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Diabetes Care Volume 41, December 2018 2669

Melanie J. Davies,1,2 David A. D’Alessio,3


Management of Hyperglycemia Judith Fradkin,4 Walter N. Kernan,5
Chantal Mathieu,6 Geltrude Mingrone,7,8
in Type 2 Diabetes, 2018. Peter Rossing,9,10 Apostolos Tsapas,11
Deborah J. Wexler,12,13 and John B. Buse14
A Consensus Report by the
American Diabetes Association
(ADA) and the European Association
for the Study of Diabetes (EASD)
Diabetes Care 2018;41:2669–2701 | https://doi.org/10.2337/dci18-0033 1
Diabetes Research Centre, University of Leices-
ter, Leicester, U.K.
2
Leicester Diabetes Centre, Leicester General

CONSENSUS REPORT
Hospital, Leicester, U.K.
3
Department of Medicine, Duke University School
of Medicine, Durham, NC
4
National Institute of Diabetes and Digestive
and Kidney Diseases, National Institutes of
Health, Bethesda, MD
5
Department of Medicine, Yale School of Med-
icine, New Haven, CT
The American Diabetes Association and the European Association for the Study of 6
Clinical and Experimental Endocrinology, UZ
Diabetes convened a panel to update the prior position statements, published in Gasthuisberg, KU Leuven, Leuven, Belgium
7
2012 and 2015, on the management of type 2 diabetes in adults. A systematic Department of Internal Medicine, Catholic Uni-
versity, Rome, Italy
evaluation of the literature since 2014 informed new recommendations. These 8
Diabetes and Nutritional Sciences, King’s College
include additional focus on lifestyle management and diabetes self-management London, London, U.K.
9
education and support. For those with obesity, efforts targeting weight loss, Steno Diabetes Center Copenhagen, Gentofte,
including lifestyle, medication, and surgical interventions, are recommended. With Denmark
10
University of Copenhagen, Copenhagen, Den-
regards to medication management, for patients with clinical cardiovascular mark
11
disease, a sodium–glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like Second Medical Department, Aristotle Univer-
peptide 1 (GLP-1) receptor agonist with proven cardiovascular benefit is recom- sity Thessaloniki, Thessaloniki, Greece
12
Department of Medicine and Diabetes Unit,
mended. For patients with chronic kidney disease or clinical heart failure and
Massachusetts General Hospital, Boston, MA
atherosclerotic cardiovascular disease, an SGLT2 inhibitor with proven benefit is 13
Harvard Medical School, Boston, MA
recommended. GLP-1 receptor agonists are generally recommended as the first 14
Department of Medicine, University of North
injectable medication. Carolina School of Medicine, Chapel Hill, NC
Corresponding author: John B. Buse, jbuse@med
.unc.edu.
The goals of treatment for type 2 diabetes are to prevent or delay complications and This article is featured in a podcast available
maintain quality of life (Fig. 1). This requires control of glycemia and cardiovascular risk at http://www.diabetesjournals.org/content/
factor management, regular follow-up, and, importantly, a patient-centered approach diabetes-core-update-podcasts.
to enhance patient engagement in self-care activities (1). Careful consideration of M.J.D. and J.B.B. were co-chairs for the Consensus
patient factors and preferences must inform the process of individualizing treatment Statement Writing Group. D.A.D’A., J.F., W.N.K.,
goals and strategies (2,3). and D.J.W. were the writing group members for
the American Diabetes Association. C.M., G.M.,
This consensus report addresses the approaches to management of glycemia in
P.R., and A.T. were writing group members for the
adults with type 2 diabetes, with the goal of reducing complications and maintaining European Association for the Study of Diabetes.
quality of life in the context of comprehensive cardiovascular risk management and This article is being simultaneously published in
patient-centered care. The principles of how this can be achieved are summarized in Diabetes Care and Diabetologia by the American
Fig. 1 and underpin the approach to management and care. These recommendations Diabetes Association and the European Associ-
are not generally applicable to patients with monogenic diabetes, secondary diabetes, ation for the Study of Diabetes.
or type 1 diabetes, or to children. © 2018 American Diabetes Association and
European Association for the Study of Diabetes.
Data Sources, Searches, and Study Selection Readers may use this article as long as the work
is properly cited, the use is educational and not
The writing group accepted the 2012 (4) and 2015 (5) editions of this position for profit, and the work is not altered. More infor-
statement as a starting point. To identify newer evidence, a search was conducted on mation is available at http://www.diabetesjournals
PubMed for randomized clinical trials (RCTs), systematic reviews, and meta-analyses .org/content/license.
2670
Consensus Report

Figure 1—Decision cycle for patient-centered glycemic management in type 2 diabetes.


Diabetes Care Volume 41, December 2018
care.diabetesjournals.org Davies and Associates 2671

published in English between 1 January studies with other medication classes. laboratories (www.ngsp.org) (11). As
2014 and 28 February 2018; eligible The greatest absolute risk reduction with any laboratory test, HbA1c has lim-
publications examined the effectiveness (ARR) comes from improving poor gly- itations (2). Because there is variability
or safety of pharmacological or nonphar- cemic control, and a more modest re- in the measurement of HbA1c, clinicians
macological interventions in adults with duction results from near normalization should exercise judgment, particularly
type 2 diabetes mellitus. Reference lists of glycemia (6). The impact of glucose when the result is close to the threshold
were scanned in eligible reports to iden- control on macrovascular complica- that might prompt a change in therapy.
tify additional articles relevant to the sub- tions is less certain. Because the bene- HbA1c results may be discrepant from the
ject. Details on the keywords and the fits of intensive glucose control emerge patient’s true mean glycemia in certain
search strategy are available at https:// slowly, while the harms can be immedi- racial and ethnic groups, and in condi-
doi.org/10.17632/h5rcnxpk8w.1. Papers ate, people with longer life expectancy tions that alter red blood cell turnover,
were grouped according to subject, and have more to gain from intensive glu- such as anemia, end-stage renal disease
the authors reviewed this new evidence to cose control. A reasonable HbA1c target (ESRD) (especially with erythropoietin
inform the consensus recommendations. for most nonpregnant adults with suffi- therapy), and pregnancy, or if an HbA1c
The draft consensus recommendations cient life expectancy to see microvascu- assay sensitive to hemoglobin variants
were peer reviewed (see “Acknowledg- lar benefits (generally ;10 years) is is used in someone with sickle cell trait
ments”), and suggestions incorporated around 53 mmol/mol (7%) or less (6). or other hemoglobinopathy. Discrep-
as deemed appropriate by the authors. Glycemic treatment targets should be ancies between measured HbA1c and
Nevertheless, though evidence-based, individualized based on patient prefer- measured or reported glucose levels
the recommendations presented herein ences and goals, risk of adverse effects should prompt consideration that one
are the opinions of the authors. of therapy (e.g., hypoglycemia and of these may not be reliable (12).
weight gain), and patient characteris- Regular self-monitoring of blood glucose
The Rationale, Importance, and tics, including frailty and comorbid (SMBG) may help with self-management
Context of Glucose-Lowering conditions (2). and medication adjustment, particularly
Treatment Atherosclerotic cardiovascular dis- in individuals taking insulin. SMBG plans
Lifestyle management, including medical ease (ASCVD) is the leading cause of should be individualized. People with
nutrition therapy (MNT), physical activ- death in people with type 2 diabetes diabetes and the health care team should
ity, weight loss, counseling for smoking (7). Diabetes confers substantial inde- use the data in an effective and timely
cessation, and psychological support, pendent ASCVD risk, and most people manner. In people with type 2 diabetes
often delivered in the context of diabetes with type 2 diabetes have additional risk not using insulin, routine glucose mon-
self-management education and support factors such as hypertension, dyslipide- itoring is of limited additional clinical
(DSMES), are fundamental aspects of mia, obesity, physical inactivity, chronic benefit while adding burden and cost
diabetes care. The expanding number kidney disease (CKD), and smoking. Nu- (13,14). However, for some individuals,
of glucose-lowering treatmentsdfrom merous studies have demonstrated glucose monitoring can provide insight
behavioral interventions to medica- the benefits of controlling modifiable into the impact of lifestyle and medica-
tions and surgerydand growing infor- ASCVD risk factors in people with di- tion management on blood glucose and
mation about their benefits and risks abetes. Substantial reductions in ASCVD symptoms, particularly when combined
provides more options for people with events and death are seen when multi- with education and support. Novel tech-
diabetes and providers, but can compli- ple ASCVD risk factors are addressed nologies, such as continuous or flash
cate decision making. In this consen- simultaneously, with long-standing ben- glucose monitoring, provide more infor-
sus statement, we attempt to provide efits (8,9). Comprehensive implementa- mation. However, in type 2 diabetes,
an approach that summarizes a large tion of evidence-based interventions has they have been associated with only
body of recent evidence for practi- likely contributed to the significant re- modest benefits (15).
tioners in the U.S. and Europe. ductions in ASCVD events and mortality
Principles of Care
Marked hyperglycemia is associated seen in people with diabetes in recent
with symptoms including frequent uri- decades (10). ASCVD risk management Consensus recommendation
nation, thirst, blurred vision, fatigue, and in its many forms is an essential part c Providers and health care systems
recurring infections. Beyond alleviat- of diabetes management that is beyond should prioritize the delivery of
ing symptoms, the aim of blood glu- the scope of this statement, but physi- patient-centered care.
cose lowering (hereafter, referred to cians should be aware of the impor-
as glycemic management) is to reduce tance of multifactorial treatment in Providing patient-centered care that
long-term complications of diabetes. type 2 diabetes (7). acknowledges multimorbidity, and is
Good glycemic management yields sub- respectful of and responsive to individ-
stantial and enduring reductions in on- Glucose Management: Monitoring ual patient preferences and barriers,
set and progression of microvascular Glycemic management is primarily as- including the differential costs of thera-
complications. This benefit has been sessed with the HbA1c test, which was the pies, is essential to effective diabetes
demonstrated most clearly early in the measure studied in trials demonstrating management (16). Shared decision mak-
natural history of the disease in studies the benefits of glucose lowering (2). The ing, facilitated by decision aids that
using metformin, sulfonylureas, and in- performance of the test is generally show the absolute benefit and risk of
sulin but is supported by more recent excellent for NGSP-certified assays and alternative treatment options, is a useful
2672 Consensus Report Diabetes Care Volume 41, December 2018

