Postgraduate Medicine

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The Dipeptidyl Peptidase-4 Inhibitors in Type 2

Diabetes Mellitus: Cardiovascular Safety

Jennifer B. Green MD

To cite this article: Jennifer B. Green MD (2012) The Dipeptidyl Peptidase-4 Inhibitors in Type 2
Diabetes Mellitus: Cardiovascular Safety, Postgraduate Medicine, 124:4, 54-61

To link to this article: http://dx.doi.org/10.3810/pgm.2012.07.2566

Published online: 13 Mar 2015.

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 C L I N I C A L F O C U S : D I A B E T E S A N D C O N C O M I TA N T D I S O R D E R S

The Dipeptidyl Peptidase-4 Inhibitors in Type 2

Diabetes Mellitus: Cardiovascular Safety

DOI: 10.3810/pgm.2012.07.2566

Jennifer B. Green, MD 1 Abstract: The dipeptidyl peptidase-4 (DPP-4) inhibitors are a relatively new class of oral anti-
Downloaded by [University of Florida] at 00:56 06 November 2015

Division of Endocrinology,
1 diabetic agents that improve glycemic control in patients with type 2 diabetes mellitus. These
Metabolism, and Nutrition,
Duke University Medical Center,
Durham, NC
agents differ in structure, but all act by inhibiting the DPP-4 enzyme. Dipeptidyl peptidase-4 inhi-
bition increases levels of the incretin hormones glucagon-like peptide-1 and glucose-dependent
insulinotropic peptide, which in turn stimulate insulin secretion in a glucose-dependent fashion.
Clinical trials have shown that DPP-4 inhibitors provide significant reductions in glycated hemo-
globin levels, with a low risk of hypoglycemia. Animal model experiments and proof-of-concept
studies suggest that the incretins favorably affect the cardiovascular system; it is possible that
these same effects may be conveyed by DPP-4 inhibitor therapy. Pooled and meta-analyses of
DPP-4 inhibitor clinical trial data have shown no increase in major adverse cardiovascular events,
and, in fact, suggest a potential cardiovascular benefit to such therapy. Long-term cardiovascular
safety trials are currently underway to more fully define and understand the cardiovascular impact
of DPP-4 therapy in patients with type 2 diabetes mellitus.
Keywords: alogliptin; cardiovascular; DPP-4 inhibitors; linagliptin; saxagliptin; sitagliptin;
vildagliptin

Type 2 Diabetes Mellitus and Cardiovascular

Correspondence: Jennifer B. Green, MD,
Division of Endocrinology, Metabolism,
and Nutrition,
Duke University Medical Center,
Duke Clinical Research Institute,
DUMC Box 3850,
2400 Pratt St., Room 7039,
North Pavilion,
Durham, NC 27705.
Tel: 919-668-8401
Fax: 919-668-7058
E-mail: green094@mc.duke.edu
Disease
Cardiovascular disease is a significant issue in the management of patients with type 2
diabetes mellitus (T2DM); the rate of cardiovascular disease in these patients is roughly
twice that of people without T2DM, even after adjusting for other cardiovascular
risk factors.1 Although it is clear that good glycemic control will reduce the risk of
microvascular and neuropathic complications, the relationship between glycemic
control and cardiovascular complications is complex. For example, long-term follow-
up of patients enrolled in the United Kingdom Prospective Diabetes Study (UKPDS)
found that patients with better glycemic control initiated shortly after diabetes diagnosis
sustained a cardiovascular benefit after 10 years.2 However, meta-analyses of more
recent trials found that initiation of very intensive glycemic control in patients with
T2DM of longer duration does not convey a cardiovascular benefit, and, in fact, might
be detrimental.3 Although optimization of control early in the disease course may be
important in reducing long-term cardiovascular risk, there is increasing recognition
that glycemic goals must be individualized.4
In addition to our limited understanding of the interplay between glycemia
and cardiovascular complications, concerns have recently emerged that specific

