). For patients who do
“Management of Diabetes in Pregnancy” for
and inform adherence. E not tolerate the intended intensity
additional information.
S92 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018
of statin, the maximally tolerated Table 9.2—Recommendations for statin and combination treatment in adults with
statin dose should be used. E diabetes
For patients with diabetes and ath- Recommended statin intensity^and
Age ASCVD combination treatment*
erosclerotic cardiovascular disease,
,40 years No None†
if LDL cholesterol is $70 mg/dL on
Yes High
maximally tolerated statin dose,
c If LDL cholesterol $70 mg/dL despite maximally tolerated statin
consider adding additional LDL-
dose, consider adding additional LDL-lowering therapy (such as
lowering therapy (such as ezetimibe ezetimibe or PCSK9 inhibitor)#
or PCSK9 inhibitor) after evaluating $40 years No Moderate‡
the potential for further athero- Yes High
sclerotic cardiovascular disease risk c If LDL cholesterol $70 mg/dL despite maximally tolerated statin
reduction, drug-specific ad-verse dose, consider adding additional LDL-lowering therapy (such as
effects, and patient preferen-ces. ezetimibe or PCSK9 inhibitor)
Ezetimibe may be preferred
*In addition to lifestyle therapy.^For patients who do not tolerate the intended intensity of statin, the
due to lower cost. A maximally tolerated statin dose should be used. †Moderate-intensity statin may be considered
Statin therapy is contraindicated in based on risk-benefit profile and presence of ASCVD risk factors. ASCVD risk factors include LDL
cholesterol $100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidney disease,
pregnancy. B
albuminuria, and family history of premature ASCVD. ‡High-intensity statin may be considered
based on risk-benefit profile and presence of ASCVD risk factors. #Adults aged ,40 years with
prevalent ASCVD were not well represented in clinical trials of non-statin–based LDL reduction.
Initiating Statin Therapy Based on Risk Before initiating combination lipid-lowering therapy, consider the potential for further ASCVD risk
Patients with type 2 diabetes have an in- reduction, drug-specific adverse effects, and patient preferences.
creased prevalence of lipid abnormalities,
contributing to their high risk of ASCVD.
Multiple clinical trials have demonstrated death and nonfatal MI) are greatest in The Risk Calculator
the beneficial effects of statin therapy on people with high baseline ASCVD risk The American College of Cardiology/
ASCVD outcomes in subjects with and (known ASCVD and/or very high LDL cho- American Heart Association ASCVD risk
without CHD (52,53). Subgroup analyses lesterol levels), but the overall benefits of calculator is generally a useful tool to esti-
of patients with diabetes in larger trials statin therapy in people with diabetes at mate 10-year ASCVD risk (my.americanheart
(54–58) and trials in patients with diabe-tes moderate or even low risk for ASCVD are .org). However, as diabetes itself confers
(59,60) showed significant primary and convincing (62,63). The relative benefit of increased risk for ASCVD and risk calcula-
secondary prevention of ASCVD events lipid-lowering therapy has been uniform tors in general do not account for the
and CHD death in patients with diabetes. across most subgroups tested (53,61), in- duration of diabetes or the presence of
Meta-analyses, including data from over cluding subgroups that varied with re-spect other complications such as albuminuria,
18,000 patients with diabetes from 14 to age and other risk factors. the risk calculator has limited use for as-
randomized trials of statin therapy (mean sessing cardiovascular risk in individuals
follow-up 4.3 years), demonstrate a 9% Risk Stratification with diabetes.
proportional reduction in all-cause mortality Two broad groups of patients exist for Recently, risk scores and other cardio-
and 13% reduction in vascular mortality for management of cardiovascular risk: those vascular biomarkers have been devel-oped
each mmol/L (39 mg/dL) re-duction in LDL with documented ASCVD (as defined for risk stratification of secondary
cholesterol (61). above) and those without; treatment is prevention patients (i.e., those who are
Accordingly, statins are the drugs of often referred to as “secondary” and “pri- already high risk because they have
choice for LDL cholesterol lowering and mary” prevention, respectively. Because ASCVD) but are not yet in widespread use
cardioprotection. Table 9.2 shows recom- risk is higher in patients with ASCVD, more (67,68). With newer, more expensive lipid-
mended lipid-lowering strategies, and Ta- intensive therapy is indicated and has been lowering therapies now available, use of
ble 9.3 shows the two statin dosing shown to be of benefit in mul-tiple large these risk assessments may help target
intensities that are recommended for use randomized cardiovascular outcomes trials these new therapies to “higher risk”
in clinical practice: high-intensity statin (61,64–66). ASCVD patients in the future.
therapy will achieve approxi-mately a 50%
reduction in LDL choles-
terol, and moderate-intensity statin Table 9.3—High-intensity and moderate-intensity statin therapy*
regimens achieve 30–50% reductions in High-intensity statin therapy (lowers LDL Moderate-intensity statin therapy
cholesterol by $50%) (lowers LDL cholesterol by 30% to 50%)
LDL cholesterol. Low-dose statin therapy is
Atorvastatin 40–80 mg Atorvastatin 10–20 mg
generally not recommended in patients
Rosuvastatin 20–40 mg Rosuvastatin 5–10 mg
with diabetes but is sometimes the only
Simvastatin 20–40 mg
dose of statin that a patient can tolerate.
Pravastatin 40–80 mg
For patients who do not tolerate the Lovastatin 40 mg
intended intensity of statin, the maximally Fluvastatin XL 80 mg
tolerated statin dose should be used. Pitavastatin 2–4 mg
As in those without diabetes, absolute *Once-daily dosing. XL, extended release.
reductions in ASCVD outcomes (CHD
care.diabetesjournals.org Cardiovascular Disease and Risk Management
S93
Primary Prevention (Patients Without ASCVD) Association and American Diabetes Asso- diabetes (27% of participants), the com-
For primary prevention, moderate-dose ciation” (69) for additional discussion. bination of moderate-intensity simvasta-tin
statin therapy is recommended for those (40 mg) and ezetimibe (10 mg) showed a
Secondary Preventions (Patients With
40 years and older (55,62,63), though significant reduction of major adverse
ASCVD)
high-intensity therapy may be considered High-intensity statin therapy is recommen- cardiovascular events with an ab-solute
on an individual basis in the context of ad- ded for all patients with diabetes and risk reduction of 5% (40% vs. 45%) and
ditional ASCVD risk factors. The evidence ASCVD. This recommendation is based on relative risk reduction of 14% (RR 0.86
is strong for patients with diabetes aged the Cholesterol Treatment Trialists’ Collab- [95% CI 0.78–0.94]) over moderate-
40– 75 years, an age-group well oration involving 26 statin trials, of which 5 intensity simvastatin (40 mg) alone (65).
represented in statin trials showing benefit. compared high-intensity versus moderate-
Statins and PCSK9 Inhibitors
The evidence is lower for patients intensity statins. Together, they found re-
Placebo-controlled trials evaluating the
aged .75 years; relatively few older pa- ductions in nonfatal cardiovascular events
addition of the PCSK9 inhibitors evolo-
tients with diabetes have been enrolled in with more intensive therapy, in patients
cumab and alirocumab to maximally
primary prevention trials. However, het- with and without diabetes (53,57,64).
tolerated doses of statin therapy in par-
erogeneity by age has not been seen in Over the past few years, there have ticipants who were at high risk for ASCVD
the relative benefit of lipid-lowering ther- been multiple large randomized trials in- demonstrated an average reduction in LDL
apy in trials that included older partici- vestigating the benefits of adding nonsta- cholesterol ranging from 36 to 59%. These
pants (53,60,61), and because older age tin agents to statin therapy, including three agents have been approved as ad-junctive
confers higher risk, the absolute benefits that evaluated further lowering of LDL therapy for patients with ASCVD or familial
are actually greater (53,65). Moderate- cholesterol with ezetimibe (65), PCSK9 hypercholesterolemia who are receiving
intensity statin therapy is recommended in inhibitors (66), and, cholesteryl es-ter maximally tolerated statin ther-apy but
patients with diabetes that are 75 years or transfer protein [CETP] inhibitors, an require additional lowering of LDL
older. However, the risk-benefit profile investigational class of drugs with some cholesterol (71,72).
should be routinely evaluated in this pop- recent supportive data (70). Each trial
The effects of PCSK9 inhibition on
ulation, with downward titration of dose found a significant benefit in the reduc-tion
ASCVD outcomes was investigated in the
performed as needed. See Section 11 of ASCVD events that was directly related
Further Cardiovascular Outcomes Re-
“Older Adults” for more details on clinical to the degree of further LDL cho-lesterol
search With PCSK9 Inhibition in Subjects
considerations for this population. lowering. These three large trials
With Elevated Risk (FOURIER) trial, which
Age <40 Years and/or Type 1 Diabetes. Very little comprised over 75,000 patients and
enrolled 27,564 patients with prior ASCVD
clinical trial evidence exists for pa-tients 250,000 patient-years of follow-up, and
and an additional high-risk feature who
with type 2 diabetes under the age of 40 approximately one-third of participants had
were receiving their maximally toler-ated
years or for patients with type 1 di-abetes diabetes. For patients with ASCVD who are
statin therapy (two-thirds were on high-
of any age. In the Heart Protection Study on high-intensity (and maximally tolerated)
intensity statin) but who still had an LDL
(lower age limit 40 years), the sub-group of statin therapy and have an LDL cholesterol
cholesterol $70 mg/dL or a non-HDL
;600 patients with type 1 dia-betes had a $70 mg/dL, the addition of nonstatin LDL-
cholesterol $100 mg/dL (66). Patients were
proportionately similar, although not lowering therapy is recom-mended after
randomized to receive subcutane-ous
statistically significant, re-duction in risk as considering the potential for further ASCVD
injections of evolocumab (either 140 mg
patients with type 2 di-abetes (55). Even risk reduction, drug-specific adverse
every 2 weeks or 420 mg every month
though the data are not definitive, similar effects, and patient preferences.
based on patient preference) ver-sus
statin treatment ap-proaches should be placebo. Evolocumab reduced LDL
Combination Therapy for LDL
considered for pa-tients with type 1 or type cholesterol by 59% from a median of 92 to
Cholesterol Lowering
2 diabetes, particularly in the presence of 30 mg/dL in the treatment arm.
Statins and Ezetimibe
other car-diovascular risk factors. Patients The IMProved Reduction of Outcomes: During the median follow-up of 2.2
below the age of 40 have lower risk of Vytorin Efficacy International Trial (IMPROVE- years, the composite outcome of cardio-
devel-oping a cardiovascular event over a IT) was a randomized con-trolled trial in vascular death, MI, stroke, hospitalization
10-year horizon; however, their lifetime risk 18,144 patients comparing the addition of for angina, or revascularization occurred in
of developing cardiovascular disease and ezetimibe to simvastatin therapy versus 11.3% vs. 9.8% of the placebo and evo-
suffering an MI, stroke, or cardiovas-cular simvastatin alone. Individuals were $50 years locumab groups, respectively, represent-
death is high. For patients under the age of of age, had experienced a recent acute ing a 15% relative risk reduction (P ,
40 years and/or who have type 1 diabetes coronary syndrome (ACS), and were treated
0.001). The combined end point of cardio-
with other ASCVD risk factors, we for an average of 6 years. Overall, the
vascular death, MI, or stroke was reduced
recommend that the patient and health by 20%, from 7.4 to 5.9% (P , 0.001).
addition of ezetimibe led to a 6.4% relative
care provider discuss the relative benefits Importantly, similar benefits were seen in
benefit and a 2% ab-solute reduction in major
and risks and consider the use of prespecified subgroup of patients with
adverse cardiovas-cular events, with the
moderate-intensity statin therapy. Please diabetes, comprising 11,031 patients (40%
degree of benefit being directly proportional to
refer to “Type 1 Diabetes Mellitus and of the trial) (73).
the change in LDL cholesterol, which was 70
Cardiovascular Disease: A Scientific mg/dL in the statin group on average and 54 Statins and CETP Inhibitors
Statement From the American Heart mg/dL in the combination group (65). In those Inhibition of CETP increases HDL choles-
with terol and further reduces LDL cholesterol.
S94 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018
This class of drugs is not likely to be dyslipidemia in individuals with type 2 (1.7–4.5 mmol/L) to statin therapy plus
avail-able for clinical use, but di-abetes. However, the evidence for extended-release niacin or placebo. The
studies pro-vide further insight into the use of drugs that target these lipid trial was halted early due to lack of effi-
the effects of LDL cholesterol frac-tions is substantially less robust cacy on the primary ASCVD outcome (first
lowering on cardiovascular events. than that for statin therapy (78). In a event of the composite of death from CHD,
A total of four trials have been con- large trial in patients with diabetes, nonfatal MI, ischemic stroke, hospi-
ducted, three of which failed to show fenofibrate failed to reduce overall talization for an ACS, or symptom-driven
benefit (74–76). Of these, one showed cardiovascular out-comes (79). coronary or cerebral revascularization) and
harm and two were stopped after a possible increase in ischemic stroke in
approx-imately 2 years and thus did not Other Combination Therapy
those on combination therapy (82).
have sufficient time or power to identify The much larger Heart Protection Study
the benefit. The final study, the Recommendations 2–Treatment of HDL to Reduce the
Randomized Evaluation of the Effects of Combination therapy (statin/fibrate) has Incidence of Vascular Events (HPS2-
Anacetrapib Through Lipid-modification not been shown to improve ath- THRIVE) trial also failed to show a benefit
(REVEAL) trial enrolled 30,449 patients erosclerotic cardiovascular disease of adding niacin to background statin
with ASCVD (70). All patients received outcomes and is generally not rec- therapy (83). A total of 25,673 patients with
intensive atorvasta-tin therapy and were ommended. A prior vascular disease were random-ized to
randomized to ana-cetrapib or placebo. Combination therapy (statin/niacin) receive 2 g of extended-release niacin and
During the median follow-up of 4.1 has not been shown to provide 40 mg of laropiprant (an antag-onist of the
years, the primary outcome (coronary addi-tional cardiovascular benefit prostaglandin D2 receptor DP1 that has
death, MI, or coronary revascularization) above statin therapy alone, may been shown to improve ad-herence to
was significantly reduced with the addi- increase the risk of stroke with niacin therapy) versus a matching placebo
tion of anacetrapib from 11.8 to 10.8%, additional side effects, and is daily and followed for a median follow-up
with a hazard ratio (HR) of 0.91 (P 5 generally not recommended. A period of 3.9 years. There was no
0.004). The relative difference in risk significant difference in the rate of coronary
Statin and Fibrate
was similar across multiple prespecified death, MI, stroke, or coronary
subgroups, including among 11,320 pa- Combination therapy (statin and fibrate) revascularization with the ad-dition of
is associated with an increased risk for niacin–laropiprant versus pla-cebo (13.2%
tients with diabetes (37% of the trial).
abnormal transaminase levels, myositis, vs. 13.7%; rate ratio, 0.96; P 5 0.29).
The benefit appeared to be related to
and rhabdomyolysis. The risk of rhabdo- Niacin–laropiprant was associ-ated with an
the reduction in LDL (and more broadly
myolysis is more common with higher increased incidence of new-onset diabetes
non-HDL) as opposed to the raising of
doses of statins and renal insufficiency (absolute excess, 1.3 percentage points; P
HDL. The mean achieved LDL
and appears to be higher when statins , 0.001) and distur-bances in diabetes
cholesterol was 63 mg/dL vs. 53 mg/dL
are combined with gemfibrozil (com- control among those with diabetes. In
at the trial midpoint in the placebo and
pared with fenofibrate) (80). addition, there was an increase in serious
anacetrapib groups, respectively. This
In the ACCORD study, in patients with adverse events associ-ated with the
study reaffirms the benefit of further
type 2 diabetes who were at high risk for gastrointestinal system, musculoskeletal
lowering of LDL cholesterol on reducing
ASCVD, the combination of fenofibrate system, skin, and, unex-pectedly, infection
cardiovascular events.
and simvastatin did not reduce the rate and bleeding.
of fatal cardiovascular events, nonfatal Therefore, combination therapy with a
Treatment of Other Lipoprotein MI, or nonfatal stroke as compared with statin and niacin is not recommended
Fractions or Targets simvastatin alone. Prespecified given the lack of efficacy on major
subgroup analyses suggested ASCVD outcomes and side effects.
Recommendation
heterogeneity in treatment effects with
For patients with fasting triglyceride
possible benefit for men with both a Diabetes With Statin Use
levels $500 mg/dL (5.7 mmol/L),
triglyceride level $204 mg/dL (2.3 Several studies have reported a modestly
evaluate for secondary causes of
mmol/L) and an HDL cholesterol level increased risk of incident diabetes with
hypertriglyceridemia and consider
#34 mg/dL (0.9 mmol/L) (81). statin use (84,85), which may be limited to
medical therapy to reduce the risk
of pancreatitis. C Statin and Niacin those with diabetes risk factors. An
The Atherothrombosis Intervention in analysis of one of the initial studies
Hypertriglyceridemia should be ad-dressed Metabolic Syndrome With Low HDL/High suggested that although statin use was
with dietary and lifestyle changes including Triglycerides: Impact on Global Health associated with diabetes risk, the cardio-
abstinence from alcohol (77). Severe Outcomes (AIM-HIGH) trial randomized vascular event rate reduction with statins
hypertriglyceridemia (.1,000 mg/dL) may over 3,000 patients (about one-third with far outweighed the risk of incident diabe-
warrant pharmacologic ther-apy (fibric acid diabetes) with established ASCVD, low tes even for patients at highest risk for
derivatives and/or fish oil) to reduce the LDL cholesterol levels (,180 mg/dL [4.7 diabetes (86). The absolute risk increase
risk of acute pancreatitis. mmol/L]), low HDL cholesterol levels (men , was small (over 5 years of follow-up, 1.2%
Low levels of HDL cholesterol, often 40 mg/dL [1.0 mmol/L] and women ,50 of participants on placebo devel-oped
associated with elevated triglyceride mg/dL [1.3 mmol/L]), and triglyceride levels diabetes and 1.5% on rosuvastatin
levels, are the most prevalent pattern of of 150–400 mg/dL developed diabetes) (86). A meta-analysis
care.diabetesjournals.org Cardiovascular Disease and Risk Management
S95
of 13 randomized statin trials with 91,140 Risk Reduction greater than the number of episodes
participants showed an odds ratio of 1.09 Aspirin has been shown to be effective of bleeding induced, although these
for a new diagnosis of diabetes, so that (on in reducing cardiovascular morbidity and compli-cations do not have equal
average) treatment of 255 patients with mortality in high-risk patients with previ- effects on long-term health (94).
statins for 4 years resulted in one ous MI or stroke (secondary prevention).
additional case of diabetes while simulta- Its net benefit in primary prevention Treatment Considerations
neously preventing 5.4 vascular events among patients with no previous cardio- In 2010, a position statement of the ADA,
among those 255 patients (85). vascular events is more controversial the American Heart Association, and the
both for patients with diabetes and for American College of Cardiology Foun-
Statins and Cognitive Function patients without diabetes (89,90). Previ- dation recommended that low-dose (75–
A recent systematic review of the U.S. Food
ous randomized controlled trials of aspi- 162 mg/day) aspirin for primary pre-vention
and Drug Administration’s (FDA’s)
rin specifically in patients with diabetes is reasonable for adults with di-abetes and
postmarketing surveillance databases,
failed to consistently show a significant no previous history of vascular disease
randomized controlled trials, and cohort,
reduction in overall ASCVD end points, who are at increased ASCVD risk and who
case-control, and cross-sectional studies
raising questions about the efficacy of are not at increased risk for bleeding (95).
evaluating cognition in patients receiving
as-pirin for primary prevention in people This now out-of-date state-ment included
statins found that published data do not re-
with diabetes, although some sex differ- sex-specific recommenda-tions for use of
veal an adverse effect of statins on cognition
ences were suggested (91–93). aspirin therapy as primary prevention in
(87). In addition, no change in cognitive
The Antithrombotic Trialists’ Collabora- persons with diabetes (95). However, since
function has been reported in studies with the that time, multiple recent well-conducted
tion published an individual patient–level
addition of ezetimibe (65) or PCSK9 inhibitors studies and meta-analyses have reported
meta-analysis (89) of the six large trials of
(66,88) to statin therapy, includ-ing among aspirin for primary prevention in the gen- a risk of heart disease and stroke that is
patients treated to very low LDL cholesterol eral population. These trials collectively equivalent if not higher in women
levels. Therefore, a concern that statins or enrolled over 95,000 participants, includ- compared with men with diabe-tes,
other lipid-lowering agents might cause ing almost 4,000 with diabetes. Overall, including among nonelderly adults. Thus,
cognitive dysfunction or dementia is not they found that aspirin reduced the risk of current recommendations for using aspirin
currently supported by evidence and should serious vascular events by 12% (RR 0.88 as primary prevention include both men
not deter their use in individuals with diabetes [95% CI 0.82–0.94]). The largest re-duction and women aged $50 years with diabetes
at high risk for ASCVD (87). was for nonfatal MI, with little effect on and at least one additional major risk factor
CHD death (RR 0.95 [95% CI 0.78–1.15]) (family history of premature ASCVD,
ANTIPLATELET AGENTS or total stroke. There was some evidence hypertension, dyslipidemia, smoking, or
of a difference in aspirin effect by sex: chronic kidney disease/ albuminuria) who
Recommendations
aspirin significantly reduced ASCVD events are not at increased risk of bleeding (e.g.,
Use aspirin therapy (75–162 mg/day) as a
in men but not in women. Conversely, older age, anemia, renal disease) (96–99).
secondary prevention strategy in those
aspirin had no effect on stroke in men but While risk calcu-lators such as those from
with diabetes and a history of
significantly reduced stroke in women. the American College of
atherosclerotic cardiovascular
However, there was no heterogeneity of Cardiology/American Heart As-sociation
disease. A effect by sex in the risk of serious vascular (my.americanheart.org) may be a useful
For patients with atherosclerotic events (P 5 0.9). tool to estimate 10-year ASCVD risk,
cardiovascular disease and docu- Sex differences in the effects of aspirin diabetes itself confers in-creased risk for
mented aspirin allergy, clopidogrel have not been observed in studies of sec- ASCVD. As a result, such risk calculators
(75 mg/day) should be used. B ondary prevention (89). In the six trials have limited utility in help-ing to assess the
Dual antiplatelet therapy (with low-dose
examined by the Antithrombotic Trialists’ potential benefits of as-pirin therapy in
aspirin and a P2Y12 inhibitor) is
Collaboration, the effects of aspirin on individuals with diabetes. Noninvasive
reasonable for a year after an acute
major vascular events were similar for pa- imaging techniques such as coronary
coronary syndrome A and may have
tients with or without diabetes: RR 0.88 computed tomography angiog-raphy may
benefits beyond this period. B (95% CI 0.67–1.15) and RR 0.87 (95% CI potentially help further tai-lor aspirin
Aspirin therapy (75–162 mg/day) may therapy, particularly in those at low risk
0.79–0.96), respectively. The CI was wider
be considered as a primary pre- (100), but are not generally recommended.
for those with diabetes because of smaller
vention strategy in those with type 1 Sex differences in the antiplatelet effect of
numbers.
or type 2 diabetes who are at in- aspirin have been sug-gested in the
Aspirin appears to have a modest ef-fect
creased cardiovascular risk. This general population (101); however, further
on ischemic vascular events, with the
includes most men and women with studies are needed to investigate the
absolute decrease in events depending on
diabetes aged $50 years who have presence of such differen-ces in individuals
the underlying ASCVD risk. The main
at least one additional major risk with diabetes.
adverse effect is an increased risk of gas-
factor (family history of premature
trointestinal bleeding. The excess risk may
atherosclerotic cardiovascular dis-
be as high as 5 per 1,000 per year in real- Aspirin Use in People <50 Years of Age
ease, hypertension, dyslipidemia, Aspirin is not recommended for those at low
world settings. In adults with ASCVD risk .
smoking, or albuminuria) and are not risk of ASCVD (such as men and women
1% per year, the number of ASCVD events
at increased risk of bleeding. C
prevented will be similar to or aged ,50 years with diabetes with no
S96 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018
other major ASCVD risk factors) as the adding ticagrelor to aspirin significantly
disease, after lifestyle management
low benefit is likely to be outweighed by reduces the risk of recurrent ischemic
and metformin, the antihyperglyce-
the risks of bleeding. Clinical judgment events including cardiovascular and coro-
mic agent canagliflozin may be con-
should be used for those at intermediate nary heart disease death (108). More
sidered to reduce major adverse
risk (younger patients with one or more studies are needed to investigate the
cardiovascular events, based on
risk factors or older patients with no risk longer-term benefits of these therapies
drug-specific and patient factors (see
fac-tors) until further research is after ACS among patients with diabetes.