strategy to arrive at the best treatment In type 2 diabetes, high-quality evi- care. Multiple factors contribute to
course for an individual (17–20). Pro- dence has consistently shown that inconsistent medication use and treat-
viders should evaluate the impact of DSMES is a cost-effective intervention ment discontinuation, including patient-
any suggested intervention, including in the health care systems studied. perceived lack of medication efficacy,
self-care regimens, in the context of DSMES significantly improves clinical fear of hypoglycemia, lack of access
cognitive impairment, limited literacy, and psychological outcomes, improves to medication, and adverse effects of
distinct cultural beliefs, and individual glycemic control, reduces hospital ad- medication (37). Medication adherence
fears or health concerns given their missions, improves patient knowledge, (including persistence) varies across
impact on treatment efficacy. and reduces the risk of all-cause mor- medication classes and careful consider-
tality (22,26–31). The best outcomes ation of these differences may help im-
DSMES are achieved in those programs with a prove outcomes (38). Ultimately, patient
theory-based and structured curricu- preference is a major factor driving the
Consensus recommendation
lum and with contact time of over choice of medication. Even in cases
c All people with type 2 diabetes
10 h. While online programs may re- where clinical characteristics suggest
should be offered access to ongo-
inforce learning, there is little evi- the use of a particular medication based
ing DSMES programs.
dence they are effective when used on the available evidence from clinical
alone (27). trials, patient preferences regarding
DSMES is a key intervention to en-
route of administration, injection de-
able people with diabetes to make
Consensus recommendation vices, side effects, or cost may prevent
informed decisions and to assume re-
c Facilitating medication adherence their use by some individuals (39).
sponsibility for day-to-day diabetes
should be specifically considered Therapeutic inertia, sometimes re-
management. DSMES is central to es-
when selecting glucose-lowering ferred to as clinical inertia, refers to
tablishing and implementing the princi-
medications. failure to intensify therapy when treat-
ples of care (Fig. 1). DSMES programs
ment targets are not met. The causes
usually involve face-to-face contact in
Suboptimal adherence, including poor of therapeutic inertia are multifacto-
group or individual sessions with trained
persistence, to therapy affects almost rial, occurring at the level of the prac-
educators, and key components are
half of people with diabetes, leading titioner, patient, and/or health care
shown in Table 1 (21–25). While DSMES
to suboptimal glycemic and cardiovas- system (40). Interventions targeting
should be available on an ongoing basis,
cular disease (CVD) risk factor control as therapeutic inertia have facilitated
critical junctures when DSMES should
well as increased risk of diabetes com- improved glycemic control and timely
occur include at diagnosis, annually,
plications, mortality, hospital admis- insulin intensification (41,42). For
when complications arise, and during
sions, and health care costs (32–36). example, multidisciplinary teams that
transitions in life and care (22).
Though this consensus recommenda- include nurse practitioners or pharma-
DSMES programs delivered from
tion focuses on medication adherence cists may help reduce therapeutic iner-
diagnosis can promote medication
tia (43,44). A fragmented health care
adherence, healthy eating, and physi- (including persistence), the principles
system may contribute to therapeutic
cal activity, and increase self-efficacy. are pertinent to all aspects of diabetes
inertia and impair delivery of patient-
centered care. A coordinated chronic
Table 1—Key components of DSMES (21,23–25)
care model, including self-management
c Evidence-based
support, decision support, delivery sys-
c Individualized to the needs of the person, including language and culture
tem design, clinical information sys-
c Has a structured theory-driven written curriculum with supporting materials
tems, and community resources and
c Delivered by trained and competent individuals (educators) who are quality assured
policies, promotes interaction between
c Delivered in group or individual settings more empowered patients and better
c Aligns with the local population needs prepared and proactive health care
c Supports the person and their family in developing attitudes, beliefs, knowledge, and skills to teams (45).
self-manage diabetes
c Includes core content; i.e., diabetes pathophysiology and treatment options; medication RECOMMENDED PROCESS FOR
usage; monitoring, preventing, detecting, and treating acute and chronic complications;
GLUCOSE-LOWERING
healthy coping with psychological issues and concerns; problem solving and dealing with
special situations (i.e., travel, fasting)
MEDICATION SELECTION: WHERE
DOES NEW EVIDENCE FROM
c Available to patients at critical times (i.e., at diagnosis, annually, when complications arise, and
when transitions in care occur)
CARDIOVASCULAR OUTCOMES
TRIALS FIT IN?
c Includes monitoring of patient progress, including health status, quality of life
c Quality audited regularly In prior consensus statements, efficacy
in reducing hyperglycemia, along with
DSMES is a critical element of care for all people with diabetes and is the ongoing process
of facilitating the knowledge, skills, and ability necessary for diabetes self-care as well as activities tolerability and safety were primary
that assist a person implementing and sustaining behaviors needed to manage their factors in glucose-lowering medication
diabetes on an ongoing basis. National organizations in the U.S. and Europe have published selection. Patient preferences, glycemic
standards to underpin DSMES. In the U.S., these are defined as DSMES “services,” whereas in targets, comorbidities, polypharmacy,
Europe they are often referred to as “programs.” Nevertheless, the broad components are similar.
side effects, and cost were additional
care.diabetesjournals.org Davies and Associates 2673

important considerations. For every in- Where the current evidence is strongest 0.74, 0.97; P 5 0.02; ARR 1.4%) for
dividual, the choice of glucose-lowering for a specific medication within a class, it all-cause mortality (47). In the Trial to
medication should be underpinned by is noted. The American Diabetes Asso- Evaluate Cardiovascular and Other Long-
lifestyle management, DSMES, and the ciation’s (ADA) Standards of Medical term Outcomes with Semaglutide in
patient-centered care principles outlined Care in Diabetes will align with this Subjects with Type 2 Diabetes (SUSTAIN
in Fig. 1. document and will be updated to reflect 6) (n 5 3,297), semaglutide compared
Figure 2 describes our new consensus new evidence as it emerges from ongoing with placebo demonstrated an ARR of
approach to glucose lowering with med- clinical trials. 2.3% with HR 0.74 for MACE (95% CI 0.58,
ications in type 2 diabetes. Because of the 0.95; P 5 0.02 for superiority) over 2.1
new evidence for the benefit of specific Consensus recommendation years, but the reduction in events ap-
medications to reduce mortality, heart c Among patients with type 2 diabe- peared to be driven by the rate of stroke
failure (HF), and progression of renal tes who have established ASCVD, rather than CVD death (48). The Exena-
disease in the setting of established SGLT2 inhibitors or GLP-1 recep- tide Study of Cardiovascular Event Low-
CVD, their use was considered compel- tor agonists with proven cardiovas- ering (EXSCEL) compared exenatide
ling in this patient group. Thus, we rec- cular benefit are recommended extended-release with placebo over
ommend that providers consider a as part of glycemic management 3.2 years in 14,752 participants with
history of CVD very early in the process (Figs. 2 and 3). type 2 diabetes. While the medication
of treatment selection. Other factors was safe (noninferior), the HR for MACE
affect the choice of glucose-lowering ASCVD is defined somewhat differ- in the entire trial was 0.91 (95% CI 0.83,
medications, particularly in the setting ently across trials, but all trials enrolled 1.0; P 5 0.06) not reaching the threshold
of patient-centered care. In addition to individuals with established CVD (e.g., for demonstrated superiority versus pla-
CVD, we recommend early consideration myocardial infarction [MI], stroke, cebo; ARR was 0.8% (49). All-cause death
of weight, hypoglycemic risk, treatment any revascularization procedure) while was lower in the exenatide arm (ARR 1%,
cost, and other patient-related factors variably including related conditions HR 0.86 [95% CI 0.77, 0.97]), but it was
that may influence treatment selection compatible with clinically significant not considered to be statistically signif-
(Figs. 2–6). atherosclerosis (e.g., transient ischemic icant in the hierarchical testing proce-
attack, hospitalized unstable angina, dure applied. Lixisenatide, a short-acting
Implications of New Evidence From amputation, congestive heart failure GLP-1 receptor agonist, did not demon-
Cardiovascular Outcomes Trials New York Heart Association [NYHA] class strate CVD benefit or harm in a trial of
The major change from prior consensus II–III, .50% stenosis of any artery, symp- patients recruited within 180 days of an
reports is based on new evidence that tomatic or asymptomatic coronary artery acute coronary syndrome admission (50).
specific sodium–glucose cotransporter disease documented by imaging, CKD Taken together, it appears that among
2 (SGLT2) inhibitors or glucagon-like with estimated glomerular filtration rate patients with established CVD, some GLP-
peptide 1 (GLP-1) receptor agonists im- [eGFR],60mL min21 [1.73]22).Most trials 1 receptor agonists may provide cardio-
prove cardiovascular outcomes, as well also included a “risk factor only” group vascular benefit, with the evidence of
as secondary outcomes such as HF and with entry criteria based on age and usually benefit strongest for liraglutide, favorable
progression of renal disease, in patients the presence of two or more cardiac risk for semaglutide, and less certain for ex-
with established CVD or CKD. Therefore, factors (46). Trials were designed to eval- enatide. There is no evidence of cardio-
an important early step in this new uate cardiovascular safety (i.e., statistical vascular benefit with lixisenatide. Adverse
approach (Fig. 3) is to consider the pres- noninferiority compared with placebo), but effects for the class are discussed in the
ence or absence of ASCVD, HF, and CKD, several showed ASCVD outcome benefit section “The Full Range of Therapeutic
conditions in aggregate affecting 15–25% (i.e., statistical superiority compared with Options: Lifestyle Management, Medica-
of the population with type 2 diabetes. placebo), including, in some cases, mortality. tion, and Obesity Management.”
While the new evidence supporting the Among GLP-1 receptor agonists, lira- Among the SGLT2 inhibitors, em-
use of particular medications in patients glutide, studied in the Liraglutide pagliflozin compared with placebo was
who also have established CVD or are at Effect and Action in Diabetes: Evalua- studied in the Empagliflozin, Cardiovas-
high risk of CVD is derived from large tion of Cardiovascular Outcome Results cular Outcome Event Trial in Type 2
cardiovascular outcomes trials (CVOTs) (LEADER) trial (n 5 9,340), demonstrated Diabetes Mellitus Patients (EMPA-REG
demonstrating substantial benefits over an ARR of 1.9% with a hazard ratio (HR) OUTCOME) in 7,020 participants with
2–5 years, it is important to remember of 0.87 (95% CI 0.78, 0.97; P 5 0.01 for type 2 diabetes and CVD. With a median
that each trial constitutes a single ex- superiority) for the primary composite follow-up of 3.1 years, the ARR was 1.6%
periment. Within each drug class, results outcome of cardiovascular death, non- and the HR was 0.86 (95% CI 0.74, 0.99;
have been heterogeneous. It is not clear fatal MI, and nonfatal stroke (major ad- P 5 0.04 for superiority) for the primary
whether there are true drug-class ef- verse cardiac events [MACE]) compared composite end point of nonfatal MI,
fects with different findings for individ- with placebo over 3.8 years. Each com- nonfatal stroke, and cardiovascular
ual medications due to differences in ponent of the composite contributed to death. The ARR was 2.2% and the HR
trial design and conduct, or whether the benefit, and the HR for cardiovascular was 0.62 (95% CI 0.49, 0.77; P , 0.001)
there are real differences between death was 0.78 (95% CI 0.66, 0.93; P 5 for cardiovascular death (51). The ARR
medications within a drug class due to 0.007; ARR 1.7%). The LEADER trial also was 2.6% and the HR was 0.68 (95% CI
properties of the individual compounds. demonstrated an HR of 0.85 (95% CI, 0.57, 0.82; P , 0.001) for death from
2674
Consensus Report

Figure 2—Glucose-lowering medication in type 2 diabetes: overall approach. CV, cardiovascular; DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1 RA, glucagon-like peptide 1 receptor agonist; SGLT2i, SGLT2 inhibitor;
SU, sulfonylurea.
Diabetes Care Volume 41, December 2018
care.diabetesjournals.org Davies and Associates 2675

Figure 3—Choosing glucose-lowering medication in those with established ASCVD, HF, and CKD. CV, cardiovascular; DPP-4i, dipeptidyl peptidase
4 inhibitor; GLP-1 RA, glucagon-like peptide 1 receptor agonist; SGLT2i, SGLT2 inhibitor; SU, sulfonylurea.
2676 Consensus Report Diabetes Care Volume 41, December 2018

Figure 4—Choosing glucose-lowering medication if compelling need to minimize weight gain or promote weight loss. GLP-1 RA, glucagon-like peptide
1 receptor agonist; T2DM, type 2 diabetes; SGLT2i, SGLT2 inhibitor; SU, sulfonylurea.
care.diabetesjournals.org Davies and Associates 2677

Figure 5—Choosing glucose-lowering medication if compelling need to minimize hypoglycemia. DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1 RA,
glucagon-like peptide 1 receptor agonist; SGLT2i, SGLT2 inhibitor.
2678 Consensus Report Diabetes Care Volume 41, December 2018

Figure 6—Choosing glucose-lowering medication if cost is a major issue. DPP-4i, dipeptidyl peptidase 4 inhibitor; SGLT2i, SGLT2 inhibitor; SU,
sulfonylurea.
care.diabetesjournals.org Davies and Associates 2679

