Potential cardiovascular effects of dipeptidyl diabetes: current evidence and ongoing trials

European Heart Journal Supplements (2012) 14 (Supplement B), B22–B29
Potential cardiovascular effects of dipeptidyl
peptidase-4 inhibitors in patients with type 2
diabetes: current evidence and ongoing trials
Ofri Mosenzon and Itamar Raz*
The Diabetes Unit, Department of Medicine, Hadassah University Hospital, Ein Kerem, PO Box 12000,
Jerusalem 91120, Israel
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients
with type 2 diabetes mellitus (T2DM). Cardiologists, who often treat patients with
CVD and T2DM, are faced with the unmet need for an agent that provides glycaemic
control yet does not pose CV risk. No antidiabetic therapy is currently indicated to
improve macrovascular outcomes. Results of studies assessing the association
between intensive antidiabetic therapy and a reduction in the risk of major CV
events in patients with T2DM have been inconsistent, and independent reports have
linked certain T2DM therapies (e.g. rosiglitazone, sulphonylureas) with negative CV
outcomes. These findings prompted the Food and Drug Administration (FDA) and the
European Medicines Agency (EMA) to develop guidelines for assessing CV risk in investigational antidiabetic therapies. The FDA guidelines specifically call for metaanalyses of completed phase 2 and 3 trials; long-term, prospective, CV safety
studies; or both. Results from meta-analyses involving dipeptidyl peptidase-4 (DPP4) inhibitors, including those approved before the issuance of the FDA guidelines,
suggest that these agents are not associated with an increase in CV risk and may potentially provide CV benefits. Prospective, large-scale, long-term trials designed in accordance with the FDA guidelines examining the CV risks and potential benefits of DPP4 inhibitors are under way. This review discusses the current evidence and ongoing
trials that may support the potential CV benefit of DPP-4 inhibitors in T2DM.
Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with diabetes.1 Patients with
diabetes are two to four times more likely to develop CVD
than those without diabetes.1 Furthermore, CVD
accounts for 50–60% of deaths in patients with type 2
diabetes mellitus (T2DM).2,3 Because of the potential
for such important consequences, the National Cholesterol Education Program identifies diabetes as a coronary
heart disease risk equivalent.4 Accumulating evidence
* Corresponding author. Tel: +972 26778021, Fax: +972 26420597.
Email: [email protected]
suggests that the negative impact of T2DM on CV status
may be attributed to a constellation of pathogenic processes, which include accelerated atherosclerosis, as
well as abnormalities in inflammatory pathways and in
endothelial, myocardial, and platelet function.5–8
Many CV therapies (e.g. antiplatelet, antilipidaemic,
antihypertensive agents) have been shown to impart CV
benefits in patients with T2DM. However, an antidiabetic
agent that both effectively reduces blood glucose levels
and improves CV outcomes in this population has yet to
be definitively identified. Current antidiabetic therapies
have been approved and introduced into practice
without definitive long-term CV safety and efficacy
data.9 Additionally, results of studies assessing the
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012.
For permissions please email: [email protected]
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Cardiovascular disease;
Dipeptidyl peptidase-4
(DPP-4) inhibitors;
Type 2 diabetes mellitus
Potential cardiovascular effects of DPP-4 inhibitors
FDA guidelines for the clinical investigation
of antidiabetic agents
In 2008, the FDA released guidelines for the evaluation of
CV risk in new antidiabetic agents.18 According to the FDA
guidelines, before submission of a New Drug Application
or Biologics License Application for antidiabetic agents,
the incidence of important CV events must be assessed
in a completed phase 2/3 clinical study programme
through an integrated meta-analysis.18 These FDA guidelines impose statistical hurdles that affect the regulatory
consequences for new antidiabetes agents (Figure 1).21
FDA guidance cites an upper bound of the two-sided
95% confidence interval (CI) of ,1.8 for the estimated
risk ratio (RR) of such events in the investigational
group vs. the control group. In the case of a CI ≥1.8, additional studies would be required before approval of the
drug to satisfy the requirement for risk assessment.18
If the upper bound of CI of pooled estimated RRs is
between 1.3 and 1.8, one or more post-marketing
safety trials should be performed to definitely demonstrate an overall upper bound CI of ,1.3 (results may
be from one adequately powered post-marketing trial
or from a trial pooled with relevant pre-marketing clinical data).18 If the upper bound of the CI is ,1.3 and
the overall risk–benefit analysis supports approval, a
post-marketing cardiovascular trial generally may not
be necessary (Figure 1).18,21
The FDA guidelines further state that newly initiated
clinical studies should include the following: (i) prospective, blinded adjudication of CV events; (ii) patients at
higher risk of CV events; and (iii) a long study duration
(e.g. ≥2 years). The FDA also recommends the use of
meta-analyses to explore the incidence of important CV
events across phase 2/3 studies, as well as the assessment of potential differences in CV RRs by subgroups
(e.g. age, patient sex, race).18 In accordance with
these regulatory requirements, long-term prospective
studies have been initiated with various antidiabetic
agents, including agents that were approved by the FDA
before the guidance was issued.
