European Heart Journal Cardiovascular Pharmacotherapy (2016) 2, 3243

doi:10.1093/ehjcvp/pvv035

REVIEW

Disease management

Cardiovascular safety of anti-diabetic drugs

R. Kumar 1*, D. M. Kerins 1,2, and T. Walther 1,3
1
Department of Pharmacology and Therapeutics, University College Cork, Ireland; 2Mercy University Hospital Cork, Ireland; and 3Center for Perinatal Medicine, Department
of Obstetrics, University of Leipzig, Leipzig, Germany

Received 22 June 2015; revised 1 September 2015; accepted 2 September 2015; online publish-ahead-of-print 7 September 2015

----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords

Diabetes mellitus Anti-diabetic agents Cardiovascular disease

Introduction
Type 2 diabetes mellitus (T2DM) is a disorder characterized by insulin resistance and a progressive decline in pancreatic b-cell function associated with increasing hyperglycaemia. Defective b-cell
function occurs early and can be detected in individuals with impaired fasting and/or post-prandial glucose levels. The UK Prospective Diabetes Study (UKPDS)1 indicated that by the time T2DM is
diagnosed, individuals have already lost up to 50% of their b-cell
function. The decline in function proceeds at 6% per year, which
is 20 times greater than that explained by normal ageing. Treatment
of T2DM is based on an interplay of patient characteristics, severity
of hyperglycaemia, and available therapeutic options. Metformin,
sulfonylureas (SUs), and thiazolidinediones (TZDs) are the most
studied of the oral medications used worldwide. They play a prominent initial role in the T2DM treatment algorithm recommended by
the American Diabetes Association (ADA) and the European Diabetes Association for the Study of Diabetes (EASD).2 Metformin
is considered to be the first-line therapy unless not it is tolerated
or is contraindicated. Second-line therapy includes SUs, TZDs,
dipeptidylpeptidase-4 (DPP-4) inhibitors, and glucagon-like
peptide-1 (GLP-1) agonist. Meglitinides also known as the nonsulfonylurea secretagogues and they are recommended as an alternative to SU therapy for patients with irregular meal times or late

post-prandial hypoglycaemia with traditional SU therapy. While it

is yet to be determined what the cardiovascular effects of
anti-diabetic drugs are, the effect of improved glycaemic control
on cardiovascular complications is well established, and in spite of
a large and growing armamentarium of anti-diabetic drugs, the majority of patients over time fail to achieve recommended treatment
goals. Cardiologists should weigh cardiovascular and other risks
against the potential benefits when prescribing medications. Therefore, it is important to clearly define the benefit and risk of current
anti-diabetic agents.

Metformin
Metformin is recommended as the first-line drug for T2DM by most
international guidelines (Figure 1). The preference for metformin over
other available drugs is based on its efficacy on blood glucose control,
tolerability, and safety.3 Moreover, metformin has a favourable action
on several risk factors, including lipids, body weight, and blood pressure (BP).4 Experimental studies have also shown that this drug could
have beneficial effects on fibrinolysis and platelet aggregation.5 In
comparison to other oral agents, metformin is regarded as the best
initial choice, resulting in a decrease in glycated haemoglobin
(HbA1c) better than or equipotent to SUs but without a risk of hypoglycaemia.3 The position statement of the EASD and ADA in 2012

* Corresponding author: Tel: + 353 214905448, Email: rajesh.kumar@ucc.ie

Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2015. For permissions please email: journals.permissions@oup.com

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Cardiovascular disease is the leading cause of morbidity and mortality among patients with diabetes, underscoring the importance of choosing
anti-diabetic drugs that do not increase cardiovascular risk but might reduce the risk of cardiovascular events. Most type 2 diabetic patients die
from cardiovascular causes despite the beneficial effects of blood pressure (BP) and lipid-lowering medications. The prevalence of patients with
cardiovascular disease and diabetes mellitus is growing exponentially. Approximately 40% of patients hospitalized with heart failure and reduced ejection fraction have diabetes mellitus. The recent trials conducted in patients with heart failure who had diabetes showed a different
response to standard medication, with these patients being more prone to develop side effects than patients with the same degree of heart
failure but without diabetes mellitus. Therefore, careful selection of drug therapy paying particular attention to cardiovascular safety is important in optimizing diabetic therapy. This review discusses the efficacy and safety of the most commonly prescribed anti-diabetic drugs in the
context of cardiovascular impact.

Cardiovascular safety

33

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Figure 1 Treatment regimen for type 2 diabetes mellitus patients.

recommends metformin as the foundation treatment for T2DM along

with diet and exercise,2 a stance that is also embraced by the
American Association of Clinical Endocrinologists.6

Efficacy
Up to the present, the UKPDS is the most extensive study assessing
metformin compared with other treatments. It aimed to study the
effect of glycaemic control on the prevention of complications,

associated morbidity and mortality in non-insulin dependent diabetes. Patients with fasting plasma glucose at entry between 6 and
15 mmol/L, were randomized to sulfonylurea, insulin, metformin
[only in overweight patients: body mass index (BMI) 2529 kg/m2],
or diet. At 3 years, metformin achieved the same reduction in fasting
plasma glucose and HbA1c as did SUs or insulin, but in addition it
reduced fasting plasma insulin and did not induce weight gain
(Table 1). Metformin was associated with fewer hypoglycaemic

34

R. Kumar et al.

Table 1

Summary of recommendation for blood pressure and lipid control for adult with diabetes

Management of diabetic CVD

...............................................................................................................................................................................
Hypertension/BP control
Target
Patients with diabetes and hypertension should be treated to a BP goal of ,140/90 mmHg
W

Patients with renal, eye, or cardiac damage should be treated to a BP goal of ,130/80 mmHg

Treatment
Patients with BP .120/80 mmHg should be advised on lifestyle changes to reduce BP
W Lifestyle changes (weight loss if overweight,  sodium intake, moderation of alcohol intake, stop smoking, and  physical activity)
For initial BP .150/100 mmHg

ACEI or ARB+thiazide diuretic or calcium channel blockers or b-blockers

If not at target (2 3 months): add b-blockers or calcium channel blocker or thiazide diuretic
W If still not at target consider, a-blockers or vasodilators or spironolactone
Dyslipidaemia management
Intensify lifestyle therapy and optimize glycaemic control for patients with elevated triglyceride levels .1.7 mmol/L and/or low HDL cholesterol
,1 mmol/L and/or LDL cholesterol .2.5 mmol/L
Lipid-lowering drug therapy with simvastatin 40 mg or atorvastatin 10 mg is recommended for primary prevention in patients with T2DM aged .40 years
regardless of baseline cholesterol
Antiplatelet therapy
Consider aspirin therapy (75162 mg/day) as a primary prevention in men .50 years or women .60 years who have at least one additional major risk
factor (family history of CVD, hypertension, smoking, dyslipidaemia, or albuminuria)
W
W

episodes when compared with SUs or insulin; although blood

glucose-lowering efficacy of all intensive therapies was similar and
clinical outcomes were superior in patients randomly assigned to
metformin. Specifically, intensive glycaemia management with metformin, but not insulin or a SUs in comparison with the diet-treated
group, was associated with significant reductions in the risk of allcause mortality, diabetes-related mortality, and myocardial infarction
(MI). A previously published Cochrane analysis also reported that
treatment with metformin of overweight diabetic patients associated
with decreased risk of cardiovascular mortality compared with any
other anti-diabetic agents or a placebo.7 Therefore, in the current
era, establishing a beneficial cardioprotective effect of metformin
on top of its glucose-lowering effect is a greater challenge.

Safety
Cardiovascular impact
Diabetic patients are at high risk of cardiovascular events, particularly of coronary heart disease by about 3-fold.8 Despite the efforts at
controlling blood glucose and associated risk factors, cardiovascular
morbidity and mortality remain higher in diabetic patients than in
the rest of the population.9 The correct treatment of hyperglycaemia is considered one of the tools for preventing cardiovascular
disease in diabetic patients.10 Many classes of drugs have been
shown to be effective as glucose-lowering agents, at least in the
short and medium term; it has been suggested that some of these
molecules, including metformin, could confer a cardiovascular protection beyond the beneficial effect of the improvement of glucose
control alone because of the reduction of total and low-density lipoprotein (LDL) cholesterol, triglycerides, body weight, and BP.11 The
UKPDS demonstrated that metformin reduced the risk of fatal
macrovascular complications compared with other modalities
(Table 1). The study found that the observed benefits included a

42% reduction in diabetes-related fatalities (compared with

diet alone, P 0.017), a 36% reduction in all-cause mortality
(P 0.011), 39% reduction in MI (P 0.01), and a 32% reduction
in any diabetes-related endpoint (P 0.002). Following UKPDS,
other studies have reported significant improvements of all-cause
mortality and cardiovascular mortality. A retrospective analysis of
patients databases in Saskatchewan, Canada stated significant reductions for all-cause mortality, and cardiovascular mortality of 40
and 36%, respectively.12 The PRESTO trial showed significant reductions of any clinical event (28%), MI (69%), and all-cause mortality (61%).12 The HOME trial reported a decreased risk of developing
macrovascular disease.13 In non-diabetic patients with normal coronary arteriography but also with two consecutive positive (ST depression .1 mm) exercise tolerance tests, an 8-week period on
metformin improved maximal ST-segment depression, Duke treadmill score, and chest pain incidence compared with a placebo.14 A
retrospective cohort study has shown that metformin therapy is a
safe treatment in diabetic patients with heart failure.15 In hospitalized patients with heart failure, metformin was associated with lower 1-year mortality and re-hospitalization rate compared with
insulin or SUs.16
Metformin-associated lactic acidosis
Metformin is considered a first-line therapy for patients with type 2
diabetes. However, metformin is contraindicated in individuals with
severe HF (New York Heart Association, NYHA, classes III IV),
due to concerns of lactic acidosis,17 a serious condition, with an estimated mortality rate of 50%.18 The increasing use of radiographic
contrast media in diagnostic and interventional procedures,
contrast-induced nephropathy (CIN) has become an important
cause of iatrogenic acute renal impairment. Metformin does not predispose to CIN, but if renal function decreases while a patient is on

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LDL, low-density lipoprotein; HDL, high-density lipoprotein; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blockers.