any cause. Canagliflozin compared with that patients with clinical CVD not meet- hospitalized HF of 5.5 vs. 8.7 events per
placebo was studied in the Canagliflozin ing individualized glycemic targets while 1,000 patient-years (55). Because HF was
Cardiovascular Assessment Study treated with metformin (or in whom neither well characterized at baseline nor
(CANVAS) Program (comprised of two metformin is contraindicated or not tol- as carefully adjudicated as it would have
similar trials, CANVAS and CANVAS- erated) should have an SGLT2 inhibitor been in a trial specifically designed to
Renal; n 5 10,142) in participants with or GLP-1 receptor agonist with proven evaluate HF outcomes, and because HF
type 2 diabetes, 66% of whom had benefit for cardiovascular risk reduction was a secondary end point in the trials,
a history of CVD. Participants were added to their treatment program. There further ongoing studies are required to
followed for a median of 3.6 years. In are no clinical trial data that support conclusively address the issue. That said,
the combined analysis of the two trials, prescribing an SGLT2 inhibitor or GLP- the significant reduction in hospitaliza-
the primary composite end point of 1 receptor agonist with the intent of tion for HF demonstrated in the two
MI, stroke, or cardiovascular death was reducing cardiovascular risk in patients study populations and the consistency
reduced with canagliflozin (26.9 vs. with an HbA1c ,53 mmol/mol (,7%). across two independent trial programs
31.5 participants per patient-year with Limited data suggest that there is no suggest to us that treatment with SGLT2
placebo; HR 0.86 [95% CI 0.75, 0.97]; heterogeneity in the cardiovascular ben- inhibitors in the setting of clinical HF may
P 5 0.02) for superiority in the pooled efits of SGLT2 inhibitors or GLP-1 recep- provide substantial benefit and should
analysis, with consistent findings in tor agonists as a function of background be specifically considered in people with
the component studies. Though there glucose-lowering therapy. Thus, back- type 2 diabetes and ASCVD and HF.
was a trend toward benefit for cardio- ground glucose-lowering therapy in pa- In the GLP-1 receptor agonist studies
vascular death, the difference from tients with clinical CVD arguably is not LEADER, SUSTAIN 6, and EXSCEL, there
placebo was not statistically significant pertinent in clinical decision making. was no significant effect on hospitaliza-
in the CANVAS Program (52). For the However, dose adjustment or discontin- tion for HF with HR 0.86 (95% CI 0.71,
SGLT2 inhibitors studied to date, it ap- uation of background medications may 1.06), 1.11 (95% CI 0.77, 1.61), and 0.94
pears that among patients with established be required to avoid hypoglycemia (95% CI 0.78, 1.13), respectively (47–49).
CVD, there is likely cardiovascular benefit, when adding a new agent to a regi- Two short-term studies of liraglutide in
with the evidence of benefit modestly men containing insulin, sulfonylurea, or patients with reduced ejection fraction
stronger for empagliflozin than canagli- glinide therapy, particularly in patients at suggested a lack of benefit in this setting
flozin. Adverse effects for the class or near glycemic goals. Full efforts to (56,57).
are discussed in the section “The Full achieve glycemic and blood pressure Among the recent cardiovascular
Range of Therapeutic Options: Lifestyle targets and to adhere to lipid, antiplate- safety outcomes trials testing DPP-4 in-
Management, Medication, and Obesity let, antithrombotic, and tobacco ces- hibitors, the Saxagliptin Assessment of
Management.” sation guidelines (7) should continue Vascular Outcomes Recorded in Patients
While the evidence of an ASCVD out- after an SGLT2 inhibitor or GLP-1 re- with Diabetes Mellitus–Thrombolysis
comes benefit for GLP-1 receptor ago- ceptor agonist is added, as such efforts in Myocardial Infarction 53 (SAVOR-
nists and SGLT2 inhibitors has been were integral to all studies that have TIMI 53) study evaluating saxagliptin
demonstrated for people with estab- demonstrated cardiovascular benefit demonstrated a significant increased risk
lished ASCVD, the evidence of benefit of these agents. of HF, with 3.5% risk of hospitalization
beyond glucose lowering has not been for HF versus 2.8% for placebo (HR 1.27;
demonstrated in those without ASCVD. Consensus recommendation 95% CI 1.07, 1.51; P 5 0.007) (58). In the
Indeed, in subgroup analyses of these c Among patients with ASCVD in subsequent Examination of Cardiovascu-
trials, lower-risk individuals have not whom HF coexists or is of special lar Outcomes with Alogliptin versus Stan-
been observed to have an ASCVD benefit. concern, SGLT2 inhibitors are rec- dard of Care (EXAMINE) study of alogliptin
While this may be due to the short time ommended (Figs. 2 and 3). there was no statistically significant dif-
frame of the studies and the low event ference in HF hospitalization (3.9% vs. 3.3%
rate in those without ASCVD, the finding Patients with type 2 diabetes are at with placebo) (59), and in the Trial Eval-
is consistent across the reported trials. increased risk of HF (53). In the EMPA- uating Cardiovascular Outcomes with
Overall, CVOTs of dipeptidyl peptidase REG OUTCOME and CANVAS CVOT stud- Sitagliptin (TECOS), the rate of hospital-
4 (DPP-4) inhibitors have demonstrated ies testing SGLT2 inhibitors, which ization for HF was 3.1% in both sitagliptin-
safety, i.e., noninferiority relative to pla- enrolled participants with ASCVD, .85% and placebo-treated patients (60).
cebo, for the primary MACE end point, of participants did not have symptomatic
but not cardiovascular benefit. HF at baseline. Yet, in both trials there
Consensus recommendation
The available evidence for cardiovas- was a clinically and statistically significant
c For patients with type 2 diabetes
cular event reduction in patients with reduction in hospitalization for HF for
and CKD, with or without CVD,
type 2 diabetes and clinical CVD is derived the SGLT2 inhibitor as compared with
consider the use of an SGLT2 in-
from trials in which the participants were placebo. In the EMPA-REG OUTCOME
hibitor shown to reduce CKD pro-
not meeting glycemic targets (HbA1c study with empagliflozin (54), the ARR
gression or, if contraindicated or
$53 mmol/mol [$7%] at baseline). Fur- was 1.4%, and the HR 0.65 (95% CI
not preferred, a GLP-1 receptor
thermore, most (;70% across trials) 0.50, 0.85), and in the CANVAS Pro-
agonist shown to reduce CKD pro-
participants were treated with metfor- gram with canagliflozin, the HR was
gression (Figs. 2 and 3).
min at baseline. Thus, we recommend 0.67 (95% CI 0.52, 0.87), with a rate of
2680 Consensus Report Diabetes Care Volume 41, December 2018

Patients with type 2 diabetes and kidney components (doubling of serum creati- emphasize foods of demonstrated health
disease are at an increased risk for car- nine, ESRD, or renal death) did not con- benefit, that minimize foods of demon-
diovascular events. A substantial number tribute substantially to the benefit. In strated harm, and that accommodate
of participants with an eGFR of 30–60 mL the DPP-4 inhibitor CVOTs, the DPP-4 in- patient preference and metabolic needs,
min–1 [1.73 m]–2 were included in EMPA- hibitors have been shown to be safe with the goal of identifying healthy di-
REG OUTCOME, CANVAS, LEADER, and from a renal perspective, with modest etary habits that are feasible and sustain-
SUSTAIN 6. An important finding in the reduction in albuminuria (64). able. Three trials of a Mediterranean
studies was reduction of the primary eating pattern reported modest weight
ASCVD outcome even among participants THE FULL RANGE OF THERAPEUTIC loss and improved glycemic control
with stage 3 CKD (eGFR 30–60 mL min–1 OPTIONS: LIFESTYLE (66–68). In one of these, people with
[1.73 m]–2). For SGLT2 inhibitors, this con- MANAGEMENT, MEDICATION, new-onset diabetes assigned to a low-
trasts with the glucose-lowering effect, AND OBESITY MANAGEMENT carbohydrate Mediterranean eating pat-
which diminishes with declining eGFR. This section summarizes the lifestyle, tern were 37% less likely to require
In addition to the primary cardiovas- medication, and obesity management glucose-lowering medications over 4
cular end points, most of the SGLT2 therapies that lower glucose or improve years compared with patients assigned
inhibitor and GLP-1 receptor agonist other outcomes in patients with type 2 to a low-fat diet (HR 0.63 [95% CI 0.51,
CVOTs reported benefit in renal end diabetes. A more comprehensive discus- 0.86]). A meta-analysis of RCTs in pa-
points, albeit as secondary outcomes. sion of these issues is available elsewhere tients with type 2 diabetes showed that
The renal outcome benefit has been (3,21,65). For more details on weight loss the Mediterranean eating pattern re-
most pronounced and consistent for medications and metabolic surgery, see duced HbA1c more than control diets
SGLT2 inhibitors. EMPA-REG OUTCOME the section “Obesity Management Beyond (mean difference 23.3 mmol/mol, 95%
(empagliflozin) demonstrated an ARR Lifestyle Intervention.” Basic information CI 25.1, 21.5 mmol/mol [20.30%, 95% CI
6.1%, HR of 0.61 (95% CI 0.53, 0.70) about specific options in each category of 20.46%, 20.14%]) (69). Low-carbohydrate,
for the composite outcome of new or therapy is summarized in Table 2. low glycemic index, and high-protein diets,
worsening nephropathy (progression to Lifestyle interventions, including MNT and the Dietary Approaches to Stop Hyper-
urine albumin/creatinine ratio .33.9 and physical activity, are effective and tension (DASH) diet all improve glycemic
mg/mmol [.300 mg/g], doubling of se- safe for improving glucose control in type control, but the effect of the Mediterra-
rum creatinine and ESRD, or death by 2 diabetes. For these reasons, they are nean eating pattern appears to be the
ESRD). The most prevalent outcome com- recommended as first-line therapies from greatest (70–72). Low-carbohydrate diets
ponent was the development of sustained the time of diagnosis and as cotherapy (,26% of total energy) produce substan-
albuminuria, but the other components for patients who also require glucose- tial reductions in HbA1c at 3 months (25.2
were each significantly reduced relative lowering medications or metabolic sur- mmol/mol, 95% CI 27.8, 22.5 mmol/mol
to placebo (61). CANVAS (canagliflozin) gery. Lifestyle management should be part [20.47%, 95% CI 20.71%, 20.23%]) and
reported an HR of 1.7 (95% CI 1.51, 1.91) of the ongoing discussion with individ- 6 months (4.0 mmol/mol, 95% CI 26.8,
for regression of albuminuria and a 40% uals with type 2 diabetes at each visit. 21.0 mmol/mol [20.36%, 95% CI 20.62%,
reduction in risk in the composite out- 20.09%]), with diminishing effects at 12
come of eGFR, ESRD, or renal death (5.5 Lifestyle Management and 24 months; no benefit of moderate
vs. 9.0 participants per 1,000 patient- carbohydrate restriction (26–45%) was
Consensus recommendation
years; HR 0.60; 95% CI 0.47, 0.77) (52). observed (73). Vegetarian eating pat-
c An individualized program of MNT
Additional trials with primary renal end terns have been shown to lower HbA1c,
should be offered to all patients.
points are ongoing in high-risk renal but not fasting glucose, compared with
populations. The Evaluation of the Ef- nonvegetarian ones (74). Very recent tri-
Medical Nutrition Therapy
fects of Canagliflozin on Renal and Car- als of different eating patterns in type 2
diovascular Outcomes in Participants MNT comprises education and support to diabetes have typically also included
with Diabetic Nephropathy (CREDENCE) help patients adopt healthy eating pat- weight reduction, hindering firm con-
trial examining canagliflozin in CKD with terns. The goal of MNT is to manage clusions regarding the distinct contribu-
proteinuria has been stopped at a planned blood glucose and cardiovascular risk tion of dietary quality.
interim analysis for achieving the primary factors to reduce risk for diabetes-related
efficacy end point (62). complications while preserving the plea- Consensus recommendation
In LEADER and SUSTAIN 6, the GLP-1 sure of eating (21). Two basic dimensions c All overweight and obese patients
receptor agonist liraglutide was associ- of MNT include dietary quality and energy with diabetes should be advised of
ated with an ARR of 1.5% and an HR of restriction. Strategies directed at each the health benefits of weight loss
0.78 (95% CI 0.67, 0.92) for new or wors- dimension can improve glycemic control. and encouraged to engage in a
ening nephropathy (63), and semaglu- Dietary Quality and Eating Patterns. There is program of intensive lifestyle man-
tide demonstrated an ARR of 2.3% no single ratio of carbohydrate, proteins, agement, which may include food
and an HR of 0.64 (95% CI 0.46, 0.88) and fat intake that is optimal for every substitution.
for new or worsening nephropathy (48). person with type 2 diabetes. Instead,
Progression of albuminuria was the there are many good options and pro- Nonsurgical Energy Restriction for Weight
most prevalent component of the com- fessional guidelines usually recommend Loss. If a patient wishes to aim for re-
posite renal end point, whereas the other individually selected eating patterns that mission of type 2 diabetes, particularly
Table 2—Glucose-lowering medications and therapies available in the U.S. or Europe and specific characteristics that may guide individualized treatment choices in
nonpregnant adults with type 2 diabetes
Medications/therapies
Class in class Primary physiological action(s) Advantages Disadvantages/adverse effects Efficacy
Lifestyle
Diet quality c Mediterranean type c Depends on diet c Inexpensive c Requires instruction Intermediate
c DASH c No side effects c Requires motivation
care.diabetesjournals.org

c Low carbohydrate c Requires lifelong behavioral change


c Vegetarian c Social barriers may exist
c Others
Physical activity c Running, walking c Energy expenditure c Inexpensive c Risk of musculoskeletal injury Intermediate
c Bicycling (including c Weight management c↓ Fall risk by increasing balance/strength c Requires motivation
stationary) c ↑ Insulin sensitivity c ? Improves mental health c Risk of foot trauma in patients with
c Swimming c ↑ Bone density neuropathy
c Resistance training c ↓ Blood pressure c Requires lifelong behavioral change
c Yoga c ↓ Weight
c Tai chi c Improves ASCVD risk factors
c Many others
Energy restriction c Individual energy c Energy restriction c Lowers glycemia c Requires motivation Variable, with potential for
restriction with or c Weight management c Reduces need for diabetes and c Requires lifelong behavioral change very high efficacy; often
without energy tracking c ↓ Hepatic and pancreatic other medications intermediate
c Programs with fat c No serious side effects
counseling c ↑ Insulin sensitivity c Improves ASCVD risk factors
c Food substitution
programs
Oral medications
Biguanides c Metformin c ↓ Hepatic glucose production c Extensive experience c GI symptoms High
c Multiple other non-insulin- c No hypoglycemia c Vitamin B12 deficiency
mediated mechanisms c Inexpensive c Use with caution or dose adjustment
for CKD stage 3B (eGFR 30–44 mL min21
[1.73 m]22)
c Lactic acidosis (rare)
SGLT2 inhibitors c Canagliflozin c Blocks glucose reabsorption c No hypoglycemia c Genital infections Intermediate–high
c Dapagliflozin by the kidney, increasing c ↓ Weight c UTI (dependent on GFR)
c Empagliflozin glucosuria c ↓ Blood pressure c Polyuria
c Ertugliflozin c ? Other tubulo-glomerular c Effective at all stages of T2DM c Volume depletion/hypotension/
effects with preserved glomerular function dizziness
c ↓ MACE, HF, CKD with some c ↑ LDL-C
agents (see text) c ↑ Creatinine (transient)
c Dose adjustment/avoidance for renal
disease
c ↑ Risk for amputation (canagliflozin)
c ↑ Risk for fracture (canagliflozin)