EMA guidelines for the clinical investigation
of antidiabetic agents
In 2010, the EMA released guidelines for the clinical investigation of antidiabetic agents similar to those
issued by the US FDA.19 According to the EMA guidelines,
antidiabetic agents should not be associated with an
increased risk for CV events.19 Importantly, these guidelines stress that exploration of potential CV effects
should occur throughout the course of the drug development programme. Clinical studies should include the following: (i) assessment of effects on atherothrombosis,
cardiac functionality, and repolarization and conduction
abnormalities in preclinical studies and (ii) the inclusion
of study populations with comorbidities and concomitant
drug regimens representative of patients treated with
antidiabetic agents in clinical practice.19 Furthermore,
the EMA recommends that clinical studies involving antidiabetic agents enrol a study population large enough to
adequately detect safety signals, include patients at high
risk for CV events, have a long-term duration of treatment (i.e. 18–24 months), and utilize prospective definitions of CV outcomes to assess CV risk accurately.19
These recent guidelines show the wider change in the
evolution of drug approval, resulting in Adaptive Licensing (AL) approaches.22 AL approaches are based on stepwise learning of the safety and efficacy of new drugs,
under acknowledged uncertainty, with repeated phases
of data gathering and regulatory evaluation. Drug approval is no longer binary but a continuous process that
relies on a combination of data from randomized
control trials (RCTs), as well as observational data and
real-world use.
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association between tight glycaemic control and a reduction in the risk of major CV events in patients with T2DM
have been inconsistent.10–13 Results from long-term, randomized clinical studies suggest that intensive therapy
with some antidiabetic agents may not only fail to
confer CV benefit but also be associated with increased
mortality compared with standard therapy.14 No antidiabetic therapy currently is indicated to improve macrovascular outcomes. However, results from a 10-year
follow-up from the UK Prospective Diabetes Study
(UKPDS) in newly diagnosed patients15 showed a significant reduction in myocardial infarction (MI) in the intensive therapy group.10 Additionally, a meta-analyses of
data from randomized clinical studies revealed a
reduced risk of major coronary events, but not of CV mortality, with intensive therapy in patients with T2DM.11–13
In the metformin treatment group, which consisted of
patients who were overweight, substantial risk reductions for MI (39%, P ¼ 0.01), and death from any cause
(36%, P ¼ 0.01) were observed during the original
trial;15 however, these results were based on a small
number of patients (n ¼ 342).
In addition to these inconsistent findings, independent
reports have linked certain commonly prescribed therapies for T2DM (rosiglitazone and sulphonylureas) with
increased CV events and mortality.16,17 Taken together,
these findings suggest the need for additional long-term
studies assessing CV risks of T2DM treatments and have
prompted the Food and Drug Administration (FDA) and
the European Medicines Agency (EMA) to develop guidelines for assessing CV risk with investigational antidiabetic therapies.18,19 In addition to providing important
CV safety information, these studies may demonstrate
CV benefits associated with these agents and address
other long-term safety issues.
Emerging evidence suggests that some newer antidiabetic therapies, such as the incretin-based glucagon-like
peptide-1 (GLP-1) analogues and dipeptidyl peptidase-4
(DPP-4) inhibitors, may help fill that need.20 The objectives of this article are to summarize the current EMA
and FDA guidelines for establishing CV safety of antidiabetic agents, review findings from recent meta-analyses
assessing the CV safety and efficacy of DPP-4 inhibitors,
and introduce ongoing trials with these therapies.