35

Cardiovascular safety

Sulfonylureas
Sulfonylurea derivatives are the oldest class of oral anti-diabetic
agents and are currently used as second-line or an add-on treatment
option for T2DM. These agents act on pancreatic b-cells by binding
adenosine triphosphate-dependent potassium channels causing a
chain of events that leads to increased insulin secretion (Table 1).
Sulfonylureas have gone through several steps of development
and are categorized as first-generation agents (chlorpropamide, tolazamide, and tolbutamide), second-generation agents (glipizide and
glyburide), and third-generation agent (glimepiride).25 The firstgeneration agents have longer half-lives, increased incidence of
hypoglycaemia, and more drug interactions. The second- and thirdgeneration agents have more rapid onsets of action, shorter halflives, and lower incidence of hypoglycaemia. Consequently, the generations differ in their pharmacokinetic, efficacy, and safety profiles.

Efficacy
Sulfonylureas can be expected to reduce fasting plasma glucose by
an average of 24 mmol/L accompanied by a decrease in HbA1c of
12%.26 In the UKPDS, treatment with SUs (glyburide or chlorpropamide) achieved an HbA1c ,7% in 50% of patients at 3 years.27
Despite this impressive initial response, only 34% of patients maintained an HbA1c ,7% at 6 years, and this number declined to 24%
at 9 years.27 Initiation of sulfonylurea treatment in a patient recently
diagnosed with T2DM who shows a random glucose .16.6 mmol/L
and an HbA1c .910% is debateable. Due to large insulin requirements, secondary to glucotoxicity patients exhibiting blood sugars
.16.6 mmol/L are unlikely to achieve acceptable glucose control
with sulfonylurea monotherapy and such patients are best treated,
at least initially, with insulin therapy. After a period of adequate glycaemic control, a trial of SUs to replace insulin therapy, alone or in
combination with metformin, may be attempted.28

Safety
Cardiovascular impact
Sulfonylureas have represented the backbone of oral therapy in
T2DM; however, there are controversies in terms of the cardiovascular safety of this anti-diabetic drug. In early 1970, the report of the
University Group Diabetes Program (UGDP) suggested that tolbutamide therapy was no more effective than diet alone and was associated with an increase in cardiovascular toxicity.29 Therefore, the
UGDP discontinued therapy with the first-generation sulfonylurea
tolbutamide, because of an increase in all-cause and cardiovascular
mortality compared with the other treatment groups. As this led
some experts to conclude that SUs, as a class, were associated
with increased cardiovascular mortality, a serious consequence of
this UGDP study has been condemnation of the therapeutic use
of an entire class of SUs drugs. Although others criticised the design
and analysis of UGDP study,30 the question of safety and efficacy of
tolbutamide and other sulfonylurea groups of drugs were raised. Later on, the UKPDS group demonstrated that treatment with SUs
showed a trend toward protection against MI rather than augmentation of cardiovascular mortality (Table 1).31 Nevertheless, a study
by Garratt et al. 32 reopened this controversy on cardiovascular side
effects of SUs when they demonstrated increased early mortality in
67 persons taking the sulfonylurea glyburide vs. 118 using insulin or
lifestyle therapy alone. This study, on the surface, seemed to condemn sulfonylureas as therapeutic agents.32 However, a critical reappraisal of this study reveals a few exciting facts. This study was
retrospective, randomization was lacking, and the use of sulfonylureas by patients in this study was not specified. The study sample was
too small to reach a decision about the cardiovascular risks of sulfonylureas. Furthermore, in the Rosiglitazone Evaluated for Cardiac
Outcomes and Regulation of Glycaemia in Diabetes (RECORD)
trial incident cardiovascular events with glyburide were not different
from those of rosiglitazone, which was later suspended in some
countries, and limited in others, for insufficient cardiovascular
safety.33 In addition, weight gain of 2 kg is common with the initiation
of sulfonylurea therapy.34 This may have an adverse impact on cardiovascular disease outcome. Finally, a smaller trial on patients with
prior cardiovascular events showed a clear superiority of metformin
over gliclazide.35

Hypoglycaemic impact
The second major concern expressed with sulfonylureas is hypoglycaemia. 21 Severe protracted hypoglycaemia is more likely with
longer-acting sulfonylureas such as glyburide.36 The timing of hypoglycaemia tends to reflect the pharmacokinetics of the sulfonylureas. Thus, glyburide has a propensity to cause inter-prandial
hypoglycaemia, whereas chlorpropamide tends to induce hypoglycaemia in the pre-breakfast period.36,37 In addition, it is possible that
acute hypoglycaemia induced by sulfonylureas, may trigger ischaemia and cardiovascular events.38 Hypoglycaemia and rapid changes
in blood glucose have been shown to increase counter regulatory
hormones such as epinephrine and norepinephrine, which may induce vasoconstriction, platelet aggregation, and thereby ischaemia.39 Therefore, selection of appropriate agents according to
each patients profile is crucial to get maximum beneficial effects
(Figure 1).

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metformin; however, there is a risk of lactic acidosis, which may be

fatal in a substantial number of cases.19 21 First evidence evolved
from case reports on metformin treatment.22 Concerns about
metformin-associated lactic acidosis have led to the practice of metformin discontinuation prior to diagnostic angiography and percutaneous coronary intervention. Evidence for the safety of
metformin has been reported in a large randomized controlled trial
(the Comparative Outcomes Study of Metformin Intervention Versus Conventional Approach study), which compared outcomes at 1
year in diabetics taking metformin (n 7227), to usual care, i.e. diabetics treated with a sulfonylurea, TZD, insulin, or any other nonmetformin monotherapy or combination therapy (n 1505).23
No cases of lactic acidosis were reported in either group. According
to guidelines from the National Institute for Health and Clinical Excellence in the UK, metformin should be withdrawn if serum creatinine is 150 mmol/L (Table 1), or the estimated glomerular
filtration rate is ,30 mL/min/1.7 m2.24 Recommendation on the
timing of discontinuing metformin prior to contrast administration
vary depending on which guidelines are studied, and range from discontinuation 48 h prior to the procedure, 24 h prior to the procedure, or on the day of the procedure.22 New data are necessary to
determine whether there is a significant problem with lactic acidosis
in those patients on metformin who undergo coronary angiography.

36

Meglitinides

Efficacy
Due to the glucose sensitive release of insulin, meglitinides cause
less hypoglycaemia in comparison with sulfonylureas. Repaglinide
has been shown to improve glycaemic control over placebo in several randomized, double-blind multicentre trials.41 A double-blind,
randomized, fixed-dose trial of 361 patients on a background diet
was performed over 24 weeks. Following a washout period, subjects
received repaglinide 1 or 4 mg with meals, or a placebo.42 From a
mean baseline of 8.7%, HbA1c increased by 1.4% in the placebo
group, while it decreased by 0.7 and 0.5% in the repaglinide 1 and
4 mg groups, respectively (P , 0.001). Repaglinide and nateglinide
monotherapies were compared over 16 weeks in subjects uncontrolled by diet and exercise. The reduction in HbA1c values from
baseline was significantly greater for repaglinide than nateglinide
(1.57 vs. 1.04%), and repaglinide had more pronounced effects on
reducing fasting plasma glucose and glucagon secretion, with no differences in post-prandial glucose and insulin secretion.43 Different
studies have compared the efficacy of meglitinides and sulfonylureas
or meglitinides and metformin. A study comparing the effects of
270 mg of nateglinide (n 16) with 20 mg of gliclazide (n 8) in
a 12-week open label prospective study found that gliclazide was
slightly more effective that nateglinide (HbA1c was 0.2% less in
the gliclazide group).44 In a 24-week multicentre study, 360 mg of
nateglinide was similarly effective as metformin 500 mg three times
a day in terms of HbA1c reduction ( 0.8% in both groups).45

