Canadian Journal of Cardiology 33 (2017) 366e377

Review
Diabetes for Cardiologists: Practical Issues in Diagnosis
and Management
G.B. John Mancini, MD,a Alice Y. Cheng, MD,b Kim Connelly, MD,c David Fitchett, MD,c
Ronald Goldenberg, MD,d Shaun G. Goodman, MD,c Lawrence A. Leiter, MD,e Eva Lonn, MD,f
Breay Paty, MD,g Paul Poirier, MD, PhD,h James Stone, MD, PhD,i
David Thompson, MD,g and Jean-Franois Yale, MDj
a
Division of Cardiology, University of British Columbia, Vancouver, British Columbia, Canada
b
Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
c
Division of Cardiology, Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, University of Toronto, Ontario, Canada
d
Endocrinology and Metabolism, North York General Hospital and LMC Diabetes & Endocrinology, Toronto, Ontario, Canada
e
Division of Endocrinology and Metabolism, Li Ka Shing Knowledge Institute and Keenan Research Centre for Biomedical Science, University of Toronto, Ontario, Canada
f
Population Health Research Institute and Department of Medicine, McMaster University, Hamilton, Ontario, Canada
g
Division of Endocrinology, University of British Columbia, Vancouver, British Columbia, Canada
h
Heart and Lung Institute, Laval University, Que bec City, Que bec, Canada
i
Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
j
Division of Endocrinology, McGill University Health Centre, McGill University, Montreal, Que bec, Canada

ABSTRACT 
RESUM 
E
Diabetes mellitus (DM), a chronic metabolic disease characterized by Le diabte sucre  (DS), une maladie me tabolique chronique
hyperglycemia, is a profound cardiovascular (CV) risk factor. It com- caracterise
e par une hyperglyce mie, est un facteur de risque car-
pounds the effects of all other risk factors, leads to premature micro- diovasculaire (CV) se rieux. Il aggrave les effets de tous les autres
and macrovascular disease, facilitates development of heart failure, facteurs de risque, conduit pre maturement aux maladies micro-
worsens the clinical course of all CV diseases, and shortens life ex- vasculaires et macrovasculaires, facilite le de veloppement de linsuf-
pectancy. Established DM, unrecognized DM, and dysglycemia that sance cardiaque, aggrave le volution clinique de toutes les maladies
may progress to DM are all commonly present at the time of presen- CV et raccourcit lespe rance de vie. Le DS e tabli, le DS non diag-
tation of overt CV disease. Thus, CV specialists and trainees frequently nostique et la dysglyce mie qui peuvent progresser vers le DS sont
treat patients with dysglycemia. The traditional and proven role of  ne
ge ralement tous pre sents au moment du tableau clinique de la
cardiologists in reducing the risk of macrovascular events in this maladie CV patente. Par conse quent, les spe
cialistes et les re
sidents
population is through aggressive lipid and blood pressure treatment. dans le domaine des maladies CV traitent fre quemment les patients
However, a more proactive role in the detection and management atteints de dysglycemie. Le rle traditionnel et ave
re des cardiologues
of DM is likely to become increasingly important as the prevalence dans la reduction du risque de
 ve
nements macrovasculaires dans cette

Diabetes mellitus (DM), a chronic metabolic condition
characterized by hyperglycemia, is 1 of the most profound
risk factors for micro- and macrovascular diseases.1-11
Received for publication April 20, 2016. Accepted July 13, 2016.
Corresponding author: G.B. John Mancini, Diamond Center, Rm
9111, 2775 Laurel St, Vancouver, British Columbia V5Z 1M9, Canada.
Tel.: 1-604-875-5477; fax: 1-604-875-5471.
E-mail: mancini@mail.ubc.ca
See page 374 for disclosure information.
Approximately 75% of patients with type 2 DM (T2DM)
will die of cardiovascular disease (CVD).2-4 T2DM is associ-
ated with a 2- to 4-fold increased risk for atherosclerotic
disease and a 4-fold increase in mortality from CVD, espe-
cially in women.4,6,7 It also poses the greatest lifetime risk of
any traditional CV risk factor for the development of coronary
artery disease (CAD) and magnies the impact of other CV
risk factors (Supplemental Fig. S1).7-11 The United Kingdom
Prospective Diabetes Study (UKPDS) showed a progressive
increase in risk for fatal and nonfatal myocardial infarction
(MI), fatal and nonfatal stroke, heart failure (HF), and