O. Mosenzon and I. Raz
Figure 1 Recent FDA guidelines impose statistical hurdles for approval of antidiabetes agents. The figure illustrates five hypothetical examples of possible hazard ratios (HRs) and the upper limit of the 95% confidence interval of a development plan. The regulatory consequences of each outcome also are
indicated. Reproduced with permission of the American Diabetes Association and Boaz Hirshberg. Copyright 2011.21
Incretin hormones and DPP-4 inhibitors
Current evidence for cardiovascular safety
and efficacy with DPP-4 inhibitors
Because phase 2 and 3 registration trials for these therapies were designed or completed before the 2008 FDA
guidance on CV risk assessment, individual, retrospective
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The incretin hormones GLP-1 and glucose-dependent
insulinotropic polypeptide (GIP) play important roles in
regulating glucose homeostasis.23 Both are released
from the gut in response to food intake and augment
insulin secretion by pancreatic b cells in a glucosedependent manner.23 In addition, GLP-1 lowers glucagon
secretion by pancreatic a cells in a glucose-dependent
manner.23 However, as part of the natural physiological
process, incretin hormones are rapidly inactivated by
the enzyme DPP-4.23 One pharmacological approach for
potentiating the actions of incretin hormones is the oral
DPP-4 inhibitors (alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin).20 Compared with older medications for T2DM, DPP-4 inhibitors are associated with a
lower risk of hypoglycaemia,24 are weight neutral,24
and do not have negative effects on blood pressure.25–27
Data from both pre-clinical28–35 and early clinical
studies36–38 support a cardioprotective effect of GLP-1. It
is suggested that this cardioprotective effect is mediated
through GLP-1R–dependent39,40 and GLP-1R–independent
mechanisms via GLP-1 metabolites.28 The evidence supporting a cardioprotective benefit for GLP-1 suggests that DPP-4
inhibition also might be associated with CV benefit based
on the associated increase in the availability of GLP-1
due to this inhibition. Additionally, preliminary evidence
suggests that DPP-4 inhibitors may have CV benefits
mediated through several other DPP-4 substrates (e.g.
stromal cell-derived factor-1, brain natriuretic peptide).20
meta-analyses of trial data were conducted to assess the
effects of DPP inhibitors on CV risk (Table 1).41–45 In all
studies, the primary endpoint was a composite of major
adverse cardiovascular events (MACE), which included
CV death, stroke, and MI at a minimum. Some trials
also included CV ischaemic events43 or hospitalization
for unstable angina pectoris42 in their MACE definitions.
The MACE endpoint was based on investigator-reported
adverse events (AEs) that were systematically categorized according to preferred terms in the Medical Dictionary for Regulatory Activities.42–44 Identified CV events
were then retrospectively43 or prospectively42,45 adjudicated by a blinded independent committee of experts
in all but the sitagliptin trial.44 Exposure-adjusted incidence rates were calculated per 1000 patient-years,
compared between the DPP-4 inhibitor therapy group
and comparator group, and expressed as RRs.
Results from these meta-analyses show RR point estimates ,1.0, with the upper bounds of the 95% CIs
below the 1.3 FDA limit for most compounds
(Table 2).41–45 The upper bound of the 95% CI was .1.8
for alogliptin41 and vildagliptin 50 mg/day.45 Taken together, these findings suggest that treatment with a
DPP-4 inhibitor is not associated with an increased risk
of CV events. Moreover, risk reductions were statistically
significant, with the upper bounds of the 95% CIs ,1.0 in
the saxagliptin and linagliptin meta-analyses, supporting
a potential reduction in CV events.42,43
A recent meta-analysis combined the results from 53
RCTs that included 20 312 patients treated with different
DPP-4 inhibitors and 13 569 controls treated with placebo
or active comparators for 24 weeks or longer. The
meta-analysis showed that the odds ratio for MACEs in
the DPP-4 inhibitor treated group compared with all
other treatment groups was reduced by 31% (odds ratio,
0.69; 95% CI, 0.53–0.90; P ¼ 0.006).46
These recent meta-analyses provide important systematically collected information regarding CV events with
Potential cardiovascular effects of DPP-4 inhibitors
Table 1 Study designs of individual meta-analysis assessing cardiovascular risk of dipeptidyl peptidase-4 inhibitors
No. of
Total no.
No. of patients
exposed to DPP-4
Patient-years of
exposure to DPP-4
Comparator treatments
3319 (3159/160)c
Not available
Placebo, glimepiride, or voglibose
Placebo, metformin, and
up-titrated glyburide
Placebo, glipizide, glimepiride,
insulin, metformin,
pioglitazone, rosiglitazone, or
Placebo, metformin, gliclazide,
acarbose, rosiglitazone,
pioglitazone, glimepiride,
sulphonylurea, or combination
10 246
12 to ≥104
13 570
7509 (1393/6116)d
DPP-4, dipeptidyl peptidase-4.
The DPP-4 inhibitor could have been taken as monotherapy, initial combination therapy, or as add-on combination therapy with other glucoselowering agents.
Phase 2 or 3.
Linagliptin 5 mg/linagliptin 10 mg.
Vildagliptin 50 mg/vildagliptin 100 mg.