Safety
Cardiovascular impact
Repaglinide has not been shown to be associated with increased
mortality and cardiovascular risk compared with metformin in a
large cohort of diabetic patients with or without previous MI.46 In
an uncontrolled randomized study involving 112 patients with

inadequately controlled T2DM not previously treated with oral

hypoglycaemic agents, the use of repaglinide was associated with
positive improvements in some parameters of cardiovascular risk,
such as homocysteine, plasminogen activator inhibitor, and lipoprotein (a).47 The previously reported randomized controlled trial in
diabetes prevention, the Nateglinide and Valsartan in Impaired
Glucose Tolerance Outcomes Research (NAVIGATOR) study, demonstrated no beneficial effect of nateglinide in stopping the progression from prediabetes to diabetes compared with placebo.48
The NAVIGATOR study group randomized 9306 adult subjects
with impaired glucose tolerance (IGT) and cardiovascular disease
or cardiovascular risk factors to receive placebo or nateglinide
(60 mg before meals, three times daily), along with a study-specific
lifestyle modification program.48 The study reported that 36.0% of
participants in the nateglinide group developed diabetes while
33.9% in the placebo group progressed to diabetes after a median
follow-up of 5.0 years (P 0.05). Compared with placebo, nateglinide lowered fasting plasma glucose by 0.03 mmol/L, but increased
2-h post-prandial glucose by 0.24 mmol/L. In addition, 10% of all
participants lost 5% of their baseline weight by 6 months; however,
the nateglinide group had an overall higher mean body weight
throughout the entire study (mean difference 0.35 kg, P , 0.001).
These agents stimulate insulin secretion with a very short half-life,
which confers them the advantages of not causing excessive hypoglycaemia, significant weight gain, and chronic hyperinsulinaemia,
which are more common with sulfonylureas.

Thiazolidinediones
Thiazolidinediones were first reported as insulin-sensitising drugs in
the early 1980s by the pharmaceutical company Takeda,49 but their
mechanism of action remained a mystery until the mid-1990s. The
discovery of the TZDs as high-affinity PPARg ligands was a major
breakthrough in the pharmacology of PPARg.50 Thiazolidinediones
(also termed glitazones) are potent insulin-sensitizers that efficiently
improve glycaemic control in T2DM patients. Three TZDs have
been FDA approved for diabetes: troglitazone, rosiglitazone, and
pioglitazone. However, despite clear benefits in glycaemic control,
this class of drugs has recently fallen into disuse due to concerns
over their side effects and adverse events. The rise and fall of
TZDs is shown by their use in ambulatory diabetes visits: from 6%
in 1997 to 41% in 2005 and down to 16% by 2012.51

Efficacy
Troglitazone was introduced in 1997 but withdrawn from the market in 2000 due to increased risk of liver failure from fulminant hepatitis.52 Rosiglitazone and pioglitazone were both FDA approved in
1999, but pioglitazone has become the TZD of choice for reasons
described below. Thiazolidinediones lower Hb1c effectively by 1%
as monotherapy in T2DM, where they particularly do not cause
hypoglycaemia like insulin or insulin secretagogues (i.e. sulfonylureas), and they can be used in combination with other anti-diabetic
agents.53 The first-line drug metformin is often mentioned as an insulin sensitizer, but its primary effect is suppression of hepatic
glucose production, whereas its effects on peripheral insulin sensitivity are quite small, variable across studies, and absent in a
meta-analysis. 54 In the same analysis, TZDs have large and

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The meglitinides are structurally different than sulfonylureas and exert their effects via SUR-1 receptor, but act similarly by regulating
ATP-dependent potassium channels in pancreatic b-cells thereby increasing insulin secretion. In the natural history of T2DM, a blunted
response of the first phase of glucose-stimulated insulin release has
been observed. An initial surge of insulin is essential to suppress
hepatic gluconeogenesis in the post-prandial period. If this mechanism fails, post-prandial hyperglycaemia is exacerbated and the
HbA1c level is adversely affected. The meglitinides were developed
to address this problem. They bind to the SUR-1 receptor in much
the same way as the sulfonylureas. However, this action is mediated
through a different binding site on the sulfonylurea receptor of the
b-cell, and these drugs have somewhat different characteristics
when compared with the sulfonylureas. Unlike the commonly
used sulfonylureas, the meglitinides have a very short onset of action
and a short half-life. The short half-life of these drugs potentiates the
effect of the first phase of insulin secretion, but the effect on the second phase is not sustained.40 Currently approved drugs in this class
include the benzoic acid derivative repaglinide, approved in 1997,
and nateglinide, a D-phenylalanine derivative, approved in 2000.41
They should be dosed half an hour prior to each meal and one of
the advantages is that they can be used in renal insufficiency.

R. Kumar et al.

37

Cardiovascular safety

consistent effects improving insulin sensitivity. Furthermore, the

ADOPT randomized controlled trial showed that rosiglitazone provided more durable glycaemic control than metformin or sulfonylurea.55 Insulin sensitization also appears to be the mechanism
whereby TZDs prevent or delay development of T2DM in individuals with pre-diabetes. The ACT NOW study involved 602 patients with IGT, pioglitazone decreased progression to T2DM by
74% over 2.4 years.56 Previous studies of patients with pre-diabetes
demonstrated that troglitazone57 or rosiglitazone58 similarly
decreased progression to diabetes. Since TZDs are the most potent
known insulin sensitizers, patients on TZDs will require lower levels
of endogenous and exogenous insulin to maintain euglycaemia.
Indeed, patients using insulin who are started on TZDs typically
reduce their insulin dose or even discontinue insulin injections.59

Safety

Glucagon-like peptide-1
Incretins are gut hormones that potentiate insulin secretion after ingestion in a glucose-dependent manner. The two best-studied incretins, glucose-dependent insulinotropic polypeptide and GLP-1,
exert their insulinotropic actions through distinct G-proteincoupled receptors highly expressed on islet b-cells.73 In addition,
GLP-1 suppresses glucagon release from pancreatic a-cells, an action that is likely to be mediated through the local release of somatostatin from islet d-cells.74 There are two current approaches to
enhancing endogenous GLP-1 action in vivo. The first approach involves incretin mimetics, which are GLP-1 analogues that mimic the
effect of GLP-1 but are resistant to degradation by DPP-4. Compounds in this class include exenatide and liraglutide. The second approach is to produce substances that increase the half-life of
endogenous GLP-1. Agents in this class include the DPP-4 inhibitors
which potentiate the incretin hormones by inhibiting the enzyme
responsible for their degradation.75 There are currently five
GLP-1 receptor agonists approved for use in type 2 diabetic patients: exenatide twice daily/once weekly, liraglutide once daily, albiglutide once weekly, lixisenatide once daily, and dulaglutide once
weekly injections.76 When selecting the most appropriate agent, a
comprehensive review of all head-to-head data indicates that exenatide and liraglutide appear to still offer the best HbA1c and weight
reduction,77 while the once weekly agents may cause less GI side
effects compared with the once daily or twice daily options.

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Cardiovascular impact
There is a greater concern with rosiglitazone than with pioglitazone.
A retrospective analysis of data from .225 000 patients60 concluded that the use of rosiglitazone was associated with an increased
risk of stroke, heart failure, and all-cause mortality in patients aged
65 years or older (Figure 1). On the basis that the risks outweigh the
benefits, rosiglitazone use was restricted in the USA to patients with
T2DM who were not effectively treated with other medications. In
late 2013, the FDA lifted their restriction on the basis of the results
from the RECORD clinical trial (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycemia in Diabetes), which
failed to reproduce the results from the 2007 meta-analysis and indicated no elevated risk of heart attack or death in patients being
treated with rosiglitazone vs. diabetes medications.61 Moreover, in
the PROspective pioglitAzone Clinical Trial In macroVascular
Events (PROactive) clinical trials, pioglitazone treatment resulted
in a non-statistically significant 10% relative risk reduction for the
primary composite endpoint [all-cause death, MI, acute coronary
syndrome (ACS)] and a statistically significant 16% reduction for
the main secondary endpoint (death, MI, and stroke) after a mean
34.5 months in 5238 T2DM patients with established cardiovascular
disease (CVD) (Table 1).62 The potential difference in heart failure
risk between pioglitazone and rosiglitazone may lie in their distinct
effects on lipoproteins, with pioglitazone showing a more beneficial
effect (triglycerides decrease 15%, high-density lipoprotein (HDL)
cholesterol increased by 10%, with no effect on LDL or in total cholesterol) than rosiglitazone (no effect on triglycerides, HDL cholesterol increased by 10%, but 5 10% increases in LDL and total
cholesterol).63 This difference on lipids may reflect weaker PPARa
agonism by pioglitazone.64 These and markers of heart failure risk
favour pioglitazone, and two studies directly measuring atherosclerotic plaques in patients with T2DM showed benefits of pioglitazone
compared with the sulfonylurea glimepiride. In the CHICAGO
study, pioglitazone slowed the progression of carotid intima media
thickness (CIMT),65 while in PERISCOPE pioglitazone actually led to
a regression in coronary atheroma volume assessed by intravascular
ultrasound.66 In the ACT NOW study of patients with pre-diabetes,
pioglitazone similarly decreased progression of CIMT.67 Despite
these impressive cardiovascular benefits with pioglitazone therapy,
its use has also declined markedly, potentially due to guilt by
association with rosiglitazone and the description of new risks for
fractures and bladder cancer.