http://dx.doi.org/10.1016/j.cjca.2016.07.512
0828-282X/ 2016 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
Mancini et al.
Diabetes for Cardiologists
continues to increase and therapies continue to improve. The latter
include antihyperglycemic therapies with proven cardiovascular safety
proles and CV event reduction properties not yet fully elucidated and
not necessarily related to glycemic control. Accordingly, the purpose of
this article is to (1) expand the interest of cardiologists in earlier stages
of the natural history of DM, when prevention or early detection might
help achieve greatest benet; (2) highlight principles of optimal gly-
cemic management, with an emphasis on add-on choices showing
promising reduction of CV events and lacking CV adverse effects; and
(3) encourage cardiologists to become proactive partners in the
multidisciplinary care needed to ensure optimal lifelong vascular
health in patients with, or who are at risk of, DM.
amputation resulting from peripheral arterial disease with
increasing glycated hemoglobin (A1c).5 DM is a major risk
factor for HF (24%-40% of patients with HF have DM)
and worsens the clinical course.12-16
Although the relationship between established DM and
CVD is strong, it is also important to note that the increased
risk of MI and stroke is present even before the formal
diagnosis of DM is made (Supplemental Fig. S2).17-20
Established DM is present in 18%-44% of patients present-
ing with CAD, with the range affected by the choice of testing
method and completeness of testing in the cohort.19,21 In the
remainder, more subtle dysglycemia is common (impaired
glucose tolerance [IGT] in 32%, impaired fasting glucose
[IFG] in 4%-5%), and, unfortunately, previously undiag-
nosed DM in 14%-22% of patients, whether presenting
electively or acutely with CAD (Fig. 1).19 This means that
cardiologists are frequently confronted with DM or early
dysglycemia. Despite this, there is currently little emphasis on
these earlier aspects of DM detection in either typical cardi-
ology practices or training programs, and this is in striking
Figure 1. Comparison of glucometabolic characterization in patients
with coronary artery disease not known to have diabetes, presenting
either acutely or electively, as determined by oral glucose tolerance
testing or fasting plasma glucose. IFG, impaired fasting glucose; IGT,
impaired glucose tolerance. Data from Bartnik et al.19 with permission
from Oxford University Press.
367
population passe par le traitement e nergique des lipides et de la
pression arterielle. Cependant, un rle plus proactif dans la de tection
et la prise en charge du DS promet de devenir de plus en plus
important alors que la pre valence continue daugmenter et les the ra-
pies continuent de same liorer. Ces dernires comprennent les traite-
ments antihyperglyce miques dont les prols 
dinnocuite
cardiovasculaire prouve e et les proprie te
s de re duction des
ve
e nements CV qui ne sont pas encore compltement e lucides et
necessairement lie s la re
gulation de la glyce
mie. En conse quence, le
but de cet article est : 1) daccrotre lintert des cardiologues quant
aux etapes pre liminaires de le volution naturelle du DS, lorsque la
prevention ou la de tection precoce aiderait obtenir de plus grands
avantages; 2) de mettre en lumire les principes de la prise en charge
optimale de la glyce mie en insistant sur les choix supple mentaires qui
demontrent une re duction prometteuse des e  ve
nements CV et lab-
sence deffets CV inde sirables; 3) dencourager les cardiologues
devenir des partenaires proactifs dans les soins multidisciplinaires
necessaires pour assurer une sante  vasculaire optimale tout au long
de la vie des patients atteints du DS ou qui sont expose s au risque den
tre atteints.
contrast to the prevalence and profound impact of DM on CV
health (Supplemental Table S1).22 Although much of this has