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therapies for T2DM may independently increase the risk of
cardiovascular events. The best-known example is that of the
thiazolidinedione, rosiglitazone. Some studies suggested that
rosiglitazone therapy might reduce cardiovascular risk via
favorable changes in inflammatory markers, blood pressure,
and/or high-density lipoprotein cholesterol; however,
meta-analyses of randomized controlled trials suggested
that rosiglitazone was associated with increased risk of
myocardial infarction, but not cardiovascular mortality.5,6
Although the analyses were based on a relatively small
number of cardiovascular events, the results were statistically
significant and led to restrictions on the use of rosiglitazone
by the US Food and Drug Administration (FDA) and
withdrawal of the drug in Europe by the European Medicines
Agency (EMA).
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The rosiglitazone meta-analyses highlighted the largely
unknown cardiovascular impact of individual glucose-
lowering medications, despite their widespread use. In 2008,
the FDA issued guidance for evaluating cardiovascular
risk in compounds being developed as new therapies for
T2DM.7 The agency continues to recommend glycated
hemoglobin level as the efficacy outcome for phase 3 stud-
ies of new diabetes medications, but clinical cardiovascular
outcomes must now also be assessed. To ensure that new
glucose-lowering therapies do not increase cardiovascular
risk to an unacceptable extent, a meta-analysis of
cardiovascular events in phase 2 and 3 trials will be required
before drug approval, and, in most cases, a long-term trial
specifically examining cardiovascular outcomes will be
required after drug approval.7 Trials designed to demonstrate
cardiovascular safety must include patients at high risk for
cardiovascular events, provide a duration of drug exposure
adequate to assess such risk, and collect and adjudicate
important cardiovascular complications, including cardio-
vascular mortality, myocardial infarction, and stroke. The
guidance does not apply retrospectively, but does apply to
compounds that were already in clinical development trials
at the time that the guidance was issued.7
The dipeptidyl peptidase-4 (DPP-4) inhibitors, also
known as “gliptins,” are a relatively new class of agents for
improving glycemic control in patients with T2DM. Their
development crosses the boundary of the FDA guidance, with
sitagliptin approved by the FDA in 2006, saxagliptin in 2009,
and linagliptin in 2011. Two additional DPP-4 inhibitors have
extensive trial data available: vildagliptin was approved by
the EMA in 2008 and alogliptin by the Japanese Ministry
of Health, Labour and Welfare in 2010. As a class,
DPP-4 inhibitors provide significant reductions in glycated
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Cardiovascular Safety of DPP-4 Inhibitors
hemoglobin levels compared with placebo and convey a low
risk of hypoglycemia.8 Now that data have been collected
in preclinical and clinical trials, it is timely to consider the
available evidence as to the cardiovascular safety of these
agents.
Methods
Relevant information was identified via PubMed search using
terms such as “dipeptidyl peptidase-4 inhibitor,” “dipeptidyl
peptidase-4 inhibition,” “incretin,” and “cardiovascular.”
Additional information was preliminarily identified via
review of scientific society meeting abstracts issued by the
American Diabetes Association and European Association
for the Study of Diabetes. Much of the information available
regarding the cardiovascular impact of the incretin-based
therapies is from very preliminary data, and a complete
review of this type of data is beyond the scope of this
review article. However, all meta-analyses that reported
cardiovascular outcomes for individual DPP-4 inhibitors
or combined analyses of the class that were published by
December 1, 2011 were included.
DPP-4 Inhibitors and the Incretin
Effect
Dipeptidyl peptidase-4 inhibitors represent the results of
many years of research into the physiologic basis for and
therapeutic potential of the incretin effect, which was first
described in the 1960s.9 Researchers noticed that patients
given oral glucose had more robust insulin secretion than
patients given glucose by intravenous infusion, even if blood
glucose levels were higher during the infusion (Figure 1A).
The enhanced responsiveness to oral glucose is mediated by
the incretins, hormones secreted within minutes of eating by
cells lining the gut, and is thought to account for approxi-
mately two-thirds of the insulin response to oral glucose.10
The 2 key incretin hormones are glucagon-like peptide-1
(GLP-1) and glucose-dependent insulinotropic peptide (GIP).
Both stimulate the secretion of insulin from pancreatic β cells
in a glucose-dependent fashion, as reviewed by Drucker.11
In addition to its effects on insulin stimulation, GLP-1
has various other physiological effects. It inhibits gastric
emptying, inhibits glucagon secretion from α cells, and
reduces food intake and body weight (possibly via indirect
effects of delayed gastric emptying and early satiety).11,12 The
role of GIP in glucagon metabolism is less well defined; it
does not appear to inhibit glucagon secretion from α cells,
and there are some indications that GIP may in fact increase
glucagon secretion.11,12
 Jennifer B. Green

Figure 1.  The incretin effect in subjects with and without type 2 diabetes mellitus. A) Control subjects (n = 8). B) Patients with type 2 diabetes mellitus (n = 14).