DPP-4 inhibitor
(no. of patients
Alogliptin41 (3489/1213)
Primary MACE endpoint
Number (%) of patients experiencing an
Saxagliptin43 (3356/1251)
Adjudicated CV death, non-fatal MI,
or non-fatal stroke
Adjudicated CV death, non-fatal MI,
non-fatal stroke, or UAP with
Adjudicated CV death, MI, stroke
Sitagliptin44 (5429/4817)
Reported CV ischaemic AEs
50 mg (1393/1555)
Adjudicated CCV death, ACS, TIA, stroke
Linagliptin42 (3319/1920)
100 mg (6116/4872)
Risk ratio (95% CI)
DPP-4 inhibitor
All comparators
9 (0.26)
5 (0.41)
0.63 (0.21–1.91)
11 (0.3)
23 (1.2)
22 (0.7)
18 (1.4)
0.6 per 100
0.9 per 100
10 (0.72)
14 (0.90)
81 (1.32)
50 (1.64)
ACS, acute coronary syndrome; AEs, adverse events; CCV, cardiovascular and cerebrovascular; CV, cardiovascular death (including fatal stroke and
MI); DPP-4, dipeptidyl peptidase-4; MACE, major adverse cardiovascular event; MI, myocardial infarction; TIA, transient ischaemic attack; UAP, unstable angina pectoris.
Cox hazards ratio.42,43
Poisson risk ratio.44
Mantel–Haenszel risk ratio.45
DPP-4 inhibitors, but have inherent limitations. Most
meta-analyses were retrospective in nature, and thus
limited by the lack of pre-specified CV definitions or
case report forms.42–45 The low incidence of CV events,
short duration of disease (mean, 3–8 years), and inclusion
of monotherapy trials suggest that many patients had less
advanced T2DM, and therefore a generally lower risk of
CVD.42,43,45 Because data were based on drug registration
trials, patients at increased CVD risk also may have been
underrepresented. Moreover, despite large total patient
exposures (10 24644 4607,43 13 570,45 523942), individual
patient exposure was ,2 years. Consequently, long-term
data are still required to test the hypothesis that these
therapies decrease CV risk.
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Table 2 Results of individual meta-analysis assessing cardiovascular risk of dipeptidyl peptidase-4 inhibitors
Table 3 Study design and inclusion criteria of ongoing cardiovascular outcome studies of dipeptidyl peptidase-4 inhibitors
DPP-4 inhibitor (clinical study)
Study design
Primary endpoint
sample size
Inclusion criteria
HbA1c (%)
Age and CV history
OAD monotherapy or
combination therapya
Treatment-naı¨ve or
SU/glinide (+MET or AGI)
≥18 years + ACS
(past 15–90 days)
Alogliptin (EXAMINE)51
R, DB, PBO-controlled,
phase 3; non-inferiority
Linagliptin (CAROLINA)52
R, DB, active-controlled
parallel-group, phase
3/4; non-inferiority
Saxagliptin (SAVOR-TIMI 53)9
R, DB, PBO-controlled,
phase 4; superiority
16 500
Sitagliptin (TECOS)53,54
R, DB, PBO-controlled,
parallel-group, phase 3;
14 000
Treatment-naı¨ve, or
antidiabetic treatment/
Stable dose(s) of
agent(s), including
40–85 years
CVD, diabetes-related end-organ
damage, ≥70 years, or ≥2 CV
risk factors
≥40 years with CVD or ≥55 years
(men) or ≥60 years (women)
with ≥1 CVD risk factor
≥50 years
Pre-existing CVD
ACS, acute coronary syndrome; AGI, a-glucosidase inhibitor; CAROLINA, Cardiovascular Outcome Study of Linagliptin versus Glimepiride in Patients with Type 2 Diabetes; CV, cardiovascular; CVD, cardiovascular
disease; DB, double-blind; DPP-4, dipeptidyl peptidase-4; EXAMINE, EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary
syndrome; HbA1C, glycated haemoglobin; MET, metformin; OAD, oral antidiabetic agent; PBO, placebo; R, randomized; SAVOR-TIMI, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes
Mellitus2Thrombolysis in Myocardial Infarction; TECOS, Trial Evaluating Cardiovascular Outcomes with Sitagliptin; SU, sulphonylurea.
Excluding other incretin-based therapy.
Excluding treatment with other antidiabetic drugs.
O. Mosenzon and I. Raz
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Potential cardiovascular effects of DPP-4 inhibitors
Ongoing cardiovascular outcome trials
with DPP-4 inhibitors
Epidemiological surveillance study
Randomized clinical trials
There are several ongoing prospective, randomized,
double-blind clinical trials assessing the CV safety of
DPP-4 inhibitors (Table 3).9,51–55 These trials address
some of the limitations of the previously conducted
meta-analyses. Specifically, these trials incorporate prospective blinded adjudication of CV events, inclusion of
patients at increased risk for CV events (e.g. advanced
age, pre-existing CVD, specific CV risk factors, renal
disease), and long treatment periods.9 Similar to the
meta-analyses, the primary MACE endpoint includes CV
death, non-fatal MI, and non-fatal stroke; the linagliptin
and sitagliptin studies also include hospitalization for
unstable angina as part of the primary MACE endpoint.9,51–55 The estimated completion dates for these
trials range from 201455 to 2018,52 with planned sample
sizes of 5400–16 500 patients. However, these trials
are event-driven, and will end when a pre-specified
number of adjudicated CV events have occurred.