been inuenced by the proven and dominant impact of
aggressive lipid lowering and blood pressure management that
is routine in cardiology practice, including in patients with
DM, the therapeutic armamentarium for patients with
DM is changing dramatically. There are now newer anti-
hyperglycemic agents that not only are safe to use in patients
with CV risk but also show CV event reduction properties
through mechanisms yet to be fully elucidated. Accordingly,
the purpose of this article is to (1) expand the interest of
cardiologists in earlier stages of the natural history of DM,
when prevention or early detection might help achieve greatest
benet; (2) highlight principles of glycemic management with
an emphasis on add-on choices that show promising re-
ductions in CV events and lack CV adverse effects; and (3)
encourage cardiologists to become proactive partners in the
multidisciplinary care needed to ensure optimal lifelong
vascular health in patients with, or who are at risk of, DM.
CV Effects of Dysglycemia
Hyperglycemia
The classication of DM is determined by the patho-
physiology. Type 1 diabetes (T1DM), the onset of which is
generally in young individuals, reects hyperglycemia-driven
mechanisms caused by insulinopenia, whereas T2DM,
generally of adult onset, reects hyperglycemia-driven
mechanisms caused by insulin resistance, relative insulin
deciency, and abnormal free fatty acid metabolism, which
are further affected by the occurrence of other CV comor-
bidities. Patients with T1DM or T2DM have a substantially
increased risk for the development of accelerated athero-
sclerosis (Fig. 2), as well as impaired autonomic CV
neural control.23-34 Diabetic cardiomyopathy, manifested as
either restrictive HF with preserved ejection fraction or
dilated HF with reduced ejection fraction, is also commonly
368
Figure 2. Effects of hyperglycemia and other mechanisms promoting atherosclerosis. IL, interleukin; TNF-a, tumor necrosis factor-a; NF-kB, nuclear
factor-kappa B; NO, nitric oxide; CAM, cell adhesion molecules. Reproduced from Armstrong et al.23 with permission from Wolters Kluwer Health.
present, even in the absence of clinical signs or symptoms or
evidence of CAD (Supplemental Fig. S3).35-38
Hypoglycemia
Because acute hypoglycemia is a major limiting factor
in the management of DM and has deleterious CV effects
mediated by multiple mechanisms, it is important for car-
diologists to encourage avoidance of hypoglycemia in their
patients (Fig. 3).39-49 Mild hypoglycemia (2.8-3.9 mmol/L)
stimulates an increase in glucagon and epinephrine, followed
by a rise in cortisol and growth hormone, often associated
with neurogenic or autonomic symptoms that are easily
treated with oral carbohydrates when recognized by the
patient.47,49-52 Severe hypoglycemia (usually  2.8 mmol/L)
refers to any low blood glucose requiring assistance from
another person. This is characterized by neuroglycopenic
symptoms (reduced glucose to the brain). Explicit ques-
tioning about such symptoms should occur in all patients
with DM who are taking antihyperglycemic agents that
Canadian Journal of Cardiology
Volume 33 2017
can cause hypoglycemiadnamely, insulin secretagogues or
insulin (Supplemental Table S2).
Risk factors for hypoglycemia include advanced age,
cognitive impairment, poor health literacy, missed or irregular
meals, food insecurity, use of insulin or insulin secretagogues,
renal impairment, diabetic neuropathy, and previous episodes
of hypoglycemia.51,53,54 Some patients with longstanding
DM, especially T1DM, experience a gradual loss of counter-
regulatory responses, particularly the loss of neurogenic
symptoms, termed hypoglycemia unawareness, which
further increases the risk for severe hypoglycemia. The
mechanism may be linked to attenuated sympathoadrenal
responses and the loss of glucose counter-regulation (hypo-
glycemia-associated autonomic failure).55