Table 8.1). C
available. Patients’ willingness to
undergo long-term aspirin therapy CORONARY HEART DISEASE
should also be con-sidered (102). Recommendations Cardiac Testing
Aspirin use in patients aged ,21 years is Candidates for advanced or invasive car-diac
generally contraindi-cated due to the Screening testing include those with 1) typical or atypical
associated risk of Reye syndrome. In asymptomatic patients, routine cardiac symptoms and 2) an ab-normal
screening for coronary artery dis- resting electrocardiogram (ECG). Exercise
Aspirin Dosing ease is not recommended as it does ECG testing without or with echo-
Average daily dosages used in most clini- not improve outcomes as long as cardiography may be used as the initial test.
cal trials involving patients with diabetes atherosclerotic cardiovascular dis- In adults with diabetes $40 years of age,
ranged from 50 mg to 650 mg but were ease risk factors are treated. A measurement of coronary artery calcium is
mostly in the range of 100–325 mg/day. Consider investigations for coronary artery also reasonable for cardiovascular risk
There is little evidence to support any disease in the presence of any of the assessment. Pharmacologic stress echo-
specific dose, but using the lowest possi- following: atypical cardiac symptoms cardiography or nuclear imaging should be
ble dose may help to reduce side effects (e.g., unexplained dyspnea, chest considered in individuals with diabetes in
(103). In the U.S., the most common low- discomfort); signs or symptoms of whom resting ECG abnormalities pre-clude
dose tablet is 81 mg. Although platelets associated vascular disease includ-ing exercise stress testing (e.g., left bundle
from patients with diabetes have altered carotid bruits, transient ischemic attack, branch block or ST-T abnormali-ties). In
function, it is unclear what, if any, effect stroke, claudication, or periph-eral addition, individuals who require stress
that finding has on the required dose of arterial disease; or electrocardio-gram testing and are unable to exercise should
aspirin for cardioprotective effects in the
abnormalities (e.g., Q waves). E undergo pharmacologic stress
patient with diabetes. Many alternate
echocardiography or nuclear imaging.
pathways for platelet activation exist that Treatment
are independent of thromboxane A2 and In patients with known atheroscle-
Screening Asymptomatic Patients
thus not sensitive to the effects of aspirin rotic cardiovascular disease, con-
The screening of asymptomatic patients with
(104). “Aspirin resistance” has been sider ACE inhibitor or angiotensin
high ASCVD risk is not recommended (109),
described in patients with diabetes when receptor blocker therapy to reduce
in part because these high-risk pa-tients
measured by a variety of ex vivo and in the risk of cardiovascular events. B
should already be receiving inten-sive
vitro methods (platelet aggregom-etry, In patients with prior myocardial in-
medical therapydan approach that provides
farction, b-blockers should be con-
measurement of thromboxane B2) (101), similar benefit as invasive revas-cularization
tinued for at least 2 years after the
but other studies suggest no impair-ment (110,111). There is also some evidence that
event. B
in aspirin response among patients with silent MI may reverse over time, adding to the
In patients with type 2 diabetes with
diabetes (105). A recent trial suggested controversy concern-ing aggressive
stable congestive heart failure,
that more frequent dosing regimens of screening strategies (112). In prospective
metformin may be used if estimated
aspi-rin may reduce platelet reactivity in studies, coronary artery calcium has been
glomerular filtration rate remains
individ-uals with diabetes (106); however, established as an in-dependent predictor of
these observations alone are insufficient to .30 mL/min but should be avoided
future ASCVD events in patients with
em-pirically recommend that higher doses in unstable or hospitalized patients
diabetes and is consistently superior to both
of aspirin be used in this group at this time. with congestive heart failure. B
the UK Prospective Diabetes Study (UKPDS)
In patients with type 2 diabetes and
It appears that 75–162 mg/day is optimal. risk engine and the Framing-ham Risk Score
established atherosclerotic cardio-
in predicting risk in this population (113–115).
vascular disease, antihyperglycemic
Indications for P2Y12 Use However, a random-ized observational trial
therapy should begin with lifestyle
A P2Y12 receptor antagonist in combina- demonstrated no clinical benefit to routine
management and metformin and
tion with aspirin should be used for at least screening of asymptomatic patients with type
subsequently incorporate an agent
1 year in patients following an ACS and 2 dia-betes and normal ECGs (116). Despite
proven to reduce major adverse car-
may have benefits beyond this period. abnormal myocardial perfusion imaging in
diovascular events and cardiovascular
Evidence supports use of either ticagrelor more than one in five patients, cardiac
mortality (currently empagliflozin and
or clopidogrel if no percutane-ous coronary outcomes were essentially equal (and very
liraglutide), after considering drug-
intervention was performed and low) in screened versus unscreened patients.
specific and patient factors
clopidogrel, ticagrelor, or prasugrel if a Accordingly, indiscriminate screening is not
(see Table 8.1). A
percutaneous coronary intervention was considered cost-effective. Studies have found
In patients with type 2 diabetes and es-
performed (107). In patients with di-abetes that a risk factor–
tablished atherosclerotic cardiovascular
and prior MI (1–3 years before),
Table 9.4—CVOTs completed after issuance of the FDA 2008 guidance
DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors
SAVOR-TIMI 53 EXAMINE TECOS ELIXA LEADER SUSTAIN-6 EXSCEL EMPA-REG CANVAS CANVAS-R
(129) (145) (132) (140) (138) (139)* (141) OUTCOME (133) (135) (135)
(n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 7,020) (n 5 4,330) (n 5 5,812)
Intervention Saxagliptin/ Alogliptin/ Sitagliptin/ Lixisenatide/ Liraglutide/ Semaglutide/ Exenatide QW/ Empagliflozin/ Canagliflozin/placebo
placebo placebo placebo placebo placebo placebo placebo placebo
Main inclusion criteria Type 2 diabetes Type 2 diabetes Type 2 Type 2 Type 2 Type 2 Type 2 diabetes Type 2 diabetes Type 2 diabetes and preexisting
and history of and ACS diabetes and diabetes and diabetes and diabetes and with or without and preexisting CVD at $30 years of age or $2
or multiple within 15–90 preexisting history of ACS preexisting preexisting preexisting CVD CVD with BMI cardiovascular risk factors at $50
risk factors for days before CVD (,180 days) CVD, kidney CVD, HF, or 2 years of age
#45 kg/m and
CVD randomization disease, or HF CKD at $50 eGFR $30
at $50 years of years of age or 2
mL/min/1.73 m
age or cardiovascular
cardiovascular risk at $60
risk at $60 years of age
years of age
A1C inclusion criteria (%) $6.5 6.5–11.0 6.5–8.0 5.5–11.0 $7.0 $7.0 6.5–10.0 7.0–10.0 7.0–10.5
Age (years)†† 65.1 61.0 65.4 60.3 64.3 64.6 62 63.1 63.3
Diabetes duration (years)†† 10.3 7.1 11.6 9.3 12.8 13.9 12 57% .10 13.5
Median follow-up (years) 2.1 1.5 3.0 2.1 3.8 2.1 3.2 3.1 5.7 2.1
Statin use (%) 78 91 80 93 72 73 74 77 75
Metformin use (%) 70 66 82 66 76 73 77 74 77
Continued on p. S98
care.diabetesjournals.org
S98 Cardiovascular Disease and Risk Management
Table 9.4—Continued
DPP-4 inhibitors GLP-1 receptor agonists SGLT2 inhibitors
SAVOR-TIMI 53 EXAMINE TECOS ELIXA LEADER SUSTAIN-6 EXSCEL EMPA-REG CANVAS CANVAS-R
(129) (145) (132) (140) (138) (139)* (141) OUTCOME (133) (135) (135)
(n 5 16,492) (n 5 5,380) (n 5 14,671) (n 5 6,068) (n 5 9,340) (n 5 3,297) (n 5 14,752) (n 5 7,020) (n 5 4,330) (n 5 5,812)
Cardiovascular death§ 1.03 0.85 1.03 0.98 0.78 0.98 0.88 0.62 0.96 (0.77–1.18)¶
(0.87–1.22) (0.66–1.10) (0.89–1.19) (0.78–1.22) (0.66–0.93) (0.65–1.48) (0.76–1.02) (0.49–0.77) 0.87 (0.72–1.06)#
MI§ 0.95 1.08 0.95 1.03 0.86 0.74 0.97 0.87 0.85 0.85
(0.80–1.12) (0.88–1.33) (0.81–1.11) (0.87–1.22) (0.73–1.00) (0.51–1.08) (0.85–1.10) (0.70–1.09) (0.65–1.11) (0.61–1.19)
Stroke§ 1.11 0.91 0.97 1.12 0.86 0.61 0.85 1.18 0.97 0.82
(0.88–1.39) (0.55–1.50) (0.79–1.19) (0.79–1.58) (0.71–1.06) (0.38–0.99) (0.70–1.03) (0.89–1.56) (0.70–1.35) (0.57–1.18)
HF hospitalization§ 1.27 1.19 1.00 0.96 0.87 1.11 0.94 0.65 0.77 HR 0.56
(1.07–1.51) (0.90–1.58) (0.83–1.20) (0.75–1.23) (0.73–1.05) (0.77–1.61) (0.78–1.13) (0.50–0.85) (0.55–1.08) (0.38–0.83)
Unstable angina 1.19 0.90 0.90 1.11 0.98 0.82 1.05 0.99 d
hospitalization§ (0.89–1.60) (0.60–1.37) (0.70–1.16) (0.47–2.62) (0.76–1.26) (0.47–1.44) (0.94–1.18) (0.74–1.34)
All-cause mortality§ 1.11 0.88 1.01 0.94 0.85 1.05 0.86 0.68 0.87 (0.74–1.01)‡‡
(0.96–1.27) (0.71–1.09) (0.90–1.14) (0.78–1.13) (0.74–0.97) (0.74–1.50) (0.77–0.97) (0.57–0.82) 0.90 (0.76–1.07)##
Worsening 1.08 d d d 0.78 0.64 d 0.61 0.60 (0.47–0.77)
nephropathy§| (0.88–1.32) (0.67–0.92) (0.46–0.88) (0.53–0.70)
d, not assessed/reported; CANVAS-R, CANVAS-Renal; CHF, congestive heart failure; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; MACE, major adverse cardiac event; UL, upper limit. Data from this table
based approach to the initial diagnostic Recent studies have also examined the SGLT2 inhibitors (particularly the preven-
evaluation and subsequent follow-up for relationship between dipeptidyl pep-tidase tion of heart failure), are being followed up
coronary artery disease fails to identify which 4 (DPP-4) inhibitors and heart failure and with new outcomes trials in patients with
patients with type 2 diabetes will have silent have had mixed results. The Saxagliptin established heart failure, both with and
ischemia on screening tests (117,118). Any Assessment of Vascular Outcomes without diabetes, to determine their
benefit of newer nonin-vasive coronary artery Recorded in Patients with Di-abetes efficacy in treatment of heart failure.
disease screening methods, such as Mellitus–Thrombolysis in Myocar-dial
computed tomography and computed Infarction 53 (SAVOR-TIMI 53) study Antihyperglycemic Therapies and
tomography angiography, to identify patient showed that patients treated with Cardiovascular Outcomes
subgroups for different treatment strategies saxagliptin (a DPP-4 inhibitor) were more In 2008, the FDA issued a guidance for
remains unproven. Although asymptomatic likely to be hospitalized for heart failure industry to perform cardiovascular out-comes
patients with di-abetes with higher coronary than were those given placebo (3.5% vs. trials for all new medications for the treatment
disease bur-den have more future cardiac 2.8%, respectively) (129). Two other re- for type 2 diabetes amid concerns of
events (113,119,120), the role of these tests cent multicenter, randomized, double-blind, increased cardiovascular risk (137).
be-yond risk stratification is not clear. Their noninferiority trials, Examination of Previously approved diabetes med-ications
rou-tine use leads to radiation exposure and Cardiovascular Outcomes with Alogliptin were not subject to the guidance. Recently
may result in unnecessary invasive testing versus Standard of Care (EXAMINE) and published cardiovascular outcomes trials
such as coronary angiography and Trial Evaluating Cardiovascular Outcomes have provided additional data on car-
revascularization procedures. The ultimate with Sitagliptin (TECOS), did not show diovascular outcomes in patients with type 2
balance of bene-fit, cost, and risks of such an asso-ciations between DPP-4 inhibitor use diabetes with cardiovascular disease or at
approach in asymptomatic patients remains and heart failure. The FDA reported that high risk for cardiovascular disease (see
controversial, particularly in the modern the hos-pital admission rate for heart failure Table 9.4). Cardiovascular outcomes trials of
setting of aggres-sive ASCVD risk factor in EXAMINE was 3.9% for patients DPP-4 inhibitors have all, so far, not shown
control. randomly assigned to alogliptin compared cardiovascular benefits relative to placebo.
with 3.3% for those randomly assigned to However, results from other new agents have
placebo (130). Alogliptin had no effect on provided a mix of results.
Lifestyle and Pharmacologic
the composite end point of cardiovas-cular EMPA-REG OUTCOME trial was a ran-
Interventions
death and hospital admission for heart domized, double-blind trial that assessed the
Intensive lifestyle intervention focusing on
failure in the post hoc analysis (HR 1.00 effect of empagliflozin, a SGLT2 inhib-itor,
weight loss through decreased caloric
[95% CI 0.82–1.21]) (131). TECOS showed versus placebo on cardiovascular outcomes
intake and increased physical activity as
no difference in the rate of heart failure in 7,020 patients with type 2 diabetes and
performed in the Action for Health in Di-
hospitalization for the sitagliptin group existing cardiovascular dis-ease. Study
abetes (Look AHEAD) trial may be con-
(3.1%; 1.07 per 100 person-years) participants had a mean age of 63 years,
sidered for improving glucose control,
compared with the placebo group (3.1%; 57% had diabetes for more than 10 years,
fitness, and some ASCVD risk factors
1.09 per 100 person-years) (132). and 99% had established cardiovascular
(121). Patients at increased ASCVD risk
should receive aspirin and a statin and A benefit on the incidence of heart fail- disease. EMPA-REG OUTCOME showed that
ACE inhibitor or ARB therapy if the patient ure has been observed with the use of over a median follow-up of 3.1 years,
has hypertension, unless there are con- some sodium–glucose cotransporter 2 treatment reduced the compos-ite outcome of
traindications to a particular drug class. (SGLT2) inhibitors. In the BI 10773 MI, stroke, and cardiovas-cular death by 14%
(Empagliflozin) Cardiovascular Outcome (absolute rate 10.5% vs. 12.1% in the
While clear benefit exists for ACE inhibitor
Event Trial in Type 2 Diabetes Mellitus placebo group, HR in the empagliflozin group
or ARB therapy in patients with diabetic
Patients (EMPA-REG OUTCOME), the ad- 0.86; 95% CI 0.74– 0.99; P = 0.04 for
kidney disease or hypertension, the bene-
dition of empagliflozin to standard care led superiority) and cardio-vascular death by 38%
fits in patients with ASCVD in the absence
to a significant 35% reduction in the (absolute rate 3.7% vs. 5.9%, HR 0.62; 95%
of these conditions are less clear, espe-
hospitalization for heart failure compared CI 0.49– 0.77; P , 0.001) (133). The FDA
cially when LDL cholesterol is concomi-
with placebo (133). Although the majority of recently added a new indication for
tantly controlled (122,123). In patients with
patients in the study did not have heart empagliflozin, to reduce the risk of major
prior MI, active angina, or heart fail-ure, b-
failure at baseline, this benefit was con- adverse car-diovascular death in adults with
blockers should be used (124).
sistent in patients with and without a prior type 2 diabetes and cardiovascular disease.
Diabetes and Heart Failure history of heart failure (134). Simi-larly, in
As many as 50% of patients with type 2 the Canagliflozin Cardiovascu-lar second large cardiovascular out-comes
diabetes may develop heart failure (125). Assessment Study (CANVAS), there was a trial program of an SGLT2 inhibi-tor,
Data on the effects of glucose-lowering 33% reduction in hospitalization for heart canagliflozin, has been reported (135). The
agents on heart failure outcomes have failure with canagliflozin versus placebo CANVAS Program integrated data from two
demonstrated that thiazolidinediones have (135). Although heart failure hos- trials, including the CANVAS trial that started
a strong and consistent relation-ship with pitalizations were prospectively adjudicated in 2009 before the ap-proval of canagliflozin
increased risk of heart failure (126–128). in both trials, the type(s) of heart failure and the CANVAS-R trial that started in 2014
Therefore, thiazolidinedione use should be events prevented were not characterized. after the approval of canagliflozin. Combining
avoided in patients with symptomatic heart These preliminary findings, which strongly both these trials, 10,142 participants with type
failure. suggest heart failure–related benefits of 2 diabetes and
S100 Cardiovascular Disease and Risk Management Diabetes Care Volume 41, Supplement 1, January 2018
high cardiovascular risk were randomized to stroke and cardiovascular death, in significant (141). A total of 14,752 pa-tients
canagliflozin or placebo and were followed for adults with type 2 diabetes and with type 2 diabetes (of whom 10,782
an average 3.6 years. The mean age of established car-diovascular disease. [73.1%] had previous cardiovascu-lar
patients was 63 years and 66% had a history Results from a moderate-sized trial of an- disease) were randomized to receive
of cardiovascular disease. The combined other GLP-1 receptor agonist, semaglutide, extended-release exenatide 2 mg or pla-
analysis of the two trials found that were consistent with the LEADER trial (139). cebo and followed for a median of 3.2
canagliflozin significantly reduced the com- Semaglutide, a once-weekly GLP-1 receptor years. The primary end point of cardio-
posite outcome of cardiovascular death, MI, agonist, has not yet been ap-proved by the vascular death, MI, or stroke occurred in
or stroke versus placebo (occurring in 26.9 FDA for the treatment of type 2 diabetes. The 839 patients (11.4%; 3.7 events per 100
vs. 31.5 participants per 1,000 patient-years; preapproval Trial to Evaluate Cardiovascular person-years) in the exenatide group and
HR 0.86 [95% CI 0.75–0.97]; P , 0.001 for and Other Long-term Outcomes with in 905 patients (12.2%; 4.0 events per 100
noninferiority; P 5 0.02 for superiority). The Semaglutide in Sub-jects With Type 2 person-years) in the placebo group (HR
specific estimates for canagliflozin versus Diabetes (SUSTAIN-6) was the initial 0.91 [95% CI 0.83–1.00]; P , 0.001 for
placebo on the primary composite randomized trial powered to test noninferiority noninferiority) but was not superior to
cardiovascular out-come were HR 0.88 of semaglutide for the purpose of initial placebo with respect to the primary end
(0.75–1.03) for the CANVAS trial, and 0.82 regulatory approval. In this study, 3,297 point (P 5 0.06 for superiority). However,
(0.66–1.01) for the CANVAS-R, with no patients with type 2 di-abetes were all-cause mortality was lower in the exe-
heterogeneity found between trials. In the randomized to receive once-weekly natide group (HR 0.86 [95% CI 0.77–0.97].
combined analysis, there was not a semaglutide (0.5 mg or 1.0 mg) or placebo for The incidence of acute pancreatitis, pan-
statistically sig-nificant difference in 2 years. The primary outcome (the first creatic cancer, medullary thyroid carci-
cardiovascular death (HR 0.87 [95% CI 0.72– occurrence of cardiovascular death, nonfatal noma, and serious adverse events did not
1.06]). The initial CANVAS trial was partially MI, or nonfatal stroke) occurred in 108 differ significantly between the two groups.
unblinded prior to completion because of the patients (6.6%) in the semaglutide group vs.
need to file interim cardiovascular outcome 146 patients (8.9%) in the placebo group (HR In summary, there are now large
data for regulatory approval of the drug (136). 0.74 [95% CI 0.58–0.95]; P , 0.001). More randomized controlled trials reporting
Of note, there was an increased risk of am- patients dis-continued treatment in the statistically significant reductions in car-
putation with canaglifozin (6.3 vs. 3.4 par- semaglutide group because of adverse diovascular events for two of the FDA-
ticipants per 1,000 patient-years; HR 1.97 events, mainly gastrointestinal. approved SGLT2 inhibitors (empagliflozin
[95% CI 1.41–2.75]) (135). and canagliflozin) and one of the FDA-
The Evaluation of Lixisenatide in Acute approved GLP-1 receptor agonists
The Liraglutide Effect and Action in Di- Coronary Syndrome (ELIXA) trial studied (liraglutide) where the majority, if not all,
abetes: Evaluation of Cardiovascular the once-daily GLP-1 receptor agonist patients in the trial had ASCVD. The
Outcome ResultsdA Long Term Evalua-tion lixisenatide on cardiovascular outcomes in empagliflozin and liraglutide trials further
(LEADER) trial was a randomized, double- patients with type 2 diabetes who had had demon-strated significant reductions in
blind trial that assessed the effect of a recent acute coronary event (140). A total cardio-vascular death. Once-weekly
liraglutide, a glucagon-like peptide 1 (GLP-1) of 6,068 patients with type 2 diabetes with exenatide did not have statistically
receptor agonist, versus placebo on a recent hospitalization for MI or unstable significant re-ductions in major adverse
cardiovascular outcomes in 9,340 pa-tients angina within the previ-ous 180 days were cardiovascu-lar events or cardiovascular
with type 2 diabetes at high risk for randomized to re-ceive lixisenatide or mortality but did have a significant
cardiovascular disease or with cardiovascu- placebo in addition to standard care and reduction in all-cause mortality. In contrast,
lar disease. Study participants with a mean were followed for a median of other GLP-1 receptor agonists have not
age of 64 years and a mean duration of approximately 2.1 years. The primary shown similar reductions in cardiovas-cular
diabetes of nearly 13 years. Over 80% of outcome of cardiovascular death, MI, events (Table 9.4). Whether the benefits of
study participants had established cardio- stroke, or hospitalization for unstable GLP-1 receptor agonists are a class effect
vascular disease. After a median follow-up of angina occurred in 406 patients (13.4%) in remains to be definitively established.
3.8 years, LEADER showed that the pri-mary the lixisenatide group vs. 399 (13.2%) in Additional large randomized trials of other
composite outcome (MI, stroke, or the placebo group (HR 1.02 [95% CI 0.89– agents in these classes are ongoing.
cardiovascular death) occurred in fewer 1.17]), which demon-strated the
participants in the treatment group (13.0%) noninferiority of lixisenatide to placebo (P , Of note, these studies examined the
when compared with the placebo group 0.001) but did not show superiority (P 5 drugs in combination with metformin (Ta-
(14.9%) (HR 0.87; 95% CI 0.78–0.97; P , 0.81). ble 9.4) in the great majority of patients for
0.001 for noninferiority; P = 0.01 for Most recently, the Exenatide Study of whom metformin was not contraindi-cated
superiority). Deaths from cardiovascular Cardiovascular Event Lowering (EXSCEL) or was tolerated. For patients with type 2
causes in the were significantly reduced in trial also reported results with the once- diabetes who have ASCVD, on life-style
the liraglutide group (4.7%) compared to the weekly GLP-1 receptor agonist extended- and metformin therapy, it is recom-mended
placebo group (6.0%) (HR 0.78; 95% CI release exenatide and found that major to incorporate an agent with strong
0.66–0.93; P = 0.007) (138). The FDA adverse cardiovascular events were nu- evidence for cardiovascular risk reduction,
recently approved use of liraglutide to reduce merically lower with use of extended- especially those with proven benefit on
the risk of major adverse car-diovascular release exenatide compared with placebo, both major adverse cardiovas-cular events
events, including heart attack, although this difference was not statistically and cardiovascular death,
care.diabetesjournals.org Cardiovascular Disease and Risk Management
S101
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Diabetes Care Volume 41, Supplement 1, January 2018 S105
Screening
At least once a year, assess urinary albumin (e.g., spot urinary albumin–
to–creatinine ratio) and estimated glomerular filtration rate in patients
with type 1 diabetes with duration of $5 years, in all patients with type
2 diabetes, and in all patients with comorbid hypertension. B
Treatment
Optimize glucose control to reduce the risk or slow the progression of diabetic
kidney disease. A
Optimize blood pressure control to reduce the risk or slow the progression of
diabetic kidney disease. A
For people with nondialysis-dependent diabetic kidney disease, dietary protein intake
should be approximately 0.8 g/kg body weight per day (the recommended daily
allowance). For patients on dialysis, higher levels of dietary protein intake
should be considered. B
In nonpregnant patients with diabetes and hypertension, either an ACE inhibitor
or an angiotensin receptor blocker is recommended for those with modestly Suggested citation: American Diabetes Association.
elevated urinary albumin–to–creatinine ratio (30–299 mg/g creatinine) B and is Microvascular complications and foot care:
Standards of Medical Care in Diabetesd2018.
strongly recommended for those with urinary albumin–to– creatinine ratio $300
Diabetes Care 2018;41(Suppl. 1):S105–S118
mg/g creatinine and/or estimated glomerular filtration
2 © 2017 by the American Diabetes Association.
rate ,60 mL/min/1.73 m . A Readers may use this article as long as the work
Periodically monitor serum creatinine and potassium levels for the is properly cited, the use is educational and not
development of increased creatinine or changes in potassium when for profit, and the work is not altered. More infor-
ACE inhibitors, angiotensin receptor blockers, or diuretics are used. B mation is available at http://www.diabetesjournals
.org/content/license.
S106 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018
collections are more burdensome and add over time as the prevalence of diabetes
Continued monitoring of urinary albumin–
little to prediction or accuracy. Mea-surement in-creases in the U.S. (3,4,11,12).
to–creatinine ratio in pa-tients with
of a spot urine sample for albumin alone An active urinary sediment (containing
albuminuria treated with an ACE
(whether by immunoassay or by using a red or white blood cells or cellular casts),
inhibitor or an angiotensin re-ceptor
sensitive dipstick test specific for albu- rapidly increasing albuminuria or nephrotic
blocker is reasonable to assess the
minuria) without simultaneously measur-ing syndrome, rapidly decreasing eGFR, or the
response to treatment and pro-gression
urine creatinine (Cr) is less expensive but absence of retinopathy (in type 1 diabe-
of diabetic kidney disease. E
susceptible to false-negative and false- tes) may suggest alternative or additional
An ACE inhibitor or an angiotensin positive determinations as a result of varia- causes of kidney disease. For patients with
receptor blocker is not recom- tion in urine concentration due to hydration. these features, referral to a nephrol-ogist
mended for the primary prevention
Normal UACR is generally defined as , for further diagnosis, including the
of diabetic kidney disease in pa-
30 mg/g Cr, and increased urinary albumin possibility of kidney biopsy, should be
tients with diabetes who have nor-
excretion is defined as $30 mg/g Cr. considered. It is rare for patients with type
mal blood pressure, normal urinary
However, UACR is a continuous 1 diabetes to develop kidney disease
albumin–to–creatinine ratio (,30
measurement, and differences within the without retinopathy. In type 2 diabetes,
mg/g creatinine), and normal esti-
normal and abnormal ranges are associ- retinopathy is only moderately sensitive
mated glomerular filtration rate. B
ated with renal and cardiovascular out- and specific for CKD caused by diabetes,
When estimated glomerular filtration
2
comes (7–9). Furthermore, because of as confirmed by kidney biopsy (13).
rate is ,60 mL/min/1.73 m , evalu-ate biological variability in urinary albumin Stage 1–2 CKD has been defined by
and manage potential complica-
excretion, two of three specimens of UACR evidence of kidney damage (usually albu-
tions of chronic kidney disease. E
collected within a 3- to 6-month period minuria) with eGFR $60 mL/min/1.73 m ,
2
Patients should be referred for
should be abnormal before con-sidering a while stages 3–5 CKD have been de-fined
evaluation for renal replacement
patient to have albuminuria. Exercise within by progressively lower ranges of eGFR
treatment if they have an estimated
24 h, infection, fever, congestive heart (14) (Table 10.1). More recently, Kidney
glomerular filtration rate ,30
2 failure, marked hyper-glycemia, Disease: Improving Global Out-comes
mL/min/1.73 m . A menstruation, and marked hypertension (KDIGO) recommended a more
Promptly refer to a physician expe-
may elevate UACR inde-pendently of comprehensive CKD staging that incor-
rienced in the care of kidney
kidney damage. porates albuminuria and is more closely
disease for uncertainty about the
eGFR should be calculated from serum associated with risks of cardiovascular
etiology of kidney disease, difficult
Cr using a validated formula. The Chronic disease (CVD) and CKD progression (2). It
management issues, and rapidly
Kidney Disease Epidemiology Collabora- has not been determined whether ap-
progressing kidney disease. B
tion (CKD-EPI) equation is generally pre- plication of the more complex system aids
ferred (2). eGFR is routinely reported by clinical care or improves health outcomes.