A) B)
80 0.6 80 0.6

0.5 0.5
60 60
IR insulin, mU/L

IR insulin, mU/L
0.4 0.4

nmol/L

nmol/L
40 0.3 40 0.3

0.2 0.2
20 20
0.1 0.1

0 0.0 0 0.0
0 60 120 180 0 60 120 180
Time, min Time, min
Oral glucose load (50 g/400 mL)
Intravenous glucose infusion
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Reproduced with permission from Diabetologia.13

Abbreviation: IR, immunoreactivity.

Figure 2 outlines the metabolism of the incretin hormones.
Both GLP-1 and GIP are released in response to food intake,
and, in turn, are rapidly metabolized by the enzyme DPP-4.
Of note, GLP-1 and GIP are released in response to glucose,
and their activities are glucose dependent.11
The Incretin System in T2DM
Patients with T2DM have a blunted incretin effect—they
secrete significantly less insulin than healthy individuals
in response to glucose, with the difference in response to
oral glucose being most dramatic when compared with
controls, as shown in Figure 1B.13 Although patients with
T2DM are known to have deficient insulinotropic responses
to the incretins, GLP-1 will retain its activity when pres-
ent at supraphysiologic levels.14 As shown in Figure 2,
DPP-4 inhibitors delay the metabolism of GLP-1 and GIP,
raising their levels, and, in turn, enhancing their actions to
improve glycemic control.11
DPP-4 Inhibitors: Cardiovascular
Effects
Could incretin-based antihyperglycemic therapies have
nonglycemic cardiovascular effects? An emerging body of
knowledge suggests that the incretins may significantly impact
the cardiovascular system. Attention has focused primarily
on GLP-1, which appears to exert potentially beneficial car-
diovascular effects, including myocardial protection from
ischemic injury15 and improved left ventricular function in
nonischemic heart failure.16 These and other mechanisms
have recently been reviewed in detail in a publication by
Ussher and Drucker.17
Studies of the cardiovascular impact of DPP-4 inhibition sug-
gest that these medications have beneficial physiologic effects,
and that these may be induced through a variety of mechanisms
of action (Table 1). Animal models of cardiovascular dis-
ease have demonstrated that DPP-4 inhibition may reduce
infarct size and improve functional recovery from ischemia,
while human studies have suggested a slight improvement in
blood pressure and improved left ventricular performance in
response to stress.18–20 Additional studies note improvement
in endothelial-dependent vasodilatation and recruitment of
endothelial progenitor cells in response to DPP-4 inhibition.21,22
Although some of the cardiovascular effects of DPP-4 inhi-
bition may be attributable to improvements in glycemia or
GLP-1 stimulation, the DPP-4 enzyme is widely expressed
in human tissues and is known to have a role in the metabo-
lism of hormones other than the incretins.23 Although not
yet proven, it is possible that DPP-4 inhibitors may induce
incretin-independent changes in the myocardium, endothe-
lium, and vasculature.
Clinical Cardiovascular Outcomes
The DPP-4 inhibitors have been studied extensively during
their development phases, with information on cardiovascular
complications typically collected as adverse events rather
than prespecified endpoints. In individual trials, the number
of cardiovascular adverse events is generally too low for
meaningful interpretation; however, compilation of outcomes

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 Cardiovascular Safety of DPP-4 Inhibitors

Figure 2.  Metabolism of the incretin hormones. Eating food stimulates the release of GLP-1 and GIP hormones. These hormones have various actions, described in more
detail in the text, including stimulating insulin release and inhibiting glucagon release. Glucagon-like peptide-1 and GIP are rapidly degraded by the DPP-4 enzyme (in the
presence of active DPP-4 enzyme, the half-life of intact incretins is ~ 2 minutes). Dipeptidyl peptidase-4 inhibitors prolong the action of GLP-1 and GIP by inhibiting their
metabolism, thus enhancing the insulin response.