Weight gain on thiazolidinediones: both fluid retention

and oedema
Weight gain of 13 kg is common in patients taking long-term TZDs
when used alone or in combination with other anti-diabetic agents.
Greater weight gains of 4 5 kg may be seen, however, when TZDs
are used in combination with insulin treatment. In a 52-week study
comparing rosiglitazone to a sulfonylurea (glyburide, median dose
7.5 mg/d), a mean weight gain of 1.9 kg was observed in both the sulfonylurea group and the rosiglitazone group at the 4-mg daily dose,
and a 2.9-kg weight gain was observed at the rosiglitazone 8-mg daily
dose.68 Similar weight gain has been observed when rosiglitazone is
added to metformin. When added to insulin therapy, however,
weight gain may be more dramatic. After 6 months of treatment,
weight gains of 4.1 and 5.4 kg were encountered when rosiglitazone,
at the 4g and 8 mg daily doses, respectively, was added to insulin
(mean dose 70 U/d), compared with a weight gain of 1 kg in patients
treated with insulin alone.69 Similar increases have been observed
with pioglitazone, either as monotherapy or in combination with
other anti-diabetic agents.70 Clinicians are most likely to see oedema as a consequence of TZD therapy when either of the TZDs
is used in combination with insulin. For instance, rosiglitazone 4 or
8 mg per day in combination with insulin was associated with a 13.1
and 16.2% incidence of oedema, respectively, compared with 4.7%
in those taking insulin alone.71 Pioglitazone at 15 or 30 mg daily in
combination with insulin resulted in a combined 15.3% incidence
of oedema, compared with 7.0% for insulin alone.72 Therefore,
the incidence of oedema is higher when either of the TZDs are
combined with insulin compared with other anti-diabetic agents
(Table 1). Patients should be instructed to monitor for weight gain
or the presence of pedal oedema. Therefore, patients with NYHA
functional class III or IV heart failure should not receive TZDs.21

38

Efficacy

Glucagon-like peptide-1 agonist liraglutide

Liraglutide influences the secretion of both pancreatic b and a-cells.
The most important effect is the glucose-dependent stimulation of
insulin secretion and reduces glucagon secretion by pancreatic
a-cells, and consequently hepatic glucose production.83 The clinical
effectiveness of liraglutide is being evaluated in the Liraglutide Effect
and Action in Diabetes, or LEAD programme. The LEAD programme has compared liraglutide with widely used classes of antidiabetic drugs in a series of randomized, double-blind, controlled,
26-week studies in 3800 patients with T2DM and blood glucose
inadequately controlled with standard oral therapies.84 The data
from these studies indicate that the addition of liraglutide to ongoing
oral anti-diabetic drugs can significantly improve glycaemic control
as well as weight loss in previously uncontrolled patients with
T2DM.85 Liraglutide 3.0 mg daily has been shown to result in sustained weight loss, improved cardiovascular risk factors and improved glycaemic control in obese individuals.86 Hence, it is also
of potential clinical value for the treatment of obesity (Figure 1).
Across the LEAD trials programme, the overall rate of hypoglycaemic events observed in patients with T2DM treated with liraglutide was generally low.87

Safety
Cardiovascular impact
Human studies of recombinant native GLP-1 have demonstrated
cardiovascular benefits including reduced arrhythmias, improved
left ventricle function, and improved endothelial function, in patients
with or without diabetes and with coronary artery disease and

chronic heart failure. 88 In addition, potential reduction in CVD

risk has been reported with incretin-based treatment in patients
with T2DM.89 Clinical studies in T2DM patients indicate GLP-1 receptor agonists protect against non-glycaemic cardiovascular risk
factors compared with the placebo and most standard anti-diabetic
agents. Retrospective analyses of data suggested a possible reduced
likelihood of having a cardiovascular event over a 1- to 4-year period
among patients who were treated with exenatide twice daily compared with other glucose-lowering agents.90 Moreover, infusion of
exenatide (0.12 pmol/kg/min) for 6 h during two consecutive days
in men with T2DM and heart failure led to significantly increased
cardiac index (P 0.003) and decreased pulmonary capillary wedge
pressure (P 0.001) compared with the placebo.91 In addition, clinical studies of patients with T2DM have examined reductions in BP,
lipid, body weight, and cardiovascular risk biomarkers, in response
to liraglutide or exenatide treatment.92

Dipeptidylpeptidase-4 inhibitors
Dipeptidylpeptidase-4 inhibition was first approved for clinical use
in 2006 with the DPP-4 inhibitor sitagliptin, and thereafter, several
other DPP-4 inhibitors have been introduced into clinical practice.
All are oral agents taken once or twice daily and are also being
developed for once-weekly administration. These agents reduce
fasting and post-prandial hyperglycaemia, have a low risk for hypoglycaemia and are weight neutral.21,93 Different DPP-4 inhibitors are
distinctive in their metabolism (saxagliptin and vildagliptin are metabolized in the liver while sitagliptin is not), their excretion, their recommended dosage, and the daily dosage that is required for
effective treatment. They are similar, however, when comparing
their efficacy regarding lowering HbA1c levels, safety profile, and patient tolerance.94 Dipeptidylpeptidase-4 inhibitors have a mechanism of action that is distinct from other oral glucose-lowering
agents. Dipeptidylpeptidase-4 is an enzyme that is widely expressed
throughout the body and abundantly expressed in endothelial cells.
The main mechanism for DPP-4 inhibition is that due to prevention
of inactivation of GLP-1 in the peripheral circulation, the increased
circulating intact GLP-1 results in stimulated insulin secretion and
inhibited glucagon secretion.

Efficacy
The efficacy of DPP-4 inhibitors on HbA1c as monotherapy or in
combination with other oral anti-diabetic agents was tested in multiple trials lasting 12 52 weeks. The treatment of T2DM with sitagliptin and vildagliptin for .12 weeks compared with the placebo
and other oral anti-diabetic drugs showed a reduction of 0.74% in
HbA1c levels. This result proved DPP-4 inhibitors were only slightly
less effective than sulfonylureas and as effective as metformin and
TZDs in regard to reducing blood glucose.94 Studies on the influence of DPP-4 inhibitors on patient weight demonstrated variable
results but are largely considered to be neutral (Figure 1). Studies regarding treatment with sitagliptin showed variability between 1.5 kg
of weight loss in 52 weeks of therapy and 1.8 kg of weight gain in 24
weeks of therapy. Studies regarding treatment with vildagliptin
showed variability between 1.8 kg of weight loss and 1.3 kg of
weight gain in 24 weeks of therapy. In a meta-analysis of various

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Glucagon-like peptide-1 agonist exenatide

Exenatide improves glycaemic control primarily by reducing postprandial hyperglycaemia, with a modest reduction in fasting plasma
glucose levels.78 A prominent feature of T2DM is a significant reduction in first-phase insulin secretion, the insulin normally secreted by
pancreatic b-cells within 10 min after an abrupt rise in plasma glucose concentrations. Exenatide has been displayed to restore
both first-phase and second-phase insulin secretion in response to
a glucose bolus in subjects with T2DM.79 The efficacy and safety of
exenatide have been assessed in placebo-controlled trials. All trials
enrolled patients with HbA1c levels of 7.511% and BMI .25 kg/m2.
In placebo-controlled trials, exenatide resulted in improved glycaemic control which was dose-related. Exenatides efficacy as
monotherapy (5- and 10-mg twice daily dosing) was explored in previous study, which demonstrated that HbA1c levels declined steadily during the first 12 weeks of treatment and remained stable at 0.7
and 0.9% below baseline.80 In particular, exenatide lowers postprandial glucose levels after breakfast and dinner to a much greater
degree than after lunch. The half-life of this agent is too short for the
pre-breakfast injection to also cover the lunch-related glucose excursion. In other studies, in which exenatide (10 mg twice daily)
was combined with either metformin or a sulfonylurea, similar improvements in HbA1c levels, with stable values of 0.8 0.9% below
baseline.81,82 In the exenatide-sulfonylurea study, 41% of patients
achieved HbA1c levels ,7.0%. Both combinations also caused
progressive weight loss.82

R. Kumar et al.

39

Cardiovascular safety

studies regarding the treatment of all three DPP-4 inhibitors, the

effect of this group of drugs on weight was neutral.95

Safety

Sodium glucose cotransporter 2

inhibitors
Sodium glucose cotransporter 2 (SGLT-2) inhibitors are a new class
of anti-diabetic drugs with a novel mechanism of action. They reduce renal glucose reabsorption in the proximal convoluted tubule,
leading to increased urinary glucose excretion.100 The first agent approved in T2DM was dapagliflozin, in late 2012, shortly followed by
canagliflozin, and more recently by empagliflozin; all three are currently approved in the USA and in the European Union.101 Unlike
many current therapies, the mechanism of action of SGLT-2 inhibitors is independent of insulin secretion or action and, therefore,
does not depend on b-cell function. This suggests that SGLT-2 inhibitors may be effective across all stages of disease progression and
carry a low risk for hypoglycaemia.21

Efficacy
All three approved SGLT-2 inhibitors induce a similar sustained
urinary glucose loss of 40 80 g/day, associated with good blood