Epidemiology of Diabetic Kidney
Disease laboratories with serum Cr, and eGFR cal-
Chronic kidney disease (CKD) is diagnosed culators are available from http://www Acute Kidney Injury
by the persistent presence of elevated urinary .nkdep.nih.gov. An eGFR ,60 mL/min/ Acute kidney injury (AKI) is usually diag-
2 nosed by a rapid increase in serum Cr,
albumin excretion (albuminuria), low 1.73 m is generally considered
estimated glomerular filtration rate (eGFR), or abnormal, though optimal thresholds for which is also reflected as a rapid decrease
other manifestations of kidney damage (1,2). clinical di-agnosis are debated (10). in eGFR, over a relatively short period of
Diabetic kidney disease, or CKD attributed to Urinary albumin excretion and time. People with diabetes are at higher
diabetes, occurs in 20– 40% of patients with eGFR each vary within people over risk of AKI than those without diabetes
diabetes (1,3–5). Di-abetic kidney disease time, and abnormal results should (15). Other risk factors for AKI include
typically develops after diabetes duration of be confirmed to stage CKD (1,2). preexisting CKD, the use of medications
10 years in type 1 diabetes, but may be that cause kidney injury (e.g., nonsteroi-dal
present at diagnosis of type 2 diabetes.
Diagnosis of Diabetic Kidney Disease anti-inflammatory drugs), and the use of
Diabetic kidney disease is usually a clinical medications that alter renal blood flow and
Diabetic kid-ney disease can progress to end-
diagnosis made based on the presence of intrarenal hemodynamics. In particu-lar,
stage re-nal disease (ESRD) requiring
albuminuria and/or reduced eGFR in the many antihypertensive medications (e.g.,
dialysis or kidney transplantation and is the
absence of signs or symptoms of other diuretics, ACE inhibitors, and angio-tensin
leading cause of ESRD in the United States
primary causes of kidney damage. The typ- receptor blockers [ARBs]) can re-duce
(6). In addition, among people with type 1 or 2
ical presentation of diabetic kidney disease is intravascular volume, renal blood flow,
diabetes, the presence of CKD markedly
considered to include a long-standing duration and/or glomerular filtration. There is a
increases cardiovascular risk (7).
of diabetes, retinopathy, albumin-uria without concern that sodium–glucose cotrans-
hematuria, and gradually pro-gressive kidney porter 2 (SGLT2) inhibitors may promote
Assessment of Albuminuria and disease. However, signs of CKD may be AKI through volume depletion, particu-larly
Estimated Glomerular Filtration Rate present at diagnosis or without retinopathy in when combined with diuretics or other
Screening for albuminuria can be most type 2 diabetes, and reduced eGFR without medications that reduce glomeru-lar
easily performed by urinary albumin–to– albuminuria has been fre-quently reported in
filtration. However, existing evidence
creatinine ratio (UACR) in a random type 1 and type 2 di-abetes and is becoming
more common from clinical trials and observational
spot urine collection (1,2). Timed or 24-h
stud-ies suggests that SGLT2
inhibitors do not
care.diabetesjournals.org Microvascular Complications and Foot Care S107
†CKD stages 1 and 2 are defined by evidence of kidney damage (1), while CKD stages 3–5 are defined by reduced eGFR with or
without evidence of kidney damage (1/2). *Kidney damage is most often manifest as albuminuria (UACR $30 mg/g Cr) but can also
include glomerular hematuria, other abnormalities of the urinary sediment, radiographic abnormalities, and other presentations.
**Risk factors for CKD progression include elevated blood pressure, glycemia, and albuminuria. ***See Table 10.2.
significantly increase AKI (16,17). Timely to therapy and disease progression and Comorbidities” for further
identification and treatment of AKI are may aid in assessing adherence to ACE in- information on immunization).
important because AKI is associated with hibitor or ARB therapy. In addition, in clin- Interventions
increased risks of progressive CKD and ical trials of ACE inhibitors or ARB therapy
Nutrition
other poor health outcomes (18). in type 2 diabetes, reducing albuminuria For people with nondialysis-dependent di-
from levels $300 mg/g Cr has been asso- abetic kidney disease, dietary protein intake
Surveillance ciated with improved renal and cardiovas- should be approximately 0.8 g/kg body weight
Albuminuria and eGFR should be moni- cular outcomes, leading some to suggest per day (the recommended daily al-lowance)
tored regularly to enable timely diagnosis that medications should be titrated to min- (1). Compared with higher levels of dietary
of diabetic kidney disease, monitor pro- imize UACR. However, this approach has protein intake, this level slowed GFR decline
gression of diabetic kidney disease, detect not been formally evaluated in prospec-tive with evidence of a greater ef-fect over time.
superimposed kidney diseases in-cluding trials. In type 1 diabetes, remission of Higher levels of dietary pro-tein intake (.20%
AKI, assess risk of CKD compli-cations, albuminuria may occur spontaneously and of daily calories from protein or .1.3 g/kg/day)
dose drugs appropriately, and determine cohort studies evaluating associa-tions of have been as-sociated with increased
whether nephrology referral is needed.
change in albuminuria with clini-cal albuminuria, more rapid kidney function loss,
Among people with existing kidney
outcomes have reported inconsistent and CVD mor-tality and therefore should be
disease, albuminuria and eGFR may
results (22,23). avoided. Reducing the amount of dietary
change due to progression of dia-betic
The prevalence of CKD complications protein below the recommended daily
kidney disease, development of a separate
correlates with eGFR. When eGFR is allowance of 0.8 g/kg/day is not
superimposed cause of kidney disease, 2
,60 mL/min/1.73 m , screening for com- recommended be-cause it does not alter
AKI, or other effects of medica-tions, as
plications of CKD is indicated (Table 10.2). glycemic measures, cardiovascular risk
noted above. Serum potassium should
Early vaccination against hepatitis B virus measures, or the course of GFR decline. In
also be monitored for patients treated with
is indicated in patients likely to progress to dialysis, protein-energy wasting is common,
ACE inhibitors, ARBs, and di-uretics
ESRD (see Section 3 “Comprehensive and in-creased dietary protein intake may be
because these medications can cause
Medical Evaluation and Assessment of
hyperkalemia or hypokalemia, which are
associated with cardiovascular
risk and mortality (19–21). For patients Table 10.2—Selected complications of CKD
2 Complication Medical and laboratory evaluation
with eGFR ,60 mL/min/1.73 m , appro-
Elevated blood pressure Blood pressure, weight
priate medication dosing should be veri-
Volume overload History, physical examination, weight
fied, exposure to nephrotoxins (e.g.,
nonsteroidal anti-inflammatory drugs Electrolyte abnormalities Serum electrolytes
and iodinated contrast) should be mini- Metabolic acidosis Serum electrolytes
mized, and potential CKD complications Anemia Hemoglobin; iron testing if indicated
should be evaluated. Metabolic bone disease Serum calcium, phosphate, PTH, vitamin 25(OH)D
The need for annual quantitative assess-
Complications of CKD generally become prevalent when eGFR falls below 60 mL/min/1.73 m 2
ment of albumin excretion after diagnosis of
(stage 3 CKD or greater) and become more common and severe as CKD progresses. Evaluation
albuminuria, institution of ACE inhibitors or of elevated blood pressure and volume overload should occur at every possible clinical contact;
ARB therapy, and achieving blood pres-sure laboratory evaluations are generally indicated every 6–12 months for stage 3 CKD, every 3–5
months for stage 4 CKD, and every 1–3 months for stage 5 CKD, or as indicated to evaluate
control is a subject of debate. Contin-ued
symptoms or changes in therapy. PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D.
surveillance can assess both response
S108 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018
necessary to help preserve muscle tubular glucose reabsorption, weight, sys- Disease and Risk Management” for fur-ther
mass and function. temic blood pressure, intraglomerular discussion). All of these trials included large
For some patients with diabetes, restric- pressure, and albuminuria and slow GFR numbers of people with kidney dis-ease (for
tion of dietary sodium may be useful to loss through mechanisms that appear example, the baseline prevalence of
control blood pressure and reduce cardio- independent of glycemia (17,38–40). albuminuria in EMPA-REG OUTCOME was
vascular risk (24), and restriction of dietary Glucagon-like peptide 1 receptor agonists 53%), and some of the cardiovascular
potassium may be necessary to control and dipeptidyl peptidase 4 inhibitors also outcomes trials (CANVAS and LEADER) were
serum potassium concentration (15,19– have direct effects on the kidney and have enriched with patients with kidney disease
21). These interventions may be most im- been reported to improve renal outcomes through eligibility criteria based on
portant for patients with reduced eGFR, for compared with placebo (41–44). albuminuria or reduced eGFR. The glucose-
whom urinary excretion of sodium and A number of large cardiovascular out- lowering effects of SGLT2 inhibitors are
potassium may be impaired. Recommen- comes trials in patients with type 2 diabetes at blunted with eGFR (17,45). However, the
dations for dietary sodium and potassium high risk for cardiovascular disease or with cardiovascular benefits of empagliflozin,
intake should be individualized on the existing cardiovascular disease (EMPA-REG canagliflozin, and liraglutide were similar
basis of comorbid conditions, medication OUTCOME [BI 10773 (Empagliflozin) Car- among participants with and without kid-ney
use, blood pressure, and laboratory data. diovascular Outcome Event Trial in Type 2 disease at baseline (40,41,45,46).
Diabetes Mellitus Patients], CANVAS With reduced eGFR, drug dosing may
Glycemia
[Canagliflozin Cardiovascular Assessment require modification (1). The U.S. Food
Intensive glycemic control with the goal of
Study], LEADER [Liraglutide Effect and Action and Drug Administration (FDA) revised
achieving near-normoglycemia has been
in Diabetes: Evaluation of Cardio-vascular guidance for the use metformin in dia-betic
shown in large prospective randomized
Outcome ResultsdA Long Term Evaluation], kidney disease in 2016 (47), recom-
studies to delay the onset and progression of mending use of eGFR instead of serum Cr
and SUSTAIN-6 [Trial to Eval-uate
albuminuria and reduced eGFR in patients to guide treatment and expanding the pool
Cardiovascular and Other Long-term
with type 1 diabetes (25,26) and type 2 di- of patients with kidney disease for whom
Outcomes With Semaglutide in Subjects With
abetes (1,27–32). Insulin alone was used to metformin treatment should be considered.
Type 2 Diabetes]) examined kidney effects as
lower blood glucose in the Diabetes Control Revised FDA guidance states that
secondary outcomes (40,41,44,45).
and Complications Trial (DCCT)/ Specifically, compared with placebo, metformin is contraindicated in patients
Epidemiology of Diabetes Interventions and 2
empagliflozin reduced the risk of incident or with an eGFR ,30 mL/min/ 1.73 m , eGFR
Complications (EDIC) study of type 1 worsening nephropathy (a composite of should be monitored while taking metfor-
diabetes, while a variety of agents were used progression to UACR .300 mg/g Cr, dou-bling min, the benefits and risks of continuing
in clinical trials of type 2 diabetes, supporting of serum Cr, ESRD, or death from ESRD) by treatment should be reassessed when
the conclusion that glycemic control itself 39% and the risk of doubling of serum Cr eGFR falls ,45 mL/min/1.73 m , metfor-min
2
helps prevent diabetic kidney disease and its 2 should not be initiated for patients with an
accompanied by eGFR #45 mL/ min/1.73 m
progression. The effects of glucose-lowering 2
by 44%; canagliflozin reduced the risk of eGFR ,45 mL/min/1.73 m , and metformin
therapies on diabetic kidney disease have
progression of albuminuria by 27% and the should be temporarily discon-tinued at the
helped define A1C targets (see Table 6.2).
risk of reduction in eGFR, ESRD, or death time of or before iodinated contrast
from ESRD by 40%; liraglu-tide reduced the imaging procedures in patients with eGFR
The presence of diabetic kidney dis-ease 2
risk of new or worsening nephropathy (a 30–60 mL/min/ 1.73 m . Other glucose-
affects the risks and benefits of in-tensive
composite of persistent UACR .300 mg/g Cr, lowering medications also re-quire dose
glycemic control and a number of specific
doubling of serum Cr, ESRD, or death from adjustment or discontinuation at low eGFR
glucose-lowering medications. In the Action to
ESRD) by 22%; and semaglutide reduced the (see Table 8.2) (1).
Control Cardiovascular Risk in Diabetes
risk of new or worsening nephropathy (a
(ACCORD) trial of type 2 di-abetes, adverse
composite of persistent UACR .300 mg/g Cr, Cardiovascular Disease and Blood Pressure
effects of intensive glyce-mic control
doubling of serum Cr, or ESRD) by 36% (each Hypertension is a strong risk factor for the
(hypoglycemia and mortality) were increased
P , 0.01). Additional trials with primary kid-ney development and progression of diabetic
among patients with kidney disease at
outcomes are needed to definitively determine kidney disease (48). Antihypertensive ther-
baseline (33,34). More-over, there is a lag
whether specific glucose-low-ering drugs apy reduces the risk of albuminuria (49–
time of at least 2 years in type 2 diabetes to
improve renal outcomes. 52), and among patients with type 1 or 2
over 10 years in type 1 diabetes for the diabetes with established diabetic kid-ney
effects of intensive glucose control to 2
Patients with diabetic kidney disease are at disease (eGFR ,60 mL/min/1.73 m and
manifest as improved eGFR out-comes
high risk of cardiovascular events, and some UACR $300 mg/g Cr), ACE inhibitor or
(31,35,36). Therefore, in some pa-tients with
SGLT2 inhibitors and glucagon-like peptide 1 ARB therapy reduces the risk of pro-
prevalent diabetic kidney disease and
receptor agonists have demonstrated gression to ESRD (53–55). Moreover, an-
substantial comorbidity, target A1C levels may
cardiovascular benefits. Namely, in EMPA- tihypertensive therapy reduces risks of
be less intensive (1,37).
REG OUTCOME, CANVAS, and LEADER, cardiovascular events (49).
Specific Glucose-Lowering Medications empagliflozin, canagliflozin, and liraglutide, Blood pressure levels ,140/90 mmHg
Some glucose-lowering medications also respectively, each re-duced cardiovascular are generally recommended to reduce
have effects on the kidney that are direct, events, evaluated as primary outcomes, CVD mortality and slow CKD progression
i.e., not mediated through glycemia. For compared with placebo (see Section 9 among people with diabetes (52). Lower
example, SGLT2 inhibitors reduce renal “Cardiovascular blood pressure targets (e.g., ,130/80
care.diabetesjournals.org Microvascular Complications and Foot Care
S109
mmHg) may be considered for patients based are effective for management of resistant
If there is no evidence of retinopathy for
on individual anticipated benefits and risks. hypertension, have been shown to reduce
one or more annual eye exam and
Patients with diabetic kidney dis-ease are at albuminuria in short-term studies of dia-
glycemia is well controlled, then
increased risk of CKD progression betic kidney disease, and may have addi-
exams every 1–2 years may be con-
(particularly those with albuminuria) and CVD tional cardiovascular benefits (65–67).
sidered. If any level of diabetic ret-
and therefore may be suitable in some cases There has been, however, an increase in
inopathy is present, subsequent
for lower blood pressure targets. hyperkalemic episodes in those on dual
dilated retinal examinations should
ACE inhibitors or ARBs are the pre- therapy, and larger, longer trials with clin-
be repeated at least annually by an
ferred first-line agent for blood pressure ical outcomes are needed before recom-
ophthalmologist or optometrist. If
treatment among patients with diabetes, mending such therapy.
retinopathy is progressing or sight-
2
hypertension, eGFR ,60 mL/min/1.73 m , Referral to a Nephrologist threatening, then examinations will
and UACR $300 mg/g Cr because of their Consider referral to a physician expe- be required more frequently. B
proven benefits for prevention of CKD rienced in the care of kidney disease when
While retinal photography may serve
progression (53–56). In general, ACE there is uncertainty about the eti-ology of
as a screening tool for reti-
inhibi-tors and ARBs are considered to kidney disease, difficult man-agement
nopathy, it is not a substitute for a
have similar benefits (57,58) and risks. In issues (anemia, secondary
comprehensive eye exam. E
the setting of lower levels of albuminuria hyperparathyroidism, metabolic bone
Women with preexisting type 1 or
(30–299 mg/g Cr), ACE inhibitor or ARB disease, resistant hypertension, or elec-
type 2 diabetes who are planning
therapy has been demonstrated to reduce trolyte disturbances), or advanced kidney
pregnancy or who are pregnant
progression to more advanced albuminuria disease (eGFR ,30 mL/min/1.73 m ) re-
2
should be counseled on the risk of
($300 mg/g Cr) and cardiovascular events quiring discussion of renal replacement development and/or progression of
but not pro-gression to ESRD (56,59). therapy for ESRD. The threshold for re- diabetic retinopathy. B
While ACE inhib-itors or ARBs are often ferral may vary depending on the fre- Eye examinations should occur be-
prescribed for albuminuria without quency with which a provider encounters
fore pregnancy or in the first
hypertension, clini-cal trials have not been patients with diabetes and kidney dis-ease.
performed in this setting to determine
trimes-ter in patients with
Consultation with a nephrologist when
whether this im-proves renal outcomes. preexisting type 1 or type 2
stage 4 CKD develops (eGFR #30
Absent kidney disease, ACE inhibitors
diabetes, and then patients should
2
mL/min/1.73 m ) has been found to re- be monitored every trimester and
or ARBs are useful to control blood pres-
duce cost, improve quality of care, and for 1 year postpartum as indicated
sure but may not be superior to alterna-tive
delay dialysis (68). However, other spe- by the degree of reti-nopathy. B
proven classes of antihypertensive
cialists and providers should also educate
therapy, including thiazide-like diuretics
their patients about the progressive na-ture Treatment
and dihydropyridine calcium channel
of diabetic kidney disease, the kidney Promptly refer patients with any level
blockers (60). In a trial of people with type preservation benefits of proactive treat-
2 diabetes and normal urine albumin of macular edema, severe
ment of blood pressure and blood glu-cose,
excretion, an ARB reduced or suppressed nonproliferative diabetic retinopa-
and the potential need for renal
the development of albuminuria but in- thy (a precursor of proliferative
replacement therapy.
creased the rate of cardiovascular events diabetic retinopathy), or any prolif-
(61). In a trial of people with type 1 di- erative diabetic retinopathy to an
DIABETIC RETINOPATHY
abetes exhibiting neither albuminuria nor ophthalmologist who is knowledge-
hypertension, ACE inhibitors or ARBs did Recommendations able and experienced in the man-
not prevent the development of diabetic Optimize glycemic control to re-duce agement of diabetic retinopathy. A
glomerulopathy assessed by kidney bi- the risk or slow the progres- The traditional standard treatment,
ARBs are not recommended for patients Optimize blood pressure and therapy, is indicated to reduce the risk
without hypertension to prevent the de- serum lipid control to reduce of vision loss in patients with high-risk
velopment of diabetic kidney disease. the risk or slow the progression proliferative diabetic retinop-athy and,
of diabetic ret-inopathy. A in some cases, severe non-
Two clinical trials studied the
proliferative diabetic retinopathy. A
combina-tions of ACE inhibitors and Screening Intravitreous injections of anti– vascular
ARBs and found no benefits on CVD or Adults with type 1 diabetes should have endothelial growth factor
diabetic kidney dis-ease, and the drug an initial dilated and compre-hensive ranibizumab are not inferior to tradi-
combination had higher adverse event eye examination by an oph- tional panretinal laser photocoagula-
rates (hyperkalemia and/or AKI) (63,64). thalmologist or optometrist within tion and are also indicated to reduce
Therefore, the combined use of ACE 5 years after the onset of diabetes. B the risk of vision loss in patients with
inhibitors and ARBs should be avoided. Patients with type 2 diabetes should
Mineralocorticoid receptor antagonists
proliferative diabetic retinopathy. A
have an initial dilated and compre- Intravitreous injections of anti– vascular
(spironolactone, eplerenone, and finere- hensive eye examination by an oph- endothelial growth factor are
none) in combination with ACE inhibitors or thalmologist or optometrist at the indicated for central-involved di-
ARBs remain an area of great interest. time of the diabetes diagnosis. B abetic macular edema, which occurs
Mineralocorticoid receptor antagonists
S110 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018
in patients treated with panretinal laser at 2 control can effectively prevent DPN and
starting at diagnosis of type 2 di-
years of follow-up (91). In addition, it was cardiac autonomic neuropathy (CAN) in
abetes and 5 years after the di-
observed that patients treated with ranibi- type 1 diabetes (97,98) and may modestly
agnosis of type 1 diabetes and
zumab tended to have less peripheral visual slow their progression in type 2 diabetes
at least annually thereafter. B
field loss, fewer vitrectomy surgeries for sec- (30), but does not reverse neuronal loss.
Assessment for distal symmetric poly-
ondary complications from their prolifera-tive Therapeutic strategies (pharmacologic and
neuropathy should include a careful
disease, and a lower risk of developing nonpharmacologic) for the relief of painful
history and assessment of either tem-
diabetic macular edema. However, a po- DPN and symptoms of autonomic
perature or pinprick sensation (small-
tential drawback in using anti-VEGF ther-apy neuropathy can potentially reduce pain
fiber function) and vibration sensation
to manage proliferative disease is that (99) and improve quality of life.
using a 128-Hz tuning fork (for large-
patients were required to have a greater
fiber function). All patients should have
number of visits and received a greater
annual 10-g monofilament test-ing to Diagnosis
number of treatments than is typically re-
identify feet at risk for ulcera- Diabetic Peripheral Neuropathy
quired for management with panretinal la-ser,
tion and amputation. B Patients with type 1 diabetes for 5 or more
which may not be optimal for some patients.
Symptoms and signs of autonomic years and all patients with type 2 diabetes
Other emerging therapies for ret-inopathy that
neuropathy should be assessed should be assessed annually for DPN
may use sustained intravitreal delivery of
in patients with microvascular using the medical history and simple
pharmacologic agents are cur-rently under
compli-cations. E clinical tests. Symptoms vary according to
investigation. In April, the FDA approved
ranibizumab for the treat-ment of diabetic the class of sensory fibers involved. The
Treatment
retinopathy. most common early symptoms are in-
Optimize glucose control to prevent
While the ETDRS (92) established the duced by the involvement of small fibers
or delay the development of neu-
benefit of focal laser photocoagulation and include pain and dysesthesias (un-
ropathy in patients with type 1
surgery in eyes with clinically significant pleasant sensations of burning and tin-
diabetes A and to slow the pro-
macular edema (defined as retinal edema gling). The involvement of large fibers may
gression of neuropathy in patients
located at or within 500 mm of the center with type 2 diabetes. B cause numbness and loss of protec-tive
of the macula), current data from well- Assess and treat patients to reduce sensation (LOPS). LOPS indicates the
designed clinical trials demonstrate that pain related to diabetic peripheral presence of distal sensorimotor poly-
intravitreal anti-VEGF agents provide a neuropathy B and symptoms of au- neuropathy and is a risk factor for di-abetic
more effective treatment regimen for tonomic neuropathy and to im- foot ulceration. The following clinical tests
central-involved diabetic macular edema prove quality of life. E may be used to assess small-and large-
than monotherapy or even combination Either pregabalin or duloxetine fiber function and protective sensation:
therapy with laser (93–95). There are cur- are recommended as initial
rently three anti-VEGF agents commonly pharmaco-logic treatments for
used to treat eyes with central-involved neuropathic pain in diabetes. A Small-fiber function: pinprick and
diabetic macular edemadbevacizumab, tem-perature sensation
ranibizumab, and aflibercept (69). The diabetic neuropathies are a heteroge- Large-fiber function: vibration percep-
In both DRS and ETDRS, laser photoco- neous group of disorders with diverse clini- tion and 10-g monofilament
agulation surgery was beneficial in re-ducing cal manifestations. The early recognition Protective sensation: 10-g monofilament
the risk of further visual loss in affected and appropriate management of neuropa-
patients, but generally not benefi-cial in thy in the patient with diabetes is important. These tests not only screen for the pres-
reversing already diminished acuity. Anti- ence of dysfunction but also predict
Diabetic neuropathy is a diagnosis of
VEGF therapy improves vision and has future risk of complications. Electrophys-
exclusion. Nondiabetic neuropathies
replaced the need for laser photocoagula-tion iological testing or referral to a neurolo-
may be present in patients with
in the vast majority of patients with diabetic gist is rarely needed, except in situations
diabe-tes and may be treatable.
macular edema (96). Most pa-tients require where the clinical features are atypical
Numerous treatment options exist for
near-monthly administration of intravitreal or the diagnosis is unclear.
symptomatic diabetic neuropathy.
therapy with anti-VEGF agents during the first In all patients with diabetes and DPN,
Up to 50% of diabetic peripheral neu-
12 months of treat-ment, with fewer injections causes of neuropathy other than diabetes
ropathy (DPN) may be asymptomatic. If
needed in sub-sequent years to maintain should be considered, including toxins
not recognized and if preventive foot
remission from central-involved diabetic (alcohol), neurotoxic medications (che-
care is not implemented, patients are at
macular edema. motherapy), vitamin B12 deficiency, hypo-
risk for injuries to their insensate feet.
thyroidism, renal disease, malignancies
Recognition and treatment of autonomic
(multiple myeloma, bronchogenic carci-
NEUROPATHY neuropathy may improve symptoms,
noma), infections (HIV), chronic inflamma-
re-duce sequelae, and improve
Recommendations tory demyelinating neuropathy, inherited
quality of life.
neuropathies, and vasculitis (100). See
Screening Specific treatment for the underlying nerve American Diabetes Association position
All patients should be assessed for damage, other than improved glycemic statement “Diabetic Neuropathy” for more
diabetic peripheral neuropathy control, is currently not available. Glycemic details (99).