Continued on p. 2682
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Table 2—Continued
Medications/therapies
Class in class Primary physiological action(s) Advantages Disadvantages/adverse effects Efficacy

c ↑ Risk for DKA (rare)


c Fournier’s gangrene (rare)
Consensus Report

c Expensive
DPP-4 inhibitors c Sitagliptin c Glucose dependent: c No hypoglycemia c Rare urticaria/angioedema Intermediate
c Vildagliptina ↑ Insulin secretion c Weight neutral c ↑ HF hospitalization (saxagliptin)
c Saxagliptin ↓ Glucagon secretion c Well tolerated c Dose adjustment/avoidance for renal
c Linagliptin disease depending on agent
c Alogliptin c ? Pancreatitis
c ? Arthralgia
c ? Bullous pemphigoid
c Expensive (U.S.); variable in Europe
Sulfonylureas c Glibenclamide/glyburide c ↑ Insulin secretion c Extensive experience c Hypoglycemia High
c Glipizide c ↓ Microvascular risk (UKPDS) c ↑ Weight
a
c Gliclazide c Inexpensive c Uncertain cardiovascular safety
c Glimepiride c Dose adjustment/avoidance for renal
disease
c High rate of secondary failure
TZDs c Pioglitazone c ↑ Insulin sensitivity c Low risk for hypoglycemia c ↑ Weight High
c Rosiglitazoneb c Durability c Edema/heart failure
c ↑ HDL-C c Bone loss
c ↓ Triacylglycerols (pioglitazone) c ↑ Bone fractures
c ↓ ASCVD events (pioglitazone: in a c ↑ LDL-C (rosiglitazone)
poststroke insulin-resistant population and c ? Bladder cancer
as secondary end point in a high-risk-of- c ? Macular edema
CVD diabetes population)
c Lower cost
Meglitinides (Glinides) c Repaglinide c ↑ Insulin secretion c ↓ Postprandial glucose excursions c Hypoglycemia Intermediate–high
c Nateglinide c Dosing flexibility c ↑ Weight
c Safe in advanced renal disease with c Uncertain cardiovascular safety
cautious dosing (especially repaglinide) c Frequent dosing schedule
c Lower cost
a-Glucosidase inhibitors c Acarbose c Slows carbohydrate c Low risk for hypoglycemia c Frequent GI side effects Low–intermediate
c Miglitol digestion/absorption c ↓ Postprandial glucose excursions c Frequent dosing schedule
c Nonsystemic mechanism of action c Dose adjustment/avoidance for renal
c Cardiovascular safety disease
c Lower cost
Bile acid sequestrants c Colesevelamb c ? ↓ Hepatic glucose c No hypoglycemia c Constipation Low–intermediate
production c ↓ LDL-C c ↑ Triacylglycerols
c ? ↑ Incretin levels c May ↓ absorption of other
medications
c Intermediate expense

Continued on p. 2683
Diabetes Care Volume 41, December 2018
Table 2—Continued
Medications/therapies
Class in class Primary physiological action(s) Advantages Disadvantages/adverse effects Efficacy

Dopamine-2 agonists c Quick-release c Modulates hypothalamic c No hypoglycemia c Headache/dizziness/syncope Low–intermediate


bromocriptineb regulation of metabolism c ? ↓ ASCVD events c Nausea
care.diabetesjournals.org

c ↑ Insulin sensitivity c Fatigue


c Rhinitis
c High cost

Injectable medications
Insulins
Long acting (basal) c Degludec (U100, U200) c Activates insulin receptor c Nearly universal response c Hypoglycemia Very high
c Detemir c ↑ Glucose disposal c Theoretically unlimited efficacy c Weight gain
c Glargine (U100, U300) c ↓ Glucose production c Once-daily injection c Training requirements
c Frequent dose adjustment for optimal
efficacy
c High cost
Intermediate acting c Human NPH c Activates insulin receptor c Nearly universal response c Hypoglycemia Very high
(basal) c ↑ Glucose disposal c Theoretically unlimited efficacy c Weight gain
c ↓ Glucose production c Less expensive than analogs c Training requirements
c Often given twice daily
c Frequent dose adjustment for optimal
efficacy
Rapid acting c Aspart (conventional and c Activates insulin receptor c Nearly universal response c Hypoglycemia Very high
fast acting) c ↑ Glucose disposal c Theoretically unlimited efficacy c Weight gain
c Lispro (U100, U200) c ↓ Glucose production c ↓ Postprandial glucose c Training requirements
c Glulisine c May require multiple daily injections
c Frequent dose adjustment for optimal
efficacy
c High cost
Inhaled rapid acting c Human insulin inhalation c Activates insulin receptor c Nearly universal response c Spirometry (FEV1) required before High
powderb c ↑ Glucose disposal c ↓ Postprandial glucose initiating, after 6 months, and
c ↓ Glucose production c More rapid onset and shorter duration annually
than rapid-acting analogs c Contraindicated in chronic lung
disease
c Not recommended in smokers
c Hypoglycemia
c Weight gain
c Training requirements
c May require multiple inhalations daily

Continued on p. 2684
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Table 2—Continued
Medications/therapies
Class in class Primary physiological action(s) Advantages Disadvantages/adverse effects Efficacy

c Frequent dose adjustment for optimal


efficacy; limited options in dosing
Consensus Report

interval
c High cost
c Respiratory side effects (e.g.,
bronchospasm, cough, decline in
FEV1)
Short acting c Human regular (U100, c Activates insulin receptor c Nearly universal response c Hypoglycemia Very high
U500) c ↑ Glucose disposal c Theoretically unlimited efficacy c Weight gain
c ↓ Glucose production c ↓ Postprandial glucose c Training requirements
c Less expensive than analogs c Frequent dose adjustment for optimal
efficacy
c May require multiple daily injections
Premixed c Many c Activates insulin receptor c Nearly universal response c Hypoglycemia Very high
c ↑ Glucose disposal c Theoretically unlimited efficacy c Weight gain
c ↓ Glucose production c Fewer injections than basal/bolus c Training requirements
before every meal c Frequent dose adjustment for optimal
c Recombinant human analogs efficacy
are less expensive c High cost (except human insulin
premix)
c Can lead to obligate eating
GLP-1 RA
Shorter acting c Exenatide c Glucose dependent: c No hypoglycemia as monotherapy c Frequent GI side effects that may be Intermediate–high
c Lixisenatide ↑ Insulin secretion c ↓ Weight transient
↓ Glucagon secretion c Excellent postprandial glucose c Modestly ↑ heart rate
c Slows gastric emptying efficacy for meals after injections c Training requirements
c ↑ Satiety c Improves cardiovascular risk c Dose adjustment/avoidance in renal
factors disease
c Acute pancreatitis (rare/uncertain)
c Very high cost
Longer acting c Dulaglutide c Glucose dependent: c No hypoglycemia as monotherapy c GI side effects, including gallbladder High–very high
c Exenatide extended- ↑ Insulin secretion c ↓ Weight disease
release ↓ Glucagon secretion c ↓ Postprandial glucose excursions c Greater ↑ heart rate
c Liraglutide c ↑ Satiety c Improves cardiovascular risk factors c Training requirements
c Semaglutide c ↓ MACE with some agents (see text) c Dose adjustment/avoidance for some
c ↓ Albuminuria with some agents agents in renal disease
(see text) c Acute pancreatitis (rare/uncertain)

Continued on p. 2685
Diabetes Care Volume 41, December 2018
Table 2—Continued
Medications/therapies
care.diabetesjournals.org

Class in class Primary physiological action(s) Advantages Disadvantages/adverse effects Efficacy

c Greater lowering of fasting c C-cell hyperplasia/medullary thyroid


glucose vs. short-acting preparations tumors (rare/uncertain; observed in
c Once-weekly dosing (except animals only)
liraglutide, which is daily) c Very high cost
Other injectables
Amylin mimetics c Pramlintideb c ↓ Glucagon secretion c ↓ Postprandial glucose excursions cHypoglycemia Intermediate
c Slows gastric emptying c ↓ Weight cFrequent dosing schedule
c ↑ Satiety c Training requirements
c Frequent GI side effects
c Very high cost
Fixed-dose c Liraglutide/degludec c Combined activities of c Enhanced glycemic efficacy vs. components c Less weight loss than GLP-1 receptor Very high
combination of GLP-1 c Lixisenatide/glargine components c Reduced adverse effects (e.g., GI, agonist alone
RA and basal insulin hypoglycemia) c Very high cost
analogs vs. components
Weight loss medications c Lorcaserinb c Reduced appetite c Mean 3–9 kg weight loss vs. placebo c High discontinuation rates from side Intermediate
c Naltrexone/bupropion c Fat malabsorption (orlistat) effects
c Orlistat c ,50% achieve $5% weight loss
c Phentermine/ c Drug-specific side effects
topiramateb c Limited durability
c Liraglutide 3 mg c High cost

Metabolic surgery c VSG c Restriction of food intake (all) c Sustained weight reduction c High initial cost Very high
c RYGB c Malabsorption (RYGB, BPD) c ↑ Rate of remission of diabetes c ↑ Risk for early and late surgical
c Adjustable gastric band c Changes in hormonal and c ↓ Number of diabetes drugs complications
c BPD possibly neuronal signaling c ↓ Blood pressure c ↑ Risk for reoperation
(VSG, RYGB, BPD) c Improved lipid metabolism c ↑ Risk for dumping syndrome
c ↑ Nutrient and vitamin malabsorption
c ↑ Risk for new-onset depression
c ↑ Risk for new-onset opioid use
c ↑ Risk for gastroduodenal ulcer
c ↑ Risk for hypoglycemia
c ↑ Risk for alcohol use disorder