Safety
Cardiovascular impact
Sodium glucose cotransporter 2 inhibitor therapy may be considered in T2DM patients with chronic heart failure with reduced ejection fraction (HFREF), because part of the SGLT-2 inhibitor
mechanism includes diuresis, which leads to a preload reduction.
This preload reduction is often needed in patients with HFREF.109
Another cardiovascular benefit of SGLT-2 inhibitors is the reduction of BP, in part due to the osmotic diuresis. A 35 mmHg reduction in systolic and 2 mmHg reduction in diastolic BP have been seen
without any compensatory increase in heart rate.110 A meta-analysis
of 27 randomized controlled trials shows that SGLT-2 inhibitors decrease systolic BP by 4.0 mmHg and diastolic BP by 1.6 mmHg.110
Also relevant for assessing CV safety is the plasma lipid profile; it
turned out that canagliflozin (and also other SGLT-2 inhibitors)
slightly increase the levels of both HDL and LDL cholesterol.111
This simultaneous increase of both lipoproteins might be a consequence of the observed haemoconcentration and probably does
not imply increased CV risk. Sodium glucose cotransporter 2 inhibitors have shown beneficial effects on CV risk factors, such as BP, lipids, HbA1c, and weight. Whether these benefits translate into
long-term reduction of CV events is unknown. According to the
current knowledge from a meta-analysis of clinical trials, including
an interim analysis of the Canagliflozin Cardiovascular Assessment
Study (CANVAS), showed that canagliflozin does not increase the
overall CV risk.112 Notably, in patients without CV disease,
canagliflozin-treated patients performed numerically better than
the comparator therapies in respect to major CV events. The CANVAS is an ongoing trial to evaluate adverse CV events with the use of
canagliflozin in diabetics with high CV risk and is expected to be
completed in 2018.113 Cardiovascular effects of dapagliflozin are
currently being studied in an ongoing Multicenter Trial to Evaluate
the Effect of Dapagliflozin on the Incidence of Cardiovascular Events
(DECLARE-TIMI58), results of which are expected to be released in

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Cardiovascular impact
Lipid profile is a crucial factor of cardiovascular risk in T2DM.
Twenty patients with T2DM and a body mass index between 28
and 40 kg/m2 were included and randomized to receive 100 mg vildagliptin or placebo.96 The results of that study indicate that DPP-4
inhibition increases post-prandial lipid mobilisation and oxidation
which contributes to the reduction of cardiovascular risk. In the
EXAMINE trial (EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with T2DM and ACS),97
5380 patients with T2DM with either acute MI or unstable angina
requiring hospitalization within the previous 15 90 days were randomized to receive alogliptin or placebo and followed up for 1.5
years. Alogliptin treatment did not improve the combined outcome
of primary endpoints including death from cardiovascular causes,
non-fatal MI, and non-fatal stroke. Similarly, in the SAVOR-TIMI trial
(Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus-Thrombolysis in Myocardial Infarction),98 16 492 patients with T2DM and history or at risk of CV
events were followed for 2.1 years and were randomized to receive
saxagliptin or placebo. In consistency with the results from EXAMINE, no improvements in cardiovascular outcomes were observed
in treatment group compared with placebo-treated patients. It
must be noted that the median follow-up period for EXAMINE and
SAVOR-TIMI was 1.5 and 2.1 years, respectively, and a longer followup period may be necessary to further confirm the results. Finally, the
results of TECOS (Trial to Evaluate Cardiovascular Outcomes after
Treatment with Sitagliptin) have clarified that increased risk of HF is
not a DPP-4 inhibitors class effect.99 In TECOS, 14 671 patients were
either assigned to sitagliptin or placebo in addition to their current
anti-diabetic therapy. Thus, all three trials suggest that DPP-4 inhibitors are basically safe from a cardiovascular standpoint but also do
not improve cardiovascular endpoints at least in the short term.

glucose-lowering efficacy in T2DM (a reduction in HbA1c of 0.7

0.8% from a starting HbA1c of 8.0%) and lowering of body weight
by 2 3 kg.102,103 In a large meta-analysis that included data from
SGLT-2 inhibitor trials predominantly involving dapagliflozin and
canagliflozin, a favourable effect on reducing HbA1c was observed
with a mean difference of 0.7% when compared with placebo.104
Empagliflozin has recently been approved for use in T2DM patients.
In a study of T2DM patients controlled with metformin only,
HbA1c was improved by a placebo-corrected mean of 0.57 with
10 mg empagliflozin and 0.64% with 25 mg empagliflozin at
24 weeks (both P 0.001 vs. placebo). 105 When empagliflozin
was investigated as an add-on therapy to metformin and sulfonylurea and to pioglitazone with or without metformin, similar results
were obtained.105 Furthermore, in a longer-term 78-week study,
10 and 25 mg empagliflozin as an add-on therapy to patients taking
basal insulin resulted in significant weight loss vs placebo (2.2 vs.
0.7 kg; P 0.01).106 Dapagliflozin was also associated with weight
loss vs. weight gain with glipizide at 52 weeks in patients inadequately controlled with metformin (3.2 vs. 1.4 kg for dapagliflozin
vs. glipizide; P 0.0001). 107 In patients with moderate chronic
kidney disease, the efficacy tends to be dampened and safety
concerns may occur.108

40
2019.114 Taken together, evidence that will define the overall balance of benefits and risks of this new drug class is anticipated within
the next 5 years.

Conclusion
Anti-diabetic agents impact on
cardiovascular morbidity and mortality

Conflict of interest: none declared.

References
1. Kim CJ, Kang HS, Schlenk EA, Chae SM. Assessment of cardiovascular risk in
adults with type 2 diabetes and metabolic syndrome: Framingham versus UKPDS
equations. Diabetes Educ 2015;41:203 213.
2. Inzucchi S, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL,
Tsapas A, Wender R, Matthews DR. Management of hyperglycaemia in type 2 diabetes, 2015: a patient-centred approach. Update to a Position Statement of the
American Diabetes Association and the European Association for the Study of
Diabetes. Diabetologia 2015;58:429 442.
3. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R,
Zinman B. Medical management of hyperglycemia in type 2 diabetes: a consensus
algorithm for the initiation and adjustment of therapy: a consensus statement of
the American Diabetes Association and the European Association for the Study
of Diabetes. Diabetes Care 2009;32:193 203.