GLP-1, GIP
actions

DPP-4
Intestinal inhibitors
Intact
Meal GLP-1, GIP GLP-1 (7–36) Rapid inactivation
release GIP by DPP-4 enzyme

Metabolites
GLP-1 (9–36)
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Abbreviations: DPP-4, dipeptidyl peptidase-4; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide-1; GLP-1 (7–36), the active form of GLP-1; GLP-1
(9–36), N-terminally truncated metabolite of GLP-1 that does not interact with the known GLP-1 receptor.

data in pooled analyses or meta-analyses may provide more
insight, and pooled cardiovascular safety analyses have been
reported for the 5 existing DPP-4 inhibitors. All 5 were either
approved or in clinical trials at the time that the FDA guidance
on cardiovascular safety was issued; thus, the trial designs
did not necessarily meet all criteria required of future trials.
In particular, many trials had not included the prospective
adjudication of cardiovascular events by an independent
endpoint committee that is now required by the FDA.7
Sitagliptin was the first DPP-4 inhibitor approved for use by
the FDA, in October 2006. Investigators were able to examine
the cardiovascular safety of sitagliptin 100 mg/day as part of
a pooled retrospective analysis of patient-level data from 19
double-blind randomized studies including 10 246 patients
with T2DM.24 Overall, 5429 patients were randomized to
sitagliptin and 4817 to comparators (with corresponding cumu-
lative exposures of 4709 patient-years for the sitagliptin group
and 3943 patient-years for the comparator group). All patient
data from clinical trials of $ 12 weeks’ duration with results
available as of July 2009 were included, with the exception
of patients with renal insufficiency (who received lower doses
per protocol) and patients from studies conducted in Japan
(where a lower starting dose was used). Endpoints were not
adjudicated but cardiovascular deaths and other major adverse
cardiovascular events (MACE), including myocardial infarc-
tion and stroke, were identified using 38 Medical Dictionary for
Regulatory Activities (MedDRA) terms prespecified before the
investigators began reviewing the data. (MedDRA is widely
used to code adverse events reported in clinical trials.) Across
both groups, 64 patients had $ 1 MACE and, although the
investigators do not report the actual numbers in each group,
sitagliptin treatment was not associated with an increased risk
of MACE compared with control groups (relative risk [RR],
0.68; 95% CI, 0.41–1.12; Figure 3).
Saxagliptin was approved by the FDA in July 2009;
phase 2 and 3 clinical trials were completed and under
FDA review when the guidance on cardiovascular safety of
therapies for T2DM was issued. Consequently, the 8 ran-
domized trials of the clinical development program were not
designed to assess cardiovascular events, but a meta-analysis
was required. To perform the meta-analysis as rigorously
as possible under the circumstances, cardiovascular events
were retrospectively identified by mapping the treating
physician’s original wording with standard MedDRA
phrases for cardiovascular, cerebrovascular, and arrhythmic
categories.25 All identified cases were then reviewed for the
treating physician’s reports of MACE (ie, cardiovascular
death, myocardial infarction, or stroke) and independently
adjudicated by 2 clinicians blinded to the treatment arm.25
Across the 8 trials, 4607 patients were included in the analy-
sis, of whom 3356 received saxagliptin (the majority at doses
of 2.5–10 mg/day, while doses of 20, 40, or 100 mg/day
were received by 150 patients in a dose-ranging study) and
1251 received various comparators; total patient-years of
exposure were 3758 in the saxagliptin group and 1293 in
the control group. During the trials, 41 patients had a MACE
reported by the treating physician (23 patients [0.7%] in the
saxagliptin group and 18 [1.4%] in the comparator group),