The annual rate of severe hypoglycemia in the Action to
Control Cardiovascular Risk in Diabetes (ACCORD), Action
in Diabetes and Vascular Disease (ADVANCE), and Veterans
Affairs Diabetes Trial (VADT) was higher in the intensive- vs
the standard-treatment groups and was associated with higher
CV mortality.56-59 However, factors other than hypoglycemia
per se may also be at play; a post hoc analysis of the
Mancini et al.
Diabetes for Cardiologists
Figure 3. Mechanisms by which hypoglycemia may affect cardiovascular events. CRP, C-reactive protein; IL-6, interleukin- 6; VEGF, vascular
endothelial growth factor. Reproduced from Desouza et al.39 with permission from the American Diabetes Association.
ACCORD trial demonstrated a paradox: more frequent epi-
sodes of hypoglycemia in the intensively treated arm were
associated with lower mortality, whereas in the standard-
therapy arm, even 1 episode of severe hypoglycemia was
associated with increased mortality.59 By contrast, an analysis
of the ADVANCE data revealed that those with a history of
severe hypoglycemia, irrespective of treatment, had increased
CV events but also nonvascular events (respiratory, digestive,
and skin conditions), suggesting that hypoglycemia may be a
risk marker for overall vulnerability to adverse outcomes rather
than a causative risk factor.60
Although specic mechanisms mediating adverse CV ef-
fects are unique to either hyperglycemia or hypoglycemia,
there are also many broad commonalities: both impair
endothelial function, augment thrombosis and platelet ag-
gregation, compromise ventricular function, and disrupt the
renin-angiotensin-aldosterone and autonomic nervous sys-
tems. Thus, from the CV perspective, both extremes are to be
avoided, and the avoidance of hypoglycemia is now more
easily achievable.61
Classication of DM and Related Conditions
The classication of DM is summarized in
Supplemental Table S3.1 T2DM accounts for 90%-95% of
all cases, and these are the most relevant for cardiologists.
Table 1 summarizes glycemic parameters used to establish
the presence of DM and prediabetes.1 The diagnostic
criteria for DM are based on thresholds of glycemia that are
associated with an increased risk of diabetic retinopathy.
The combination of IFG (6.1-6.9 mmol/L) and an A1c of
369
6.0%-6.4% has been shown to be predictive of 100%
progression to T2DM over 5.6 years.62
Screening for DM and Identifying Opportunities
for Prevention
Screening for DM using fasting plasma glucose (FPG) or
A1c, or both, is recommended every 3 years in individuals 
40 years of age or those at high risk for the development of
DM based on, eg, a risk calculator such as the Canadian
Diabetes Risk Questionnaire (CANRISK).63,64 More frequent
or earlier testing, or both, should be considered in those with
additional risk factors for DM, including the presence of
coronary, cerebrovascular, and peripheral vascular disease
(Supplemental Table S4).21,63,64 A 75-g oral glucose tolerance
test (OGTT) should be considered in patients with IFG or
A1c in the prediabetes range. Most individuals with predia-
betes (60%) have coinciding metabolic syndrome (Table 2), as
do the majority (72%) with overt T2DM.65,66 In addition,
metabolic syndrome is of relevance to the cardiologist because
it is associated with a 2-fold increased risk of CVD as well as a
5-fold increased risk of T2DM.67 The CANRISK approach
considers risk factors not weighed in the assessment of
metabolic syndrome (age, body mass index, exercise habits,
fruit and vegetable intake, family history of T2DM).63,64
Evaluation in these ways identies opportunities to prevent
T2DM.68 A 5% loss in body weight and regular physical
activity of 150 minutes weekly have been shown to reduce the
risk of T2DM by 58% in those at risk.69,70 Metformin is less
effective but can also reduce the risk of progression in those
370 Canadian Journal of Cardiology
Volume 33 2017