S112 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018
Diabetic Autonomic Neuropathy and inadequate lubrication (103). Lower medication side effects is recommended
The symptoms and signs of autonomic urinary tract symptoms manifest as uri-nary to achieve pain reduction and improve
neuropathy should be elicited carefully during incontinence and bladder dysfunction quality of life (113–115).
the history and physical examination. Major (nocturia, frequent urination, urination ur- Pregabalin, a calcium channel a2-d
clinical manifestations of diabetic au-tonomic gency, and weak urinary stream). Evaluation subunit ligand, is the most extensively
neuropathy include hypoglycemia of bladder function should be performed for studied drug for DPN. The majority of
unawareness, resting tachycardia, ortho- individuals with diabetes who have recur-rent studies testing pregabalin have reported
static hypotension, gastroparesis, constipa- urinary tract infections, pyelonephritis, favorable effects on the proportion of
tion, diarrhea, fecal incontinence, erectile incontinence, or a palpable bladder. participants with at least 30–50% im-
dysfunction, neurogenic bladder, and sudo- provement in pain (112,114,116–119).
motor dysfunction with either increased or Treatment However, not all trials with pregabalin
decreased sweating. Glycemic Control have been positive (112,114,120,121),
Cardiac Autonomic Neuropathy. CAN is as- Near-normal glycemic control, imple- es-pecially when treating patients with
sociated with mortality independently of mented early in the course of diabetes, has ad-vanced refractory DPN (118).
other cardiovascular risk factors (101,102). been shown to effectively delay or prevent Adverse effects may be more severe in
In its early stages, CAN may be completely the development of DPN and CAN in older pa-tients (122) and may be
asymptomatic and detected only by de- patients with type 1 diabetes (104–107).
attenuated by lower starting doses and
creased heart rate variability with deep Although the evidence for the benefit of
more gradual titration.
breathing. Advanced disease may be near-normal glycemic con-trol is not as
Duloxetine is a selective norepineph-
associated with resting tachycardia (.100 strong for type 2 diabetes, some studies
rine and serotonin reuptake inhibitor.
bpm) and orthostatic hypotension (a fall in have demonstrated a mod-est slowing of
Doses of 60 and 120 mg/day showed
systolic or diastolic blood pres-sure by .20 progression without re-versal of neuronal
efficacy in the treatment of pain associ-
mmHg or .10 mmHg, re-spectively, upon loss (30,108). Specific glucose-lowering
ated with DPN in multicenter random-
standing without an appropriate increase in strategies may have dif-ferent effects. In a
ized trials, although some of these had
heart rate). CAN treatment is generally post hoc analysis, par-ticipants, particularly
high drop-out rates (112,114,119,121).
focused on allevi-ating symptoms. men, in the Bypass Angioplasty
Duloxetine also appeared to improve
Revascularization Investi-gation in Type 2
neuropathy-related quality of life (123).
Gastrointestinal Neuropathies. Gastrointes- Diabetes (BARI 2D) trial treated with insulin
In longer-term studies, a small increase
tinal neuropathies may involve any por-tion sensitizers had a lower incidence of distal
in A1C was reported in people with dia-
of the gastrointestinal tract with symmetric pol-yneuropathy over 4 years
betes treated with duloxetine compared
manifestations including esophageal than those treated with insulin/sulfonylurea
with placebo (124). Adverse events may
dysmotility, gastroparesis, constipation, (109).
be more severe in older people, but may
diarrhea, and fecal incontinence. Gastro- Neuropathic Pain be attenuated with lower doses and
paresis should be suspected in individuals Neuropathic pain can be severe and can slower titrations of duloxetine.
with erratic glycemic control or with up-per impact quality of life, limit mobility, and Tapentadol is a centrally acting opioid
gastrointestinal symptoms without another contribute to depression and social dys- analgesic that exerts its analgesic effects
identified cause. Exclusion of or-ganic function (110). No compelling evidence through both m-opioid receptor agonism
causes of gastric outlet obstruction or exists in support of glycemic control or and noradrenaline reuptake inhibition.
peptic ulcer disease (with esophago- lifestyle management as therapies for Extended-release tapentadol was ap-
gastroduodenoscopy or a barium study of neuropathic pain in diabetes or proved by the FDA for the treatment of
the stomach) is needed before consider- prediabe-tes, which leaves only neuropathic pain associated with diabe-tes
ing a diagnosis of or specialized testing for pharmaceutical in-terventions (111). based on data from two multicenter clinical
gastroparesis. The diagnostic gold Pregabalin and duloxetine have re- trials in which participants ti-trated to an
standard for gastroparesis is the ceived regulatory approval by the FDA, optimal dose of tapentadol were randomly
measurement of gastric emptying with Health Canada, and the European Medi- assigned to continue that dose or switch to
scintigraphy of di-gestible solids at 15-min cines Agency for the treatment of neu- placebo (125,126). However, both used a
intervals for 4 h after food intake. The use ropathic pain in diabetes. The opioid design enriched for patients who
13
of C octanoic acid breath test is tapentadol has regulatory approval in the responded to tapentadol and therefore
emerging as a viable alternative. U.S. and Canada, but the evidence of its their results are not gener-alizable. A
Genitourinary Disturbances. Diabetic auto- use is weaker (112). Comparative recent systematic review and meta-
nomic neuropathy may also cause genito- effectiveness studies and trials that in- analysis by the Special Interest Group on
urinary disturbances, including sexual clude quality-of-life outcomes are rare, so Neuropathic Pain of the Inter-national
dysfunction and bladder dysfunction. In treatment decisions must consider each Association for the Study of Pain found the
men, diabetic autonomic neuropathy may patient’s presentation and comor-bidities evidence supporting the effec-tiveness of
cause erectile dysfunction and/or and often follow a trial-and-error approach. tapentadol in reducing neu-ropathic pain to
retrograde ejaculation (99). Female sexual Given the range of partially ef-fective be inconclusive (112). Therefore, given the
dysfunction occurs more frequently in treatment options, a tailored and stepwise high risk for addic-tion and safety concerns
those with diabetes and presents as de- pharmacologic strategy with careful compared with the relatively modest pain
creased sexual desire, increased pain dur- attention to relative symptom im- reduction, the use of extended-release
ing intercourse, decreased sexual arousal, provement, medication adherence, and tapentadol is
care.diabetesjournals.org Microvascular Complications and Foot Care
S113
not generally recommended as a intraurethral prostaglandins, vacuum de- Foot ulcers and amputation, which are
first-or second-line therapy. vices, or penile prostheses. As with DPN consequences of diabetic neuropathy
Tricyclic antidepressants, gabapentin, treatments, these interventions do not and/or peripheral arterial disease (PAD),
venlafaxine, carbamazepine, tramadol, change the underlying pathology and nat- are common and represent major causes
and topical capsaicin, although not ap- ural history of the disease process but may of morbidity and mortality in people with
proved for the treatment of painful DPN, improve the patient’s quality of life. diabetes. Early recognition and treatment
may be effective and considered for the of patients with diabetes and feet at risk for
FOOT CARE
treatment of painful DPN (99,112,114). ulcers and amputations can delay or
Orthostatic Hypotension Recommendations prevent adverse outcomes.
Treating orthostatic hypotension is chal- Perform a comprehensive foot The risk of ulcers or amputations
lenging. The therapeutic goal is to mini-mize eval-uation at least annually to is in-creased in people who have
postural symptoms rather than to restore identify risk factors for ulcers the following risk factors:
normotension. Most patients re-quire both and amputa-tions. B
Poor glycemic control
nonpharmacologic measures (e.g., ensuring All patients with diabetes should Peripheral neuropathy with LOPS
adequate salt intake, avoid-ing medications have their feet inspected at Cigarette smoking
every visit. C Foot deformities
that aggravate hypoten-sion, or using
Preulcerative callus or corn
compressive garments over the legs and Obtain a prior history of ulceration, PAD
abdomen) and pharmacologic measures. amputation, Charcot foot, angio- History of foot ulcer
plasty or vascular surgery, cigarette Amputation
Physical activity and exercise should be
Visual impairment
encouraged to avoid decondi-tioning, which is smoking, retinopathy, and renal dis- Diabetic kidney disease (especially
known to exacerbate or-thostatic intolerance, ease and assess current symptoms pa-tients on dialysis)
and volume repletion with fluids and salt is of neuropathy (pain, burning, numb-
critical. Midodrine and droxidopa are ness) and vascular disease (leg fa- Clinicians are encouraged to review
approved by the FDA for the treatment of tigue, claudication). B American Diabetes Association
orthostatic hypotension. The examination should include in- screening recommendations for further
spection of the skin, assessment details and practical descriptions of how
Gastroparesis
of foot deformities, neurological to perform components of the
Treatment for diabetic gastroparesis may
assessment (10-g monofilament comprehensive foot examination (129).
be very challenging. Dietary changes may
testing with at least one other as-
be useful, such as eating multiple small
sessment: pinprick, temperature, Evaluation for Loss of Protective
meals and decreasing dietary fat and fiber
vibration), and vascular Sensation
intake. Withdrawing drugs with adverse
assessment including pulses in the All adults with diabetes should undergo a
effects on gastrointestinal motility includ-
legs and feet. B comprehensive foot evaluation at least
ing opioids, anticholinergics, tricyclic an-
Patients with symptoms of claudi-cation annually. Detailed foot assessments may
tidepressants, glucagon-like peptide 1
or decreased or absent pedal pulses occur more frequently in patients with
receptor agonists, pramlintide, and pos-
should be referred for ankle-brachial histories of ulcers or amputations, foot
sibly dipeptidyl peptidase 4 inhibitors, may
index and for further vas-cular deformities, insensate feet, and PAD (130).
also improve intestinal motility (127, 128).
assessment as appropriate. C Foot inspections should occur at every visit
In cases of severe gastroparesis,
A multidisciplinary approach is rec- in all patients with diabetes. To assess risk,
pharmacologic interventions are needed.
ommended for individuals with foot clinicians should ask about history of foot
Only metoclopramide, a prokinetic agent,
ulcers and high-risk feet (e.g., dialysis ulcers or amputation, neu-ropathic and
is approved by the FDA for the treatment
patients and those with Charcot foot, peripheral vascular symp-toms, impaired
of gastroparesis. However, the level of
prior ulcers, or amputation). B vision, renal disease, tobacco use, and
evidence regarding the benefits of meto-
Refer patients who smoke or who have foot care practices. A general inspection of
clopramide for the management of gas-
histories of prior lower-extremity skin integrity and musculoskeletal
troparesis is weak, and given the risk for
complications, loss of protective sen- deformities should be performed. Vascular
serious adverse effects (extrapyramidal
sation, structural abnormalities, or pe- assessment should include inspection and
signs such as acute dystonic reactions,
ripheral arterial disease to foot care palpation of pedal pulses.
drug-induced parkinsonism, akathisia, and
tardive dyskinesia), its use in the treat- specialists for ongoing preventive
care and life-long surveillance. C The neurological exam performed as
ment of gastroparesis beyond 5 days is no
Provide general preventive foot part of the foot examination is designed to
longer recommended by the FDA or the
self-care education to all patients identify LOPS rather than early neurop-
European Medicines Agency. It should be
with diabetes. B athy. The 10-g monofilament is the most
reserved for severe cases that are unre-
The use of specialized therapeutic useful test to diagnose LOPS. Ideally, the
sponsive to other therapies (128).
footwear is recommended for high- 10-g monofilament test should be per-
Erectile Dysfunction formed with at least one other assess-ment
risk patients with diabetes includ-
In addition to treatment of hypogonad-ism (pinprick, temperature or vibration
ing those with severe neuropathy,
if present, treatments for erectile
foot deformities, or history of am-
dysfunction may include phosphodiester-
putation. B
ase type 5 inhibitors, intracorporeal or
S114 Microvascular Complications and Foot Care Diabetes Care Volume 41, Supplement 1, January 2018
sensation using a 128-Hz tuning fork, or when patients with neuropathy present with healing compared to comprehensive
ankle reflexes). Absent monofilament the acute onset of a red, hot, swollen foot wound care in patients with chronic di-
sensation suggests LOPS, while at least or ankle, and Charcot neuroarthrop-athy abetic foot ulcers (138). A systematic re-
two normal tests (and no abnormal test) should be excluded. Early diagnosis and view by the International Working Group
rules out LOPS. treatment of Charcot neuroarthrop-athy is on the Diabetic Foot of interventions to
the best way to prevent defor-mities that improve the healing of chronic dia-betic
Evaluation for Peripheral Arterial increase the risk of ulceration and foot ulcers concluded that analysis of the
Disease amputation. The routine prescription of evidence continues to present meth-
Initial screening for PAD should include a therapeutic footwear is not generally odological challenges as randomized con-
history of decreased walking speed, leg recommended. However, patients should trolled studies remain few with a majority
fatigue, claudication, and an assessment be provided adequate information to aid in being of poor quality (135). HBOT also
of the pedal pulses. Ankle-brachial index selection of appropriate footwear. Gen-eral does not seem to have a significant effect
testing should be performed in patients footwear recommendations include a broad on health-related quality of life in patients
with symptoms or signs of PAD. and square toe box, laces with three or four with diabetic foot ulcers (139,140). A re-
eyes per side, padded tongue, qual-ity cent review concluded that the evidence to
Patient Education
lightweight materials, and sufficient size to date remains inconclusive regarding the
All patients with diabetes and particularly
accommodate a cushioned insole. Use of clinical and cost-effectiveness of HBOT as
those with high-risk foot conditions (his-
custom therapeutic footwear can help an adjunctive treatment to stan-dard
tory of ulcer or amputation, deformity,
reduce the risk of future foot ulcers in high- wound care for diabetic foot ulcers (141).
LOPS, or PAD) and their families should
risk patients (130,132). Results from the recently published Dutch
be provided general education about risk
Most diabetic foot infections are poly- DAMOCLES (Does Applying More Oxygen
factors and appropriate management
microbial, with aerobic gram-positive cocci. Cure Lower Extremity Sores?) trial
(131). Patients at risk should understand
staphylococci and streptococci are the demonstrated that HBOT in patients with
the implications of foot deformities, LOPS,
most common causative organisms. diabetes and ischemic wounds did not
and PAD; the proper care of the foot, in-
Wounds without evidence of soft tissue or significantly improve complete wound
cluding nail and skin care; and the impor-
bone infection do not require antibiotic healing and limb salvage (142). The
tance of foot monitoring on a daily basis.
therapy. Empiric antibiotic therapy can be Centers for Medicare & Medicaid Ser-vices
Patients with LOPS should be educated on
narrowly targeted at gram-positive cocci in currently covers HBOT for diabetic foot
ways to substitute other sensory modalities
many patients with acute infections, but ulcers that have failed a standard course of
(palpation or visual inspection using an un-
those at risk for infection with antibiotic- wound therapy when there are no
breakable mirror) for surveillance of early
resistant organisms or with chronic, previ- measurable signs of healing for at least 30
foot problems.
ously treated, or severe infections require consecutive days (143). HBOT should be a
The selection of appropriate footwear
broader-spectrum regimens and should be topic of shared decision-making before
and footwear behaviors at home should
referred to specialized care centers (133). treatment is considered for selected
also be discussed. Patients’ understand-
Foot ulcers and wound care may re-quire patients with diabetic foot ulcers (143).
ing of these issues and their physical abil-
care by a podiatrist, orthopedic or vascular
ity to conduct proper foot surveillance and
surgeon, or rehabilitation spe-cialist
care should be assessed. Patients with References
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Kranke P, Bennett MH, Martyn-St James M, controlled clinical trial. Diabetes Care 2016;39: a health technology assessment. Ont Health
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Data-base Syst Rev 2015;6:CD004123 lationship between hyperbaric oxygen therapy et al. Hyperbaric oxygen therapy in the
L ondahl¨ M, K a t zm a n P, N i l s s o n A, and quality of life in participants with chronic treatment of ischemic lower extremity ulcers in
Hammarlund C. Hyperbaric oxygen diabetic foot ulcers: data from a randomized patients with diabetes: results of the DAMO2CLES
therapy facilitates healing of chronic foot controlled trial. Acta Diabetol 2017;54:823– multicenter randomized clinical trial. Diabetes Care.
ulcers in pa-tients with diabetes. Diabetes 26 October 2017 [Epub ahead of print]. DOI:
Care 2010;33: 998–1003 Boulton AJM. The Diabetic Foot [Internet], 2000. https://doi.org/10.2337/dc17-0654
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e - b l in d , r a n d om i ze d therapy for the treatment of diabetic foot ulcers: Undersea Hyperb Med 2015;42:205–247
Diabetes Care Volume 41, Supplement 1, January 2018 S119
Recommendations
Consider the assessment of medical, psychological, functional, and social geriatric
domains in older adults to provide a framework to determine targets and ther-
apeutic approaches for diabetes management. C
Screening for geriatric syndromes may be appropriate in older adults
expe-riencing limitations in their basic and instrumental activities of
daily living as they may affect diabetes self-management and be
related to health-related quality of life. C
NEUROCOGNITIVE FUNCTION Older adults with diabetes should be and, conversely, severe hypoglycemia has
carefully screened and monitored for cog- been linked to increased risk of de-mentia.
Recommendation
nitive impairment (2). Several organiza- Therefore, it is important to rou-tinely
Screening for early detection of
tions have released simple assessment screen older adults for cognitive
mild cognitive impairment or de-
tools, such as the Mini-Mental State Ex- dysfunction and discuss findings with the
mentia and depression is
amination (15) and the Montreal Cogni-tive patients and their caregivers. Hypoglyce-
indicated for adults 65 years of
Assessment (16), which may help to mic events should be diligently monitored
age or older at the initial visit and
identify patients requiring neuropsycho- and avoided, whereas glycemic targets
annually as ap-propriate. B
logical evaluation, particularly those in and pharmacologic interventions may need
whom dementia is suspected (i.e., experi- to be adjusted to accommodate for the
Older adults with diabetes are at higher
encing memory loss and decline in their changing needs of the older adult (2).
risk of cognitive decline and institution-
basic and instrumental activities of daily
alization (6,7). The presentation of cog-
living). Annual screening for cognitive im-
nitive impairment ranges from subtle TREATMENT GOALS
pairment is indicated for adults 65 years of
executive dysfunction to memory loss and
age or older for early detection of mild Recommendations
overt dementia. People with diabetes have
cognitive impairment or dementia Older adults who are otherwise healthy
higher incidences of all-cause de-mentia,
(4). People who screen positive for cogni- with few coexisting chronic illnesses
Alzheimer disease, and vascular dementia
tive impairment should receive diagnostic and intact cognitive func-tion and
than people with normal glu-cose tolerance
assessment as appropriate, including re- functional status should have lower
(8). The effects of hyper-glycemia and
ferral to a behavioral health provider for glycemic goals (A1C ,7.5% [58
hyperinsulinemia on the brain are areas of
formal cognitive/neuropsychological mmol/mol]), while those with multiple
intense research. Clinical trials of specific
evaluation (17). coexisting chronic ill-nesses,
interventionsdincluding cholinesterase
cognitive impairment, or functional
inhibitors and glutamater-gic
dependence should have less
antagonistsdhave not shown positive HYPOGLYCEMIA stringent glycemic goals (A1C
therapeutic benefit in maintaining or sig-
nificantly improving cognitive function or in
Recommendation ,8.0–8.5% [64–69 mmol/mol]). C
Hypoglycemia should be avoided in c Glycemic goals for some older
preventing cognitive decline (9). Pilot
older adults with diabetes. It adults might reasonably be relaxed
studies in patients with mild cognitive im-
should be assessed and managed as part of individualized care, but
pairment evaluating the potential bene-fits
by ad-justing glycemic targets and hyperglycemia leading to symp-
of intranasal insulin therapy and metformin
phar-macologic interventions. B toms or risk of acute hyperglycemic
therapy provide insights for future clinical
complications should be avoided in
trials and mechanistic stud-ies (10–12).
It is important to prevent hypoglycemia to all patients. C
reduce the risk of cognitive decline (18) Screening for diabetes complica-
The presence of cognitive impairment
and other major adverse outcomes. In- tions should be individualized in
can make it challenging for clinicians to older adults. Particular attention
tensive glucose control in the Action to
help their patients to reach individualized should be paid to complications
Control Cardiovascular Risk in Diabetes-
glycemic, blood pressure, and lipid targets. Memory in Diabetes study (ACCORD that would lead to functional im-
Cognitive dysfunction makes it difficult for MIND) was not found to have benefits on pairment. C
patients to perform complex self-care brain structure or cognitive function during Treatment of hypertension to indi-
tasks, such as glucose monitoring and ad- follow-up (14). Of note, in the Diabetes vidualized target levels is indicated
justing insulin doses. It also hinders their Control and Complications Trial (DCCT), in most older adults. C
ability to appropriately maintain the tim-ing no significant long-term declines in cogni- Treatment of other cardiovascular risk
and content of diet. When clinicians are tive function were observed though par- factors should be individualized in
managing patients with cognitive dys- ticipants had relatively high rates of older adults considering the time
function, it is critical to simplify drug reg- recurrent severe hypoglycemia (19). It is frame of benefit. Lipid-lowering
imens and to involve caregivers in all also important to carefully assess and re- therapy and aspirin therapy may
aspects of care. assess patients’ risk for worsening of gly- benefit those with life expectancies
Poor glycemic control is associated with cemic control and functional decline. Older at least equal to the time frame of
a decline in cognitive function (13), and adults are at higher risk of hypogly-cemia primary prevention or secondary in-
longer duration of diabetes is associated for many reasons, including insulin tervention trials. E
with worsening cognitive function. There deficiency necessitating insulin therapy and
are ongoing studies evaluating whether progressive renal insufficiency. In ad-dition, Rationale
preventing or delaying diabetes onset may older adults tend to have higher rates of The care of older adults with diabetes is
help to maintain cognitive function in older unidentified cognitive deficits, causing complicated by their clinical, cognitive, and
adults. However, studies examining the difficulty in complex self-care activities functional heterogeneity. Some older
effects of intensive glycemic and blood (e.g., glucose monitoring, adjusting insulin individuals may have developed diabetes
pres-sure control to achieve specific doses, etc.). These cognitive deficits have years earlier and have significant compli-
targets have not demonstrated a reduction been associated with increased risk of cations, others are newly diagnosed and
in brain func-tion decline (14). hypoglycemia, may have had years of undiagnosed
S121
Self-management
diabetes with resultant complications, and
health
Life
active.
caregivers.
and
self-management
comorbidity
Status
11.1).
their
pressure,bloodglycemia,forgoalstreatmentconsideringforFramework—1.11Table (2)diabeteswithadultsolderindyslipidemiaand
‡goalA1CReasonableRationalestatuscharacteristics/healthPatient LipidspressureBloodglucoseBedtimeglucosepreprandialorFasting
status)functional expectancyandcognitiveintactillnesses, mmol/mol)(585%.7,liferemainingLongerchroniccoexisting(fewHealthy toleratednotormmol/L)3.8–0.(5mmol/L)2.7–0.(5contraindicatedunlessStatinmmHg140/90,mg/dL150–90mg/dL130–90
riskfallvulnerability,impairment)cognitivehypoglycemiamoderate-to-mildorimpairmentsburden,treatmentADLinstrumental12or toleratednotormmol/L)0.10–6.(5mmol/L)3.8–0.(5highexpectancy,lifeillnesses*chroniccoexistingcontraindicatedunlessStatinmmHg140/90,mg/dL180–100mg/dL150–90mmol/mol)
(640%.8,remainingIntermediate(multipleComplex/intermediate
dependencies) primary)ADL12orimpairment thansomorepreventionuncertaintfibenecognitivesevere-to-moderateor(secondarystatinwithmmol/L)1.11–1.(6mmol/L)0.10–6.(5makesexpectancyillnesses**chronicstage-end tfibeneoflikelihoodConsidermmHg150/90,mg/dL200–110mg/dL180–100mmol/mol)
(69†5%.8,liferemainingLimitedor(LTChealthcomplex/poorVery
.hea lingwoundpoorandsyndrome,hyperosmola rhyp erglycem icde hydration ,glyc osu ria,fro mris ksac utet hean dvaluesg luco sehigherfrequentmoretopatients expo semaytheyasreco mme ndednot aremm ol/m ol)(695% .8ab ovet arge tsA1 CLoo ser.m mo l/L)1.(11mg/dL200 ;ofg lucoseaverageestim atedantoequatesmmo l/mo l)(695%.8ofA 1C†. expe ctan cylife redu ceca ntly fisig niandstatu sfun ctio nalof impairmentorsymptoms cant fisig nicau semaycance r,metastaticun cont rolled ordialysis,requirin gdiseasekidneych ronicdisease,lungd ependent-ox ygen orfailureh eart cong estiv e4–3 stag eassuchillnes s,ch ronicstag e-endsingleao fpre senc e**T he.