4. Malin SK, Nightingale J, Choi S-E, Chipkin SR, Braun B. Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose
tolerant adults. Obesity (Silver Spring, MD) 2013;21.
5. de Jager J, Kooy A, Schalkwijk C, van der Kolk J, Lehert P, Bets D, Wulffele MG,
Donker AJ, Stehouwer CD. Long-term effects of metformin on endothelial function in type 2 diabetes: a randomized controlled trial. J Intern Med 2014;275:
59 70.
6. Handelsman Y, Bloomgarden ZT, Grunberger G, Umpierrez G, Zimmerman RS,
Bailey TS, Blonde L, Bray GA, Cohen AJ, Dagogo-Jack S, Davidson JA, Einhorn D,
Ganda OP, Garber AJ, Garvey WT, Henry RR, Hirsch IB, Horton ES, Hurley DL,
Jellinger PS, Jovanovic L, Lebovitz HE, LeRoith D, Levy P, McGill JB, Mechanick JI,
Mestman JH, Moghissi ES, Orzeck EA, Pessah-Pollack R, Rosenblit PD, Vinik AI,
Wyne K, Zangeneh F. American association of clinical endocrinologists and
American college of endocrinology clinical practice guidelines for developing
a diabetes mellitus comprehensive care plan 2015. Endocr Pract 2015;21:1 87.
7. Hemmingsen B, Schroll JB, Wetterslev J, Gluud C, Vaag A, Sonne DP,
Lundstrm LH, Almdal T. Sulfonylurea versus metformin monotherapy in patients
with type 2 diabetes: a cochrane systematic review and meta-analysis of randomized clinical trials and trial sequential analysis. CMAJ Open 2014;2:E162 E175.
8. Cea Soriano L, Johansson S, Stefansson B, Rodriguez LA. Cardiovascular events
and all-cause mortality in a cohort of 57,946 patients with type 2 diabetes: associations with renal function and cardiovascular risk factors. Cardiovasc Diabetol 2015;
14:38.
9. Halter JB, Musi N, McFarland Horne F, Crandall JP, Goldberg A, Harkless L,
Hazzard WR, Huang ES, Kirkman MS, Plutzky J, Schmader KE, Zieman S,
High KP. Diabetes and cardiovascular disease in older adults: current status and
future directions. Diabetes 2014;63:2578 2589.
10. Holman RR, Sourij H, Califf RM. Cardiovascular outcome trials of glucoselowering drugs or strategies in type 2 diabetes. Lancet 2014;383:2008 2017.
11. Pawlyk AC, Giacomini KM, McKeon C, Shuldiner AR, Florez JC. Metformin
pharmacogenomics: current status and future directions. Diabetes 2014;63:
2590 2599.
12. Kao J, Tobis J, McClelland RL, Heaton MR, Davis BR, Holmes DR Jr, Currier JW.
Relation of metformin treatment to clinical events in diabetic patients undergoing
percutaneous intervention. Am J Cardiol 2004;93:1347 1350.
13. Kooy A, de Jager J, Lehert P et al. Long-term effects of metformin on metabolism
and microvascular and macrovascular disease in patients with type 2 diabetes
mellitus. Arch Intern Med 2009;169:616 625.
14. Jadhav S, Ferrell W, Greer IA, Petrie JR, Cobbe SM, Sattar N. Effects of metformin
on microvascular function and exercise tolerance in women with angina and
normal coronary arteries: a randomized, double-blind, placebo-controlled study.
J Am Coll Cardiol 2006;48:956963.
15. Shah DD, Fonarow GC, Horwich TB. Metformin therapy and outcomes in patients with advanced systolic heart failure and diabetes. J Cardiac Failure 2010;
16:200 206.
16. Masoudi FA, Inzucchi SE, Wang Y, Havranek EP, Foody JM, Krumholz HM. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and
heart failure: an observational study. Circulation 2005;111:583 590.
17. Monami M, Mannucci E. Dipeptidyl peptidase-4 inhibitors and heart failure: friends
or foes? Curr Cardiovasc Risk Rep 2015;9:1 8.
18. Seidowsky A, Nseir S, Houdret N, Fourrier F. Metformin-associated lactic acidosis: a prognostic and therapeutic study. Crit Care Med 2009;37:2191 2196.
19. Thomas CC, Bakris G. Metformin nephrotoxicity insights: will they change clinical
management? J Diabetes 2014;6:111 112.
20. Baerlocher MO, Asch M, Myers A. Metformin and intravenous contrast. Canadian
Med Assoc J 2013;185:E78.
21. Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C,
Escaned J, Hammes HP, Huikuri H, Marre M, Marx N, Mellbin L, Ostergren J,
Patrono C, Seferovic P, Uva MS, Taskinen MR, Tendera M, Tuomilehto J,
Valensi P, Zamorano JL; ESC Committee for Practice Guidelines (CPG),
Zamorano JL, Achenbach S, Baumgartner H, Bax JJ, Bueno H, Dean V, Deaton
C, Erol C, Fagard R, Ferrari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh
P, Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Sirnes
PA, Tamargo JL, Tendera M, Torbicki A, Wijns W, Windecker S; Document
Reviewers, De Backer G, Sirnes PA, Ezquerra EA, Avogaro A, Badimon L,
Baranova E, Baumgartner H, Betteridge J, Ceriello A, Fagard R, Funck-Brentano
C, Gulba DC, Hasdai D, Hoes AW, Kjekshus JK, Knuuti J, Kolh P, Lev E, Mueller
C, Neyses L, Nilsson PM, Perk J, Ponikowski P, Reiner Z, Sattar N, Schachinger V,
Scheen A, Schirmer H, Stromberg A, Sudzhaeva S, Tamargo JL, Viigimaa M,
Vlachopoulos C, Xuereb RG. ESC guidelines on diabetes, pre-diabetes, and
cardiovascular diseases developed in collaboration with the EASD: the Task Force
on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of
Cardiology (ESC) and developed in collaboration with the European Association
for the Study of Diabetes (EASD). Eur Heart J 2013;34:3035 3087.

Downloaded from http://ehjcvp.oxfordjournals.org/ by guest on August 30, 2016

Patients with T2DM have an inherent, elevated risk for cardiovascular disease that likely begins well in advance of a diagnosis of chronic
hyperglycaemia. Data describing cardiovascular benefits with metformin are encouraging, with studies showing reductions in any
diabetes-related endpoint, diabetes-related death, and all-cause
mortality. Evidence for the safety of sulfonylurea therapy is still conflicting, but compared with metformin therapy, sulfonylurea use has
been associated with an increased risk of developing heart failure,
especially at higher doses. Meglitinide therapy with repaglinide has
been shown to decrease cardiovascular markers including markers
of inflammation, platelet activation, and lipid parameters, although
less effectively than metformin. The TZD pioglitazone has also
been shown to lower the composite of all-cause mortality, non-fatal
MI, and stroke in patients with T2DM at high risk for macrovascular
events. Thiazolidinediones use, primarily rosiglitazone, is contraindicated in patients with heart failure, as it has been shown to increase
the risk of heart failure. Incretin-based therapies including GLP-1
agonists and DPP-4 inhibitors have potential positive effects on
the cardiovascular system. The GLP-1 analogue exenatide is associated with a significantly decreased risk of CVD and CVD-related
hospitalizations in patients with T2DM. Sodium glucose cotransporter 2 inhibitors are novel oral glucose-lowering agents though, the
potential for cardiovascular benefits from the SGLT-2 inhibitors remains to be established. There is ample evidence also to suggest that
a multifactorial approach to diabetes care, which targets glycaemic
control in addition to treatment of hypertension and dyslipidaemia,
will significantly decrease cardiovascular risk. Cardiovascular risk reduction in diabetes, rather than focusing upon glycaemic management alone, should aim to reduce plasma glucose in addition to
cholesterol and BP (Table 1). The results of ongoing clinical trials
will provide further evidence about the cardiovascular safety and
perhaps efficacy of diabetes drugs. These trials will certainly help
to further refine therapeutic guidelines in the future.

R. Kumar et al.

Cardiovascular safety

47. Schramm TK, Gislason GH, Vaag A, Rasmussen JN, Folke F, Hansen ML, Fosbl EL,
Kber L, Norgaard ML, Madsen M, Hansen PR, Torp-Pedersen C. Mortality and
cardiovascular risk associated with different insulin secretagogues compared with
metformin in type 2 diabetes, with or without a previous myocardial infarction: a
nationwide study. Eur Heart J 2011;32:1900 1908.
48. Holman RR, Haffner SM, McMurray JJ, Bethel MA, Holzhauer B, Hua TA,
Belenkov Y, Boolell M, Buse JB, Buckley BM, Chacra AR, Chiang FT,
Charbonnel B, Chow CC, Davies MJ, Deedwania P, Diem P, Einhorn D,
Fonseca V, Fulcher GR, Gaciong Z, Gaztambide S, Giles T, Horton E, Ilkova H,
Jenssen T, Kahn SE, Krum H, Laakso M, Leiter LA, Levitt NS, Mareev V,
Martinez F, Masson C, Mazzone T, Meaney E, Nesto R, Pan C, Prager R,
Raptis SA, Rutten GE, Sandstroem H, Schaper F, Scheen A, Schmitz O, Sinay I,
Soska V, Stender S, Tamas G, Tognoni G, Tuomilehto J, Villamil AS, Vozar J,
Califf RM. Effect of nateglinide on the incidence of diabetes and cardiovascular
events. N Engl J Med 2010;362:1463 1476.
49. Fujita T, Sugiyama Y, Taketomi S, Sohda T, Kawamatsu Y, Iwatsuka H, Suzuoki Z.
Reduction of insulin resistance in obese and/or diabetic animals by
5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878,
U-63,287, ciglitazone), a new antidiabetic agent. Diabetes 1983;32:804 810.
50. Mansour M. The roles of peroxisome proliferator-activated receptors in the
metabolic syndrome. Prog Mol Biol Transl Sci 2014;121:217 266.
51. Turner LW, Nartey D, Stafford RS, Singh S, Alexander GC. Ambulatory treatment
of type 2 diabetes in the U.S., 1997 2012. Diabetes Care 2014;37:985 992.
52. Kohlroser J, Mathai J, Reichheld J, Banner BF, Bonkovsky HL. Hepatotoxicity due
to troglitazone: report of two cases and review of adverse events reported to the
United States Food and Drug Administration. Am J Gastroenterol 2000;95:
272 276.
53. Soccio RE, Chen ER, Lazar MA. Thiazolidinediones and the promise of insulin
sensitization in type 2 diabetes. Cell Metabolism 2014;20:573 591.
54. Natali A, Ferrannini E. Effects of metformin and thiazolidinediones on suppression
of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 2006;49:434 441.
55. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG,
Lachin JM, ONeill MC, Zinman B, Viberti G. Glycemic durability of rosiglitazone,
metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427 2443.
56. DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA, Buchanan TA,
Clement SC, Henry RR, Hodis HN, Kitabchi AE, Mack WJ, Mudaliar S,
Ratner RE, Williams K, Stentz FB, Musi N, Reaven PD. Pioglitazone for diabetes
prevention in impaired glucose tolerance. N Engl J Med 2011;364:1104 1115.
57. Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E, Ehrmann DA,
Walker EA, Fowler SE, Nathan DM, Kahn SE. Prevention of type 2 diabetes
with troglitazone in the diabetes prevention program. Diabetes 2005;54:
1150 1156.
58. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M,
Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance
or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:
1096 1105.
59. Yau H, Rivera K, Lomonaco R, Cusi K. The future of thiazolidinedione therapy in
the management of type 2 diabetes mellitus. Curr Diab Rep 2013;13:329341.
60. Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, Ali F, Sholley C, Worrall C,
Kelman JA. Risk of acute myocardial infarction, stroke, heart failure, and death
in elderly Medicare patients treated with rosiglitazone or pioglitazone. JAMA
2010;304:411 418.
61. Mahaffey KW, Hafley G, Dickerson S, Burns S, Tourt-Uhlig S, White J, Newby LK,
Komajda M, McMurray J, Bigelow R, Home PD, Lopes RD. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J 2013;
166:240 249 e1.
62. Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M,
Moules IK, Skene AM, Tan MH, Lefe`bvre PJ, Murray GD, Standl E, Wilcox RG,
Wilhelmsen L, Betteridge J, Birkeland K, Golay A, Heine RJ, Koranyi L,
Laakso M, Mokan M, Norkus A, Pirags V, Podar T, Scheen A, Scherbaum W,
Schernthaner G, Schmitz O, Skrha J, Smith U, Taton J; PROactive investigators.
Secondary prevention of macrovascular events in patients with type 2 diabetes
in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279 1289.
63. Chiquette E, Ramirez G, Defronzo R. A meta-analysis comparing the effect of
thiazolidinediones on cardiovascular risk factors. Arch Intern Med 2004;164:
2097 2104.
64. Sakamoto J, Kimura H, Moriyama S, Odaka H, Momose Y, Sugiyama Y, Sawada H.
Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem Biophys Res Commun 2000;278:704 711.
65. Mazzone T, Meyer PM, Feinstein SB, Davidson MH, Kondos GT, DAgostino RB Sr,
Perez A, Provost JC, Haffner SM. Effect of pioglitazone compared with glimepiride