Table 1. Glycemic criteria for diagnosis of DM and prediabetes DM diagnosis in these ethnicities are uncertain. A1c should be
Criteria Prediabetes DM used with caution for diagnosis in the elderly, because values
Fasting plasma glucose* (mmol/L) 6.1-6.9 (IFG)  7.0
rise by about 0.1% for every decade above age 40 years. A1c is
A1c, %y 6.0-6.4  6.5 not recommended for diagnostic purposes in children or ad-
2-h plasma glucose in a 75-g oral 7.8-11.0 (IGT)  11.1 olescents, pregnant women, those with cystic brosis, or those
glucose tolerance test, (mmol/L) with suspected T1DM. (Supplemental Fig. S4 provides a
DM, diabetes mellitus; IFG, impaired fasting glucose; IGT, impaired diagnostic algorithm for DM diagnosis and is complementary
glucose tolerance; T1DM, type 1 diabetes mellitus. to Table 1).
* No caloric intake for 8 h; random plasma glucose value  11.1 suggests Diagnosis in patients with CVD is especially important in
DM. both the ambulatory and acutely hospitalized cardiac patient.
y
Standardized and validated assay; absence of factors affecting accuracy of A cross-sectional survey of 4004 patients with stable CAD
A1c; abnormality conrmed on second test in asymptomatic patient; not to be demonstrated that 29% had undetected DM, and screening
used for suspected T1DM. Modied from Goldenberg et al.1 with permission
with an OGTT detected 96% of cases, whereas combining
from Elsevier.
the FPG and A1c test identied 81% (Supplemental
Fig. S5).21,72 However, in acute coronary syndrome (ACS),
with IGT.69 Acarbose can also be considered but is less FPG can be transiently elevated in the rst 2 days and is
practical because of potential side effects.71 unreliable for establishing a diagnosis of DM.73 Although
IGT is the predominant glucose abnormality in ACS
(Fig. 1),19 an OGTT is rarely performed in that setting and
Establishing a Diagnosis of DM may also be unreliable if done within 4-5 days of the event.73
As indicated in Table 1, there are multiple ways to establish Thus, for cardiologists seeing a patient in an acute in-hospital
a diagnosis of DM, but there are many advantages to using setting, the most pragmatic approach is an A1c test that is then
A1c.1 It can be measured at any time of day and is more followed up electively. Cardiologists should ensure that those
convenient and less variable than FPG or 2-hour PG in a 75-g with an A1c value  6.5% undergo a conrmatory measure-
OGTT. However, A1c may be inaccurate in hemoglobinop- ment 4-8 weeks after discharge, and those with an A1c value of
athies, iron deciency, hemolytic anemias, and severe hepatic 6.0%-6.4% should have an OGTT 6-8 weeks after discharge
and renal disease, and so FPG or a 2-hour OGTT should be (Fig. 4).20 (For urgent treatment of hyperglycemia, see the
used in these settings. Certain ethnic groups, such as African Management of Patients With DM and/or Hyperglycemia Dur-
and Native North Americans, Hispanics, and Asians, have A1c ing ACS section of the Supplemental Material).
values that are up to 0.4% higher than those in white patients
at similar levels of glycemia, and the specic A1c thresholds for
General Management of Hyperglycemia
Table 2. Harmonized denition of the metabolic syndrome: 3 or more Individualization of targets and goals
criteria required for diagnosis
Guidelines support the concept of targeting A1c and
Measure Categorical cut points
individualizing A1c goals to minimize micro- and macro-
Elevated waist circumference Men Women vascular complications while maximizing safety
(population- and
country-specic cut points)
(Supplemental Fig. S6).57,74-77 For the vast majority of pa-
 Canada, United States  102 cm  88 cm tients, including those with CVD, the A1c goal is  7%,74
 Europids, Middle-Eastern, Sub-  94 cm  80 cm because this has been shown to reduce microvascular com-
Saharan African, Mediterranean plications and potentially macrovascular complications, a
 Asians, Japanese, South and  90 cm  80 cm benet that may take 10-15 years to become
Central Americans
Elevated TG (drug treatment for  1.7 mmol/L manifested.57,77-80 However, there is a minority of patients in
elevated TG is an alternative whom a higher A1c target of 7.1%-8.5% is reasonable. These
indicator*) are patients with a shorter life expectancy, frailty, an inability
Reduced HDL-C (drug treatment for < 1.0 mmol/L in men to detect hypoglycemia, or severe comorbidities that render
reduced HDL-C is an alternative < 1.3 mmol/L in women
indicator*)
them at high risk of hypoglycemia.
Elevated blood pressure Systolic  130 mm Hg or
(antihypertensive drug treatment diastolic  85 mm Hg, Tailoring monitoring methods of glycemic control
in a patient with a history of or both
hypertension is an alternative Glycemic control is most commonly assessed by A1c testing
indicator) at a laboratory or with self-monitored blood glucose (SMBG)
Elevated FPG (drug treatment of  5.6 mmol/L levels.20,81 Excluding invalidating conditions (see the Estab-
elevated glucose is an alternative
indicator) lishing a Diagnosis of DM section), the A1c test result reects
the amount of A1c and overall glucose control over the pre-
FPG, fasting plasma glucose; HDL-C, high-density lipoprotein choles-
terol; TG, triglyceride.
vious 3 months and should be measured every 3 months and
* The most commonly used drugs for elevated TG and reduced HDL-C then every 6 months once glycemic goal is achieved. However,
are brates and nicotinic acid. A patient taking 1 of these drugs can be pre- A1c will not be adequate to assess daily hyper- or hypoglyce-
sumed to have high TG levels and low HDL-C. High-dose u-3 fatty acids mia caused by changes in food or activity, so SMBG can
presumes high triglycerides. Modied from Alberti et al.65 with permission still be very useful. If the patient is taking an anti-
from Wolters Kluwer Health. hyperglycemic agent that can cause hypoglycemia, SMBG
Mancini et al. 371
Diabetes for Cardiologists