(47)m oreorve fihav emaypat ie ntsman ybutthree,leastatmeanwe”multip le,“B y.stro keandinfarct ion,m yoca rdia ld ise ase, kidne ychronic worseor3stag einc ontinence,hyperten sion ,falls ,em phys ema,depression,fa ilure ,hea rtconges tivec ance r,arth ritis ,inclu demayandma nagementlif estyle ormedica tions requiretoeno ughseriou scon ditio nsareilln esse schro nic* Coex istin g.bu rden treatmen tund ueorhypoglyce mia seve reorrecurrentw itho utac hiev ableifindiv idua lanforset bemaygoalA1ClowerA‡ .livingda ilyofactiv itiesA DL,. timeoverchan gemayprefere ncesandstatu shealths ’patie ntaA ddit io na lly,.in dividualiz ation trea tmentofaspectimp ortantanis preferen cesc aregiverandp atientofCo nsid erat ion.c ateg oryp articu lara intofa llcle arlyw illpa tient everyNot .con cept sgen eralarecategoriesc hara cteristicpatien tThe .dia bete swith adultsold erind yslip idem iaan dpre ssure,bloodg lycem ia,forgo alstreatmentconsid erin gforf rameworkcon sens usarepre sent sThis
care.diabetesjournals.org
S122 Older Adults Diabetes Care Volume 41, Supplement 1, January 2018
Once-daily basal insulin injection ther- institutional quality assessment. LTC excursions without the practitioner being
apy is associated with minimal side facil-ities should develop their own notified. Providers may make adjustments
ef-fects and may be a reasonable policies and procedures for prevention to treatment regimens by telephone, fax, or
option in many older patients. Multiple and man-agement of hypoglycemia. order directly at the LTC facilities pro-vided
daily injec-tions of insulin may be too they are given timely notification from a
complex for the older patient with Resources
standardized alert system.
advanced diabetes complications, life- Staff of LTC facilities should receive ap- The following alert strategy could
limiting coexisting chronic illnesses, or propriate diabetes education to improve be considered:
limited functional status.
the management of older adults with Call provider immediately: in case of low
Other Factors to Consider diabetes. Treatments for each patient blood glucose levels (#70 mg/dL [3.9
The needs of older adults with diabetes should be individualized. Special man- mmol/L]). Low finger-stick blood
and their caregivers should be evaluated agement considerations include the glucose values should be confirmed
to construct a tailored care plan. Social need to avoid both hypoglycemia and by laboratory glucose measurement.
difficulties may impair their quality of life the metabolic complications of diabe-tes Call as soon as possible: a) glucose values
and increase the risk of functional de- and the need to provide adequate between 70 and 100 mg/dL (be-tween
pendency (38). The patient’s living situa- diabetes training to LTC staff (2,40). For 3.9 and 5.6 mmol/L) (regimen may
tion must be considered, as it may affect more information, see the ADA posi-tion need to be adjusted), b) glu-cose
diabetes management and support. So-cial statement “Management of Diabetes in values greater than 250 mg/dL (13.9
and instrumental support networks (e.g., Long-term Care and Skilled Nursing Fa- mmol/L) within a 24-h period,
adult children, caretakers) that pro-vide cilities” (38). glucose values greater than 300 mg/dL
instrumental or emotional support for older (16.7 mmol/L) over 2 consecu-tive
adults with diabetes should be included in Nutritional Considerations days, d) when any reading is too high
An older adult residing in an LTC facility for the glucometer, or e) the pa-tient is
diabetes management discus-sions and
may have irregular and unpredictable meal sick, with vomiting or other malady that
shared decision-making.
consumption, undernutrition, an-orexia, can reflect hyperglycemic crisis and
Older adults in assisted living facilities
and impaired swallowing. Further-more, may lead to poor oral intake, thus
may not have support to administer their
therapeutic diets may inadvertently lead to requiring regimen adjustment.
own medications, whereas those living in a
decreased food intake and contrib-ute to
nursing home (community living cen-ters)
unintentional weight loss and un- END-OF-LIFE CARE
may rely completely on the care plan and
dernutrition. Diets tailored to a patient’s
nursing support. Those receiving pal-liative
culture, preferences, and personal goals Recommendations
care (with or without hospice) may require
might increase quality of life, satisfaction When palliative care is needed in
an approach that emphasizes comfort and
with meals, and nutrition status (41). older adults with diabetes, strict
symptom management, while
blood pressure control may not be
deemphasizing strict metabolic and blood
Hypoglycemia necessary, and withdrawal of ther-
pressure control. Older adults with diabetes in LTC are es- apy may be appropriate. Similarly,
pecially vulnerable to hypoglycemia. They the intensity of lipid management
TREATMENT IN SKILLED NURSING
have a disproportionately high number of can be relaxed, and withdrawal of
FACILITIES AND NURSING HOMES
clinical complications and comorbidities lipid-lowering therapy may be ap-
Recommendations that can increase hypoglycemia risk: propriate. E
Consider diabetes education for the impaired cognitive and renal function, Overall comfort, prevention of dis-
staff of long-term care facilities to slowed hor-monal regulation and tressing symptoms, and preserva-
improve the management of older counterregulation, suboptimal hydration, tion of quality of life and dignity are
adults with diabetes. E variable appetite and nutritional intake, primary goals for diabetes man-
Patients with diabetes residing in polypharmacy, and slowed intestinal agement at the end of life. E
long-term care facilities need absorption (42). Emerging studies suggest
care-ful assessment to establish that insulin and noninsu-lin agents confer The management of the older adult at the
glycemic goals and to make similar glycemic outcomes and rates of end of life receiving palliative medicine or
appropriate choices of glucose- hypoglycemia in LTC popula-tions (30,43). hospice care is a unique situation. Overall,
lowering agents based on their Another consideration for the LTC set- palliative medicine promotes comfort,
clinical and functional status. E ting is that unlike the hospital setting, med- symptom control and prevention (pain, hy-
ical providers are not required to evaluate poglycemia, hyperglycemia, and dehydra-
Management of diabetes in the long-term the patients daily. According to federal tion), and preservation of dignity and
care (LTC) setting (i.e., nursing homes and guidelines, assessments should be done at quality of life in patients with limited life
skilled nursing facilities) is unique. Individ- least every 30 days for the first 90 days expectancy (40,44). A patient has the right
ualization of health care is important in all after admission and then at least once to refuse testing and treatment, whereas
patients; however, practical guidance is every 60 days. Although in practice the providers may consider withdrawing
needed for medical providers as well as patients may actually be seen more fre- treatment and limiting diagnostic testing,
the LTC staff and caregivers (39). Training quently, the concern is that patients may including a reduction in the frequency of
should include diabetes detection and have uncontrolled glucose levels or wide finger-stick testing (45). Glucose targets
S124 Older Adults Diabetes Care Volume 41, Supplement 1, January 2018
should aim to prevent hypoglycemia and Young-Hyman D, de Groot M, Hill-Briggs F, Type 2 Diabetes Study. Diabetes Care 2014;37:
hyperglycemia. Treatment interventions need Gonzalez JS, Hood K, Peyrot M. Psychosocial 507–515
care for people with diabetes: a position state- The Diabetes Control and Complications Trial/
to be mindful of quality of life. Care-ful
ment of the American Diabetes Association. Di- Epidemiology of Diabetes Interventions (DCCT/
monitoring of oral intake is warranted. The abetes Care 2016;39:2126–2140 EDIC) Study Research Group. Long-term effect of
decision process may need to involve the The National Academy of Sciences. Cognitive diabetes and its treatment on cognitive function. N
patient, family, and caregivers, lead-ing to a aging: progress in understanding and opportuni- Engl J Med 2007;356:1842–1852
care plan that is both convenient and effective ties for action [Internet], 2015. Institute of Med- Selvin E, Coresh J, Brancati FL. The
for the goals of care (46). The pharmacologic
icine. Available from http://nationalacademies burden and treatment of diabetes in elderly
.org/hmd/Reports/2015/Cognitive- individ-uals in the U.S. Diabetes Care
therapy may include oral agents as first line, Aging.aspx. Accessed 3 October 2016 2006;29:2415– 2419
followed by a sim-plified insulin regimen. If Kimbro LB, Mangione CM, Steers WN, et al. Bandeen-Roche K, Seplaki CL, Huang J, et al.
needed, basal in-sulin can be implemented, Depression and all-cause mortality in persons Frailty in older adults: a nationally representative
accompanied by oral agents and without with diabetes mellitus: are older adults at profile in the United States. J Gerontol A Biol Sci
higher risk? Results from the Translating Med Sci 2015;70:1427–1434
rapid-acting insu-lin. Agents that can cause
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gastrointestinal symptoms such as nausea or Geriatr Soc 2014; 62:1017–1022 mia and incidence of frailty and lower extremity
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S126 Diabetes Care Volume 41, Supplement 1, January 2018
TYPE 1 DIABETES
Three-quarters of all cases of type 1 diabetes are diagnosed in individuals ,18 years of
age (although recent data using genetic risk scoring would suggest that over 40% of
patients with autoimmune diabetes are diagnosed over the age of 30 years) (1). The
provider must consider the unique aspects of care and management of children and
adolescents with type 1 diabetes, such as changes in insulin sensitivity related to physical
growth and sexual maturation, ability to provide self-care, supervision in the child care and
school environment, and neurological vulnerability to hypoglycemia and hyperglycemia in
young children, as well as possible adverse neurocognitive effects of diabetic ketoacidosis
(DKA) (2,3). Attention to family dynamics, developmental stages, and physiological
differences related to sexual maturity are all essential in developing and implementing an
optimal diabetes treatment plan (4). Due to the nature of clinical research in children, the
recommendations for children and adolescents are less likely to be based on clinical trial
evidence. However, expert opinion and a review of available and relevant experimental
data are summarized in the American Diabetes Association (ADA) position statement
“Type 1 Diabetes Through the Life Span” (5) and have been updated in the ADA position
statement “Type 1 Diabetes in Children and Adolescents: A Position Statement by the
American Diabetes Association” (6).
A multidisciplinary team of specialists trained in pediatric diabetes management and
Suggested citation: American Diabetes
sensitive to the challenges of children and adolescents with type 1 diabetes and their Associa-tion. 12. Children and adolescents:
families should provide care for this population. It is essential that diabetes self- Standards of Medical Care in Diabetesd2018.
management education and support (DSMES), medical nutrition therapy, and psycho- Diabetes Care 2018;41(Suppl. 1):S126–S136
social support be provided at diagnosis and regularly thereafter in a developmentally © 2017 by the American Diabetes Association.
appropriate format that builds on prior knowledge by individuals experienced with the Readers may use this article as long as the work
is properly cited, the use is educational and not
educational, nutritional, behavioral, and emotional needs of the growing child and family. for profit, and the work is not altered. More infor-
The appropriate balance between adult supervision and independent self-care should be mation is available at http://www.diabetesjournals
defined at the first interaction and reevaluated at subsequent visits. .org/content/license.
care.diabetesjournals.org Children and Adolescents S127
of mental health problems related to di- that near normalization of blood glucose
improve glycemic control. Benefits
abetes distress, fear of hypoglycemia (and levels was more difficult to achieve in ad-
of continuous glucose monitoring
hyperglycemia), symptoms of anxiety, dis- olescents than in adults. Nevertheless, the
correlate with adherence to ongo-
ordered eating behaviors as well as eating increased use of basal-bolus regimens,
ing use of the device. B
disorders, and symptoms of depression insulin pumps, frequent blood glucose
Automated insulin delivery systems
(25). Consider assessing youth for diabe- monitoring, goal setting, and improved pa-
improve glycemic control and re-
tes distress, generally starting at 7 or 8 tient education in youth from infancy
duce hypoglycemia in adolescents
years of age (15). Consider screening for through adolescence have been associa-
and should be considered in adoles-
depression and disordered eating be- ted with more children reaching the blood
cents with type 1 diabetes. B
haviors using available screening tools glucose targets recommended by ADA
(10,26). With respect to disordered eat-ing, An A1C goal of,7.5% (58 mmol/mol) (42–45), particularly in those families in
it is important to recognize the unique and
is recommended across all which both the parents and the child with
dangerous disordered eating behavior of
pediatric age-groups. E diabetes participate jointly to perform the
insulin omission for weight control in type 1 required diabetes-related tasks. Further-
Current standards for diabetes man-
diabetes (27). The pres-ence of a mental more, studies documenting neurocognitive
agement reflect the need to lower glu-
health professional on pediatric imaging differences related to hyperglyce-
multidisciplinary teams high-lights the
cose as safely as possible. This should mia in children provide another motivation
importance of attending to the
be done with stepwise goals. When for lowering glycemic targets (2).
psychosocial issues of diabetes. These
estab-lishing individualized glycemic
In selecting glycemic goals, the long-
psychosocial factors are signifi-cantly
targets, special consideration should be
term health benefits of achieving a lower
related to nonadherence, suboptimal given to the risk of hypoglycemia in
A1C should be balanced against the risks
glycemic control, reduced quality of life, young children (aged ,6 years) who are
of hypoglycemia and the developmental
and higher rates of acute and chronic di- often unable to recognize, articulate,
burdens of intensive regimens in children
abetes complications. and/or manage hypoglycemia.
and youth. In addition, achieving lower
Type 1 diabetes can be associated with
A1C levels is more likely to be related to
Glycemic Control adverse effects on cognition during child-
setting lower A1C targets (46,47). A1C and
hood and adolescence. Factors that
Recommendations blood glucose goals are presented in Table
contribute to adverse effects on brain
The majority of children and adoles- 12.1.
development and function include young
cents with type 1 diabetes should be
age or DKA at onset of type 1 diabetes,
treated with intensive insulin Autoimmune Conditions
severe hypoglycemia at ,6 years of age,
regimens, either via multiple daily
and chronic hyperglycemia (28,29). How- Recommendation
injections or continuous subcutane-
ever, meticulous use of new therapeutic Assess for the presence of autoim-
ous insulin infusion. A
modalities, such as rapid- and long-acting mune conditions associated with
All children and adolescents with
insulin analogs, technological advances type 1 diabetes soon after the di-
type 1 diabetes should self-monitor
(e.g., continuous glucose monitors, low- agnosis and if symptoms develop. B
blood glucose levels multiple times
glucose suspend insulin pumps, and au-
daily, including premeal, prebed-
tomated insulin delivery systems), and Because of the increased frequency of
time, and as needed for safety in
intensive self-management education now other autoimmune diseases in type 1 di-
specific clinical situations such as
make it more feasible to achieve ex-cellent abetes, screening for thyroid dysfunction
exercise, driving, or for symptoms
glycemic control while reducing the and celiac disease should be considered
of hypoglycemia. B
incidence of severe hypoglycemia (30–39). (48,49). Periodic screening in asymptom-
c Continuous glucose monitoring
A strong relationship exists be-tween atic individuals has been recommended,
should be considered in children and
frequency of blood glucose moni-toring and but the optimal frequency and benefit of
adolescents with type 1 diabe-tes,
glycemic control (32–41). screening are unclear.
whether using injections or
continuous subcutaneous insulin in- The Diabetes Control and Complica- Although much less common than thy-
fusion, as an additional tool to help tions Trial (DCCT), which did not enroll roid dysfunction and celiac disease, other
children ,13 years of age, demonstrated autoimmune conditions, such as Addison
Table 12.1—Blood glucose and A1C goals for children and adolescents with type 1 diabetes
Blood glucose goal range
Before meals Bedtime/overnight A1C Rationale
90–130 mg/dL 90–150 mg/dL ,7.5% A lower goal (,7.0% [53 mmol/mol]) is reasonable if it can be
(5.0–7.2 mmol/L) (5.0–8.3 mmol/L) (58 mmol/mol) achieved without excessive hypoglycemia
Key concepts in setting glycemic goals:
c Goals should be individualized, and lower goals may be reasonable based on a benefit-risk assessment.
c Blood glucose goals should be modified in children with frequent hypoglycemia or hypoglycemia unawareness.
c Postprandial blood glucose values should be measured when there is a discrepancy between preprandial blood glucose values and A1C
levels and to assess preprandial insulin doses in those on basal-bolus or pump regimens.
care.diabetesjournals.org Children and Adolescents S129
disease (primary adrenal insufficiency), au- Celiac Disease provided that further testing is performed
toimmune hepatitis, autoimmune gastritis, (verification of endomysial antibody pos-
Recommendations
dermatomyositis, and myasthenia gravis, itivity on a separate blood sample). It is
Screen individuals with type 1 dia-
occur more commonly in the population with also advisable to check for HLA types in
betes for celiac disease soon after
type 1 diabetes than in the general pediatric patients who are diagnosed without a
the diagnosis of diabetes by mea-
population and should be assessed and small intestinal biopsy. Asymptomatic at-
suring IgA tissue transglutaminase
monitored as clinically indicated. risk children should have an intestinal
antibodies, with documentation of
biopsy (61).
normal total serum IgA levels or, if
Thyroid Disease In symptomatic children with type 1 di-
IgA deficient, IgG tissue transglut-
abetes and confirmed celiac disease, gluten-
Recommendations amine and deamidated gliadin
free diets reduce symptoms and rates of
Consider testing individuals with type anti-bodies. B
hypoglycemia (62). The challenging die-tary
1 diabetes for antithyroid per- Repeat screening within 2 years of
restrictions associated with having both type
oxidase and antithyroglobulin an- diabetes diagnosis and then again
1 diabetes and celiac disease place a
tibodies soon after the diagnosis. after 5 years and consider more fre-
significant burden on individuals. Therefore, a
E quent screening in children who
biopsy to confirm the diag-nosis of celiac
Measure thyroid-stimulating hor- have symptoms or a first-degree
disease is recommended, especially in
mone concentrations at diagnosis relative with celiac disease. B asymptomatic children, be-fore endorsing
when clinically stable or soon after Individuals with biopsy-confirmed significant dietary changes. A gluten-free diet
glycemic control has been estab- celiac disease should be placed on was beneficial in asymp-tomatic adults with
lished. If normal, consider a gluten-free diet and have a positive antibodies confirmed by biopsy (63).
recheck-ing every 1–2 years or consultation with a dietitian experi-
sooner if the patient develops enced in managing both diabetes
and celiac disease. B Management of Cardiovascular
symptoms sugges-tive of thyroid
Risk Factors
dysfunction, thyro-megaly, an
Hypertension
abnormal growth rate, or an Celiac disease is an immune-mediated
unexplained glycemic varia-tion. A dis-order that occurs with increased fre- Recommendations
quency in patients with type 1 diabetes Screening
(1.6–16.4% of individuals compared with Blood pressure should be measured at
Autoimmune thyroid disease is the most
0.3–1% in the general population) each routine visit. Children found to
common autoimmune disorder associated
(48,49, 56–58,59). have high-normal blood pressure
with diabetes, occurring in 17–30% of
Screening. Screening for celiac disease in- (systolic blood pressure or diastolic
patients with type 1 diabetes (50). At the
cludes measuring serum levels of IgA and blood pressure $90th percentile for
time of diagnosis, about 25% of children
tissue transglutaminase antibodies, or, with age, sex, and height) or hy-
with type 1 diabetes have thy-roid IgA deficiency, screening can include
autoantibodies (51); their presence is pertension (systolic blood pressure
measuring IgG tissue transglutaminase an- or diastolic blood pressure $95th
predictive of thyroid dysfunctiond most tibodies or IgG deamidated gliadin peptide percentile for age, sex, and height)
commonly hypothyroidism, al-though antibodies. Because most cases of celiac should have elevated blood pressure
hyperthyroidism occurs in ;0.5% of patients disease are diagnosed within the first 5 confirmed on 3 separate days. B
with type 1 diabetes (52, 53). For thyroid years after the diagnosis of type 1 diabe-
autoantibodies, a recent study from tes, screening should be considered at the
Sweden indicated antithyroid peroxidase time of diagnosis and repeated at 2 and Treatment
antibodies were more predic-tive than then 5 years (58). Initial treatment of high-normal blood
antithyroglobulin antibodies in multivariate Although celiac disease can be diag- pressure (systolic blood pres-sure or
analysis (54). Thyroid func-tion tests may nosed more than 10 years after diabetes diastolic blood pressure consistently
be misleading (euthyroid sick syndrome) if diagnosis, there are insufficient data after 5 $90th percentile for age, sex, and
performed at the time of diagnosis owing years to determine the optimal screen-ing height) includes die-tary modification
to the effect of previous hyperglycemia, frequency. Measurement of tissue and increased exercise, if
ketosis or ketoacidosis, weight loss, etc. transglutaminase antibody should be con- appropriate, aimed at weight control.
Therefore, if performed at diagnosis and sidered at other times in patients with If target blood pres-sure is not
slightly abnormal, thy-roid function tests symptoms suggestive of celiac disease reached within 3–6 months of
should be performed soon after a period of (58). A small-bowel biopsy in antibody- initiating lifestyle inter-vention,
metabolic stability and good glycemic positive children is recommended to pharmacologic treatment
control. Subclinical hypothyroidism may be confirm the diagnosis (60). European should be considered. E
associated with increased risk of guidelines on screening for celiac disease In addition to lifestyle modification,
symptomatic hypoglyce-mia (55) and in chil-dren (not specific to children with pharmacologic treatment of hyper-
reduced linear growth rate. type 1 diabetes) suggest that biopsy may tension (systolic blood pressure or
Hyperthyroidism alters glucose metabo- not be necessary in symptomatic children diastolic blood pressure consistently
lism and usually causes deterioration of with high antibody titers (i.e., greater than $95th percentile for age, sex, and
glycemic control. 10 times the upper limit of normal) height) should be considered as
S130 Children and Adolescents Diabetes Care Volume 41, Supplement 1, January 2018
to test for prediabetes or diabetes Given the necessity of long-term weight All youth with type 2 diabetes and their
in children and adolescents. B management for children and families should receive compre-
adolescents with type 2 diabetes, hensive diabetes self-management
In the last decade, the incidence and prev- lifestyle intervention should be based education and support that is specific
alence of type 2 diabetes in adolescents on a chronic care model and offered to youth with type 2 diabetes and
has increased dramatically, especially in in the context of diabetes care. E culturally competent. B
ra-cial and ethnic minority populations (97). Youth with diabetes, like all chil-dren,
A few recent studies suggest oral glucose should be encouraged to The general treatment goals for youth with
tolerance tests or fasting plasma glucose participate in at least 60 min of type 2 diabetes are the same as those for
values as more suitable diagnostic tests moderate to vigorous physical ac- youth with type 1 diabetes. A
than A1C in the pediatric population, es- tivity per day (and strength training multidisciplinary diabetes team, including a
pecially among certain ethnicities (98). on at least 3 days/week) B and to physician, diabetes nurse educator, reg-
However, many of these studies do not decrease sedentary behavior. C istered dietitian, and psychologist or social
recognize that diabetes diagnostic criteria Nutrition for youth with type 2 di-abetes, worker, is essential. In addition to blood
are based on long-term health outcomes, like all children, should fo-cus on glucose control, initial treatment must in-
and validations are not currently available healthy eating patterns that clude management of comorbidities such
in the pediatric population (99). ADA ac- emphasize consumption of nutrient- as obesity, dyslipidemia, hypertension, and
knowledges the limited data supporting dense, high-quality foods and microvascular complications.
A1C for diagnosing type 2 diabetes in chil- decreased consumption of calorie- Current treatment options for youth-
dren and adolescents. Although A1C is not dense, nutrient-poor foods, partic- onset type 2 diabetes are limited to two
recommended for diagnosis of diabe-tes in ularly sugar-added beverages. B approved drugsdinsulin and metformin
children with cystic fibrosis or symp-toms (95). Presentation with ketosis or ke-
suggestive of acute onset of type 1 Pharmacologic Management toacidosis requires a period of insulin
diabetes and only A1C assays without in- Initiate pharmacologic therapy, in therapy until fasting and postprandial gly-
terference are appropriate for children with addition to lifestyle therapy, at di- cemia have been restored to normal or
hemoglobinopathies, ADA continues to agnosis of type 2 diabetes. A near-normal levels. Metformin therapy may
recommend A1C for diagnosis of type 2 In metabolically stable patients be used as an adjunct after resolu-tion of
diabetes in this population (100,101). (A1C ,8.5% and asymptomatic), ketosis/ketoacidosis. Initial treat-ment
metformin is the initial pharmaco- should also be with insulin when the
Diagnostic Challenges logic treatment of choice if renal distinction between type 1 diabetes and
Given the current obesity epidemic, distin- 2
function is .30 ml/min/1.73 m . A type 2 diabetes is unclear and in patients
guishing between type 1 and type 2 diabe- Youth with marked hyperglycemia who have random blood glucose concen-
tes in children can be difficult. Overweight (blood glucose $250 mg/dL [13.9 trations 250 mg/dL (13.9 mmol/L) and/or
and obesity are common in children with mmol/L], A1C$8.5% [69 mmol/mol]) A1C $8.5% (69 mmol/mol) (105).
type 1 diabetes (102), and diabetes- without ketoacidosis at diagnosis Patients and their families must priori-
associated autoantibodies and ketosis may who are symptomatic with poly-uria, tize lifestyle modifications such as eating a
be present in pediatric patients with polydipsia, nocturia, and/or weight balanced diet, achieving and maintaining a
features of type 2 diabetes (including loss should be treated ini-tially with healthy weight, and exercising regularly. A
obesity and acanthosis nigricans) (103). At basal insulin while met-formin is family-centered approach to nutrition and
onset, DKA occurs in ;6% of youth aged initiated and titrated to maximally lifestyle modification is essential in children
10–19 years with type 2 diabetes (104). tolerated dose to achieve with type 2 diabetes, and nutrition recom-
Accurate diagnosis is critical, as treatment A1C goal. E mendations should be culturally appropri-
regimens, educational approaches, die- When the A1C target is no longer met ate and sensitive to family resources (see
tary advice, and outcomes differ markedly with metformin monotherapy, or if Section 4 “Lifestyle Management”). Given
between patients with the two diagnoses. contraindications or intolerable side the complex social and environmental
effects of metformin develop, basal context surrounding youth with type 2 di-
insulin therapy should be initiated. E abetes, individual-level lifestyle interven-
Management In patients initially treated with basal tions may not be sufficient to target the
Recommendations insulin and metformin who are complex interplay of family dynamics,
meeting glucose targets based on mental health, community readiness, and
Lifestyle Management home blood glucose monitoring, the broader environmental system (95).