Downloaded from http://ehjcvp.oxfordjournals.org/ by guest on August 30, 2016

22. Goergen SK, Rumbold G, Compton G, Harris C. Systematic review of current guidelines, and their evidence base, on risk of lactic acidosis after administration of contrast medium for patients receiving metformin. Radiology 2010;254:261269.
23. Cryer DR, Nicholas SP, Henry DH, Mills DJ, Stadel BV. Comparative outcomes
study of metformin intervention versus conventional approach the COSMIC
Approach Study. Diabetes Care 2005;28:539 543.
24. Maznyczka A, Myat A, Gershlick A. Discontinuation of metformin in the setting of
coronary angiography: clinical uncertainty amongst physicians reflecting a poor
evidence base. EuroIntervention 2012;7:1103 1110.
25. Hamaguchi T, Hirose T, Asakawa H, Itoh Y, Kamado K, Tokunaga K, Tomita K,
Masuda H, Watanabe N, Namba M. Efficacy of glimepiride in type 2 diabetic patients treated with glibenclamide. Diabetes Res Clin Pract 2004;66(suppl.):
S129 S132.
26. Shankar RR, Xu L, Golm GT, ONeill EA, Goldstein BJ, Kaufman KD, Engel SS. A
comparison of glycaemic effects of sitagliptin and sulfonylureas in elderly patients
with type 2 diabetes mellitus. Int J Clin Pract 2015;69:626 631.
27. Thule P, Umpierrez G. Sulfonylureas: a new look at old therapy. Curr Diabetes Rep
2014;14:1 8.
28. Tran L, Zielinski A, Roach AH, Jende JA, Householder AM, Cole EE, Atway SA,
Amornyard M, Accursi ML, Shieh SW, Thompson EE. The pharmacologic treatment of type 2 diabetes: injectable medications. Ann Pharmacother 2015;49:
700 714.
29. Seltzer HS. A summary of criticisms of the findings and conclusions of the University Group Diabetes Program (UGDP). Diabetes 1972;21:976 979.
30. Schwartz TB, Meinert CL. The UGDP controversy: thirty-four years of contentious ambiguity laid to rest. Perspect Biol Med 2004;47:564 574.
31. Riddle MC. Sulfonylureas differ in effects on ischemic preconditioningis it time
to retire glyburide? J Clin Endocrinol Metabolism 2003;88:528 530.
32. Garratt KN, Brady PA, Hassinger NL, Grill DE, Terzic A, Holmes DR Jr.
Sulfonylurea drugs increase early mortality in patients with diabetes mellitus after
direct angioplasty for acute myocardial infarction. J Am Coll Cardiol 1999;33:
119 124.
33. Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, Jones NP,
Komajda M, McMurray JJ. Rosiglitazone evaluated for cardiovascular outcomes in
oral agent combination therapy for type 2 diabetes (RECORD): a multicentre,
randomised, open-label trial. Lancet 2009;373:2125 2135.
34. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular
disease in type 2 diabetes. Eur Heart J 2015;36:2288 2296.
35. Hong J, Zhang Y, Lai S, Lv A, Su Q, Dong Y, Zhou Z, Tang W, Zhao J, Cui L,
Zou D, Wang D, Li H, Liu C, Wu G, Shen J, Zhu D, Wang W, Shen W,
Ning G. Effects of metformin versus glipizide on cardiovascular outcomes in
patients with type 2 diabetes and coronary artery disease. Diabetes Care 2013;
36:1304 1311.
36. Clemens KK, Clemens KK, McArthur E, Dixon SN, Fleet JL, Hramiak I, Garg AX.
The hypoglycemic risk of glyburide (glibenclamide) compared with modifiedrelease gliclazide. Can J Diabetes 2015;39:308 316.
37. Brietzke SA. Oral antihyperglycemic treatment options for type 2 diabetes mellitus. Med Clin North America 2015;99:87106.
38. Pistrosch F, Ganz X, Bornstein SR, Birkenfeld AL, Henkel E, Hanefeld M. Risk of
and risk factors for hypoglycemia and associated arrhythmias in patients with type
2 diabetes and cardiovascular disease: a cohort study under real-world conditions.
Acta Diabetol 2015;52:1 7.
39. Joy NG, Tate DB, Davis SN. Counterregulatory responses to hypoglycemia differ
between glimepiride and glyburide in non diabetic individuals. Metabolism 2015;
64:729 737.
40. Fuhlendorff J, Rorsman P, Kofod H, Brand CL, Rolin B, MacKay P, Shymko R,
Carr RD. Stimulation of insulin release by repaglinide and glibenclamide involves
both common and distinct processes. Diabetes 1998;47:345 351.
41. Stein SA, Lamos EM, Davis SN. A review of the efficacy and safety of oral antidiabetic drugs. Expert Opin Drug Saf 2013;12:153 175.
42. Jovanovic L, Dailey G, Huang W-C, Strange P, Goldstein BJ. Repaglinide in type 2
diabetes: a 24-week, fixed-dose efficacy and safety study. J Clin Pharmacol 2000;40:
49 57.
43. Rosenstock J, Hassman DR, Madder RD, Brazinsky SA, Farrell J, Khutoryansky N,
Hale PM. Repaglinide versus nateglinide monotherapy: a randomized, multicenter
study. Diabetes Care 2004;27:1265 1270.
44. Miwa S, Watada H, Ohmura C, Tanaka Y, Kawamori R. Efficacy and safety of once
daily gliclazide (20 mg/day) compared with nateglinide. Endocr J 2004;51:393398.
45. Horton ES, Clinkingbeard C, Gatlin M, Foley J, Mallows S, Shen S. Nateglinide
alone and in combination with metformin improves glycemic control by reducing
mealtime glucose levels in type 2 diabetes. Diabetes Care 2000;23:1660 1665.
46. Derosa G, Mugellini A, Ciccarelli L, Crescenzi G, Fogari R. Comparison of glycaemic control and cardiovascular risk profile in patients with type 2 diabetes during treatment with either repaglinide or metformin. Diabetes Res Clin Pract 2003;
60:161 169.

41

42

66.

67.

68.

69.

70.

72.
73.
74.

75.

76.
77.
78.

79.

80.

81.

82.

83.

84.
85.

86.
87.