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 Jennifer B. Green

Table 1.  Nonglycemic Effects of the DPP-4 Inhibitors

Study Type DPP-4 Inhibitor Model/Population Effect Study
Animal models
Sitagliptina Mouse ischemia model Decreased infarct size Ye et al30
Sitagliptina Diabetic mice post-MI Reduced mortality Sauvé et al20
Sitagliptina I/R injury mouse Improved functional recovery Sauvé et al20
Alogliptin Nondiabetic and diabetic Reduced atherosclerotic lesions Ta et al31
ApoE-deficient mice in diabetic mice
Alogliptin LDL receptor–deficient mouse Reduced plaque burden and Shah et al32
inflammation
Linagliptina I/R injury rat Decreased infarct size Hocher et al33
Linagliptina Chronic renal insufficiency Decreased markers of LV Chaykovska et al34
rat dysfunction and cardiac fibrosis
Human studies
Hypertension Sitagliptina Patients with mild-to-moderate Small but significant decrease in Mistry et al18
hypertension (but without diabetes) blood pressure
Coronary artery disease Sitagliptina Patients with coronary artery Improved LV performance in Read et al19
disease undergoing dobutamine response to stress
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stress echocardiography
T2DM Sitagliptina Patients with T2DM Increased circulating levels of Fadini et al22
endothelial progenitor cells
T2DM Vildagliptin Patients with T2DM Improved endothelium-dependent van Poppel et al21
vasodilatation
a
Approved by the US Food and Drug Administration for use in the United States.
Abbreviations:  ApoE, apolipoprotein E; DPP-4, dipeptidyl peptidase-4; I/R, ischemia and reperfusion; LDL, low-density lipoprotein; LV, left ventricular; MI, myocardial
infarction; T2DM, type 2 diabetes mellitus.

and 40 had a MACE adjudicated by the treatment-blinded
clinicians (22 [0.7%] in the saxagliptin group and 18 [1.4%]
in the comparator group). The authors of the meta-analysis
are careful to point out the limitations of their approach,
especially as the number of events was low. Nevertheless,
statistical analyses showed no increase in the risk of MACE,
and possibly even a reduction in risk; for MACE reported by
the treating physician, the RR was 0.44 (95% CI, 0.24–0.82),
while for independently adjudicated MACE, the RR was
0.42 (95% CI, 0.23–0.80; Figure 3).

Figure 3.  Meta-analyses of DPP-4 inhibitor phase 3 trials: safety analyses of major adverse cardiovascular events.

Alogliptin (HR, 95% Cl) 4702

Linagliptina (HR, 95% Cl) 5239

Saxagliptina (HR, 95% Cl) 4607

Sitagliptina (RR, 95% Cl) 10 246

Vildagliptin (RR, 95% Cl) 13 570

0.125 0.25 0.5 1 2 4

DPP-4 inhibitor better Control better

a
Approved by the US Food and Drug Administration for use in the United States. Major adverse cardiovascular events were not adjudicated in all analyses; further details are
provided in the text. Hazard ratios were calculated for alogliptin, linagliptin, and saxagliptin using Cox proportional regression modeling. Relative risk was calculated for sitagliptin
using the exact procedures for the Poisson processes, and for vildagliptin using a Mantel–Haenszel estimate. Note that outcomes for alogliptin are based on preliminary data
presented at the American Diabetes Association Scientific Sessions 2010.28
Abbreviations: DPP-4, dipeptidyl peptidase-4; HR, hazard ratio; RR, relative risk.