In most trials, the primary MACE endpoint is considered
a CV safety outcome to rule out an excess risk of events.
However, some trials include evaluation of efficacy in
their statistical plans. For example, the SAVOR-TIMI 53
trial is a superiority trial powered to assess the effect
of saxagliptin on the reduction in CV events.9 In this
study, patients with documented type 2 diabetes, glycated haemoglobin (HbA1C,) ≥6.5% and ≤12.0%, and
either a history of established CV disease (secondary prevention) or multiple risk factors for vascular disease but
without established CV disease (primary prevention) are
being randomized. By enrolling patients with diabetes
who are at high risk for CV complications, SAVOR-TIMI
53 is designed and powered to test for the superiority
of saxagliptin vs. placebo and to exclude definitively
any excess risk. Moreover, with few study limitations
on concomitant use of other diabetic therapy, SAVORTIMI 53 will evaluate the efficacy and safety of saxagliptin across a broad spectrum of patients with T2DM. In
the Examination of Cardiovascular Outcomes: Alogliptin
versus Standard of Care in Patients with Type 2 Diabetes
Mellitus and Acute Coronary Syndrome (EXAMINE)
trial, the superiority of alogliptin to placebo for the
primary MACE composite will be evaluated if noninferiority is first demonstrated for the safety endpoint.51
Similar to the SAVOR-TIMI 53 study, the higher-risk
CV study population (acute coronary syndrome in the
past 15–90 days) included in EXAMINE will test for the
superiority of alogliptin and exclude any excess risk.
Thus, findings from these ongoing clinical studies will
not only provide practitioners with information regarding
the CV safety of DPP-4 inhibitors but also give important
insights as to whether some of these agents are effective
in reducing CV morbidity and mortality in patients
with T2DM.
Cardiovascular disease greatly contributes to morbidity
and mortality in patients with T2DM. There currently
is an unmet need for a safe and effective antidiabetic
therapy that provides both glycaemic control and CV
benefits in patients with T2DM. No antidiabetic
therapy currently is indicated to improve macrovascular
outcomes. Results of studies assessing the association
between intensive antidiabetic therapy and a reduction
in the risk of major CV events in patients with T2DM have
been inconsistent, and independent reports have linked
certain T2DM therapies (e.g. rosiglitazone, sulphonylureas) with adverse CV outcomes. In the light of these
issues, the FDA released guidelines in 2008 for evaluating the CV safety of T2DM medications. Preliminary evidence from meta-analyses suggests that DPP-4 inhibitors
may reduce CV events in patients with T2DM. However,
as of yet, no antidiabetic agent has been definitively
proven to provide CV benefits in this patient population.
Ongoing randomized trials designed in accordance with
FDA guidelines and ongoing epidemiological surveillance
studies are examining the CV safety and efficacy of
DPP-4 inhibitors. These trials do not allow direct
comparison of the agents, and even limited comparison
will be difficult, given the differences in inclusion/
exclusion criteria and in primary endpoints. Nonetheless, these trials may provide unique opportunities to
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Although clinical trials provide valuable information on
the efficacy, safety, and CV outcomes associated with
T2DM therapies, it often takes years to obtain such
results, which must be interpreted in the context of a
controlled trial. In contrast, epidemiological databases
provide additional real-time information on the safety
of T2DM medications in real-world patients that can be
evaluated repeatedly as evidence accumulates.
The US FDA Sentinel Initiative is an active, sustainable
system that is being developed to leverage existing electronic, de-identified healthcare data from 100 million
patients to monitor the safety profile and AEs associated
with marketed medications, including the incidence of
MIs in patients taking oral T2DM treatments.47,48 To assist
in the development of the Sentinel System, a Mini-Sentinel
pilot project using electronic health information obtained
from claims data, in-patient and out-patient medical
records, and patient registries is ongoing.48,49 Additionally,
a prospective cohort study with data obtained from the
Mini-Sentinel database will compare the incidence of
acute MIs in patients receiving saxagliptin with those
using other approved antidiabetic therapies [sitagliptin,
long-acting insulin, pioglitazone, and second-generation
sulphonylureas (glimepiride, glipizide, and glyburide/glibenclamide)].50 In the future, findings from this study may
be compared with results from the prospective, controlled
large-scale outcomes study of saxagliptin, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with
Diabetes Mellitus-Thrombolysis in Myocardial Infarction
gather valuable information about these agents. Additional data regarding the overall safety of DPP-4 inhibitors in the treatment of diabetes will certainly be
elucidated. Most importantly, data from these trials
will provide definitive conclusions on the potential CV
benefits of this class of agents used to treat patients
with T2DM.