More details available in ADA’s Standards of Medical Care in Diabetesd2018 (3). Glucose-lowering efficacy of drugs by change in HbA1c: .22 mmol/mol (2%) very high, 11–22 mmol/mol (1–2%)
high, 6–11 mmol/mol (0.5–1.5%) intermediate, ,6 mmol/mol (0.5%) low. aNot licensed in the U.S. for type 2 diabetes. bNot licensed in Europe for type 2 diabetes. BPD, biliopancreatic diversion;
DKA, diabetic ketoacidosis; FEV1, forced expiratory volume in 1 s on pulmonary function testing; GI, gastrointestinal; GLP-1 RA, glucagon-like peptide 1 receptor agonist; HDL-C, HDL-cholesterol; LDL-C,
LDL-cholesterol; RYGB, Roux-en-Y gastric bypass; VSG, vertical sleeve gastroplasty; T2DM, type 2 diabetes mellitus; UTI, urinary tract infection.
Davies and Associates
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2686 Consensus Report Diabetes Care Volume 41, December 2018

within 6 years of diagnosis, evidence- in reducing HbA1c by about 6.6 mmol/mol monotherapy, and the potential for
based weight management programs are (0.6%) (81–84). Of these modalities, some some weight loss. Some studies have
often successful. evidence suggests that aerobic exer- suggested a benefit for preventing
The most effective nonsurgical strat- cise and the combination of aerobic ex- CVD (98), but this has not been supported
egies for weight reduction involve food ercise and resistance training may be by the results of a recent meta-analysis
substitution and intensive, sustained more effective than resistance training (99). However, metformin may lower risk
counseling (e.g., 12–26 individual coun- alone (85), but this remains controver- for cardiovascular mortality compared
seling sessions over 6–12 months). sial. When considering exercise interven- with sulfonylurea therapy (100). Rare
Among adults with type 2 diabetes, tions, special considerations are required cases of lactic acidosis have been re-
meal replacement (825–853 kcal/day for individuals with CVD, uncontrolled ported, usually in the setting of severe
[3,450–3,570 kJ/day] formula diet for retinopathy or nephropathy, and severe illness or acute kidney injury. Therefore,
3–5 months) followed by gradual rein- neuropathy. A wide range of physical metformin should be omitted in the set-
troduction of food and intensive coun- activity, including leisure time activities ting of severe illness, vomiting, or de-
seling resulted in 9-kg placebo-adjusted (e.g., walking, swimming, gardening, jog- hydration. Metformin may result in lower
weight loss at 1 year and high rates of ging, tai chi, and yoga) can significantly serum vitamin B12 concentration; there-
diabetes remission (46% vs. 4%; odds reduce HbA1c (86–90). In general, super- fore, periodic monitoring and supple-
ratio [OR] 19.7 [95% CI 7.8, 49.8]) com- vision of exercise and motivational strat- mentation is generally recommended
pared with best usual practice (75). In egies, such as monitoring using a step if levels are deficient, particularly in
terms of intensive behavioral interven- counter, can improve the effect of exer- those with anemia or neuropathy (101).
tions, the Action for Health in Diabetes cise on HbA1c compared with advice Because of its high efficacy in lowering
(Look AHEAD) trial (76) randomized alone (84,91). The combination of dietary HbA1c, good safety profile, and low cost,
5,145 overweight or obese patients change for weight reduction and physical metformin remains the first-line medica-
with type 2 diabetes to an intensive exercise improves hyperglycemia and tion for management of type 2 diabetes.
lifestyle program that promoted energy reduces cardiovascular risk factors more
restriction, incorporating meal replace- than dietary interventions or physical SGLT2 Inhibitors
ments to induce and sustain weight loss, activity alone (92). SGLT2 inhibitors are oral medications
along with increased physical activity that reduce plasma glucose by enhancing
compared with standard diabetes edu- Medications for Lowering Glucose urinary excretion of glucose (102). The
cation and support in the control group. Metformin glucose-lowering efficacy of these med-
After 9.6 years, weight loss was greater Metformin is an oral medication that ications is dependent on renal function.
in the intervention group (8.6% vs. 0.7% reduces plasma glucose via multiple mech- Initiation and continuation of SGLT2 in-
at 1 year; 6.0% vs. 3.5% at study end; anisms. It is available as an immediate- hibitors are restricted by eGFR and re-
both P , 0.05). HbA1c also fell in the release formulation that is typically quire intermittent monitoring of renal
intervention group despite less use of administered twice a day and as ex- function (refer to European Medicines
glucose-lowering medications. Cardio- tended-release formulations for once- Agency and U.S. Food and Drug Ad-
vascular event rates were not reduced, daily or twice-daily administration. The ministration prescribing information
but there were numerous other bene- formulations are equally effective with for current recommendations). These
fits. In a 12-month trial, 563 adults with no consistent differences in side effect medications are of high efficacy in low-
type 2 diabetes who were randomized profile (93). Dosages of immediate- ering glucose in the setting of normal
to Weight Watchers compared with stan- release metformin start at 500 mg once renal function (51,52,103). All SGLT2 in-
dard care had a 2.1% net weight loss or twice a day with meals and should be hibitors are associated with a reduction
(24.0% vs. 21.9%; P , 0.001), a 5.3 increased as tolerated to a target dosage in weight and blood pressure. Alone or
mmol/mol (23.5 vs. 11.8 mmol/mol; of 1,000 mg twice a day. The maximum with metformin, they do not increase the
P 5 0.020) net absolute improvement in daily dose is 2,550 mg in the U.S. and risk for hypoglycemia. Empagliflozin and
HbA1c (0.48% [20.32% vs. 10.16%]), and 3,000 mg in the European Union, though canagliflozin have cardiac and renal ben-
a greater reduction in use of glucose- doses above 2,000 mg are generally efits in patients with established or at
lowering medications (226% vs. 112%; associated with little additional efficacy high risk of ASCVD. Cardiac and renal
P , 0.001) (77). Similar programs have and poorer tolerability (94). Gastroin- benefits have been demonstrated down
resulted in a net 3-kg weight loss over testinal symptoms are common and to an eGFR of 30 mL min–1 [1.73 m]–2,
12–18 months (78–80). dose dependent, and may improve over though currently none of the SGLT2
time or with dose reduction. Metformin inhibitors have been approved for
Physical Activity
should not be used in patients with an use by regulators at an eGFR below
Consensus recommendation eGFR ,30 mL min–1 [1.73 m]–2 and dose 45 mL min–1 [1.73 m]–2 (see the section
c Increasing physical activity improves reduction should be considered when “Recommended Process for Glucose-
glycemic control and should be en- the eGFR is ,45 mL min–1 [1.73 m]–2 Lowering Medication Selection: Where
couraged in all people with type 2 (95–97). Caution should be taken when Does New Evidence From Cardiovascular
diabetes. conditions are present that may re- Outcomes Trials Fit In?”) (51,52,61). The
duce eGFR. Advantages of metformin class is associated with increased risk for
Aerobic exercise, resistance training, and include its high efficacy, low cost, min- mycotic genital infections (mostly vagi-
the combination of the two are effective imal hypoglycemia risk when used as nitis in women, balanitis in men) (51,
care.diabetesjournals.org Davies and Associates 2687

52,104,105). Case reports of diabetic receptor agonists reduce weight (110); Process for Glucose-Lowering Medica-
ketoacidosis with SGLT2 inhibitors in the reduction ranges from about 1.5 kg tion Selection: Where Does New Evi-
type 2 diabetes continue to raise con- to 6.0 kg over about 30 weeks of ther- dence From Cardiovascular Outcomes
cern, though increased rates have not apy (110,117). Liraglutide and semaglutide Trials Fit In?”).
been confirmed in large trials (102,106). have been shown to improve cardiovas-
Therefore, the SGLT2 inhibitors should cular outcomes (47,48) (see the section Thiazolidinediones
be used with caution and appropriate “Recommended Process for Glucose- Thiazolidinediones (TZDs) (pioglitazone
patient education should be provided for Lowering Medication Selection: Where and rosiglitazone) are oral medications
those with insulin deficiency. SGLT2 in- Does New Evidence From Cardiovascu- that increase insulin sensitivity and are
hibitors have been associated with an lar Outcomes Trials Fit In?”). The most of high glucose-lowering efficacy (129–
increased risk of acute kidney injury, common side effects of GLP-1 receptor 131). TZDs increase HDL-cholesterol
dehydration, and orthostatic hypoten- agonists are nausea, vomiting, and di- (132,133), and pioglitazone has been
sion; caution should be taken when arrhea, though these tend to diminish shown to reduce cardiovascular end
SGLT2 inhibitors are used in combina- over time. GLP-1 receptor agonists have points (132,134–138) and hepatic steato-
tion with diuretics and/or ACE inhibi- minimal risk for hypoglycemia, but may hepatitis (139), but without conclusive
tors and angiotensin receptor blockers. increase the hypoglycemic potential evidence for benefit. TZDs are associated
Canagliflozin has been associated with of insulin and sulfonylureas when com- with the best evidence among glucose-
increased risk for lower-limb amputa- bined with those medications (118). lowering medications for glycemic du-
tion (6.3 canagliflozin vs. 3.4 per 1,000 Contrary to early signals, GLP-1 receptor rability (140). However, these notable
patient-years with placebo after 3.1 agonists do not seem to substan- benefits must be balanced with safety
years; HR 1.97 [95% CI 1.41, 2.75]) (52). tially increase risk for pancreatitis, pan- concerns regarding fluid retention and
Similarly, fracture risk has been reported creatic cancer, or bone disease (119). congestive heart failure (136,140,141),
with canagliflozin (15.4 vs. 11.9 partici- They are associated with increased risk weight gain (132,136,140–142), bone
pants with fracture per 1,000 patient- of gallbladder events (120). Semaglu- fracture (143,144), and, possibly, bladder
years; HR 1.26 [95% CI 1.04, 1.52]) (52). It tide was associated with increased ret- cancer (145). Lower-dose therapy (e.g.,
is uncertain whether amputation and inopathy complications in the SUSTAIN pioglitazone 15–30 mg) mitigates weight
fractures are class effects. 6 trial (HR 1.76, 95% CI 1.11, 2.78), largely gain and edema, but the broader ben-
among those with baseline retinopa- efits and harms of low-dose TZD therapy
GLP-1 Receptor Agonists
thy who had rapid improvement of have not been evaluated.
GLP-1 receptor agonists are currently glycemic control (48). While this ob-
delivered by subcutaneous injection. servation remains unexplained, this is Sulfonylureas
These medications stimulate insulin se- also a recognized effect of intensifica- Sulfonylureas are oral medications that
cretion and reduce glucagon secretion tion of glycemic control with insulin. lower glucose by stimulating insulin se-
in a glucose-dependent manner, im-
DPP-4 Inhibitors cretion from pancreatic b-cells. They are
prove satiety, and promote weight loss
DPP-4 inhibitors are oral medications that inexpensive, widely available, and have
(107,108). Structural differences among
increase insulin secretion and reduce glu- high glucose-lowering efficacy (146).
GLP-1 receptor agonists affect dura-
tion of action, and their formulation cagon secretion in a glucose-dependent Sulfonylureas were used as part of the
and dosing may affect efficacy for glu- manner. They have moderate glucose- glucose-lowering regimen in the UK Pro-
cose-lowering and weight reduction as lowering efficacy (121,122). DPP-4 inhib- spective Diabetes Study (UKPDS) (147)
well as side effect profile and cardio- itors are well tolerated, have a neutral and Action in Diabetes and Vascular
vascular effects (109). Dulaglutide, effect on weight, and have minimal risk of Disease: Preterax and Diamicron MR
exenatide extended-release, and sema- hypoglycemia when used as monotherapy Controlled Evaluation (ADVANCE) (148)
glutide are administered once weekly (123). When added to sulfonylurea ther- trials, which both demonstrated reduc-
(108,109). Liraglutide and lixisenatide apy, however, the risk for hypoglycemia is tions in microvascular complications. Sul-
are administered once daily, and exena- increased 50% compared with sulfonyl- fonylureas are associated with weight
tide is available in a twice-daily formu- urea therapy alone (124). The recom- gain and risk for hypoglycemia and down
lation. GLP-1 receptor agonists have high mended dose for each DPP-4 inhibitor titration of dose to reduce the risk of
glucose-lowering efficacy, but with var- is determined and needs to be adjusted hypoglycemia results in higher HbA1c
iation within the drug class (110,111). based on renal function; linagliptin is the (146,149,150). Sulfonylureas are known
Evidence suggests that the effect may exception as it has minimal renal excretion. to be associated with a lack of durable
be greatest for semaglutide once weekly, Rare but increased rates of pancreatitis effect on glucose lowering (144,151). The
followed by dulaglutide and liraglutide, (125) and musculoskeletal side effects weight gain associated with sulfonyl-
closely followed by exenatide once have been reported (126). CVOTs dem- ureas is relatively modest in large cohort
weekly, and then exenatide twice daily onstrated the cardiovascular safety but studies and the incidence of severe hy-
and lixisenatide (110,112–116). The short- no cardiovascular benefit of three DPP-4 poglycemia is lower than with insulin
acting medications exenatide twice daily inhibitors (saxagliptin, alogliptin, and (152). Important differences among sul-
and lixisenatide have greater postpran- sitagliptin) as well as imbalances regard- fonylureas affect both safety and effi-
dial effects, at least after the meals with ing HF for saxagliptin and alogliptin cacy. Glibenclamide (known as glyburide
which they are administered. All GLP-1 (127,128) (see the section “Recommended in the U.S. and Canada) has a higher risk
2688 Consensus Report Diabetes Care Volume 41, December 2018