A1C Screening for T2DM in Pa ents with ACS

6.5 6.0 - 6.4 < 6.0

Symptoms Symptoms
present absent

Repeat A1C in 4-8 weeks

post-discharge

2-h PG 75-g OGTT

6-8 weeks
6.5 < 6.0 6.0 - 6.4 post-discharge

11.1 mmol/L 7.8 11 mmol/L < 7.8 mmol/L

Diagnosis is Likely normal

IGT
diabetes glucose regula on

Start diabetes Start diabetes Annual

management preven on monitoring with
program program A1C

Figure 4. Screening for type 2 diabetes mellitus in patients with acute coronary syndromes, including polyuria, polydipsia, weight loss. A1c, glycated
hemoglobin; ACS, acute coronary syndrome; IGT, impaired glucose tolerance; T2DM, type 2 diabetes mellitus; OGGT, oral glucose tolerance test.
Modied from Gholap et al.20 with permission from Jon Wiley & Sons, Inc.

should be performed, and the frequency depends on the agent
(insulin secretagogue [ie, sulfonylurea or meglitinide]: SMBG
1 or more times per day; insulin: SMBG at least daily and
sometimes more frequently, based on the frequency of in-
jections). In contrast, if the patient is taking anti-
hyperglycemic agents that do not cause hypoglycemia, SMBG
is optional and can be infrequent, ie, several times a week at
different times of the day to determine the effects of lifestyle
such as exercise.
Matching therapeutic options to patient characteristics
Insulin is the treatment of choice in patients with T1DM
resulting from absolute insulin deciency and in patients with
T2DM who are metabolically decompensated because of
marked hyperglycemia. In stable T2DM, there are a number
of options (noninsulin and insulin) that counteract the diverse
mechanisms contributing to hyperglycemia. These factors and
the mechanisms of action of available classes of agents are
summarized in Figure 5 (the ominous octet).82-86
In T2DM, metformin is the traditional rst choice (Fig. 6)
(except if metabolic decompensation is acutely present), and
when needed, metformin is followed by add-on agents
(Fig. 7).84,86 Of particular relevance to the CV specialist is the
newly emerging opportunity to improve CV outcomes, ensure
CV safety (including avoidance of HF), and avoid hypoglyce-
mia (Fig. 7).87-95 Recently, the sodium-glucose cotransporter-2
(SGLT2) inhibitor CV outcome trial using empagliozin
372 Canadian Journal of Cardiology
Volume 33 2017

Figure 5. Mechanism of action of antihyperglycemic medication classes based on the pathophysiology of type 2 diabetes mellitus known as the
ominous octet. DPP-4, dipeptidyl peptidase 4; GLP-1, glucagon-like peptide 1; SGLT2, sodium-glucose cotransporter 2. Modied from DeFronzo82
with permission from the American Diabetes Association.

demonstrated superiority with reduction in CV death, hospi- properties.97,98 The 2016 Canadian Diabetes Association
talization for HF, and all-cause mortality compared to pla- Clinical Practice Guidelines Update recommends the use of an
cebo.96 Mechanisms of benet remain speculative but assuredly SGLT2 inhibitor with proven CV benet in patients with
are not related solely or at all to antihyperglycemic T2DM and clinical CVD in addition to existing