Overweight or obese youth with type basal insulin can be tapered over 2–
When insulin treatment is not required,
2 diabetes and their families 6 weeks by decreasing the insulin
initiation of metformin is recommended.
should be provided with develop- dose by 10–30% every few days. A
The Treatment Options for Type 2 Diabe-
mentally and culturally appropriate Use of medications not approved by tes in Adolescents and Youth (TODAY)
comprehensive lifestyle programs the U.S. Food and Drug study found that metformin alone pro-vided
that are integrated with diabetes Administra-tion for youth with type durable glycemic control (A1C #8% [64
management to achieve 7–10% 2 diabetes is not recommended
mmol/mol] for 6 months) in approxi-mately
de-crease in excess weight. C outside of re-search trials. B
half of the subjects (106). To date,
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Diabetes Care Volume 41, Supplement 1, January 2018 S137
DIABETES IN PREGNANCY
The prevalence of diabetes in pregnancy has been increasing in the U.S. The
majority is gestational diabetes mellitus (GDM) with the remainder primarily
preexisting type 1 diabetes and type 2 diabetes. The rise in GDM and type 2
diabetes in parallel with obesity both in the U.S. and worldwide is of particular
concern. Both type 1 diabetes and type 2 diabetes in pregnancy confer significantly
greater maternal and fetal risk than GDM, with some differences according to type of
diabetes as outlined below. In general, specific risks of uncontrolled diabetes in
pregnancy include spontaneous abortion, fetal anomalies, preeclampsia, fetal
demise, macrosomia, neonatal hy-poglycemia, and neonatal hyperbilirubinemia,
among others. In addition, diabetes in pregnancy may increase the risk of obesity
and type 2 diabetes in offspring later in life (1,2).
PRECONCEPTION COUNSELING
Recommendations
Starting at puberty, preconception counseling should be incorporated
into rou-tine diabetes care for all girls of childbearing potential. A
Family planning should be discussed and effective contraception should be
prescribed and used until a woman is prepared and ready to become Suggested citation: American Diabetes Associa-
pregnant. A tion. 13. Management of diabetes in pregnancy:
Preconception counseling should address the importance of glycemic Standards of Medical Care in Diabetesd2018.
control as close to normal as is safely possible, ideally A1C ,6.5% (48 Diabetes Care 2018;41(Suppl. 1):S137–S143
mmol/mol), to reduce the risk of congenital anomalies. B © 2017 by the American Diabetes Association.
Readers may use this article as long as the work
is properly cited, the use is educational and not
All women of childbearing age with diabetes should be counseled about the impor-
for profit, and the work is not altered. More infor-
tance of tight glycemic control prior to conception. Observational studies show an mation is available at http://www.diabetesjournals
increased risk of diabetic embryopathy, especially anencephaly, microcephaly, .org/content/license.
S138 Management of Diabetes in Pregnancy Diabetes Care Volume 41, Supplement 1, January 2018
congenital heart disease, and caudal re- Preconception counseling visits should in- with insulin dosage and to avoid
gression, directly proportional to eleva- clude rubella, syphilis, hepatitis B virus, hyper-glycemia or hypoglycemia.
tions in A1C during the first 10 weeks of and HIV testing, as well as Pap smear, Referral to a registered dietitian is
pregnancy. Although observational stud-ies cervical cultures, blood typing, prescrip-tion important in order to establish a food
are confounded by the association be- of prenatal vitamins (with at least 400 mg plan and insulin-to-carbohydrate ratio
tween elevated periconceptional A1C and of folic acid), and smoking cessa-tion and to determine weight gain goals.
other poor self-care behaviors, the quan- counseling if indicated. Diabetes-specific
tity and consistency of data are convinc- testing should include A1C, thyroid-
Insulin Physiology
ing and support the recommendation to stimulating hormone, creatinine, and Early pregnancy is a time of insulin sensi-
optimize glycemic control prior to con- urinary albumin–to–creatinine ratio; review tivity, lower glucose levels, and lower in-
ception, with A1C ,6.5% (48 mmol/mol) of the medication list for potentially sulin requirements in women with type 1
associated with the lowest risk of congen- teratogenic drugs, i.e., ACE inhibitors (8), diabetes. The situation rapidly reverses as
ital anomalies (3,4). angiotensin receptor blockers (8), and insulin resistance increases exponentially
There are opportunities to educate all statins (9,10); and referral for a compre- during the second and early third trimes-
women and adolescents of reproductive hensive eye exam. Women with preexist- ters and levels off toward the end of the
age with diabetes about the risks of ing diabetic retinopathy will need close third trimester. In women with normal
unplanned pregnancies and improved monitoring during pregnancy to ensure that pancreatic function, insulin production is
maternal and fetal outcomes with preg- retinopathy does not progress. sufficient to meet the challenge of this
nancy planning (5). Effective preconcep- physiological insulin resistance and to
tion counseling could avert substantial maintain normal glucose levels. However,
GLYCEMIC TARGETS
health and associated cost burdens in in women with GDM or preexisting dia-
IN PREGNANCY
offspring (6). Family planning should be betes, hyperglycemia occurs if treatment is
discussed, and effective contraception Recommendations not adjusted appropriately.
should be prescribed and used until a Fasting and postprandial self-monitoring of
woman is prepared and ready to blood glucose are recom-mended in Glucose Monitoring
become pregnant. both gestational diabetes mellitus and Reflecting this physiology, fasting and
To minimize the occurrence of compli- preexisting diabetes in pregnancy to postprandial monitoring of blood glucose is
cations, beginning at the onset of puberty achieve glycemic con-trol. Some recommended to achieve metabolic con-trol
or at diagnosis, all women with diabetes of women with preexisting diabetes in pregnant women with diabetes. Pre-
childbearing potential should receive should also test blood glu- prandial testing is also recommended for
education about 1) the risks of malforma- cose preprandially. B women with preexisting diabetes using in-
tions associated with unplanned pregnan- Due to increased red blood cell turn- sulin pumps or basal-bolus therapy, so that
cies and poor metabolic control and 2) the over, A1C is slightly lower in normal premeal rapid-acting insulin dosage can be
use of effective contraception at all times pregnancy than in normal nonpreg- adjusted. Postprandial monitoring is associ-
when preventing a pregnancy. nant women. The A1C target in preg- ated with better glycemic control and lower
Preconception counseling using develop- nancy is 6–6.5% (42–48 risk of preeclampsia (11–13). There are no
mentally appropriate educational tools mmol/mol); ,6% (42 mmol/mol) may adequately powered randomized trials
enables adolescent girls to make well- be opti-mal if this can be achieved comparing different fasting and postmeal
informed decisions (5). Preconception without significant hypoglycemia, but glycemic targets in diabetes in pregnancy.
counseling resources tailored for adoles- the target may be relaxed to ,7% (53 Similar to the targets recommended by
cents are available at no cost through the mmol/mol) if necessary to pre-vent the American College of Obstetri-cians and
American Diabetes Association (ADA) (7). hypoglycemia. B Gynecologists (14), the ADA-
recommended targets for women with type
Preconception Testing Pregnancy in women with normal glucose 1 or type 2 diabetes (the same as for
metabolism is characterized by fasting GDM; described below) are as follows:
Recommendation
levels of blood glucose that are lower than
Women with preexisting type 1 or type
in the nonpregnant state due to insulin- Fasting ,95 mg/dL (5.3 mmol/L) and
2 diabetes who are planning
independent glucose uptake by the fetus either
pregnancy or who have become
pregnant should be counseled on the
and placenta and by postpran-dial One-hour postprandial ,140 mg/dL
hyperglycemia and carbohydrate in- (7.8 mmol/L) or
risk of development and/or
progression of diabetic retinopathy.
tolerance as a result of diabetogenic Two-hour postprandial ,120 mg/dL
placental hormones. In patients with pre- (6.7 mmol/L)
Dilated eye examinations should oc-
existing diabetes, glycemic targets are
cur before pregnancy or in the first
usually achieved through a combination of These values represent optimal control if
trimester, and then patients should
insulin administration and medical nu-trition they can be achieved safely. In practice, it
be monitored every trimester and for
therapy. Because glycemic targets in may be challenging for women with type 1
1-year postpartum as indicated by
pregnancy are stricter than in nonpreg-nant diabetes to achieve these targets without
the degree of retinopathy and as
individuals, it is important that women with hypoglycemia, particularly women with a
recommended by the eye care
diabetes eat consistent amounts of history of recurrent hypoglycemia or hypo-
provider. B
carbohydrates to match glycemia unawareness.
care.diabetesjournals.org Management of Diabetes in Pregnancy
S139
If women cannot achieve these targets plasma glucose ,95 mg/dL [5.3 mmol/L])
used, but both cross the placenta
without significant hypoglycemia, the ADA who meet glucose goals after a week of
to the fetus, with metformin likely
suggests less stringent targets based on clin- medical nutrition therapy can safely per-
cross-ing to a greater extent than
ical experience and individualization of care. form self-monitoring of blood glucose
glyburide. All oral agents lack long-
every other day, rather than daily (26).
A1C in Pregnancy term safety data. A
Observational studies show the lowest Metformin, when used to treat Medical Nutrition Therapy
rates of adverse fetal outcomes in polycystic ovary syndrome and Medical nutrition therapy for GDM is an
association with A1C ,6–6.5% (42–48 in-duce ovulation, need not be individualized nutrition plan developed
mmol/mol) early in gestation (4,15–17). con-tinued once pregnancy between the woman and a registered di-
Clinical trials have not evaluated the risks has been confirmed. A etitian familiar with the management of
and benefits of achieving these targets, GDM (27,28). The food plan should pro-
and treatment goals should account for the GDM is characterized by increased risk of vide adequate calorie intake to promote
risk of ma-ternal hypoglycemia in setting macrosomia and birth complications and fetal/neonatal and maternal health, achieve
an individ-ualized target of ,6% (42 an increased risk of maternal type 2 diabe- glycemic goals, and promote ap-propriate
mmol/mol) to ,7% (53 mmol/mol). Due to tes after pregnancy. The association of gestational weight gain. There is no
physio-logical increases in red blood cell macrosomia and birth complications with definitive research that identifies a specific
turn-over, A1C levels fall during normal oral glucose tolerance test (OGTT) results optimal calorie intake for women with GDM
pregnancy (18,19). Additionally, as A1C is continuous with no clear inflection points or suggests that their calorie needs are
represents an integrated measure of glu- (20). In other words, risks increase with different from those of pregnant women
cose, it may not fully capture postprandial progressive hyperglycemia. Therefore, all without GDM. The food plan should be
hyperglycemia, which drives macrosomia. women should be tested as outlined in based on a nutrition assessment with
Thus, although A1C may be useful, it Section 2 “Classification and Diagnosis of guidance from the Dietary Reference
should be used as a secondary measure Diabetes.” Although there is some het- Intakes (DRI). The DRI for all pregnant
of glycemic control in pregnancy, after self- erogeneity, many randomized controlled women recommends a minimum of 175 g
monitoring of blood glucose. trials suggest that the risk of GDM may be of carbo-hydrate, a minimum of 71 g of
In the second and third trimesters, reduced by diet, exercise, and lifestyle protein, and 28 g of fiber. As is true for all
A1C ,6% (42 mmol/mol) has the lowest counseling, particularly when interven-tions nutrition therapy in patients with diabetes,
risk of large-for-gestational-age infants, are started during the first or early in the the amount and type of carbohydrate will
whereas other adverse outcomes in- second trimester (21–23). im-pact glucose levels, especially postmeal
crease with A1C $6.5% (48 mmol/mol). excursions.
Lifestyle Management
Taking all of this into account, a target of
After diagnosis, treatment starts with Pharmacologic Therapy
6–6.5% (42–48 mmol/mol) is recom- Women with greater initial degrees of hy-
medical nutrition therapy, physical activ-
mended but ,6% (42 mmol/mol) may be perglycemia may require earlier initiation of
ity, and weight management depending
optimal as pregnancy progresses. pharmacologic therapy. Treatment has
on pregestational weight, as outlined in
These levels should be achieved without been demonstrated to improve perinatal
the section below on preexisting type 2
hypoglycemia, which, in addition to the outcomes in two large randomized stud-ies
diabetes, and glucose monitoring aiming
usual adverse sequelae, may increase as summarized in a U.S. Preventive
for the targets recommended by the Fifth
the risk of low birth weight. Given the Services Task Force review (29). Insulin is
International Workshop-Conference on
alteration in red blood cell kinetics the first-line agent recommended for
Gestational Diabetes Mellitus (24):
during pregnancy and physiological treatment of GDM in the U.S. While indi-
changes in glycemic parameters, A1C vidual randomized controlled trials sup-port
Fasting ,95 mg/dL (5.3 mmol/L) and
levels may need to be monitored more
either the efficacy and short-term safety of
frequently than usual (e.g., monthly). metformin (30,31) and glyburide (32) for
One-hour postprandial ,140 mg/dL
MANAGEMENT OF GESTATIONAL (7.8 mmol/L) or the treatment of GDM, both agents cross
DIABETES MELLITUS Two-hour postprandial ,120 mg/dL the placenta. There is not agree-ment
(6.7 mmol/L) regarding the comparative advan-tages
Recommendations and disadvantages of the two oral agents;
Lifestyle change is an essential com- the most recent systematic re-view of
Depending on the population, studies sug-
ponent of management of gesta- randomized controlled trials com-paring
gest that 70–85% of women diagnosed
tional diabetes mellitus and may metformin and glyburide for GDM found no
with GDM under Carpenter-Coustan or
suffice for the treatment of many clear differences in maternal or neonatal
National Diabetes Data Group (NDDG) cri-
women. Medications should be outcomes (33). A more recent randomized
teria can control GDM with lifestyle mod-
added if needed to achieve glyce- controlled trial demon-strated that
ification alone; it is anticipated that this
mic targets. A proportion will be even higher if the lower glyburide and metformin are comparable
Insulin is the preferred medication for
International Association of the Diabetes oral treatments for GDM regarding glucose
treating hyperglycemia in gestational control and ad-verse effects. In this study,
and Pregnancy Study Groups (IADPSG)
diabetes mellitus as it does not cross they were combined, with data
diagnostic thresholds are used. A re-cent
the placenta to a measurable extent. demonstrating a high efficacy rate with a
randomized controlled trial suggests that
Metformin and glyburide may be significantly
women with mild GDM (fasting
S140 Management of Diabetes in Pregnancy Diabetes Care Volume 41, Supplement 1, January 2018
reduced need for insulin, with a possible this approach would reduce morbidity, save
and type 2 diabetes in pregnancy
advantage for metformin over glyburide lives, and lower health care costs (49).
because it does not cross the pla-
as first-line therapy (34). However, more
centa, and because oral agents Type 1 Diabetes
definitive studies are required in this
are generally insufficient to Women with type 1 diabetes have an in-
area. Long-term safety data are not
overcome the insulin resistance in creased risk of hypoglycemia in the first
available for any oral agent (35).
type 2 dia-betes and are trimester and, like all women, have al-tered
Sulfonylureas ineffective in type 1 di-abetes. E counterregulatory response in pregnancy
Concentrations of glyburide in umbilical cord
that may decrease hypoglyce-mia
plasma are approximately 70% of maternal The physiology of pregnancy necessitates awareness. Education for patients and
levels (36). Glyburide was associated with a frequent titration of insulin to match family members about the preven-tion,
higher rate of neonatal hypoglycemia and changing requirements and underscores recognition, and treatment of hypo-
macrosomia than insulin or metfor-min in a the importance of daily and frequent self- glycemia is important before, during, and
2015 systematic review (37). monitoring of blood glucose. In the first after pregnancy to help to prevent and
Metformin trimester, there is often a decrease in total manage the risks of hypoglycemia. Insulin
Metformin was associated with a lower risk of daily insulin requirements, and women, resistance drops rapidly with delivery of the
neonatal hypoglycemia and less maternal particularly those with type 1 di-abetes, placenta. Women become very insu-lin
weight gain than insulin in 2015 systematic may experience increased hypo-glycemia. sensitive immediately following deliv-ery
reviews (37–39); however, metformin may In the second trimester, rapidly increasing and may initially require much less insulin
slightly increase the risk of prematu-rity. insulin resistance requires weekly or than in the prepartum period.
Furthermore, nearly half of patients with GDM biweekly increases in insulin dose to
Pregnancy is a ketogenic state, and
who were initially treated with metformin in a achieve glycemic targets. In general, a
women with type 1 diabetes, and to a lesser
randomized trial needed insulin in order to smaller proportion of the total daily dose
extent those with type 2 diabetes, are at risk
achieve acceptable glu-cose control (30). should be given as basal insulin (,50%)
for diabetic ketoacidosis at lower blood glu-
Umbilical cord blood levels of metformin are and a greater proportion (.50%) as prandial
cose levels than in the nonpregnant state.
higher than simul-taneous maternal levels insulin. Late in the third tri-mester, there is
Women with preexisting diabetes, espe-cially
(40,41). None of these studies or meta- often a leveling off or small decrease in
type 1 diabetes, need ketone strips at home
analyses evaluated long-term outcomes in insulin requirements. Due to the complexity
and education on diabetic ketoaci-dosis
the offspring. Pa-tients treated with oral of insulin manage-ment in pregnancy,
prevention and detection. In addition, rapid
agents should be informed that they cross the referral to a specialized center offering
implementation of tight glycemic con-trol in
placenta, and although no adverse effects on team-based care (with team members
the setting of retinopathy is associ-ated with
the fetus have been demonstrated, long-term including high-risk obste-trician,
worsening of retinopathy (50).
studies are lacking. endocrinologist, or other provider
experienced in managing pregnancy in Type 2 Diabetes
women with preexisting diabetes, dietitian, Type 2 diabetes is often associated with
Randomized, double-blind, controlled
nurse, and social worker, as needed) is obesity. Recommended weight gain during
trials comparing metformin with other
rec-ommended if this resource is available. pregnancy for overweight women is 15–25 lb
therapies for ovulation induction in women
None of the currently available and for obese women is 10–20 lb (51).
with polycystic ovary syndrome have not
insulin preparations have been Glycemic control is often easier to achieve in
demonstrated benefit in prevent-ing
spontaneous abortion or GDM (42), and demonstrated to cross the placenta. women with type 2 diabetes than in those
with type 1 diabetes but can require much
there is no evidence-based need to
Preeclampsia and Aspirin higher doses of insulin, sometimes
continue metformin in such patients once
necessitating concentrated insulin formula-
pregnancy has been confirmed (43–45).
Recommendation tions. As in type 1 diabetes, insulin require-
Insulin Women with type 1 or type 2 dia- ments drop dramatically after delivery. The
Insulin may be required to treat hypergly- betes should be prescribed low- risk for associated hypertension and other
cemia, and its use should follow the dose aspirin 60–150 mg/day comorbidities may be as high or higher with
guidelines below. Both multiple daily in- (usual dose 81 mg/day) from the type 2 diabetes as with type 1 diabetes, even
sulin injections and continuous subcuta- end of the first trimester until the if diabetes is better controlled and of shorter
neous insulin infusion are reasonable baby is born in order to lower the apparent duration, with pregnancy loss
alternatives, and neither has been shown risk of preeclampsia. A appearing to be more prevalent in the third
to be superior during pregnancy (46). trimester in women with type 2 dia-betes
Diabetes in pregnancy is associated with
compared with the first trimester in women
MANAGEMENT OF PREEXISTING an increased risk of preeclampsia (47).
with type 1 diabetes (52,53).
TYPE 1 DIABETES AND TYPE 2 Based upon the results of clinical trials, the
DIABETES IN PREGNANCY U.S. Preventive Services Task Force PREGNANCY AND DRUG
Insulin Use recommends the use of low-dose aspirin CONSIDERATIONS
(81 mg/day) as a preventive medication
Recommendation Recommendations
after 12 weeks of gestation in women who
Insulin is the preferred agent for man- In pregnant patients with diabetes
are at high risk for preeclampsia (48). A
agement of both type 1 diabetes and chronic hypertension, blood
cost-benefit analysis has concluded that
care.diabetesjournals.org Management of Diabetes in Pregnancy
S141
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S144 Diabetes Care Volume 41, Supplement 1, January 2018
High-quality hospital care for diabetes requires both hospital care delivery
standards, often assured by structured order sets, and quality assurance
standards for process improvement. “Best practice” protocols, reviews, and
guidelines (2) are inconsistently implemented within hospitals. To correct this,
hospitals have established protocols for structured patient care and structured
order sets, which include computerized physi-cian order entry (CPOE).
Suggested citation: American Diabetes As-
Considerations on Admission sociation. 14. Diabetes care in the hospital:
Initial orders should state the type of diabetes (i.e., type 1 or type 2 diabetes) or no Standards of Medical Care in Diabetesd2018.
previous history of diabetes. Because inpatient insulin use (5) and discharge orders (6) Diabetes Care 2018;41(Suppl. 1):S144–S151
can be more effective if based on an A1C level on admission (7), perform an A1C test on © 2017 by the American Diabetes Association.
all patients with diabetes or hyperglycemia admitted to the hospital if the test has not been Readers may use this article as long as the work
is properly cited, the use is educational and not
performed in the prior 3 months. In addition, diabetes self-management knowledge and
for profit, and the work is not altered. More infor-
behaviors should be assessed on admission and diabetes self-management edu-cation mation is available at http://www.diabetesjournals
(DSME) should be provided, if appropriate. DSME should include appropriate .org/content/license.
care.diabetesjournals.org Diabetes Care in the Hospital
S145
skills needed after discharge, such as therapy is started, a target glucose range
hyperglycemia starting at a threshold
tak-ing antihyperglycemic medications, of 140–180 mg/dL (7.8–10.0 mmol/L) is
$180 mg/dL (10.0 mmol/L). Once
mon-itoring glucose, and recognizing recommended for the majority of critically
insulin therapy is started, a target
and treating hypoglycemia (2). ill and noncritically ill patients (2). More
glucose range of 140–180 mg/dL
stringent goals, such as ,140 mg/dL (7.8
Physician Order Entry (7.8–10.0 mmol/L) is recommended
mmol/L), may be appropriate for se-lected
for the majority of critically ill pa-
Recommendation patients, as long as this can be achieved
Insulin should be administered using tients and noncritically ill patients. A
without significant hypoglyce-mia.
validated written or computerized More stringent goals, such as 110– 140
Conversely, higher glucose ranges may be
protocols that allow for predefined mg/dL (6.1–7.8 mmol/L), may be
acceptable in terminally ill pa-tients, in
adjustments in the insulin dosage appropriate for selected pa-tients, if
patients with severe comorbid-ities, and in
based on glycemic fluctuations. E this can be achieved with-out
inpatient care settings where frequent
significant hypoglycemia. C
glucose monitoring or close nurs-ing
The National Academy of Medicine rec- supervision is not feasible.
ommends CPOE to prevent medication- Standard Definition of Glucose Clinical judgment combined with on-
related errors and to increase efficiency Abnormalities going assessment of the patient’s clinical
in medication administration (8). A Co- Hyperglycemia in hospitalized patients is
status, including changes in the trajectory
chrane review of randomized controlled de-fined as blood glucose levels .140
of glucose measures, illness severity, nu-
trials using computerized advice to im- mg/dL (7.8 mmol/L) (2,16). Blood glucose
tritional status, or concomitant medica-
prove glucose control in the hospital levels that are persistently above this level
tions that might affect glucose levels (e.g.,
found significant improvement in the may require alterations in diet or a change
glucocorticoids), should be incorpo-rated
per-centage of time patients spent in the in medications that cause hypergly-cemia.
into the day-to-day decisions re-garding
target glucose range, lower mean blood An admission A1C value $6.5% (48
insulin doses (2).
glucose levels, and no increase in hypo- mmol/mol) suggests that diabetes
glycemia (9). Thus, where feasible, preceded hospitalization (see Section 2
there should be structured order sets “Classification and Diagnosis of Diabe-tes”) BEDSIDE BLOOD
(2,16). The hypoglycemia alert value in GLUCOSE MONITORING
that provide computerized advice for
glucose control. Electronic insulin order hospitalized patients is defined as blood Indications
templates also improve mean glucose glucose #70 mg/dL (3.9 mmol/L) In the patient who is eating meals, glu-
levels without increasing hypoglycemia and clinically significant hypoglyce-mia cose monitoring should be performed
in patients with type 2 diabetes, so as glucose values ,54 mg/dL (3.0 before meals. In the patient who is not
structured insulin or-der sets should be mmol/L). Severe hypoglycemia is eating, glucose monitoring is advised
incorporated into the CPOE (10). defined as that associated with severe ev-ery 4–6 h (2). More frequent blood
cognitive impairment regardless of blood glu-cose testing ranging from every 30
glucose level (17). min to every 2 h is required for patients
Diabetes Care Providers in the Hospital
Appropriately trained specialists or spe- receiv-ing intravenous insulin. Safety
Moderate Versus Tight Glycemic standards should be established for
cialty teams may reduce length of stay, Control blood glucose monitoring that prohibit
improve glycemic control, and improve A meta-analysis of over 26 studies, includ-
the sharing of fingerstick lancing
outcomes, but studies are few (11,12). A ing the Normoglycemia in Intensive Care
devices, lancets, and needles (21).
call to action outlined the studies needed Evaluation–Survival Using Glucose Algo-
to evaluate these outcomes (13). Details of rithm Regulation (NICE-SUGAR) study, Point-of-Care Meters
team formation are available from the showed increased rates of severe hypo- Point-of-care (POC) meters have limitations
Society of Hospital Medicine and the Joint glycemia (defined in the analysis as blood for measuring blood glucose. Although the
Commission standards for programs. glucose ,40 mg/dL [2.2 mmol/L]) and U.S. Food and Drug Administration (FDA) has
mortality in tightly versus moderately standards for blood glucose meters used by
Quality Assurance Standards
controlled cohorts (18). Recent random- lay persons, there have been ques-tions
Even the best orders may not be carried
ized controlled studies and meta-analyses about the appropriateness of these criteria,
out in a way that improves quality, nor are
in surgical patients have also reported that especially in the hospital and for lower blood
they automatically updated when new ev-
targeting moderate perioperative blood glucose readings (22). Signifi-cant
idence arises. To this end, the Joint Com-
glucose levels to ,180 mg/dL (10 mmol/L) discrepancies between capillary, ve-nous, and
mission has an accreditation program for
is associated with lower rates of mortality arterial plasma samples have been observed
the hospital care of diabetes (14), and the
and stroke compared with a liberal target in patients with low or high hemoglobin
Society of Hospital Medicine has a work-
glucose .200 mg/dL (11.1 mmol/L), concentrations and with hypoperfusion. Any
book for program development (15).