O. Mosenzon and I. Raz
The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical
The authors wish to acknowledge Scientific Connexions
(Newtown, PA, USA), funded by Bristol-Myers Squibb
(Princeton, NJ, USA) and AstraZeneca (Wilmington, DE,
USA), for providing writing and editorial support.
1. American Diabetes Association. Diabetes Statistics. http://www.
diabetes.org/diabetes-basics/diabetes-statistics/ (accessed 4 January
2. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD,
Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S,
McCarren M, Vitek ME, Henderson WG, Huang GD. VADT Investigators.
Glucose control and vascular complications in veterans with type 2
diabetes. N Engl J Med 2009;360:129–139.
3. Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and
causes of death in the WHO Multinational Study of Vascular Disease
in Diabetes. Diabetologia 2001;44(Suppl 2):S14–S21.
4. Expert Panel on Detection, Evaluation, and Treatment of High Blood
Cholesterol in Adults. Executive summary of the third report of the
National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in
Adults (Adult Treatment Panel III). JAMA 2001;285:2486–2497.
5. Wagenknecht LE, Zaccaro D, Espeland MA, Karter AJ, O’Leary DH,
Haffner SM. Diabetes and progression of carotid atherosclerosis: the
insulin resistance atherosclerosis study. Arterioscler Thromb Vasc
Biol 2003;23:1035–1041.
6. Avogaro A, Albiero M, Menegazzo L, de Kreutzenberg S, Fadini GP.
Endothelial dysfunction in diabetes: the role of reparatory mechanisms. Diabetes Care 2011;34(Suppl 2):S285–S290.
7. Nathanson D, Nystro
¨m T. Hypoglycemic pharmacological treatment of
type 2 diabetes: targeting the endothelium. Mol Cell Endocrinol
8. Xu J, Zou MH. Molecular insights and therapeutic targets for diabetic
endothelial dysfunction. Circulation 2009;120:1266–1286.
9. Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J, Hirshberg B,
Ohman P, Price DL, Chen R, Udell J, Raz I. The design and rationale of
the Saxagliptin Assessment of Vascular Outcomes Recorded in
Downloaded from by guest on October 15, 2014
Conflict of interest: O.M.: Consultant for AstraZeneca, Speakers Bureau: AstraZeneca, Merck Sharp & Dohme, Sanofi, Lilly,
Novo Nordisk, and Novartis. I.R.: Advisory Board: AstraZeneca,
Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, and Novo
Nordisk; Consultant: Andromeda, AstraZeneca/Bristol-Myers
Squibb, Eli Lilly, Johnson & Johnson, HealOr, Insuline, Teva,
and TransPharma; Speakers Bureau: AstraZeneca, Bristol-Myers
Squibb, Eli Lilly, Johnson & Johnson, Novo Nordisk, and Roche;
Honoraria European Society of Cardiology 2012 presentation:
AstraZeneca/Bristol-Myers Squibb.
patients with diabetes mellitus–Thrombolysis in Myocardial Infarction
(SAVOR-TIMI) 53 Study. Am Heart J 2011;162:818–825.
Holman RR, Paul SK, Bethel A, Matthews DR, Neil HAW. 10-Year
follow-up of intensive glucose control in type 2 diabetes. N Engl J
Med 2008;359:1577–1589.
Control Group, Turnbull FM, Abraira C, Anderson RJ, Byington RP,
Chalmers JP, Duckworth WC, Evans GW, Gerstein HC, Holman RR,
Moritz TE, Neal BC, Ninomiya T, Patel AA, Paul SK, Travert F,
Woodward M. Intensive glucose control and macrovascular outcomes
in type 2 diabetes. Diabetologia 2009;52:2288–2298.
Mannucci E, Monami M, Lamanna C, Gori F, Marchionni N. Prevention
of cardiovascular disease through glycemic control in type 2 diabetes:
a meta-analysis of randomized clinical trials. Nutr Metab Cardiovas
Dis 2009;19:604–612.
Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S,
Preiss D, Erqou S, Sattar N. Effect of intensive control of glucose on
cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009;
ACCORD Study Group. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med 2011;364:818–828.
UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837–853.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial
infarction and death from cardiovascular causes. N Engl J Med 2007;
Tzoulaki I, Molokhia M, Curcin V, Little MP, Millett CJ, Ng A,
Hughes RI, Khunti K, Wilkins MR, Majeed A, Elliott P. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study
using UK general practice research database. BMJ 2009;339:b4731.
doi: 10.1136/bmj.b4731.