Prediabetes DM
Glucose Status at 2-h glucose A1C A1C Metabolic
Time of Diagnosis 7.8-11.0 mmol/L 6.58.4% 8.5% Decompensa on
Set and Monitor LIFESTYLE Goals (weight loss and exercise)
Therapeu c
Interven ons at If lifestyle goals If lifestyle goals Start METFORMIN INSULIN.
Time of Diagnosis unlikely to be unlikely to be and op mize Consider
met, consider met, start dosage within 3 Me ormin in
star ng METFORMIN and months, consider addi on to
METFORMIN (or op mize dosage simultaneous insulin. Op mize
acarbose) and within 3 months addi on of dosages within 3
op mize dosage SECOND agent months
within 3 months
3 months a er Screen for Every 3 months, op mize doses of exis ng agents or add
diagnosis and development of another agent from dierent class to achieve A 1C goal
beyond DM annually

A empt to achieve A1C Goal within 36 months

Figure 6. Treatment of patients fullling criteria for prediabetes and DM. A1c, glycated hemoglobin.
Mancini et al. 373
Diabetes for Cardiologists

Figure 7. Individualization of antihyperglycemic agents after metformin stratied by cardiovascular considerations, risk of hypoglycemia, and other
safety features (green favourable feature; red unfavourable feature; no color neutral feature or data not available). QID, 4 times daily; TID, 3
times daily. *Self-monitoring of blood glucose is optional when hypoglycemia is indicated as none or rare but mandatory when indicated as
yes. zPrimary end point for cardiovascular (CV) safety trials include nonfatal myocardial infarction, nonfatal stroke, and CV death (major adverse
cardiac event). yAvailable in combination with metformin. xIn this class, information regarding heart failure for linagliptin is not available; a heart
failure caution is noted in Canada for saxagliptin, whereas in the United States this caution is also associated with alogliptin. {Gliclazide was used
in a trial testing lower vs conventional A1c targets with signicant sulfonylurea use in the non-gliclazide arm. jjAvailable in combination with
rosiglitazone.

CKD Stage 5 4 3 2/1

eGFR (mL/min/1.73 m2) < 15 15 - 24 25 - 29 30 - 44 45 - 49 50 - 59 60
Class Drug
Biguanide Me ormin 500 mg BID/TID 850mg TID/1000 mg
BID
Incre n Agents: Liraglu de 1.8 mg sc daily 1.8 mg sc daily
GLP-1 Receptor Agonists Dulaglu de 0.75 1.5 mg sc per week 1.5 mg sc per week
Exena de 5 mcg sc BID 10 mcg sc BID/2 mg per week
SGLT2 Inhibitors Empagliflozin 25 mg daily 25 mg daily
Canagliflozin 100 mg daily 300 mg daily
Dapagliflozin 10 mg daily
Incre n Agents: Aloglip n 6.25 mg daily 12.5 mg daily 25 mg daily
DPP-4 Inhibitors Sitaglip n 25 mg daily 50 mg daily 100 mg daily
Saxaglip n 2.5 mg daily 5 mg
Linaglip n 5 mg/d 5 mg daily
Thiazolidinediones Pioglitazone Risk of heart failure 45 mg daily
Rosiglitazone 8 mg daily
Insulins Glargine basal insulin sc dosing
Other basal/bolus insulins sc dosing
Thiazolidinediones Pioglitazone Risk of heart failure 45 mg daily
Rosiglitazone 8 mg daily
Weight Loss Agent Orlistat 120 mg TID
Alpha-glucosidase Inhibitor Acarbose 100 mg TID
Insulin Secretagogues: Nateglinide 120 mg TID
Megli nides Repaglinide 4 mg QID (with food)
Insulin Secretagogues: Gliclazide hypoglycemia 160 mg BID or 120 mg daily (MR formula on)
Sulfonylureas Glimepiride 4 mg BID
Glyburide hypoglycemia 10 mg BID