whereas no significant ad-ditional benefit glucose result that does not correlate with the
GLYCEMIC TARGETS was found with more strict glycemic control pa-tient’s clinical status should be confirmed
IN HOSPITALIZED PATIENTS (,140 mg/dl [7.8 mmol/L]) (19,20). Insulin through conventional laboratory glucose
therapy should be initiated for treatment of tests. The FDA established a separate cat-
Recommendations
persistent hyperglycemia starting at a egory for POC glucose meters for use in
Insulin therapy should be initi- threshold $180 mg/dL (10.0 mmol/L). Once health care settings and has released
ated for treatment of persistent
insulin
S146 Diabetes Care in the Hospital Diabetes Care Volume 41, Supplement 1, January 2018
guidance on in-hospital use with stricter shown to be the best method for achiev- Type 1 Diabetes
standards (23). Before choosing a ing glycemic targets. Intravenous insulin For patients with type 1 diabetes, dosing
device for in-hospital use, consider the infusions should be administered based insulin based solely on premeal glucose
device’s approval status and accuracy. on validated written or computerized levels does not account for basal insulin
protocols that allow for predefined ad- requirements or caloric intake,
Continuous Glucose Monitoring increasing both hypoglycemia and
justments in the infusion rate, account-
Continuous glucose monitoring (CGM)
ing for glycemic fluctuations and insulin hyperglycemia risks and potentially
provides frequent measurements of in-
dose (2). leading to diabetic ketoacidosis (DKA).
terstitial glucose levels, as well as direc-
Typically, basal insulin dosing schemes
tion and magnitude of glucose trends, Noncritical Care Setting are based on body weight, with some
which may have an advantage over Outside of critical care units, scheduled evidence that patients with renal
POC glucose testing in detecting and re- insulin regimens are recommended to insufficiency should be treat-ed with
ducing the incidence of hypoglycemia manage hyperglycemia in patients with lower doses (34). An insulin regimen
. Several inpatient studies have shown diabetes. Regimens using insulin with basal and correction com-ponents
that CGM use did not improve glu-cose analogs and human insulin result in sim- is necessary for all hospitalized patients
control but detected a greater num-ber ilar glycemic control in the hospital set- with type 1 diabetes, with the addition of
of hypoglycemic events than POC ting (30). nutritional insulin if the pa-tient is eating.
testing (25). However, a recent review The use of subcutaneous rapid- or
has recommended against using CGM Transitioning Intravenous to Subcutaneous
short-acting insulin before meals or ev-
in adults in a hospital setting until more Insulin
ery 4–6 h if no meals are given or if the
safety and efficacy data become When discontinuing intravenous insulin,
patient is receiving continuous enteral/
available (25). a transition protocol is associated with
parenteral nutrition is indicated to correct
less morbidity and lower costs of care
hyperglycemia (2). Basal insulin or a
ANTIHYPERGLYCEMIC AGENTS and is therefore recommended. A pa-
basal plus bolus correction insulin
IN HOSPITALIZED PATIENTS tient with type 1 or type 2 diabetes being
regimen is the preferred treatment for
Recommendations
transitioned to outpatient subcutane-ous
noncritically ill patients with poor oral
A basal plus bolus correction insulin insulin should receive subcutaneous
intake or those who are taking nothing
regimen, with the addition of nutri- basal insulin 2–4 h before the
by mouth (NPO). An insulin regimen with
tional insulin in patients who have intravenous insulin is discontinued.
basal, nutritional, and correction
good nutritional intake, is the pre- Converting to basal insulin at 60–80% of
components is the pre-ferred treatment
ferred treatment for noncritically ill the daily infusion dose has been shown
for noncritically ill hos-pitalized patients
patients. A to be effective (2,35,36). For patients
with good nutritional intake.
continuing regi-mens with concentrated
Sole use of sliding scale insulin If the patient is eating, insulin injec-
in the inpatient hospital setting insulin in the in-patient setting, it is
tions should align with meals. In such in-
is strongly discouraged. A important to ensure the correct dosing
stances, POC glucose testing should be
by utilizing an individ-ual pen and
performed immediately before meals. If
In most instances in the hospital setting, cartridge for each patient, meticulous
oral intake is poor, a safer procedure is
insulin is the preferred treatment for glyce- pharmacist supervision of the dose
to administer the rapid-acting insulin
mic control (2). However, in certain circum- administered, or other means (37,38).
imme-diately after the patient eats or to
stances, it may be appropriate to continue count the carbohydrates and cover the Noninsulin Therapies
home regimens including oral antihyper- amount ingested (30). The safety and efficacy of noninsulin anti-
glycemic medications (26). If oral medica- A randomized controlled trial has hyperglycemic therapies in the hospital
tions are held in the hospital, there should shown that basal-bolus treatment im- setting is an area of active research. A few
be a protocol for resuming them 1– 2 days proved glycemic control and reduced recent randomized pilot trials in gen-eral
before discharge. Insulin pens are the hos-pital complications compared with medicine and surgery patients re-ported
subject of an FDA warning be-cause of sliding scale insulin in general surgery that a dipeptidyl peptidase 4 inhibitor alone
potential blood-borne diseases, and care patients with type 2 diabetes (31). or in combination with basal insulin was
should be taken to follow the label insert Prolonged sole use of sliding scale well tolerated and re-sulted in similar
“For single patient use only.” Recent insulin in the in-patient hospital setting glucose control and fre-quency of
reports, however, have indicated that the is strongly dis-couraged (2,13). hypoglycemia compared with a basal-bolus
inpatient use of insulin pens ap-pears to be While there is evidence for using pre- regimen (39–41). However, a recent FDA
safe and may be associated with improved mixed insulin formulations in the outpa- bulletin states that providers should
nurse satisfaction com-pared with the use tient setting (32), a recent inpatient study consider discontinuing saxagliptin and
of insulin vials and syringes (27–29). of 70/30 NPH/regular insulin versus alogliptin in people who develop heart
basal-bolus therapy showed comparable failure (42). A review of antihyper-glycemic
glycemic control but significantly in- medications concluded that glucagon-like
Insulin Therapy creased hypoglycemia in the group re- peptide 1 receptor agonists show promise
Critical Care Setting ceiving premixed insulin (33). Therefore, in the inpatient setting (43); however, proof
In the critical care setting, continuous premixed insulin regimens are not rou- of safety and effi-cacy awaits the results of
intravenous insulin infusion has been tinely recommended for in-hospital use. randomized
care.diabetesjournals.org Diabetes Care in the Hospital
S147
controlled trials (44). Moreover, the treating hypoglycemia for each patient. MEDICAL NUTRITION
gas-trointestinal symptoms An American Diabetes Association THERAPY IN THE HOSPITAL
associated with the glucagon-like (ADA) consensus report suggested that The goals of medical nutrition therapy in
peptide 1 receptor ago-nists may be a pa-tient’s overall treatment regimen be the hospital are to provide adequate cal-
problematic in the inpatient setting. re-viewed when a blood glucose value of ories to meet metabolic demands, opti-
Regarding the sodium–glucose trans- #70 mg/dL (3.9 mmol/L) is identified mize glycemic control, address personal
porter 2 (SGLT2) inhibitors, the FDA because such readings often predict im- food preferences, and facilitate creation of
includes warnings about DKA and uro- minent severe hypoglycemia (2). a discharge plan. The ADA does not
sepsis (45), urinary tract infections, and Episodes of hypoglycemia in the endorse any single meal plan or specified
kidney injury (46) on the drug labels. A hospi-tal should be documented in percentages of macronutrients. Current
recent review suggested SGLT2 inhibi- the medical record and tracked (2). nutrition recommendations advise indi-
tors be avoided in severe illness, when vidualization based on treatment goals,
ketone bodies are present, and during Triggering Events physiological parameters, and medication
prolonged fasting and surgical proce- Iatrogenic hypoglycemia triggers may in- use. Consistent carbohydrate meal plans
dures (3). Until safety and effectiveness clude sudden reduction of corticosteroid are preferred by many hospitals as they
are established, SGLT2 inhibitors cannot dose, reduced oral intake, emesis, new facilitate matching the prandial insulin dose
be recommended for routine in-hospital NPO status, inappropriate timing of short- to the amount of carbohydrate con-sumed
use. acting insulin in relation to meals, reduced (51). Regarding enteral nutritional therapy,
infusion rate of intravenous dextrose, un- diabetes-specific formulas ap-pear to be
HYPOGLYCEMIA expected interruption of oral, enteral, or superior to standard formulas in controlling
Recommendations parenteral feedings, and altered ability of postprandial glucose, A1C, and the insulin
A hypoglycemia management pro-tocol the patient to report symptoms (3). response (52).
should be adopted and imple- When the nutritional issues in the hos-
Predictors of Hypoglycemia
mented by each hospital or hospital pital are complex, a registered dietitian,
In one study, 84% of patients with an ep-
system. A plan for preventing and knowledgeable and skilled in medical nu-
isode of severe hypoglycemia (,40
treating hypoglycemia should be trition therapy, can serve as an individual
mg/dL [2.2 mmol/L]) had a prior episode
established for each patient. Epi- inpatient team member. That person
of hy-poglycemia (,70 mg/dL [3.9
sodes of hypoglycemia in the hospi- should be responsible for integrating in-
mmol/L]) during the same admission
tal should be documented in the formation about the patient’s clinical con-
(47). In an-other study of hypoglycemic
medical record and tracked. E episodes (,50 mg/dL [2.8 mmol/L]), 78%
dition, meal planning, and lifestyle habits
The treatment regimen should be and for establishing realistic treatment
of pa-tients were using basal insulin,
reviewed and changed as neces- goals after discharge. Orders should also
with the incidence of hypoglycemia
sary to prevent further hypoglyce- indicate that the meal delivery and nutri-
peaking be-tween midnight and 6 A.M.
mia when a blood glucose value is Despite recog-nition of hypoglycemia,
tional insulin coverage should be coordi-
#70 mg/dL (3.9 mmol/L). C 75% of patients did not have their dose
nated, as their variability often creates the
possibility of hyperglycemic and hy-
of basal insulin changed before the next
Patients with or without diabetes may poglycemic events.
insulin adminis-tration (48).
ex-perience hypoglycemia in the
hospital setting. While hypoglycemia is Prevention SELF-MANAGEMENT IN
associated with increased mortality, Common preventable sources of iatro- THE HOSPITAL
hypoglycemia may be a marker of genic hypoglycemia are improper pre- Diabetes self-management in the hospital
underlying disease rather than the scribing of hypoglycemic medications, may be appropriate for select youth and adult
cause of increased mor-tality. However, inappropriate management of the first patients (53,54). Candidates include patients
until it is proven not to be causal, it is episode of hypoglycemia, and nutrition– who successfully conduct self-management
prudent to avoid hypoglyce-mia. Despite insulin mismatch, often related to an of diabetes at home, have the cognitive and
the preventable nature of many inpatient unexpected interruption of nutrition. Stud- physical skills needed to successfully self-
episodes of hypoglyce-mia, institutions ies of “bundled” preventative therapies administer insulin, and perform self-
are more likely to have nursing protocols including proactive surveillance of gly- monitoring of blood glucose. In addition, they
for hypoglycemia treat-ment than for its cemic outliers and an interdisciplinary data- should have adequate oral intake, be
prevention when both are needed. driven approach to glycemic man-agement proficient in carbohydrate estimation, use
A hypoglycemia prevention and man- showed that hypoglycemic epi-sodes in the multiple daily insulin in-jections or continuous
agement protocol should be adopted and hospital could be prevented. Compared subcutaneous in-sulin infusion (CSII) pump
implemented by each hospital or hospital with baseline, two such stud-ies found that therapy, have stable insulin requirements, and
system. There should be a standardized hypoglycemic events fell by 56% to 80% un-derstand sick-day management. If self-
hospital-wide, nurse-initiated hypogly- (49,50). The Joint Commis-sion management is to be used, a protocol should
cemia treatment protocol to immedi-ately recommends that all hypoglycemic include a requirement that the patient, nursing
address blood glucose levels of episodes be evaluated for a root cause and staff, and physician agree that pa-tient self-
#70 mg/dL (3.9 mmol/L), as well as in- the episodes be aggregated and re-viewed management is appropriate. If
dividualized plans for preventing and to address systemic issues.
S148 Diabetes Care in the Hospital Diabetes Care Volume 41, Supplement 1, January 2018
CSII is to be used, hospital policy and Correctional insulin coverage should be mg/dL (4.4–10.0 mmol/L).
pro-cedures delineating guidelines for added as needed before each feeding. For Perform a preoperative risk assessment for
CSII therapy, including the changing patients receiving continuous periph-eral or patients at high risk for ischemic heart
of infu-sion sites, are advised (55). central parenteral nutrition, regu-lar insulin disease and those with autono-mic
may be added to the solution, particularly if neuropathy or renal failure.
STANDARDS FOR
.20 units of correctional insulin have been Withhold metformin the day of surgery.
SPECIAL SITUATIONS
required in the past 24 h. A starting dose of Withhold any other oral hypoglycemic
Enteral/Parenteral Feedings 1 unit of human regular insulin for every 10 agents the morning of surgery or pro-
For patients receiving enteral or paren-teral
g dextrose has been recommended (57), to cedure and give half of NPH dose or
feedings who require insulin, insulin should
be adjusted daily in the solution. 60–80% doses of a long-acting analog
be divided into basal, nutritional, and
Correctional insulin should be administered or pump basal insulin.
correctional components. This is par-ticularly
subcutaneously. For full enteral/parenteral Monitor blood glucose at least every
important for people with type 1 diabetes to
feeding guid-ance, the reader is 4–6 h while NPO and dose with
ensure that they continue to receive basal
encouraged to consult review articles short-acting insulin as needed.
insulin even if the feedings are discontinued.
(2,58) and see Table 14.1.
One may use the pa-tient’s preadmission A review found that perioperative gly-
basal insulin dose or a percentage of the total Glucocorticoid Therapy cemic control tighter than 80–180 mg/dL
daily dose of insulin when the patient is being Glucocorticoid type and duration of action (4.4–10.0 mmol/L) did not improve out-
fed (usually 30 to 50% of the total daily dose must be considered in determining insulin comes and was associated with more hy-
of insulin) to estimate basal insulin re- treatment regimens. Once-a-day, short- poglycemia (62); therefore, in general,
quirements. However, if no basal insulin was acting glucocorticoids such as prednisone tighter glycemic targets are not advised. A
used, consider using 5 units of NPH/ detemir peak in about 4 to 8 h (59), so cover-age recent study reported that, compared with
insulin subcutaneously every 12 h or 10 units with intermediate-acting (NPH) insulin may the usual insulin dose, on average a ;25%
of insulin glargine every 24 h (56). For be sufficient. For long-acting gluco- reduction in the insulin dose given the
patients receiving continu-ous tube feedings, corticoids such as dexamethasone or mul- evening before surgery was more likely to
the total daily nutri-tional component may be tidose or continuous glucocorticoid use, achieve perioperative blood glu-cose levels
calculated as 1 unit of insulin for every 10–15 long-acting insulin may be used (26,58). in the target range with de-creased risk for
g carbo-hydrate per day or as a percentage of For higher doses of glucocorticoids, in- hypoglycemia (63).
the total daily dose of insulin when the pa- creasing doses of prandial and supplemen- In noncardiac general surgery pa-tients,
tient is being fed (usually 50 to 70% of the tal insulin may be needed in addition to basal insulin plus premeal regular or short-
total daily dose of insulin). Correc-tional basal insulin (60). Whatever orders are acting insulin (basal-bolus) cov-erage has
insulin should also be administered started, adjustments based on antici-pated been associated with improved glycemic
subcutaneously every 6 h using human changes in glucocorticoid dosing and POC control and lower rates of peri-operative
regular insulin or every 4 h using a rapid- glucose test results are critical. complications compared with the traditional
acting insulin such as lispro, aspart, or gluli-
sliding scale regimen (reg-ular or short-
sine. For patients receiving enteral bolus Perioperative Care
acting insulin coverage only with no basal
feedings, approximately 1 unit of regu-lar Many standards for perioperative
dosing) (31,64).
human insulin or rapid-acting insulin should care lack a robust evidence base.
be given per 10–15 g carbohydrate However, the following approach
Diabetic Ketoacidosis and
subcutaneously before each feeding. (61) may be con-sidered:
Hyperosmolar Hyperglycemic State
Target glucose range for the peri- There is considerable variability in the
operative period should be 80–180 presentation of DKA and hyperosmolar
IV, intravenous; SQ, subcutaneous; TDD, total daily dose; TPN, total parenteral nutrition.
care.diabetesjournals.org Diabetes Care in the Hospital
S149
hyperglycemic state, ranging from eugly- be discharged to varied settings, including Discharge summaries should be trans
cemia or mild hyperglycemia and acidosis home (with or without visiting nurse ser-vices), mitted to the primary physician as
to severe hyperglycemia, dehydration, and assisted living, rehabilitation, or skilled nursing soon as possible after discharge.
coma; therefore, treatment individu- facilities. For the patient who is discharged to Appointment-keeping behavior is en-
alization based on a careful clinical and home or to assisted liv-ing, the optimal hanced when the inpatient team
laboratory assessment is needed (65). program will need to con-sider diabetes type sched-ules outpatient medical follow-
up prior to discharge.
Management goals include restoration and severity, effects of the patient’s illness on
of circulatory volume and tissue perfu-sion, blood glucose levels, and the patient’s
It is recommended that the following
resolution of hyperglycemia, and correction capacities and desires.
areas of knowledge be reviewed and ad-
of electrolyte imbalance and ketosis. It is An outpatient follow-up visit with the
dressed prior to hospital discharge:
also important to treat any correctable primary care provider, endocrinologist, or
underlying cause of DKA such as sepsis. diabetes educator within 1 month of dis-
Identification of the health care pro-
charge is advised for all patients having vider who will provide diabetes
In critically ill and mentally obtunded hyperglycemia in the hospital. If glycemic care after discharge.
patients with DKA or hyperosmolar hy- medications are changed or glucose con- Level of understanding related to the
perglycemic state, continuous intra-venous trol is not optimal at discharge, an earlier diabetes diagnosis, self-monitoring
insulin is the standard of care. However, appointment (in 1–2 weeks) is preferred, of blood glucose, explanation of
there is no significant differ-ence in and frequent contact may be needed to home blood glucose goals, and
when to call the provider.
outcomes for intravenous regular insulin avoid hyperglycemia and hypoglycemia. A
Definition, recognition, treatment,
versus subcutaneous rapid-acting analogs recent discharge algorithm for glycemic
and prevention of hyperglycemia
when combined with aggressive fluid medication adjustment based on admis- and hypoglycemia.
management for treating mild or moderate sion A1C found that the average A1C in Information on consistent nutrition
DKA (66). Patients with uncom-plicated patients with diabetes after discharge was habits.
DKA may sometimes be treated with significantly improved (6). Therefore, if an If relevant, when and how to take blood
glucose–lowering medications,
subcutaneous insulin in the emer-gency A1C from the prior 3 months is un-
including insulin administration.
department or step-down units (67), an available, measuring the A1C in all patients Sick-day management.
approach that may be safer and more with diabetes or hyperglycemia admitted to Proper use and disposal of needles
cost-effective than treatment with the hospital is recommended. and syringes.
intravenous insulin (68). If subcutaneous Clear communication with outpatient
administration is used, it is important to providers either directly or via hospital It is important that patients be pro-
provide adequate fluid replacement, nurse discharge summaries facilitates safe transi- vided with appropriate durable medical
training, frequent bedside testing, infection tions to outpatient care. Providing informa- equipment, medications, supplies (e.g.,
treatment if warranted, and ap-propriate tion regarding the cause of hyperglycemia insulin pens), and prescriptions along
follow-up to avoid recurrent DKA. Several (or the plan for determining the cause), re- with appropriate education at the time of
studies have shown that the use of lated complications and comorbidities, and dis-charge in order to avoid a potentially
bicarbonate in patients with DKA made no recommended treatments can assist out- dan-gerous hiatus in care.
difference in resolution of acidosis or time patient providers as they assume ongoing
PREVENTING ADMISSIONS
to discharge, and its use is generally not care. AND READMISSIONS
recommended (69). For fur-ther The Agency for Healthcare Research
information regarding treatment, re-fer to
Preventing Hypoglycemic Admissions
and Quality (AHRQ) recommends that,
in Older Adults
recent in-depth reviews (3,70). at a minimum, discharge plans include
Insulin-treated patients 80 years of age or
the following (72):
older are more than twice as likely to visit
TRANSITION FROM THE the emergency department and nearly five
ACUTE CARE SETTING Medication Reconciliation times as likely to be admitted for insulin-
The patient’s medications must be cross- related hypoglycemia than those 45–64
Recommendation
checked to ensure that no chronic years of age (73). However, older adults
There should be a structured dis-
medications were stopped and to en-sure with type 2 diabetes in long-term care
charge plan tailored to the individ- the safety of new prescriptions. facilities taking either oral antihyper-
ual patient with diabetes. B
Prescriptions for new or changed glycemic agents or basal insulin have sim-
med ication should be filled and ilar glycemic control (74), suggesting that
A structured discharge plan tailored to the reviewed with the patient and oral therapy may be used in place of in-
individual patient may reduce length of family at or before discharge.
sulin to lower the risk of hypoglycemia for
hospital stay and readmission rates and in-
Structured Discharge Communication some patients. In addition, many older
crease patient satisfaction (71). Therefore,
adults with diabetes are overtreated (75),
there should be a structured discharge Information on medication changes, with half of those maintaining an A1C ,7%
plan tailored to each patient. Discharge pending tests and studies, and being treated with insulin or a sulfonylurea,
planning should begin at admission and be follow-up needs must be accurately
updated as patient needs change. and promptly communicated to
Transition from the acute care setting is outpa-tient physicians.
a risky time for all patients. Inpatients may
S150 Diabetes Care in the Hospital Diabetes Care Volume 41, Supplement 1, January 2018
which are associated with hypoglycemia. unknown diabetes in the ICU. Crit Care recommendations from an ASHP
To further lower the risk of hypoglycemia- Med 2015;43:e541–e550 Foundation ex-pert consensus panel. Am J
Institute of Medicine. Preventing Medica-tion Health Syst Pharm 2013;70:1404–1413
related admissions in older adults,
Errors. Aspden P, Wolcott J, Bootman JL, Boyd JC, Bruns DE. Quality specifications for
providers may, on an individual basis, relax Cronenwett LR, Eds. Washington, DC, The glucose meters: assessment by simulation
A1C tar-gets to ,8% or ,8.5% in patients Na-tional Academies Press, 2007 model-ing of errors in insulin dose. Clin Chem
with shortened life expectancies and Gillaizeau F, Chan E, Trinquart L, et al. 2001;47: 209–214
signifi-cant comorbidities (refer to Section Comput-erized advice on drug dosage to U.S. Food and Drug Administration. Blood Glu-cose
improve prescrib-ing practice. Cochrane Monitoring Test Systems for Prescription Point-of-
11 “Older Adults” for detailed criteria). Database Syst Rev 2013; 11:CD002894 Care Use: Guidance for Industry and Food and Drug
Wexler DJ, Shrader P, Burns SM, Cagliero E. Administration Staff [Internet], 2016. Available from
Preventing Readmissions Effectiveness of a computerized insulin order https://www.fda.gov/downloads/
In patients with diabetes, the readmission template in general medical inpatients with type 2 medicaldevices/deviceregulationandguidance/
diabetes: a cluster randomized trial. Diabe-tes guidancedocuments/ucm380325.pdf. Accessed
rate is between 14 and 20% (76). Risk
Care 2010;33:2181–2183 November 2016
factors for readmission include lower so-
Wang YJ, Seggelke S, Hawkins RM, et al. Im- Wallia A, Umpierrez GE, Rushakoff RJ, et al.;
cioeconomic status, certain racial/ethnic pact of glucose management team on DTS Continuous Glucose Monitoring in the
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admission, and recent prior hospitaliza-tion type 2 diabetes admitted to the medical inpatient use of continuous glucose monitoring. J
(76). Of interest, 30% of patients with two service. Endocr Pract 2016;22:1401–1405 Diabetes Sci Technol 2017;11:1036–1044
Garg R, Schuman B, Bader A, et al. Effect of Gomez AM, Umpierrez GE. Continuous
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000002323 Inzucchi SE; Society of Hospital Medicine
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been reported, including an intervention investigators. Pathways to quality inpatient man- insulin order sets and protocols: effective
program targeting ketosis-prone patients agement of hyperglycemia and diabetes: a call to design and im-plementation strategies. J
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(80). For people with diabetic kid-ney Association Inpatient Diabetes Certification.
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S152 Diabetes Care Volume 41, Supplement 1, January 2018
the components of diabetes care, general treatment goals and guidelines, and tools
to evaluate quality of care. Members of the ADA Professional Practice Committee, a
multidisciplinary expert committee, are responsible for updating the Standards of
Care annually, or more frequently as warranted. For a detailed description of ADA
standards, statements, and reports, as well as the evidence-grading system for
ADA’s clinical practice recommendations, please refer to the Standards of Care
Introduction. Readers who wish to comment on the Standards of Care are invited to
do so at professional.diabetes.org/SOC.
resources, and a system of communication Driving” (http://care.diabetesjournals that nearly 80,000 inmates have diabe-tes,
with parents and the child’s diabetes pro- .org/content/37/Supplement_1/S97). correctional institutions should have written
vider. See the ADA position statement policies and procedures for the
“Care of Young Children With Diabetes in Diabetes and Employment (4) management of diabetes and for the train-
the Child Care Setting” (http://care First publication: 1984 (revised 2009) Any ing of medical and correctional staff in
.diabetesjournals.org/content/37/10/ person with diabetes, whether insulin diabetes care practices. See the ADA
2834). treated or noninsulin treated, should be el- position statement “Diabetes Manage-ment
igible for any employment for which he or in Correctional Institutions” (http://
Diabetes and Driving (3) she is otherwise qualified. Employment de- care.diabetesjournals.org/content/37/
First publication: 2012 cisions should never be based on gener- Supplement_1/S104).