Food and Drug Administration: Guidance for Industry. Diabetes
Mellitus-Evaluation Cardiovascular Risk in New Antidiabetic Therapies
to Treat Type 2 Diabetes. 2008. http://www.fda.gov/downloads/
European Medicines Agency. Guideline on Clinical Investigation of
Medicinal Products in the Treatment of Diabetes Mellitus. January
2010. http://www.emea.europa.eu/docs/en_GB/document_library/
Scientific_guideline/2010/02/WC500073570.pdf (accessed 12 January
Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system.
Endocr Rev 2012;33:187–215.
Hirshberg B, Raz I. Impact of the U.S. Food and Drug Administration
cardiovascular assessment requirements on the development of
novel antidiabetes drugs. Diabetes Care 2011;34(Suppl 2):S101–S106.
Eichler HG, Oye K, Baird LG, Abadie E, Brown J, Drum CL, Ferguson J,
Garner S, Honig P, Hukkelhoven M, Lim JC, Lim R, Lumpkin MM,
Neil G, O’Rourke B, Pezalla E, Shoda D, Seyfert-Margolis V, Sigal EV,
Sobotka J, Tan D, Unger TF, Hirsch G. Adaptive licensing: taking the
next step in the evolution of drug approval. Clin Pharmacol Ther
Drucker JD, Nauck MA. The incretin system: glucagon-like peptide-1
receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696–1705.
AACE/ACE Summary of Key Benefits and Risks of Medications. https://
www.aace.com/files/glycemic-control-algorithm-ppt.pdf (accessed 12
January 2012).
Cobble ME, Frederich R. Saxagliptin for the treatment of type 2 diabetes mellitus: assessing cardiovascular data. Cardiovasc Diabetol
Schernthaner G, Barnett AH, Emser A, Patel S, Troost J, Woerle HJ,
von Eynatten M. Safety and tolerability of linagliptin: a pooled analysis of data from randomized controlled trials in 3572 patients
with type 2 diabetes mellitus. Diabetes Obes Metab 2012;14:470–8.
´n B. Dipeptidyl peptidase-4 inhibitors: clinical data and clinical
implications. Diabetes Care 2007;30:1344–1350.
Ban K, Noyan-Ashraf H, Hoefer J, Bolz S-S, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1
Potential cardiovascular effects of DPP-4 inhibitors
pre-specified, prospective, and adjudicated meta-analysis from a
large phase III program. Cardiovasc Diabetol 2012;11:3.
Frederich R, Alexander JH, Fiedorek FT, Donovan M, Berglind N,
Harris S, Chen R, Wolf R, Mahaffey KW. A systematic assessment of
cardiovascular outcomes in the saxagliptin drug development
program for type 2 diabetes mellitus. Postgrad Med 2010;122:16–27.
Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H,
Musser BJ, Davies MJ, Kaufman KD, Goldstein BJ. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data
from 10,246 patients with type 2 diabetes. BMC Endocr Disord
Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M,
Kothny W. Assessing the cardio-cerebrovascular safety of vildagliptin:
meta-analysis of adjudicated events form a large phase III type 2 diabetes population. Diabetes Obes Metab 2010;12:485–494.
Monami M, Dicembrini I, Martelli D, Mannucci E. Safety of dipeptidyl
peptidase-4 inhibitors: a meta-analysis of randomized clinical trials.
Curr Med Res Opin 2011;27(Suppl 3):57–64.
The Sentinel Initiative. May 2008. http://www.fda.gov/downloads/
Safety/FDAsSentinelInitiative/UCM124701.pdf (accessed 10 January
Behrman RE, Benner JS, Brown JS, McClellan M, Woodcock J, Platt R.
Developing the sentinel system—a national resource for evidence development. N Engl J Med 2011;364:498–499.
FDA’s Sentinel Initiative-Background. http://www.fda.gov/Safety/
FDAsSentinelInitiative/ucm149340.htm. (accessed 10 January 2012).
Selby J, Fireman B, Butler M. Report to FDA on a protocol for active
surveillance of acute myocardial infarction in association with use of
a pharmaceutical agent. 26 October 2010. http://www.mini-sentinel.
AMI_Surveillance_Protocol_and_Appendices_ABC.pdf (accessed 10
January 2012).
White WB, Bakris GL, Bergenstal RM, Cannon CP, Cushman WC,
Fleck P, Heller S, Mehta C, Nissen SE, Perez A, Wilson C, Zannad F.
EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE): a cardiovascular safety study of the
dipeptidyl peptidase 4 inhibitor alogliptin in patients with type 2 diabetes with acute coronary syndrome. Am Heart J 2011;162:620–626.