of hypoglycemia compared with other of injection, and glycemic targets, has a dose of glargine for equivalent efficacy
sulfonylureas (153). Glipizide, glimepiride, greater impact on the adverse effects of (165–167).
and gliclazide may have a lower risk for insulin than differences among insulin Not all patients have their blood glu-
hypoglycemia compared with other sul- formulations. cose adequately controlled with basal
fonylureas (152,154). Adverse cardio- insulin. In particular, patients with higher
vascular outcomes with sulfonylureas in Basal Insulin. Basal insulin refers to pretreatment HbA1c, higher BMI, longer
some observational studies have raised longer-acting insulin that is meant to duration of disease, and a greater num-
concerns, although findings from recent cover the body’s basal metabolic insulin ber of oral glucose-lowering medications
systematic reviews have found no in- requirement (regulating hepatic glucose are more likely to require intensified
crease in all-cause mortality compared production), in contrast to bolus or pran- therapy (168).
with other active treatments (152). As dial insulin, which is meant to reduce
newer-generation sulfonylureas appear glycemic excursions after meals. Basal Other Insulin Formulations. Short- and
to confer a lower risk of hypoglycemia insulin is the preferred initial insulin rapid-acting insulin formulations admin-
and have favorable cost, efficacy, and formulation in patients with type 2 istered at mealtime are generally used
safety profiles, sulfonylureas remain a rea- diabetes. Options include once- or twice- to intensify basal insulin therapy in
sonable choice among glucose-lowering daily administration of intermediate- patients not meeting glycemic targets.
medications, particularly when cost is an acting NPH or detemir insulin and the Options include human regular insulin,
important consideration. Patient educa- once-daily administration of glargine various analogs (aspart, glulisine, and
tion and use of low or variable dosing with (U100 or U300) or degludec (U100 or lispro), formulations (faster insulin as-
later generation sulfonylureas may be U200). Long-acting insulin analogs (de- part, lispro U200), biosimilars (lispro),
used to mitigate the risk of hypoglyce- gludec [U100 or U200], glargine [U100 and insulins with different routes of
mia. Greatest caution in this regard is and U300], detemir) have a modestly administration (inhaled). Rapid-acting
warranted for people at high risk of lower absolute risk for hypoglycemia com- insulin analogs have a modestly lower
hypoglycemia, such as older patients pared with NPH insulin, but cost more risk for hypoglycemia compared with
and those with CKD. (157–160). However, in real-world set- human regular insulin but at a higher
tings where patients are treated to con- cost. Various premixed formulations of
Insulin ventional treatment targets, initiation of human and analog insulins are available
Numerous formulations of insulin are NPH compared with determir or glargine and continue to be widely used in some
available with differing durations of ac- U100 did not increase hypoglycemia- regions, though they tend to have an
tion. Human insulins (NPH, regular [R], related emergency department visits or increased risk of hypoglycemia as com-
and premixed combinations of NPH and hospital admissions (161). When com- pared with basal insulin alone (Table 2
R) are recombinant DNA-derived human paring human and analog insulins, cost and Fig. 7).
insulin, while insulin analogs have been differences can be large while differ-
designed to change the onset or duration ences in hypoglycemia risk are mod- Other Glucose-Lowering Medications
of action. The main advantage of insulin est and differences in glycemic efficacy Other oral glucose-lowering medications
over other glucose-lowering medications minimal. (i.e., meglitinides, a-glucosidase inhibitors,
is that insulin lowers glucose in a dose- Degludec is associated with a lower colesevelam, quick-release bromocriptine,
dependent manner over a wide range, to risk of severe hypoglycemia compared pramlintide) are not used commonly in
almost any glycemic target as limited by with glargine U100 insulin when target- the U.S. and some are not licensed at all in
hypoglycemia. Older formulations of in- ing intensive glycemic control in patients Europe. No major new scientific informa-
sulin have also demonstrated reduction with long-standing type 2 diabetes at tion on these medications has emerged
in microvascular complications and with high risk of CVD; absolute incidence in recent years. Their basic characteristics
long-term follow-up, all-cause mortality, difference of 1.7% over 2 years (rate are listed in Table 2.
and diabetes-related death (147,155). ratio 0.60; P , 0.001 for superiority;
Beyond hypoglycemia, the disadvan- OR 0.73; P , 0.001 for superiority) Obesity Management Beyond Lifestyle
tages of insulin include weight gain and (162). Biosimilar formulations are now Intervention
the need for injection, frequent titration available for glargine with similar efficacy Medications for Weight Loss
for optimal efficacy, and glucose moni- profile and lower cost (163). No insulin Several clinical practice guidelines rec-
toring (156). has been shown to reduce risk for CVD ommend weight-loss medications as
The effectiveness of insulin is highly (156), but data suggest that glargine an optional adjunct to intensive lifestyle
dependent on its appropriate use; pa- U100 and degludec do not increase management for patients with obesity,
tient selection and training; adjustment risk for MACE (162,164). particularly if they have diabetes
of dose for changes in diet, activity, or Concentrated formulations of de- (169–171). Others do not (172). Several
weight; and titration to acceptable, gludec (U200) and glargine (U300) are medications and medication combina-
safe glucose targets. Formulations of available that allow injection of a re- tions approved in the U.S. or Europe
intermediate- and long-acting insulin duced volume, a convenience for patients for weight loss have been found to
have different timings of onset, durations on higher doses. Glargine U300 is asso- improve glucose control in people with
of action, and risks of hypoglycemia. ciated with a lower risk of nocturnal diabetes (173,174). One glucose-lowering
However, the way in which insulin is ad- hypoglycemia compared with glargine medication, liraglutide, is also ap-
ministered, including the dose, timing U100 but requires a 10–14% higher proved for the treatment of obesity
care.diabetesjournals.org Davies and Associates 2689

Figure 7—Intensifying to injectable therapies. FRC, fixed-ratio combination; GLP-1 RA, glucagon-like peptide 1 receptor agonist; FBG, fasting blood
glucose; FPG, fasting plasma glucose; max, maximum; PPG, postprandial glucose.
2690 Consensus Report Diabetes Care Volume 41, December 2018

at a higher dose (175). Cost, side effects, use, including drug and alcohol use and
preferred to initial combination
and modest efficacy limit the role of cigarette smoking (186). People with
therapy.
pharmacotherapy in long-term weight diabetes presenting for metabolic sur-
management. gery also have increased rates of depres-
In most patients, type 2 diabetes is a
sion and other major psychiatric disorders
Metabolic Surgery progressive disease, a consequence gen-
(187). These factors should be assessed
erally attributed to a steady decline of
Consensus recommendation preoperatively and during follow-up. Met-
insulin secretory capacity. The practical
c Metabolic surgery is a recommended abolic surgery should be performed in
impact of gradual loss of b-cell function is
treatment option for adults with high-volume centers with multidisciplin-
that achieving a glycemic target with
type 2 diabetes and 1) a BMI ary teams that are experienced in the
monotherapy is typically limited to sev-
$40.0 kg/m2 (BMI $37.5 kg/m2 management of diabetes and gastrointes-
eral years. Stepwise therapy (i.e., adding
in people of Asian ancestry) or 2) tinal surgery. Long-term lifestyle support
medications to metformin to maintain
a BMI of 35.0–39.9 kg/m2 (32.5– and routine monitoring of micronutrient
HbA1c at target) is supported by clinical
37.4 kg/m2 in people of Asian an- and nutritional status must be provided
trials (3). While there is some support for
cestry) who do not achieve durable to patients after surgery (188,189).
initial combination therapy due to the
weight loss and improvement in greater initial reduction of HbA1c than
comorbidities with reasonable non- PUTTING IT ALL TOGETHER:
STRATEGIES FOR can be provided by metformin alone
surgical methods. (190,191), there is little evidence that
IMPLEMENTATION
For an increasing number of patients, this approach is superior to sequential
Metabolic surgery is highly effective in
presence of specific comorbidities (e.g., addition of medications for maintaining
improving glucose control (176–178)
ASCVD, HF, CKD, obesity), safety con- glycemic control or slowing the progres-
and often produces disease remission
cerns (e.g., risk of hypoglycemia), or health sion of diabetes. However, since the
(179–182). The effects can be sustained
care environment (e.g., cost of medica- absolute effectiveness of most oral med-
for at least 5 years (177,182). Benefits
tions) mandate a specific approach to ications rarely exceeds an 11 mmol/mol
include a reduction in the number of
the choice of glucose-lowering medica- (1%) reduction in HbA1c, initial combi-
glucose-lowering medications needed to
tion. These are considered in Figs. 2–6. nation therapy may be considered in
achieve glycemic targets (178,179).
For patients not reaching their target patients presenting with HbA1c levels
Several clinical practice guidelines
HbA1c, it is important to re-emphasize more than 17 mmol/mol (1.5%) above
and position statements recommend
lifestyle measures, assess adherence, and their target. Fixed-dose formulations can
consideration of metabolic surgery
arrange timely follow-up (e.g., within improve medication adherence when
as a treatment option for adults with
combination therapy is used (192), and
type 2 diabetes and 1) a BMI $40.0 3–6 months) (Fig. 1).
may help achieve glycemic targets more
kg/m2 (BMI $37.5 kg/m2 in people of Initial Monotherapy rapidly (100). Potential benefits of com-
Asian ancestry) or 2) a BMI of 35.0–
bination therapy need to be weighed
39.9 kg/m2 (32.5–37.4 kg/m2 in people Consensus recommendation
c Metformin is the preferred initial against the exposure of patients to mul-
of Asian ancestry) who do not achieve
glucose-lowering medication for tiple medications and potential side ef-
durable weight loss and improvement in
most people with type 2 diabetes. fects, increased cost, and, in the case of
comorbidities with reasonable nonsurgi-
fixed combination medications, less flex-
cal methods (65,183). Because baseline
Metformin remains the preferred option ibility in dosing.
BMI does not predict surgical benefits on
glycemia or hard outcomes and the im- for initiating glucose-lowering medica- Choice of Glucose-Lowering
provement in glycemic control occurs early tion in type 2 diabetes and should be Medication After Metformin
through weight-independent mechanisms added to lifestyle measures in newly
diagnosed patients. This recommenda- Consensus recommendation
(183), metabolic surgery may be considered
tion is based on the efficacy, safety, c The selection of medication added
for those with a BMI of 30.0–34.9 kg/m2
tolerability, low cost, and extensive to metformin is based on patient
(27.5–32.4 in people of Asian ancestry)
clinical experience with this medication. preference and clinical character-
who do not achieve durable weight loss
Results from a substudy of UKPDS (n 5 istics. Important clinical charac-
and improvement in comorbidities with
342) showed benefits of initial treatment teristics include the presence of
reasonable nonsurgical methods.
with metformin on clinical outcomes established ASCVD and other co-
Adverse effects of bariatric surgery,
related to diabetes, with less hypoglyce- morbidities such as HF or CKD; the
which vary by procedure, include surgical
mia and weight gain than with insulin or risk for specific adverse medication
complications (e.g., anastomotic or sta-
sulfonylureas (98). effects, particularly hypoglycemia
ple line leaks, gastrointestinal bleeding,
and weight gain; as well as safety,
intestinal obstruction, the need for re- Initial Combination Therapy
tolerability, and cost (Figs. 2–6).
operation), late metabolic complications Compared With Stepwise Addition of
(e.g., protein malnutrition, mineral defi- Glucose-Lowering Medication
ciency, vitamin deficiency, anemia, hypo- As detailed in the “Medications for Low-
Consensus recommendation
glycemia), and gastroesophageal reflux ering Glucose” section, the glucose-
c The stepwise addition of glucose-
(184,185). Patients who undergo meta- lowering medications that can be added
lowering medication is generally
bolic surgery may be at risk for substance to metformin have distinct profiles of
care.diabetesjournals.org Davies and Associates 2691