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Vildagliptin was approved by the EMA in 2008,
although it is not approved for use in the United States.
For vildagliptin, cardiovascular events from all phase 3
clinical trials had been prospectively adjudicated by an
independent, blinded cardiovascular adjudication commit-
tee.26 Meta-analysis of confirmed cardiovascular events in
25 phase 3 trials completed by May 2009 could therefore
be performed using the methodology outlined in the FDA
guidance. Phase 2 studies were not included, as prospective
adjudication was performed for only phase 3 studies.26 The
analysis included 13 570 patients with T2DM. The majority
received vildagliptin 100 mg/day (n = 6116; 7034 patient-
years’ exposure); 1393 received vildagliptin 50 mg/day
(686 patient-years’ exposure). As with other meta-analyses,
placebo and active comparators were grouped together
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(n  = 6061; 6460 patient-years’ exposure). For the group
randomized to vildagliptin 100 mg/day, 81 of 6116 (1.3%)
patients had an event, compared with 80 of 4872 (1.6%)
patients in the comparator group (RR, 0.84; 95% CI,
0.62–1.14), while for vildagliptin 50 mg/day, 10 of 1393
(0.7%) patients had an event, compared with 14 of 1555
(0.9%) patients receiving comparator (RR, 0.88; 95% CI,
0.37–2.11; Figure 3).26 The analysis showed no increased
risk of the composite endpoint of cardiovascular death,
acute coronary syndrome (incorporating myocardial infarc-
tion and angina pectoris), transient ischemic attack (with
imaging evidence of infarction), and stroke with vildagliptin
100 mg/day or 50 mg/day versus comparators, although in
the analysis of vildagliptin 50 mg/day, the CI was wider due
to the smaller number of patients randomized to this dose.
Because linagliptin is the most recently approved
DPP-4 inhibitor, investigators were able to prespecify a
meta-analysis of all cardiovascular events from 8 phase 3,
randomized, double-blind, controlled trials of $ 12 weeks’
duration, with cardiovascular events prospectively adjudi-
cated by a blinded, independent expert committee.27 The
primary endpoint analyzed was a composite of cardiovascular
death, nonfatal stroke, nonfatal myocardial infarction, and
hospitalization for unstable angina pectoris. Of the 5239
patients included, 3319 received linagliptin (3159 received
5 mg/day, 160 received 10 mg/day; total patient-years’
exposure, 2060) and 1920 received comparator (total patient-
years’ exposure, 1372). The primary composite endpoint was
reported to occur in 11 patients in the linagliptin group (0.3%)
and in 23 patients in the comparator group (1.2%), dem-
onstrating no apparent increase in cardiovascular risk, and
possibly a decreased risk, with linagliptin versus comparators
(hazard ratio [HR], 0.34; 95% CI, 0.16–0.70; Figure 3).27
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Cardiovascular Safety of DPP-4 Inhibitors
In 2010, alogliptin was approved in Japan, although
it has not yet been approved in the United States. The
cardiovascular safety of alogliptin in patients with
T2DM was evaluated using all 8 phase 2 and 3 controlled
clinical trials from its development program. 28 Most
patients randomized to alogliptin received 12.5 mg/day
(n = 1603) or 25 mg/day (n = 1757), with the remainder
receiving various doses in phase 2 studies; in total, 3489
patients were included in the alogliptin arm and 1213 in
the comparator arm. Cardiovascular events were defined
as cardiovascular death, nonfatal myocardial infarction,
and nonfatal stroke, and were evaluated by an indepen-
dent adjudication committee blinded to treatment (details
of the methods used and whether cardiovascular events
were collected prospectively or retrospectively have not
been published at the time of writing). During the studies,
there were 9 cardiovascular events (0.2%) in the alogliptin
group and 5 (0.4%) in the comparator group (HR, 0.63;
95% CI, 0.21–1.91; Figure 3).
Taken together, these meta-analyses indicate a benign
and perhaps favorable cardiovascular safety profile for
the DPP-4 inhibitors. The individual analyses of all of the
DPP-4 inhibitors have yielded an HR for major cardiovas-
cular events that is , 1 for all of the agents in the class,
and in 2 cases (linagliptin and saxagliptin), the CIs are also
suggestive of a cardiovascular benefit. This is further sup-
ported by a recent meta-analysis by Monami et al,29 which
included all DPP-4 inhibitor trials published by March
2011 that were $ 24 weeks long and that reported the
incidence of MACE. Across the 42 trials identified (total
exposure, 21 922 patient-years; 20 312 for DPP-4 inhibitors
and 13 569 for comparators), DPP-4 inhibitors were
associated with a significantly lower risk of MACE versus
comparator treatment (odds ratio, 0.69; 95% CI, 0.53–0.90;
P = 0.006).29
However, it is essential to note that cardiovascular
benefit cannot be conclusively determined with the cur-
rently available information. Cardiovascular safety can
only be adequately assessed in large trials designed to
prospectively collect and adjudicate adequate numbers
of cardiovascular events, which enroll patients with an
enhanced cardiovascular risk and provide a duration of
drug exposure long enough to determine the cardiovascular
impact of such therapy. The impact of the DPP-4 inhibitors
on cardiovascular outcomes is being prospectively studied
in 4 ongoing trials (Table 2) that will rigorously test the
cardiovascular safety of these 4 members of the class in
patients with T2DM.
 Jennifer B. Green