CAROLINA: Cardiovascular outcome study of linagliptin versus glimepiride in patients with type 2 diabetes. http://clinicaltrials.gov/ct2/
show/NCT01243424?term=NCT01243424&rank=1 (accessed 15 November 2011).
TECOS. Sitagliptin cardiovascular outcome study (0431-082 AM1)
NCT00790205&rank=1 (accessed 15 November 2011).
Bethel MA, Green J, Califf RM, Holman RR. Rationale and design of the
Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS).
[Abstract]. Diabetes 2009;78(Suppl 1):A639.
SAVOR-TIMI. Does saxagliptin reduce the risk of cardiovascular events
when used alone or added to Other Diabetes Medications (SAVORTIMI53). http://clinicaltrials.gov/ct2/show/NCT01107886 (accessed
15 November 2011).
Downloaded from by guest on October 15, 2014
receptor-dependent and -ndependent pathways. Circulation 2008;
Bose AK, Mocanu MM, Carr RD, Brand CL, Yellon DM. Glucagon-like
peptide 1 can directly protect the heart against ischemia/reperfusion
injury. Diabetes 2005;54:146–151.
Bose AK, Mocanu MM, Carr RD, Yellon DM. Glucagon like peptide-1 is
protective against myocardial ischemia/reperfusion injury when
given either as a preconditioning mimetic or at reperfusion in an isolated rat heart model. Cardiovasc Drugs Ther 2005;19:9–11.
Huisamen B, Genis A, Marais E, Lochner A. Pre-treatment with a
DPP-4 inhibitor is infarct sparing in hearts from obese, pre-diabetic
rats. Cardiovasc Drugs Ther 2011;25:13–20.
Nikolaidis LA, Doverspike A, Hentosz T, Zourelias L, Shen Y-T, Elahi D,
Shannon RP. Glucagon-like peptide-1 limits myocardial stunning following brief coronary occlusion and reperfusion in conscious
canines. J Pharmacol Exp Ther 2005;312:303–308.
Poornima I, Bown SB, Bhashyam S, Parikh P, Bolukoglu H, Shannon RP.
Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure-prone rat. Circ Heart Fail 2008;1:153–160.
Timmers L, Henriques JPS, de Kleijn DPV, D Vries JH, Kemperman H,
Steendijk P, Verlaan WJ, Kerver M, Piek JJ, Doevendans PA,
Pasterkamp G, Hoefer IE. Exenatide reduces infarct size and improves
cardiac function in a porcine model of ischemia and reperfusion
injury. J Am Coll Cardiol 2009;53:501–510.
Zhao T, Parikh P, Bhashyam S, Bolukoglu H, Poornima I, Shen Y-T,
Shannon RP. Direct effects of glucagon-like peptide-1 on myocardial
contractility and glucose uptake in normal and postischemic isolated
rat hearts. J Pharmacol Exp Ther 2006;317:1106–1113.
Halbirk M, Nørrelund H, Møller N, Holst JJ, Schmitz O, Nielsen R,
Nielsen-Kudsk JE, Nielsen SS, Nielsen TT, Eiskjær H, Bøtker HE,
Wiggers H. Cardiovascular and metabolic effects of 48-h glucagonlike peptide-1 infusion in compensated chronic patients with heart
failure. Am J Physiol Heart Circ Physiol 2010;298:H1096–H1102.
Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D,
Shannon RP. Effects of glucagon-like peptide-1 in patients with
acute myocardial infarction and left ventricular dysfunction after
successful reperfusion. Circulation 2004;109:962–965.
Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like
peptide-1 infusion improves left ventricular ejection faction and
functional status in patient with chronic heart failure. J Cardiac
Fail 2006;12:694–699.
Xiao Y-F, Nikolskaya A, Jaye DA, Sigg DC. Glucagon-like peptide-1
enhances cardiac L-type Ca2+ currents via activation of the cAMPdependent protein kinase A pathway. Cardiovasc Diabetol 2011;10:
Hausenloy DJ, Yellon DM. New directions for protecting against ischaemia–reperfusion injury: targeting the reperfusion injury
salvage kinase (RISK)-pathway. Cardiovasc Res 2004;61:448–460.
White WB, Gorelick PB, Fleck P, Smith N, Wilson C, Pratley R. Cardiovascular events in patients receiving alogliptin: a pooled analysis of
randomized clinical trials. In: 70th Scientific Sessions of the American Diabetes Association, Orlando, FL, 2010. Abstract 391-PP.
Johansen OE, Eubacher N, Von Eynatten M, Patel S, Woerle HJ. Cardiovascular risk with linagliptin in patients with type 2 diabetes: a