Figure 8. General guidance for renal dosing of antihyperglycemic drugs. Doses shown are the maximal recommended doses based on estimated
glomerular ltration rate (eGFR) (red not recommended or contraindicated; yellow use cautiously, reduce dose if possible or monitor renal function
closely, or both; green safe). BID, twice daily; CKD, chronic kidney disease; sc, subcutaneously; QID, 4 times daily; TID; 3 times daily.
374
antihyperglycemic therapy in those patients who are not at the
glycemic target to reduce CV and all-cause mortality.86 Also, the
recently published results of the Liraglutide Effect and Action in
Diabetes: Evaluation of Cardiovascular Outcome Results
(LEADER) study (liraglutide) and a recent press release from
the SUSTAIN 6 study (once weekly semaglutide, not currently
available) show not just CV safety but also CV superiority.99,100
The rationale for concomitant avoidance of hypoglycemia
when making therapeutic choices was reviewed in the earlier
section, Individualization of Targets and Goals. The agents
with the highest risk of hypoglycemia include insulin and
insulin secretagogues because they directly raise circulating
insulin levels. These 2 classes account for 25% of
medication-related hospital admissions seen in emergency
departments in the United States.101 The incretins, which
potentiate glucose-stimulated insulin release through direct
receptor ligand binding (glucagon-like peptide-1 receptor
antagonists [GLP-1 RA]) or inhibition of the enzyme
responsible for degradation of GLP-1 (dipeptidyl peptidase
inhibitors), have a low risk of hypoglycemia.102 SGLT2
inhibitors, which function independently of insulin, block
the reabsorption of glucose in the proximal renal tubule,
cause glycosuria, and reduce circulating glucose levels and
therefore result in a low risk of hypoglycemia.103 Metformin
and thiazolidinediones, classied as insulin sensitizers,
improve glucose uptake, thereby reducing overall insulin
secretion and resulting in a low risk of hypoglycemia. Finally,
renal dysfunction, another CV risk factor and a factor that
affects the dosing of many CV drugs, should be considered
in patients taking antihyperglycemic agents. Figure 8 pro-
vides general guidance in this regard.77,83,88-91,96,104-108
Special Circumstances
Many circumstances require a multidisciplinary team
approach to ensure optimal management that can be
enhanced when the CV specialist is proactive.2,109 Because the
management of women with CVD and DM or in the peri-
pregnancy period is uncommon, and because medication
management during procedures such as diagnostic catheteri-
zation and hyperglycemia management in the setting of ACS
or coronary artery bypass grafting are already components of
existing guidelines, only brief summaries and the relevant key
references are included in the Special Circumstances section of
the Supplementary Material.
Conclusions
Without de-emphasizing the traditional and proven role of
cardiologists in ensuring CV risk reduction in patients with
and those without DM through aggressive blood pressure and
dyslipidemia management, a more proactive role for cardiol-
ogists is rapidly emerging and will become increasingly
important as the prevalence of DM increases along with the
accumulation of evidence that antihyperglycemic medications
have CV benets that are independent of their glucose-
lowering properties. Cardiologists are often in a position to
care for patients who either have DM or demonstrate features
of early or even undiagnosed DM. Moreover, comprehensive
CV risk factor control, which includes DM management,
has been shown to improve the prognosis of patients with
Canadian Journal of Cardiology
Volume 33 2017
DM with or without established CVD.80,96,99,110,111 In a
recently updated summary of lifelong competencies expected
of general cardiologists, cardiovascular disease prevention and
knowledge of guideline recommendations for the evaluation
and management of hypertension, dyslipidemia, and diabetes
is emphasized.112 This article provides a practical summary
and starting point for lling a common knowledge gap among
cardiologists regarding basic principles of DM diagnosis and
management while advancing the concept of comprehensive
CV risk reduction in patients with, or at risk of, diabetes who
are commonly seen in general cardiology practices.
Funding Sources
The authors acknowledge logistical support provided by
Bridge Medical Communications, Toronto, Ontario through
a contract with Merck, Canada for the independent consensus
meeting of the authors. The preparation, content, in-
terpretations and recommendations are the sole responsibility
of the authors.
Disclosures
For disclosure information, please see the Author Conict of
Interest Declarations section of the Supplementary Material.
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Supplementary Material
To access the supplementary material accompanying this
article, visit the online version of the Canadian Journal of
Cardiology at www.onlinecjc.ca and at http://dx.doi.org/10.
1016/j.cjca.2016.07.512.