Table 2.  Cardiovascular Outcome Trials with DPP-4 Inhibitors

Trial Study Comparator ∼ N Patients Composite Primary Estimated
Drug Endpoint Completion
EXAMINE35 Alogliptin Placebo 5400 Men and women aged $ 18 years with CV death, nonfatal MI, or December 2014
T2DM; acute coronary syndrome (15–90 nonfatal stroke
days before randomization)
CAROLINA36 Linagliptin Glimepiride 6000 Men and women aged 40–85 years with CV death, nonfatal MI, September 2018
T2DM; preexisting CV disease or diabetes nonfatal stroke, or
end-organ damage, or age $ 70 years, hospitalized unstable angina
or $ 2 specified CV risk factors
SAVOR-TIMI Saxagliptin Placebo 16 500 Men and women aged $ 40 years with CV death, nonfatal MI, or May 2015
5337 T2DM; preexisting CV disease or multiple nonfatal ischemic stroke
CV risk factors
TECOS38 Sitagliptin Placebo 14 000 Men and women aged $ 50 years with CV death, nonfatal MI, December 2014
T2DM; preexisting CV disease nonfatal stroke, or
hospitalized unstable angina
At the time of writing, no cardiovascular outcomes trial was listed for vildagliptin on www.ClinicalTrials.gov.
Abbreviations: CAROLINA, Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Patients with Type 2 Diabetes; CV, cardiovascular; DPP-4, dipeptidyl
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peptidase-4; EXAMINE, Cardiovascular Outcomes Study of Alogliptin in Subjects with Type 2 Diabetes and Acute Coronary Syndrome; MI, myocardial infarction; SAVOR-
TIMI 53, Does Saxagliptin Reduce the Risk of Cardiovascular Events When Used Alone or Added to Other Diabetes Medications; T2DM, type 2 diabetes mellitus; TECOS,
Sitagliptin Cardiovascular Outcome Study.

Conclusion Conflict of Interest Statement

Given the challenge of providing effective glycemic control
and minimizing the risk of complications in patients with
T2DM, DPP-4 inhibitors have the potential to provide an
attractive therapeutic option. These agents have been studied
extensively in preclinical and clinical trials, with no suggestion
of increased cardiovascular events in preliminary analyses.
Although not conclusive, the evidence currently available
suggests that the DPP-4 inhibitors have a benign or perhaps
favorable cardiovascular safety profile. These findings need
to be confirmed via the long-term studies that are currently
underway, which have been designed to specifically assess the
impact of each individual agent on cardiovascular outcomes.
The wealth of data generated by these large, long-term studies
will not only provide information on cardiovascular safety, but
will also shed further light on the relationship between glyce-
mic control and cardiovascular disease in patients with T2DM.
Acknowledgments
This work was supported by Boehringer Ingelheim
Pharmaceuticals, Inc (BIPI). Writing and editorial assistance
was provided by Linda Merkel and Geraldine Thompson of
Envision Scientific Solutions, and was contracted by BIPI for
these services. The author meets criteria for authorship as rec-
ommended by the International Committee of Medical Journal
Editors (ICMJE), was fully responsible for all content and edi-
torial decisions, and was involved at all stages of manuscript
development. The author received no compensation related
to the development of the manuscript.
Jennifer B. Green, MD has received institutional grant
support from Amylin Pharmaceuticals, Inc., Medtronic, Inc.,
and Merck & Co., Inc.; consultancy fees from Medtronic,
Inc.; speaker’s fees from Merck & Co., Inc. and Takeda
Pharmaceutical Company; and has been compensated for
providing CME presentations by the American Association
of Endocrinologists (AACE) and Taking Control of Your
Diabetes (TCOYD).
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