on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA

2006;296:2572 2581.
Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, De
Larochellie` re R, Staniloae CS, Mavromatis K, Saw J, Hu B, Lincoff AM,
Tuzcu EM. Comparison of pioglitazone vs glimepiride on progression of
coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008;299:1561 1573.
Saremi A, Schwenke DC, Buchanan TA, Hodis HN, Mack WJ, Banerji M, Bray GA,
Clement SC, Henry RR, Kitabchi AE, Mudaliar S, Ratner RE, Stentz FB, Musi N,
Tripathy D, DeFronzo RA, Reaven PD. Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors.
Arterioscler Thromb Vasc Biol 2013;33:393 399.
Tang WHW, Francis GS, Hoogwerf BJ, Young JB. Fluid retention after initiation
of thiazolidinedione therapy in diabetic patients with established chronic heart
failure. J Am Coll Cardiol 2003;41:1394 1398.
Nesto RW, Bell D, Bonow RO, Fonseca V, Grundy SM, Horton ES, Le Winter M,
Porte D, Semenkovich CF, Smith S, Young LH, Kahn R. Thiazolidinedione use, fluid
retention, and congestive heart failure: a consensus statement from the American
Heart Association and American Diabetes Association. Circulation 2003;108:
2941 2948.
Aghamohammadzadeh N, Niafar M, Dalir Abdolahinia E, Najafipour F, Mohamadzadeh Gharebaghi S, Adabi K, Dalir Abdolahinia E, Ahadi H. The effect of pioglitazone on weight, lipid profile and liver enzymes in type 2 diabetic patients. Ther
Adv Endocrinol Metab 2015;6:5660.
Raskin P, Rendell M, Riddle MC, Dole JF, Freed MI, Rosenstock J. A randomized
trial of rosiglitazone therapy in patients with inadequately controlled insulintreated type 2 diabetes. Diabetes Care 2001;24:1226 1232.
Clar C, Royle P, Waugh N. Adding pioglitazone to insulin containing regimens in
type 2 diabetes: systematic review and meta-analysis. PLoS ONE 2009;4:e6112.
Hwang JI, Yun S, Moon MJ, Park CR, Seong JY. Molecular evolution of GPCRs:
GLP1/GLP1 receptors. J Mol Endocrinol 2014;52:T15 T27.
Hansen L, Hartmann B, Bisgaard T, Mineo H, Jrgensen PN, Holst JJ. Somatostatin
restrains the secretion of glucagon-like peptide-1 and -2 from isolated perfused
porcine ileum. Am J Physiol Endocrinol Metab 2000;278: E1010 E1018.
Wei Q, Sun YQ, Zhang J. Exendin-4, a glucagon-like peptide-1 receptor agonist,
inhibits cell apoptosis induced by lipotoxicity in pancreatic b-cell line. Peptides
2012;37:18 24.
Ryan D, Acosta A. GLP-1 receptor agonists: nonglycemic clinical effects in weight
loss and beyond. Obesity (Silver Spring) 2015;23:1119 1129.
Trujillo JM, Nuffer W, Ellis SL. GLP-1 receptor agonists: a review of head-to-head
clinical studies. Ther Adv Endocrinol Metabolism 2015;6:19 28.
Patsch JR, Miesenbock G, Hopferwieser T, Muhlberger V, Knapp E, Dunn JK,
Gotto AM Jr, Patsch W. Relation of triglyceride metabolism and coronary artery
disease. Studies in the postprandial state. Arteriosclerosis Thromb Vasc Biol 1992;12:
1336 1345.
Fehse F, Trautmann M, Holst JJ, Halseth AE, Nanayakkara N, Nielsen LL,
Fineman MS, Kim DD, Nauck MA. Exenatide augments first- and second-phase
insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2005;90:5991 5997.
Moretto TJ, Milton DR, Ridge TD, Macconell LA, Okerson T, Wolka AM,
Brodows RG. Efficacy and tolerability of exenatide monotherapy over 24 weeks
in antidiabetic drugnaive patients with type 2 diabetes: a randomized, doubleblind, placebo-controlled, parallel-group study. Clin Ther 2008;30:1448 1460.
Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide
(exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients
with type 2 diabetes. Diab Care 2004;27:2628 2635.
DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformintreated patients with type 2 diabetes. Diab Care 2005;28:1092 1100.
Schwasinger-Schmidt T, Robbins DC, Williams SJ, Novikova L, Stehno-Bittel L.
Long-term liraglutide treatment is associated with increased insulin content and
secretion in b-cells, and a loss of a-cells in ZDF rats. Pharmacol Res 2013;76:
58 66.
Barnett AH. New treatments in type 2 diabetes: a focus on the incretin-based
therapies. Clin Endocrinol 2009;70:343 353.
Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, Zdravkovic M,
During M, Matthews DR. Efficacy and safety comparison of liraglutide, glimepiride,
and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diab Care 2009;32:84 90.
Ng SY, Wilding JP. Liraglutide in the treatment of obesity. Expert Opin Biol Ther
2014;14:1215 1224.
Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, OlveraAlvarez I, Hale PM, Zdravkovic M, Bode B. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III,
double-blind, parallel-treatment trial. The Lancet 2009;373:473481.

88. Ceriello A, Esposito K, Testa R, Bonfigli AR, Marra M, Giugliano D. The possible
protective role of glucagon-like peptide 1 on endothelium during the meal and
evidence for an endothelial resistance to glucagon-like peptide 1 in diabetes.
Diab Care 2011;34:697 702.
89. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev
2012;33:187 215.
90. Ratner R, Han J, Nicewarner D, Yushmanova I, Hoogwerf BJ, Shen L. Cardiovascular safety of exenatide BID: an integrated analysis from controlled clinical trials
in participants with type 2 diabetes. Cardiovasc Diabetol 2011;10:22.
91. Nathanson D, Ullman B, Lofstrom U, Hedman A, Frick M, Sjoholm A, Nystrom T.
Effects of intravenous exenatide in type 2 diabetic patients with congestive heart
failure: a double-blind, randomised controlled clinical trial of efficacy and safety.
Diabetologia 2012;55:926 935.
92. Lorber D. GLP-1 receptor agonists: effects on cardiovascular risk reduction.
Cardiovasc Ther 2013;31:238249.
93. Herman GA, Stein PP, Thornberry NA, Wagner JA. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin. Clin Pharmacol Ther
2007;81:761 767.
94. Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk
factors. Diab Care 2011;34:S276 S278.
95. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Effect
of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor,
and metformin on glycemic control in patients with type 2 diabetes. Diab Care
2007;30:1979 1987.
96. Boschmann M, Engeli S, Dobberstein K, Budziarek P, Strauss A, Boehnke J,
Sweep FC, Luft FC, He Y, Foley JE, Jordan J. Dipeptidyl-peptidase-iv inhibition augments postprandial lipid mobilization and oxidation in type 2 diabetic patients. J
Clin Endocrinol Metab 2009;94:846 852.
97. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fleck PR,
Mehta CR, Kupfer S, Wilson C, Lam H, White WB. Heart failure and mortality
outcomes in patients with type 2 diabetes taking alogliptin versus placebo in
EXAMINE: a multicentre, randomised, double-blind trial. The Lancet 2015;385:
2067 2076.
98. Schuetz CA, Ong SH, Bluher M. Clinical trial simulation methods for estimating
the impact of DPP-4 inhibitors on cardiovascular disease. Clinicoecon Outcomes
Res 2015;7:313 323.
99. Green JB, Bethel MA, Armstrong PW, Buse JB, Engel SS, Garg J, Josse R,
Kaufman KD, Koglin J, Korn S, Lachin JM, McGuire DK, Pencina MJ, Standl E,
Stein PP, Suryawanshi S, Van de Werf F, Peterson ED, Holman RR. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med 2015;373:
232 242.
100. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance
after sodium glucose cotransporter 2 (SGLT2) inhibition. Diab Care 2015;38:
1730 1735.
101. Bays H. Sodium glucose co-transporter Type 2 (SGLT2) inhibitors: targeting the
kidney to improve glycemic control in diabetes mellitus. Diab Ther 2013;4:
195 220.
102. Abdul-Ghani MA, DeFronzo RA. Lowering plasma glucose concentration by inhibiting renal sodium-glucose cotransport. J Intern Med 2014;276:352 363.
103. Hasan FM, Alsahli M, Gerich JE. SGLT2 inhibitors in the treatment of type 2 diabetes. Diab Res Clin Pract 2014;104:297 322.
104. Vasilakou D, Karagiannis T, Athanasiadou E, Mainou M, Liakos A, Bekiari E,
Sarigianni M, Matthews DR, Tsapas A. Sodium glucose cotransporter 2 inhibitors
for type 2 Diabetes A systematic review and meta-analysis. Ann Intern Med 2013;
159:262 274.
105. Haring H-U, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC,
Woerle HJ. Empagliflozin as add-on to metformin in patients with type 2 diabetes:
a 24-week, randomized, double-blind, placebo-controlled trial. Diab Care 2014;
37:1650 1659.
106. Rosenstock J, Jelaska A, Wang F, Kim G, Broedl U, Woerle HJ, Bajaj HS. Empagliflozin as add on to basal insulin for 78 weeks improves glycemic control with
weight loss in insulin-treated type 2 diabetes (T2DM). Canadian J Diab 2013;37:
S32.
107. Nauck MA, Del Prato S, Meier JJ, Duran-Garca S, Rohwedder K, Elze M, Parikh SJ.
Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes
who have inadequate glycemic control with metformin: a randomized, 52-week,
double-blind, active-controlled noninferiority trial. Diab Care 2011;34:
2015 2022.
108. Nauck MA. Update on developments with SGLT2 inhibitors in the management
of type 2 diabetes. Drug Des Dev Ther 2014;8:1335 1380.
109. Braunwald E. Heart failure. JACC Heart Fail 2013;1:1 20.
110. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects
of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens 2014;8:262 75.e9.

Downloaded from http://ehjcvp.oxfordjournals.org/ by guest on August 30, 2016

71.

R. Kumar et al.

Cardiovascular safety

111. Monami M, Nardini C, Mannucci E. Efficacy and safety of sodium glucose

co-transport-2 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical
trials. Diabetes Obes Metab 2014;16:457 466.
112. Haas B, Eckstein N, Pfeifer V, Mayer P, Hass MDS. Efficacy, safety and regulatory status of SGLT2 inhibitors: focus on canagliflozin. Nutr Diabetes 2014;4:
e143.

43
113. Neal B, Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Stein P, Desai M, Shaw W,
Jiang J, Vercruysse F, Meininger G, Matthews D. Rationale, design, and baseline
characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)
a randomized placebo-controlled trial. Am Heart J 2013;166:217223 e11.
114. Bailey CJ. Interpreting adverse signals in diabetes drug development programs.
Diab Care 2013;36:2098 2106.

Downloaded from http://ehjcvp.oxfordjournals.org/ by guest on August 30, 2016