action, efficacy, and adverse effects Intensification Beyond Two minimal benefits or if harm outweighs
(100,193). The early introduction of basal Medications any benefit. In particular, ceasing or reduc-
insulin is well established, in particu- ing the dose of medications that have
Consensus recommendation
lar when HbA1c levels are very high an increased risk of hypoglycemia is im-
c Intensification of treatment be-
(.97 mmol/mol [.11%]), symptoms portant when any new glucose-lowering
yond dual therapy to maintain
of hyperglycemia are present, or there treatment (lifestyle or medication) is
glycemic targets requires consider-
is evidence of ongoing catabolism (e.g., started (Fig. 7) (40). HbA1c levels below
ation of the impact of medication
weight loss). This constellation of symp- 48 mmol/mol (6.5%) or substantially be-
side effects on comorbidities, as
toms can occur in type 2 diabetes but low the individualized glycemic target
well as the burden of treatment
suggest insulin deficiency and raise the should prompt consideration of stopping
and cost.
possibility of autoimmune (type 1) or or reducing the dose of medications with
pancreatogenic diabetes in which insu- The lack of a substantial response to one risk of hypoglycemia or weight gain.
lin would be the preferred therapy. or more noninsulin therapies should
Addition of Injectable Medications
While this remains the usual strategy raise the issue of adherence and, in those
for patients when HbA1c levels are very with weight loss, the possibility that the Consensus recommendation
high, SGLT2 inhibitors (194) and GLP-1 patient has autoimmune (type 1) or c In patients who need the greater
receptor agonists (195) have demon- pancreatogenic diabetes. However, it glucose-lowering effect of an in-
strated efficacy in patients with HbA1c is common in people with long-standing jectable medication, GLP-1 recep-
levels exceeding 75 mmol/mol (9%), with diabetes to require more than two tor agonists are the preferred
the additional benefits of weight reduc- glucose-lowering agents, often including choice to insulin. For patients
tion and reduced risk of hypoglycemia. insulin. Compared with the knowledge with extreme and symptomatic hy-
Evidence from clinical trials supports base guiding dual therapy of type 2 di- perglycemia, insulin is recom-
the use of several of the SGLT2 inhibitors abetes, there is less evidence guiding mended (Fig. 7).
and GLP-1 receptor agonists as add-on these choices (205). In general, inten-
therapy for people with type 2 diabetes sification of treatment beyond two See the “Insulin” and “Basal Insulin”
with an HbA1c .53 mmol/mol (.7%) and medications follows the same general sections in “Medications for Lowering
established CVD (48,51,52). However, principles as the addition of a second Glucose” for more medication details.
since only 15–20% of patients with medication, with the assumption that the Patients often prefer combinations of
type 2 diabetes conform to the charac- efficacy of third and fourth medications oral medications to injectable medications.
teristics of patients in these trials, other will be generally less than expected. The range of combinations available with
clinical features need to be considered No specific combination has demon- current oral medications allows many peo-
in the majority when selecting second strated superiority except for those ple to reach glycemic targets safely. How-
medications to add to metformin (Figs. that include insulin and GLP-1 receptor ever, there is currently no evidence that
2–6) (149,196–204). agonists that have broad ranges of gly- any single medication or combination has
Sulfonylureas and insulin are associ- cemic efficacy. As more medications durable effects and, for many patients, in-
ated with an increased risk for causing are added, there is an increased risk jectable medications become necessary
hypoglycemia and would not be pre- of adverse effects. It is important to within 5–10 years of diabetes diagnosis.
ferred for patients in whom this is a consider medication interactions and Evidence from trials comparing GLP-1
concern. Furthermore, hypoglycemia is whether regimen complexity may be- receptor agonists and insulin (basal, pre-
distressing and so may reduce treatment come an obstacle to adherence. Finally, mixed, or basal-bolus) shows similar or
adherence (Fig. 5). For patients prioritiz- with each additional medication comes even better efficacy in HbA1c reduction
ing weight loss or weight maintenance increased costs, which can affect patient (212,213). GLP-1 receptor agonists
(Fig. 4), important considerations include burden, medication-taking behavior, and have a lower risk of hypoglycemia and
the weight reduction associated with medication effectiveness (193,205–211). are associated with reductions in body
SGLT2 inhibitors and GLP-1 receptor While most patients require intensi- weight compared with weight gain with
agonists, the weight neutrality of DPP-4 fication of glucose-lowering medica- insulin (212,214). Some GLP-1 receptor
inhibitors, and the weight gain associ- tions, some require medication reduction agonists allow for once-weekly injec-
ated with sulfonylureas, basal insulin, or discontinuation of medication, partic- tions, as opposed to daily or more often
and TZDs. An important consideration ularly if the therapy is ineffective or is for insulin. Based on these consider-
for society in general and for many exposing patients to a higher risk of side ations, a GLP-1 receptor agonist is the
patients in particular is the cost of effects such as hypoglycemia or when preferred option in a patient with a def-
medications; sulfonylureas, pioglita- glycemic goals have changed due to a inite diagnosis of type 2 diabetes who
zone, and recombinant human insulins change in clinical circumstances (e.g., needs injectable therapy. However, the
are relatively inexpensive, although development of comorbidities or even tolerability and high cost of GLP-1 re-
their cost may vary across regions. healthy aging). A guiding principle is that ceptor agonists are important limita-
Short-term acquisition costs, longer- for all therapies the response should be tions to their use. If additional glucose
term treatment cost, and cost-effective- reviewed at regular intervals, including lowering is needed despite therapy with
ness should be considered in clinical the impact on efficacy (HbA1c, weight) a long-acting GLP-1 receptor agonist, the
decision making when data are available and safety; the therapy should be addition of basal insulin is a reason-
(Fig. 6). stopped or the dose reduced if there are able option (215,216).
2692 Consensus Report Diabetes Care Volume 41, December 2018

Alternatively, the addition of insulin to meta-analysis that studied the combi- a modestly greater reduction in HbA1c
oral medication regimens is well estab- nation of either SGLT2 inhibitors or DPP- with basal-prandial regimens com-
lished. In particular, using basal insulin 4 inhibitors with insulin, the SGLT2 pared with biphasic insulin regimens,
in combination with oral medications is inhibitor–insulin combination was associ- but at the expense of greater weight
effective, and has less hypoglycemia and ated with a greater reduction in HbA1c, gain (233–235). While still commonly
weight gain than combinations using an advantage in terms of body weight used, we do not generally advocate
premixed insulin formulations or pran- and no increase in the rates of hypo- premixed insulin regimens, particularly
dial insulin (217). A standard approach glycemia (222,223). Depending on those administered three times daily,
for optimizing basal insulin regimens is baseline HbA1c, glycemic profile, and for routine use when intensifying insulin
to titrate the dose based on a target fast- individual response, the insulin dose regimens (Fig. 7).
ing glucose concentration, which is a sim- may need to be reduced to prevent Continuous insulin infusion using in-
ple index of effectiveness. Either NPH hypoglycemia when adding an SGLT2 sulin pumps may have a role in a small
insulin or long-acting insulin analogs are inhibitor. minority of people with type 2 diabetes
efficacious for controlling fasting glu- The combination of basal insulin and (236).
cose, although basal analog formulations a GLP-1 receptor agonist has high effi-
Access and Cost
show reduced risks of hypoglycemia, cacy, with recent evidence from clinical
particularly overnight, when titrated to trials demonstrating the benefits of Consensus recommendation
the same fasting glucose target as NPH this combination to lower HbA 1c and c Access, treatment cost, and in-
insulin (157,218). limit weight gain and hypoglycemia surance coverage should all be
Beyond Basal Insulin compared with intensified insulin reg- considered when selecting glucose-
imens (224,225). Most data come from lowering medications.
Consensus recommendation studies in which a GLP-1 receptor ago-
c Patients who are unable to main- nist is added to basal insulin. However, The availability of glucose-lowering
tain glycemic targets on basal in- there is evidence that insulin added to a medications, patient support systems,
sulin in combination with oral GLP-1 receptor agonist can also effectively and blood glucose-monitoring devices
medications can have treatment lower HbA1c, although some weight gain can differ worldwide, depending on a
intensified with GLP-1 receptor ag- results (215). Fixed-ratio combinations region’s economy, culture, and health
onists, SGLT2 inhibitors, or prandial of insulin and GLP-1 receptor agonists care system. Cost of and access to newer
insulin (Figs. 7 and 8). are available and can decrease the medications and insulin remain impor-
number of injections compared with tant issues throughout the world. Al-
It has become common practice to ap- administering the medications sepa- though the economics of diabetes care
proach insulin use in people with type 2 rately (226–228). is complex and broadly includes the costs
diabetes by following the established A final approach to glycemic manage- to society of diabetic complications and
paradigms developed for those with ment when basal insulin plus oral med- long-term outcomes, the cost of drugs
type 1 diabetes. This includes multiple ications is insufficient to achieve HbA1c and the affordability of treatment are
daily injections with doses of insulin targets is intensified insulin regimens often the primary basis for decision
analogs before meals that are adjusted (Figs. 7 and 8). DSMES focused on insulin making. Within health care systems, var-
based on ambient blood glucose and therapy is particularly helpful when in- iance in medication coverage is based on
meal constituents. While this is reason- tensified insulin therapy is considered. different assessments of cost-effectiveness.
able for people with type 2 diabetes Referral to a diabetes specialist team This results in huge disparities in the
who are lean, insulinopenic, and sensi- should be considered in cases where cost of new and old glucose-lowering
tive to exogenous insulin, it ignores the the provider is uncomfortable or unfa- medications in some countries, limiting
substantial differences in pathophysiol- miliar with intensification, poor out- access to the full range of diabe-
ogy between most people with type 2 comes continue despite intensification, tes therapies in large segments of the
diabetes and type 1 diabetes. Most peo- or patients have other issues that com- population, and creating a two-tiered
ple with type 2 diabetes are obese and plicate intensification. Intensified insulin system of treatment. Since glycemic
insulin resistant, requiring much larger regimens include 1) one or more daily management remains a cornerstone of
doses of insulin and experiencing lower injections of rapid- or short-acting insulin the prevention of diabetes complica-
rates of hypoglycemia than those with before meals (prandial insulin) or 2) tions, these disparities raise questions
type 1 diabetes. In patients with type 2 switching to one to three daily admin- of fairness, equity, and overall public
diabetes, weight gain is a particularly istrations of a fixed combination of short- health. Nonetheless, the use of less
problematic side effect of insulin use. and long-acting insulin (premixed or expensive agents, such as metformin,
Recent evidence supports the effective- biphasic insulins) (229,230). When adding sulfonylureas, and human insulin, remain
ness of combinations of insulin with prandial insulin, giving one injection with effective options (Figs. 2 and 6). Redou-
glucose-lowering medications that do the largest meal of the day is a simple and bling lifestyle management efforts can
not increase body weight. For example, safe approach (231). Over time, if glyce- also have great impact, but behavioral
SGLT2 inhibitors can be added to insulin mic targets are not met with one dose of intervention and support can also be
regimens to lower blood glucose levels prandial insulin daily, additional prandial costly, and socioeconomic barriers to
without increasing insulin doses, weight injections can be added to other meals improving lifestyle are well described
gain, or hypoglycemia (219–221). In a (232). Results of meta-analyses suggest (237).
care.diabetesjournals.org Davies and Associates 2693

Figure 8—Considering oral therapy in combination with injectable therapies. DKA, diabetic ketoacidosis; DPP-4i, dipeptidyl peptidase 4 inhibitor; GLP-1
RA, glucagon-like peptide 1 receptor agonist; SGLT2i, SGLT2 inhibitor; SU, sulfonylurea.

Emerging Technology to specific treatment recommendations KEY KNOWLEDGE GAPS


There is an increasing call for the use of supported by real-time algorithms. Despite over 200 years of research on
technology and telemedicine to improve Telemedicine incorporates multiple types lifestyle management of diabetes and
patients’ health (238). Many types of of communication services, such as two- more than 50 years of comparative-
inputs can be digitalized, such as blood way video, e-mail, texting, smartphones, effectiveness research in diabetes,
glucose levels, time spent exercising, tablets, wireless monitors, decision sup- innumerable unanswerecd questions
steps walked, energy ingested, medica- port tools, and other forms of telecom- regarding the management of type 2
tion doses administered, blood pressure, munication technologies. Results overall diabetes remain. In the context of
and weight. Patterns in these variables suggest a modest improvement in glyce- our current consensus recommenda-
can be identified by software, leading mic control (239,240). tions, the following is an incomplete
2694 Consensus Report Diabetes Care Volume 41, December 2018