People with diabetes who wish to operate alizations or stereotypes regarding the
motor vehicles are subject to a great vari-ety effects of diabetes. When questions arise References
of licensing requirements applied by both about the medical fitness of a person with Jackson CC, Albanese-O’Neill A, Butler KL,
state and federal jurisdictions, which may diabetes for a particular job, a health care et al. Diabetes care in the school setting: a
position statement of the American
lead to loss of employment or signif-icant professional with expertise in treating
Diabetes Association. Diabetes Care
restrictions on a person’s license. Presence of diabetes should perform an individualized 2015;38:1958– 1963
a medical condition that can lead to assessment. See the ADA position state- Siminerio LM, Albanese-O’Neill A, Chiang JL,
significantly impaired conscious-ness or ment “Diabetes and Employment” (http:// et al. Care of young children with diabetes in
care.diabetesjournals.org/content/37/ the child care setting: a position statement of
cognition may lead to drivers being evaluated
the American Diabetes Association. Diabetes
for their fitness to drive. People with diabetes Supplement_1/S112).
Care 2014;37:2834–2842
should be individually as-sessed by a health American Diabetes Association. Diabetes and
care professional knowl-edgeable in diabetes Diabetes Management in Correctional driving. Diabetes Care 2014;37:(Suppl. 1):S97–S103
if license restrictions are being considered, Institutions (5) American Diabetes Association. Diabetes
First publication: 1989 (revised 2008) and employment. Diabetes Care
and patients should be counseled about
2014;37(Suppl. 1): S112–S117
detecting and avoid-ing hypoglycemia while People with diabetes in correctional fa- American Diabetes Association. Diabetes
driving. See the ADA position statement cilities should receive care that meets management in correctional institutions. Diabe-
“Diabetes and national standards. Because it is estimated tes Care 2014;37(Suppl. 1):S104–S111
PROFESSIONAL PRACTICE COMMITTEE DISCLOSURES
The following financial or other conflicts of interest cover the period 12 months before December 2017
Other research
Member Employment Research grant support
Rita R. Kalyani, MD, MHS, FACP (Chair) Johns Hopkins University, Baltimore, MD None None
Christopher P. Cannon, MD Brigham and Women’s Hospital, Amgen, Arisaph, Boehringer Ingelheim, None
Boston, MA Bristol-Myers Squibb, Daiichi Sankyo,
Janssen, Merck, Takeda
Andrea L. Cherrington, MD, MPH University of Alabama, Birmingham, AL None None
Donald R. Coustan, MD The Warren Alpert Medical School of Brown None None
University, Providence, RI
Ian H. de Boer, MD, MS University of Washington, Seattle, WA Research grant from ADA Medtronic,
Abbott
Hope Feldman, CRNP, FNP-BC Abbottsford-Falls Family Practice & None None
Counseling, Philadelphia, PA
Judith Fradkin, MD National Institute of Diabetes and Digestive None None
and Kidney Diseases, Bethesda, MD
David Maahs, MD, PhD Stanford University, School of Medicine, Medtronic, Dexcom, Roche, Insulet, None
Stanford, CA Bigfoot
Melinda Maryniuk, MEd, RD, CDE Joslin Diabetes Center, Boston, MA None None
Medha N. Munshi, MD Beth Israel Deaconess Medical Center, None Common
Harvard Medical School, Boston, MA Sensing
Joshua J. Neumiller, PharmD, Washington State University, Spokane, WA
CDE, FASCP None None
Guillermo E. Umpierrez, MD, CDE, Emory University, Atlanta, GA Sanofi, Novo Nordisk, Merck, Boehringer None
FACE, FACP Ingelheim, AstraZeneca
Sandeep Das, MD, MPH^ University of Texas Southwestern Medical None None
Center
Mikhail Kosiborod, MD^ University of Missouri-Kansas City School of None None
Medicine
William T. Cefalu, MD (Staff)† American Diabetes Association, Arlington, VA Sanofi*# None
Erika Gebel Berg, PhD (Staff) American Diabetes Association, Arlington, VA None None
Tamara Darsow, PhD (Staff) American Diabetes Association, Arlington, VA None None
Matthew P. Petersen (Staff) American Diabetes Association, Arlington, VA None None
Sacha Uelmen, RDN, CDE (Staff) American Diabetes Association, Arlington, VA None None
care.diabetesjournals.org Disclosures S155
Speakers’ bureau/
^American College of Cardiologyddesignated representative (Section 9); *$$10,000 per year from company to individual; #grant or contract is to university or
other employer; †prior to joining ADA, no active disclosures.
S156 Diabetes Care Volume 41, Supplement 1, January 2018
Index
A1C testing bile acid sequestrants, S79, S81 Cholesterol Treatment Trialists’
in African Americans, S15, S58 blood pressure control. see Collaboration, S93
in children, adolescents, S58, hypertension bromocriptine, S79, S81 cholesteryl ester transfer protein (CETP)
S128 clinical trials, S59–S60 inhibi-tors, S93, S94
CVD and, S59–S60 canagliflozin, S79, S81, S99–S100, Chronic Care Model, S8–S10,
diagnostic, S14–S15 S108 cancer, S32 S28 CKD. see kidney disease
glycemic targets and, S60–S61 CANVAS Program, S99–S100, S108 classification, S4, S13–S14
goals, S58–S59 CANVAS-R trial, S100 cognitive impairment/dementia, S32, S95,
hemoglobinopathies in, S15 capsaicin, S113 S120 colesevelam, S79, S81
limitations, S57 carbamazepine, S113 community health workers (CHWs), S10
mean glucose and, S57–S58 carbohydrates, S40–S42 comorbidities evaluation, assessment
microvascular complications and, cardiac autonomic neuropathy, anxiety disorders, S34
S59 in older adults, S121 S112 cardiovascular disease autoimmune diseases,
prediabetes screening, S16 A1C testing and, S59–S60 S32 cancer, S32
in pregnancy, S139 antiplatelet agents, S95–S96 cognitive impairment/dementia,
recommendations, S57 assessment of, S86 S32 depression, S34–S35
red blood cell turnover, S15 asymptomatic patients, screening, disordered eating behaviors,
acarbose, S79, S81 S96–S99 S35 fatty liver disease, S33
ACCORD BP trial, S87, S88 atherosclerotic, S5, S75, S86 fractures, S33
ACCORD MIND trial, S120 cardiac testing, S96–S99 hearing impairment, S33
ACCORD trial, S32–S33, S59–S61, S94, children, adolescents, S129–S131 HIV, S33–S34
S108 ACE inhibitors, S89, S91, S109, S141 coronary heart disease, S96–S101 hyperglycemia/hypoglycemia, S32–S33
acute kidney injury (AKI), S89, S106–S107 heart failure, S99 medical evaluation, S29–S32
ADAG study, S57–S58, S61–S62 hypertension/blood pressure control, nutrition therapy, S33
ADA Statements, S1 S86–S91 obstructive sleep apnea, S34
adolescents. see children and adolescents pancreatitis, S33
lifestyle management, S99 lipid
ADVANCE BP trial, S87, S88 patient-centered collaborative care,
management, S5, S91–S95
ADVANCE trial, S59–S61 medications, clinical trials, S97– S28–S29
advocacy position statements, S152– S100 prevention of, S53 primary periodontal disease, S34
S153 Affordable Care Act, S9, S133 prevention, S93 psychosocial/emotional disorders, S34,
age in A1C testing, S15, S20 revisions summary, S5 S45–S46
a-glucosidase inhibitors, S79, risk stratification, S92–S93 recommendations, S28
S81 AIM-HIGH trial, S94 secondary prevention, S93 revisions summary, S4
albiglutide, S80, S81 statins, S33, S91–S95 serious mental illness, S35
alcohol, S40, S42–S43, S70, S88, type 1 diabetes, S93 statins, S33
S94, S111 Alli (orlistat), S68 celiac disease, S129 testosterone levels, S34
alogliptin, S79, S81, S97–S99 CGM. see continuous glucose monitoring Consensus Reports, S1
amylin mimetics, S74, S80, S81 (CGM) Charcot neuroarthropathy, S114 continuous glucose monitoring (CGM)
anacetrapib, S94 children and adolescents children, adolescents,
angiotensin receptor blockers, S89, A1C testing in, S58, S128 S128 described, S56–
S91, S109, S141 autoimmune diseases, S128–S129 S57 flash, S56
antihyperglycemic therapy, S5, S67, celiac disease, S129 hospital care, S146
S75–S76, S96–S100, S146–S147 comorbidities, S133 hybrid closed-loop systems,
antihypertensive medications, S89– continuous glucose monitoring, S128 S57 recommendations, S55
S91, S109, S141 CVD risk factor management, S129–S131 revisions summary, S4–S5
antiplatelet agents, S95–S96 DSMES, S127 type 1 diabetes, S73–S74
Antithrombotic Trialists’ Collaboration, dyslipidemia in, S130 continuous subcutaneous insulin infusion
S95 anti-VEGF, S109–S111 glycemic control, S128 (CSII), S74, S147–S148
anxiety disorders, S34 hypertension in, S129–S130 contraception, S141
ASCVD. see cardiovascular disease hypoglycemia, S61–S62 Contrave (naltrexone/bupropion),
aspart, S80, S82 kidney disease, S131 S69 coronary heart disease, S96–
ASPIRE trial, S57 lifestyle management, S132 S101 correctional facilities, S153
aspirin resistance, S96 mature minor rule, S127 cost-effectiveness model, S52–
aspirin therapy, S95–S96, S140 neuropathy, S131 S53 costs
atherosclerotic cardiovascular disease. see pediatric to adult care transition, S133 of medications, S81–S82
cardiovascular disease pharmacologic therapy, S132–S133 reduction strategies, system-level, S9
atorvastatin, S92 physical activity/exercise, S43–S44, S52 cystic fibrosis–related diabetes screening, S24
autoimmune diseases, S32, S128–S129 prediabetes screening, S4, S5, S16,
autonomic neuropathy, S44, S111–S113 S19, S20 dapagliflozin, S79, S81
psychosocial issues, S127– DASH diet, S41
INDEX
diabetes distress, S35, S45–S46, S128 Diabetes classification, S13 HPS2-THRIVE trial, S94
Prevention Program, S52–S53 Diabetes contraception, S141 hyperbaric oxygen therapy,
Prevention Recognition Program, S52 diabetes definition, S20–S21 S114 hyperglycemia, S9–S10,
self-management education and diagnosis, S21–S22 S32, S60 hyperkalemia, S89
support (DSMES), S8, S38–S39, management of, S139–S140 hyperosmolar hyperglycemic state, S148–
S53, S127 diabetic retinopathy, S44, nutrition in, S139 S149 hypertension
S109–S111 Diabetic Retinopathy Study, pharmacologic therapy, S139–S140 antihypertensive medications, S89–
S110, S111 diagnosis physical activity and, S44 S91, S109, S141
ADA risk test, S18 postpartum care, S141 in children, adolescents, S129–
community screening, S20 prevalence of, S137 S130 clinical trials, S87
confirmation of, S15 testing recommendations, S20 kidney disease and, S108–S109
monogenic syndromes, S22– type 2 diabetes and, S141 lifestyle management, S88–S89
S25 one-step strategy, S21, glargine, S80, S82, S148 meta-analyses of trials, S87 in
S22 revisions summary, S4 glimepiride, S79, S81 older adults, S120, S121
testing interval, S20 glipizide, S10, S79, S81 in pregnancy, S87
tests, criteria, S14, S15 two- GLP-1 agonists resistant, S89–S90
step strategy, S21, S22 characterization, S69, S74, screening, diagnosis, S87
disordered eating behaviors, S76 in CKD, S108 treatment, individualization of, S87–
S35 dopamine-2 agonists, clinical trials, S97–S98, S88 treatment goals, S87
S79, S81 DPP-4 inhibitors S100 costs of, S81–S82 treatment recommendations, S90
characterization, S83 older adults, S122 treatment strategies, S88–S91
clinical trials, S97–S99 pharmacology, S79–S80 hypertriglyceridemia, S94
costs, S81 stopping therapy, S83 hypoglycemia
hospital care, S146–S147 glucagon, S62 anxiety disorders and, S34
older adults, S122 glulisine, S80, S82 assessment of, S32–S33
pharmacology, S76, S79 glyburide, S79, S81, S140 children/older adults, S61–
driving, S153 glycemic management. see also A1C S62 classification of, S61
dulaglutide, S80, S81 testing control, assessment of, S55 cognitive decline/impairment, S61
duloxetine, S112 intercurrent illness, S62 food insecurity and, S9–S10
physical activity and, S44 glucagon, S62
e-cigarettes, S44–S45 recommendations, S55, S60 hospital care, S147
EDIC study, S59 revisions summary, S4–S5 iatrogenic, S147
ELIXA trial, S97–S98, S100 self-monitoring of blood glucose mortality, S61
empagliflozin, S79, S81, S97–S98, (SMBG), S55–S56, S60 nocturnal, S57
S100, S108 EMPA-REG OUTCOME, in older adults, S120, S123
S97–S99, S108 employment, S153 HAPO study, S21 physical activity and, S44
end-of-life care, S122–S124 hearing impairment, S33 predictors of, S147
eplerenone, S109 erectile hemoglobinopathies, S15 prevention, S62, S147
dysfunction, S113 ETDRS trial, hepatitis B, S29, S32 recommendations, S61
S110, S111 evidence-grading herbal supplements, S40, S42 symptoms of, S61
system (ADA), S2 EXAMINE, HIV, S33–S34 treatment, S62
S97–S99 homelessness, S10 triggering events, S147
exenatide, exenatide ER, S79, hospital care hypoglycemia unawareness, S34, S57, S61, S62
S81, S97–S98, S100 admission, S144–S145
exercise/physical activity, S43–S44, admission/readmission prevention,
S52, S66–S67 immune-mediated diabetes,
S149–S150 S17 immunizations, S29–S30
EXSCEL trial, S97–S98, S100
antihyperglycemic agents, S146–S147 IMPROVE-IT trial, S93
eye disease, S44, S109–S111
critical care units, S146 incretin-based therapies, S69, S74, S76,
ezetimide, S92, S93
delivery standards, S144–S145 S81, S97–S98
diabetes care providers, S145 influenza, S29, S32
fats (dietary), S40, S42 diabetes self-management, S147– insulin therapy
fatty liver disease, S33 S148 discharge planning, S149 basal, S82
fenofibrate, S94 DKA, S148–S149 bolus, S82–S83
fibrate, S94 DPP-4 inhibitors, S146–S147 carbohydrate intake and, S42
finerenone, S109 enteral/parenteral feedings, S148 combination injectable, S83
flash CGM device, S56 glucocorticoid therapy, S148 concentrated preparations, S83
flexibility training, S43 glucose abnormalities definitions, S145 correctional, in hospital care, S148
fluvastatin, S92 glucose monitoring, bedside, S145–S146 costs, S82
food insecurity, S9–S10 glycemic control, moderate vs. tight, S145 CSII/CGM, S74
foot care, S5, S113–S114 glycemic targets, S145 food insecurity patients, S10
FOURIER trial, S93 hyperosmolar hyperglycemic in GDM, S140
FPG testing, S14 state, S148–S149 hospital care, S146, S148
fractures, S33 hypoglycemia, S147 inhaled, S83
insulin therapy, S146, S148 older adults, S122–S123
gabapentin, S113 medical nutrition therapy, S147 pharmacology, S80
gastrointestinal neuropathies, medication reconciliation, S149 premixed, S83
S112 gastroparesis, S113 perioperative care, S148 SMBG, S55–S56, S60
GDM. see gestational diabetes physician order entry, S145 type 1 diabetes, S73–S74
mellitus generalized anxiety disorder, posttransplantation diabetes therapy, S25 type 2 diabetes, S76, S78, S82–S83
S34 genitourinary disturbances, S112 quality assurance standards, S145
gestational diabetes mellitus. see also revisions summary, S6
pregnancy HOT trial, S87, S88 jail, S153
S158 Index Diabetes Care Volume 41, Supplement 1, January 2018
kidney disease medical nutrition therapy (MNT), S29, S38– diet, physical activity, behavioral
acute kidney injury, S89, S106– S43, S52, S91, S107–S108, S139, therapy, S43–S44, S52, S66–S67
S107 albuminuria assessment, S147. see also nutrition therapy medications, S67–S69 metabolic
S106 children, adolescents, Medicare, S39 surgery, S67–S70 prediabetes
S131 complications of, S107 medications. see also specific drugs and screening, S16 prediabetes testing
diagnosis of, S106 drug classes recommendations,
eGFR assessment, S106 cardiovascular outcomes trials, S77– S4, S5
epidemiology, S106 S81 combination therapy, S75–S81, recommendations, S65, S66
glucose-lowering medications, S108 S83, S93 compliance, S8–S9 treatment options,
glycemic control, S108 concomitant, S67 S66 obstructive sleep
hypertension and, S108–S109 costs, S81–S82 apnea, S34 older adults
interventions, S107–S109 CVOTs, S97–S100 A1C in, S121
nutrition therapy, S107–S108 diabetes screening, S20 admission/readmission prevention,
physical activity and, S44 efficacy, safety assessment, S149–S150
proteins, dietary, S42 S67 obesity management, alert strategy, S123
recommendations, S105–S106 S67–S69 pharmacology, S79– aspirin use in, S96
revisions summary, S5 S80 recommendations, S53 assisted living facilities, S123
screening, S105 type 1 diabetes, S73–S75 type 2 cognitive impairment/dementia, S32,
stages, S106, S107 diabetes, S75–S83 Mediterranean S95, S120
surveillance, S107 diet, S33, S41, S42 CVD primary prevention,
treatment, S105–S106 meglitinides (glinides), S79, S93 hypertension in, S120,
Kumamoto Study, S59 S81 metformin S121 hypoglycemia, S61–
A1C guidelines, S4 S62 hypoglycemia in, S120,
in CKD, S108 S123 insulin therapy, S122–
language barriers, S10 coronary heart disease, S96 S123 LTC facilities, S123
laropiprant, S94 costs, S81 nutrition, S123
LEADER trial, S97–S98, S100, CVD risk reduction agents with, palliative, end-of-life care, S122–
S108 lifestyle management S100– S101 S124 pharmacologic therapies,
cardiovascular disease, S99 in GDM, S140 S122–S123 recommendations,
children, adolescents, S132 cost- pharmacology, S79 S119 revisions summary, S5
effectiveness model, S52–S53 type 1 diabetes, S74 statins, S33, S91–S95
DSMES, S8, S38–S39, S53 treatment goals, S60, S120–S122
type 2 diabetes, S53, S75–S78
gestational diabetes mellitus,
metoclopramide, S113 micronutrients, in orlistat (Alli), S68 orlistat
S139 hypertension, S88–S89 MNT, S40, S42 microvascular (Xenical), S68 orthostatic
lipids, S91 complications, S5. see also hypotension, S113
nutrition therapy, S39–S43, S52 specific conditions
physical activity/exercise, S43–S44, miglitol, S79, S81
S52, S66–S67 palliative, end-of-life care, S122–S124 pancreas,
mineralocorticoid receptor antagonists, pancreatic islet transplantation, S33,
psychosocial issues, S34, S45– S91, S109 S74–S75
S46 recommendations, S38 mobile apps, S52
revisions summary, S4 smoking
pancreatitis, S33
modified plate method, S42 patient-centered care, S7–S8, S28–
cessation, S44–S45 technology
platforms, S52 weight, S41, S29 Patient-Centered Medical Home,
S52, S66–S67, S88 nateglinide, S79, S81 S8 PCSK9 inhibitors, S92–S95
linagliptin, S79, S81 National Diabetes Education Program, pediatric to adult care transition, S133
lipase inhibitors, S68 S8 National Quality Strategy, S9 periodontal disease, S34 peripheral arterial
lipid management neonatal diabetes screening, S22–S23 disease, S114 peripheral neuropathy, S44,
nephropathy. see kidney disease S111–S113 pharmacotherapy. see
in children and adolescents,
neuropathic pain, S112–S113
medications; specific
S130 hypertriglyceridemia,
S94 lifestyle modifications, neuropathy, S44, S111–S113, S131 medications by name phentermine
S91 revisions summary, S5 new-onset diabetes after transplantation (Lomaira), S68 photocoagulation
statins, S33, S91–S95 (NODAT), S24–S25 surgery, S109–S111 physical
therapy, monitoring, S91 niacin, S94 activity/exercise, S43–S44, S52,
NPH, S80, S82, S83, S148 S66–S67
liraglutide (Saxenda), S69, S80,
S81, S82, S97–S98, S108 nutrition therapy pioglitazone, S79, S81
lispro, S80, S82 alcohol, S40, S42–S43, S88 pitavastatin, S92
carbohydrates, S40–S42 plant-based diets, S41
lixisenatide, S80, S81, S82, S97–
S98, S100 Lomaira (phentermine), comorbidities, S33 plasma glucose testing, S15
S68 Look AHEAD trial, S66, S99 DASH diet, S41 pneumococcal pneumonia, S29, S32
lorcaserin (Belviq), S68 fats (dietary), S40, S42 point-of-care (POC) meters, S145–S146
in GDM, S139 population health
loss of protective sensation (LOPS),
S111, S113–S114 herbal supplements, S40, care delivery systems, S8
lovastatin, S92 S42 hospital care, S147 Chronic Care Model, S8–S10,
kidney disease, S107–S108 S28 community support, S10
lifestyle management, S39–S43, S52 defined, S7
maturity-onset diabetes/young Mediterranean diet, S33, S41, S42 food insecurity, S9–S10
(MODY), S23–S24 older adults, S123 homelessness, S10
meal planning, S39–S43, S52, S88, proteins, S40, S42 language barriers, S10
S107–S108 medical evaluation patient-centered care,
immunizations, S29–S30 S7–S8 recommendations,
pre-exercise, S44 obesity management S7 revisions summary, S4
recommendations, S29 assessment, S65–S66 social context, determinants, S9
referrals, S32, S46, S109 diabetes screening, S20
system-level improvement
strategies, S8
care.diabetesjournals.org Index S159
posttransplantation diabetes screening, S24–S25 SAVOR-TIMI 53, S97–S99 children and adolescents, S126–S131
pramlintide, S77, S80, S81 saxagliptin, S79, S81, S97–S98 classification, S13–S14
pravastatin, S92 Saxenda (liraglutide), S69, S80–S82, S97–S98, CVD/A1C and, S59
prediabetes S108 diagnosis (see diagnosis)
described, S16 schizophrenia, S35 disordered eating behaviors in, S35
increased risk categories, S17 school, child care, S127, S152–S153 idiopathic, testing for, S17
screening, S4, S15–S16 scientific reviews, S2 insulin therapy, S73–S74
screening in asymptomatic adults, S16, SEARCH study, S130 medications, S73–S75
S19–S20 self-monitoring of blood glucose (SMBG), pathophysiology, S14
serious mental illness, S35 S55–S56, S60 physical activity/exercise, S43–S44
pregabalin, S112 semaglutide, S97–S98, S100, S108 predictors, S14
pregnancy. see also gestational diabetes mellitus SGLT2 inhibitors retinopathy and, S110
A1C in, S139 characterization, S74 risk testing, S17
antihypertensive medications, S90–S91, S141 clinical trials, S97–S100 stages of, S14
glucose monitoring, S138–S139 costs, S81 surgical treatment, S74–S75
glycemic targets in, S138 hospital care, S147 testing recommendations, S16–S17
hypertension in, S87 kidney disease, S106–S108 type 2 diabetes
insulin physiology, S138 older adults, S122 age as risk factor, S20
lactation, S141 pharmacology, S76, S79 BMI as risk factor, S20
medications contraindicated, S91, stopping therapy, S83 children and adolescents, S19, S20, S131–S133
S140–S141 shoes, S114 classification, S13–S14
postpartum care, S141 simvastatin, S92–S94 CVD/A1C and, S59
preconception counseling, testing, sitagliptin, S79, S81, S97–S99 described, S19
S137–S138 smoking cessation, S44–S45, S130–S131 diagnosis (see diagnosis)
preeclampsia, aspirin and, S140 sodium, S40, S42, S88, S107–S108 DKA in, S19
preexisting diabetes, S140 spironolactone, S91, S109 ethnicity as risk factor, S20
prevalence of diabetes in, S137 SPRINT trial, S87, S88 hypertriglyceridemia, S94
retinopathy and, S110 SSRIs, S68 medications, S75–S83
revisions summary, S5–S6 Standards of Care statements, S1, S3 pathophysiology, S14
prison, S153 statins, S33, S91–S95 physical activity/exercise, S43–S44
Professional Practice Committee (PPC), S3 sulfonylureas prevention/delay, S4, S51–S53
proteins, S40, S42 costs, S81 proteins, dietary, S42
psychosis, S35 food insecurity patients, S10 retinopathy and, S110
psychosocial/emotional disorders, S34, S45–S46 in GDM, S140 risk-based screening, S19
P2Y12 receptor antagonists, S96 older adults, S122 screening in asymptomatic adults, S16,
pharmacology, S79 S19–S20
Qsymia (phentermine/topiramate), S68 stopping therapy, S83 screening in dental practices, S20
type 2 diabetes, S76 serious mental illness, S35
race/ethnicity in A1C testing, S15, S20 SUSTAIN-6, S97–S98, S100, S108 testing recommendations, S17–S19
sweeteners (nonnutritive), S41, S43 weight management, S41, S52
ranibizumab, S109–S111
REMOVAL trial, S74 UK Prospective Diabetes Study (UKPDS), S59, S96
repaglinide, S79, S81 tai chi, S43
retinal photography, S109, S110 tapentadol, S112–S113
retinopathy, S44, S109–S111, S131 TECOS, S97–S99 VADT trial, S59, S60
REVEAL trial, S94 testosterone levels, S34 venlafaxine, S113
risk management thiazolidinediones, S76, S79, S81, S83, S122
calculator, S92–S93 thyroid disease, S129 weight management, S41, S52, S66–S67, S88
revisions summary, S5 tobacco, S44–S45
statins based on, S92 tramadol, S113 Xenical (orlistat), S68
stratification, S92 tricyclic antidepressants, S113
rosiglitazone, S79, S81 2-h PG testing, S14
rosuvastatin, S92, S95 type 1 diabetes yoga, S43