discussion of vexing issues that must be preference, and other patient-recorded approaches is enormous, evidence is des-
addressed. outcome measures. Patients and other perately needed. Different models of
Evolving areas of current investiga- stakeholders should have more input care are being implemented globally.
tion will provide improvements in dia- into trial designs and outcomes. Prag- Defining optimal cost-effective approaches
betes care and hold great hope for new matic designs will enhance generaliz- to care, particularly in the management
treatments. ability of results and reduce cost. of patients (multimorbidity), is essential.
Better application of “real-world ev- New questions arise from the recent
c Implementation science. The tools idence” will complement randomized cardiovascular outcomes studies. Do
available to prevent and treat diabetes trial evidence. the cardiovascular and renal benefits of
are vastly improved. However, imple- c Drug development. New medications SGLT2 inhibitors and GLP-1 receptor ag-
mentation of effective innovation has will require demonstration of broad onists demonstrated in patients with
lagged behind. efficacy for glucose, comorbidities established CVD extend to lower-risk
c Basic science. Our understanding of and/or complications, as well as safety patients? Is there additive benefit of
the basic mechanisms of diabetes, the and tolerability to compete in the use of GLP-1 receptor agonists and
development of complications, and marketplace. SGLT2 inhibitors for prevention of car-
the treatment of both, though contin- c Complications. Steatohepatitis, HF, diovascular and renal events? If so, in
uously advancing, has highlighted how nonalbuminuric CKD, chronic mental what populations?
much we do not know. illness, and other emerging issues are Addressing these and other vital clin-
c Personalized/precision medicine. complications in diabetes that may ical questions will require additional in-
Though promising, these –omics and supplant classical microvascular and vestment in basic, translational, clinical,
big data approaches addressing both macrovascular disease in importance and implementation research. More
personal and environmental factors and impact. Understanding optimal time- and cost-efficient research para-
and their interaction are largely un- diagnostic, screening, and treatment digms to address patient-centered end
realized in diabetes care and will strategies is urgently needed. points will need to be developed through
require large investments and coordi- regulatory reform and leveraging infor-
nation to have impact. Other areas of importance include bet- matics and coordinated learning health
c Informatics. The benefits and role ter segmentation of “type 2 diabetes,” as care systems. The increasing burden of
of enhanced monitoring of glucose well as appropriate diagnosis of second- cardiorenal metabolic disease in terms
and other variables leveraged with ary diabetes, which should allow more of incidence, prevalence, and cost is
real-time informatics-based approaches informed individualization of care. Better an existential threat to society. Urgent
to adapt treatment on an individual data on optimal approaches to diabetes attention to improve prevention and
basis has great potential but has not management in frail and older adult treatment is of the essence.
been elucidated. patients is urgently required considering The management of hyperglycemia in
c Overweight/obesity. Current therapy the controversy around glycemic targets type 2 diabetes has become extraor-
is clearly inadequate. Innovation in and the benefits and harms of specific dinarily complex with the number of
methods and implementation would treatments from lifestyle management glucose-lowering medications now avail-
transform diabetes prevention and to medications. Current approaches to the able. Patient-centered decision making
care. Understanding the biology, psy- management of type 2 diabetes in ado- and support and consistent efforts to
chology, and sociology of obesity to lescents and young adults do not seem to improve diet and exercise remain the
identify pharmacological, behavioral, alter the loss of b-cell function and most foundation of all glycemic management.
and political approaches to preventing individuals in this age-group quickly Initial use of metformin, followed by
and treating this principal cause of transition to insulin therapy. Studies addition of glucose-lowering medications
type 2 diabetes is essential. to guide optimal therapy in this emerging based on patient comorbidities and con-
c Lifestyle management and DSMES. population with a terrifyingly high risk of cerns is recommended as we await an-
Though the benefits of these ap- early disability is an immediate need. swers to the many questions that remain.
proaches are clear, better paradigms There are enduring questions that
on how to target, individualize, and continue to challenge guideline develop-
sustain the effects are needed. ment. For example, does metformin pro-
Acknowledgments. The authors would like to
c b-Cell function. Preserving and en- vide cardiovascular benefit in patients acknowledge Mindy Saraco (Associate Director,
hancing b-cell function is perceived with type 2 diabetes early in the natural Scientific & Medical Communication), Gedeon
as the holy grail of diabetes and yet history of diabetes, as suggested by the Topacio (Finance & Project Manager, Research &
effective techniques are inadequately UKPDS? Is metformin’s role as first-line Scientific Programs), and Erika Berg (Director,
Scientific & Medical Affairs) from the American
developed. medication management truly evidence- Diabetes Association as well as Mary Hata (Ex-
c Translational research. There is a huge based or a quirk of history? Though the ecutive Assistant) and Petra Niemann (Executive
gap between the knowledge gained rationale for early combination therapy Assistant) from EASD for their help with the
from clinical trials and application of targeting normal levels of glycemia in development of the consensus report and re-
that information in clinical practice. early diabetes is seductive, clinical trial lated meetings/presentations. The authors
would like to also acknowledge Mike Bonar
This gap should be filled with prag- evidence to support specific combina- (Creative Director) and Charlie Franklin (De-
matic studies and other designs that tions and targets is essentially nonexis- sign Assistant) from the Leicester Diabetes Cen-
include costs, measures of patient tent. As the cost implications for these tre, Leicester, U.K., who provided considerable
care.diabetesjournals.org Davies and Associates 2695

support in drafting and amending the figures. The and grants from Merck and Ligand outside the 3. American Diabetes Association. 8. Pharma-
authors also acknowledge Francesco Zaccardi submitted work. J.F. has nothing to disclose. J.F.’s cologic approaches to glycemic treatment: Stan-
(PhD, Clinical Research Fellow, University of input into this consensus report is from her own dards of Medical Care in Diabetesd2018.
Leicester, Leicester, U.K.) and David Kloecker perspective and the report does not reflect the Diabetes Care 2018;41(Suppl. 1):S73–S85
(Medical Student, University of Leicester) who view of the National Institutes of Health, De- 4. Inzucchi SE, Bergenstal RM, Buse JB, et al.;
assisted with extracting PubMed articles and partment of Health and Human Services, or the Position Statement of the American Diabetes
identifying relevant records by title and abstract; U.S. Government. W.N.K. has nothing to disclose. Association (ADA) and the European Associ-
Francesco Zaccardi helped to define the initial C.M. reports grants and personal fees from Novo ation for the Study of Diabetes (EASD). Man-
search strategy and prepare the Excel file. The Nordisk, grants and personal fees from Sanofi, agement of hyperglycaemia in type 2 diabetes
authors acknowledge the invited peer reviewers grants and personal fees from Merck Sharp & a patient-centered approach. Position state-
who provided comments on an earlier draft of Dohme, grants and personal fees from Eli Lilly ment of the American Diabetes Association
this report: Amanda Adler (Addenbroke’s Hospital, and Company, grants and personal fees from (ADA) and the European Association for the
Cambridge, U.K.), Kåre I. Birkeland (University of Novartis, personal fees from Bristol-Myers Squibb, Study of Diabetes (EASD). Diabetologia 2012;
Oslo, Oslo, Norway), James J. Chamberlain (St. personal fees from AstraZeneca, grants and 55:1577–1596
Mark’s Hospital, Salt Lake City, UT), Jill P. Crandall personal fees from Boehringer Ingelheim, per- 5. Inzucchi SE, Bergenstal RM, Buse JB, et al.
(Albert Einstein College of Medicine, New York sonal fees from Hanmi Pharmaceuticals, grants Management of hyperglycaemia in type 2 di-
City, NY), Ian H. de Boer (University of Washington, and personal fees from Roche Diagnostics, grants abetes, 2015: a patient-centred approach. Up-
Seattle, WA), Stefano Del Prato (University of and personal fees from Medtronic, grants and date to a position statement of the American
Pisa, Pisa, Italy), George Dimitriadis (Athens Uni- personal fees from Intrexon, grants and personal Diabetes Association and the European Associ-
versity, Athens, Greece), Sean Dinneen (National fees from Abbott, and personal fees from UCB, ation for the Study of Diabetes. Diabetologia
University of Ireland, Galway, Ireland), Vivian A. outside the submitted work. G.M. reports grants 2015;58:429–442
Fonseca (Tulane University, New Orleans, LA), and personal fees from Novo Nordisk, personal 6. Riddle MC, Gerstein HC, Holman RR, et al.
Simon R. Heller (University of Sheffield, Sheffield, fees from Johnson & Johnson, and personal fees A1C targets should be personalized to maxi-
U.K.), Richard I.G. Holt (University of Southampton, from Fractyl Inc., during the conduct of the study. mize benefits while limiting risks. Diabetes Care
Southampton, U.K.), Silvio E. Inzucchi (Yale Uni- P.R. reports grants and nonfinancial and other 2018;41:1121–1124
versity, New Haven, CT), Eric L. Johnson (University support from Novo Nordisk, grants and other 7. American Diabetes Association. 9. Cardiovas-
of North Dakota, Grand Forks, ND), Joshua support from AstraZeneca, other support from cular disease and risk management: Standards
J. Neumiller (Washington State University, Spo- Bayer, other support from Boehringer Ingelheim, of Medical Care in Diabetesd2018. Diabetes
kane, WA), Kamlesh Khunti (University of Leicester, other support from Merck Sharp & Dohme, and Care 2018;41(Suppl. 1):S86–S104
Leicester, U.K.), Harald H. Klein (Ruhr University of other support from Eli Lilly, during the conduct of 8. Gæde P, Oellgaard J, Carstensen B, et al. Years
Bochum, Bochum, U.K.), Line Kleinebreil (Hôpital the study. A.T. reports nonfinancial support from of life gained by multifactorial intervention in
national de Saint Maurice, Saint-Maurice, France), the European Association for the Study of Di- patients with type 2 diabetes mellitus and micro-
José Manuel Fernández-Real (Universitat de Gi- abetes during the conduct of the study; grants albuminuria: 21 years follow-up on the Steno-2
rona, Girona, Spain), Sally M. Marshall (Newcastle and other support from Boehringer Ingelheim, randomised trial. Diabetologia 2016;59:2298–
University, Newcastle upon Tyne, U.K.), Manel grants and other support from Novo Nordisk, 2307
Mata-Cases (Institut Universitari d’Investigació en other support from Novartis, grants and other 9. Khunti K, Kosiborod M, Ray KK. Legacy ben-
Atenció Primària Jordi Gol [IDIAP Jordi Gol], Bar- support from Sanofi, grants and other support efits of blood glucose, blood pressure and lipid
celona, Spain), David R. Matthews (University of from AstraZeneca, grants from GSK, and grants control in individuals with diabetes and cardio-
Oxford, Oxford, U.K.), David M. Nathan (Mas- and other support from European Foundation for vascular disease: time to overcome multifactorial
sachusetts General Hospital, Boston, MA), Michael the Study of Diabetes, outside the submitted therapeutic inertia? Diabetes Obes Metab 2018;
A. Nauck (Diabetes Center Bochum-Hattingen, work. D.J.W. has nothing to disclose. J.B.B. has 20:1337–1341
St. Josef-Hospital, Ruhr-University, Bochum, provided consultation to Adocia, AstraZeneca, 10. Gregg EW, Sattar N, Ali MK. The changing
Germany), Frank Nobels (OLV-Hospital, Aalst, Eli Lilly, GI Dynamics, Intarcia, MannKind, face of diabetes complications. Lancet Diabetes
Belgium), Richard E. Pratley (Florida Hospital NovaTarg, Novo Nordisk, Senseonics, and vTv Endocrinol 2016;4:537–547
Diabetes Institute, Orlando, FL), Maria Jose Therapeutics with fees paid to the University 11. Little RR, Rohlfing CL, Sacks DB. Status of
Redondo (Baylor College of Medicine, Houston, of North Carolina. He has received grant support HbA1c measurement and goals for improvement:
TX), Michael R. Rickels (University of Pennsylvania, from AstraZeneca, Johnson & Johnson, Novo from chaos to order for improving diabetes care.
Philadelphia, PA), Matthew C. Riddle (Oregon Nordisk, Sanofi, and vTv Therapeutics. He is a Clin Chem 2011;57:204–214
Health & Science University, Portland, OR), Julio consultant to Neurimmune AG. He holds stock 12. American Diabetes Association. 2. Classifi-
Rosenstock (Diabetes and Endocrine Center, Dallas, options in Mellitus Health, PhaseBio, and Stabil- cation and diagnosis of diabetes: Standards of
TX), Giorgio Sesti (Magna Graecia University of ity Health. He is supported by a grant from the Medical Care in Diabetesd2018. Diabetes Care
Catanzaro, Catanzaro, Italy), Neil Skolnik (Abington National Institutes of Health (UL1TR002489). No 2018;41(Suppl. 1):S13–S27
Family Medicine, Jenkintown, PA), Krzysztof Strojek other potential conflicts of interest relevant to 13. Mannucci E, Antenore A, Giorgino F, Scavini
(Silesian Medical University, Zabrze, Poland), Jennifer this article were reported. M. Effects of structured versus unstructured
Trujillo (University of Colorado, Denver, CO), Author Contributions. All authors were re- self-monitoring of blood glucose on glucose
Guillermo E. Umpierrez (Emory University, sponsible for drafting the article and revising it control in patients with non-insulin-treated
Atlanta, GA), and Jennifer Wyckoff (University critically for important intellectual content. All type 2 diabetes: a meta-analysis of randomized
of Michigan, Ann Arbor, MI). authors approved the version to be published. controlled trials. J Diabetes Sci Technol 2018;12:
Funding. This activity was funded by the Amer- Data Availability. The details of the search 183–189
ican Diabetes Association and the European strategy, the results, and the classification 14. Young LA, Buse JB, Weaver MA, et al.;
Association for the Study of Diabetes. for the included articles are available at Monitor Trial Group. Glucose self-monitoring
Duality of Interest. M.J.D. reports personal fees https://dx.doi.org/10.17632/h5rcnxpk8w.1. in non–insulin-treated patients with type 2 di-
and grants from Boehringer Ingelheim, Janssen, abetes in primary care settings: a randomized
Novo Nordisk, and Sanofi and personal fees from References trial. JAMA Intern Med 2017;177:920–929
AstraZeneca, Eli Lilly, Gilead Sciences Ltd., Intarcia/ 1. Rodriguez-Gutierrez R, Gionfriddo MR, 15. Anjana RM, Kesavadev J, Neeta D, et al. A
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