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

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

European Heart Journal Supplements (2012) 14 (Supplement B), B22–B29
doi:10.1093/eurheartj/sus003
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
KEYWORDS
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.
Introduction
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;
Guidelines;
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.
B23
B24
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
B25
Table 1 Study designs of individual meta-analysis assessing cardiovascular risk of dipeptidyl peptidase-4 inhibitors
DPP-4
inhibitorsa
No. of
trialsb
Study
duration
(weeks)
Total no.
of
patients
No. of patients
exposed to DPP-4
inhibitor
Patient-years of
exposure to DPP-4
inhibitorb
Comparator treatments
3489
3319 (3159/160)c
3356
Not available
2060
3758
Placebo
Placebo, glimepiride, or voglibose
Placebo, metformin, and
up-titrated glyburide
Placebo, glipizide, glimepiride,
insulin, metformin,
pioglitazone, rosiglitazone, or
combination
Placebo, metformin, gliclazide,
acarbose, rosiglitazone,
pioglitazone, glimepiride,
sulphonylurea, or combination
Alogliptin41
Linagliptin42
Saxagliptin43
8
8
8
12226
18252
16–116
4702
5239
4607
Sitagliptin44
19
12–106
10 246
5429
4709
Vildagliptin45
25
12 to ≥104
13 570
7509 (1393/6116)d
686/7034d
DPP-4, dipeptidyl peptidase-4.
a
The DPP-4 inhibitor could have been taken as monotherapy, initial combination therapy, or as add-on combination therapy with other glucoselowering agents.
b
Phase 2 or 3.
c
Linagliptin 5 mg/linagliptin 10 mg.
d
Vildagliptin 50 mg/vildagliptin 100 mg.
DPP-4 inhibitor
(no. of patients
treated/comparator)
Alogliptin41 (3489/1213)
Primary MACE endpoint
Number (%) of patients experiencing an
event
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
hospitalization
Adjudicated CV death, MI, stroke
Sitagliptin44 (5429/4817)
Reported CV ischaemic AEs
Vildagliptin45
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)
0.34
(0.1620.70)a
22 (0.7)
18 (1.4)
0.6 per 100
patient-years
0.9 per 100
patient-years
0.43
(0.2320.80)a
0.68
(0.4121.12)b
10 (0.72)
14 (0.90)
81 (1.32)
50 (1.64)
0.88
(0.3722.11)c
0.84
(0.6221.14)c
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.
a
Cox hazards ratio.42,43
b
Poisson risk ratio.44
c
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
B26
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
Planned
sample size
Inclusion criteria
HbA1c (%)
Medications
Age and CV history
OAD monotherapy or
combination therapya
+Insulin
Treatment-naı¨ve or
MET + AGIb
SU/glinide (+MET or AGI)
≥18 years + ACS
(past 15–90 days)
Alogliptin (EXAMINE)51
R, DB, PBO-controlled,
phase 3; non-inferiority
Safety
5400
6.5–11.0
Linagliptin (CAROLINA)52
R, DB, active-controlled
(glimepiride)
parallel-group, phase
3/4; non-inferiority
Safety/efficacy
6000
7.0–10.0
6.5–8.5
Saxagliptin (SAVOR-TIMI 53)9
R, DB, PBO-controlled,
phase 4; superiority
Efficacy/safety
16 500
6.5–12.0
Sitagliptin (TECOS)53,54
R, DB, PBO-controlled,
parallel-group, phase 3;
non-inferiority
Safety
14 000
6.5–8.0
6.5–7.5
Treatment-naı¨ve, or
antidiabetic treatment/
insulina
Stable dose(s) of
antihyperglycaemic
agent(s), including
insulin
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.
a
Excluding other incretin-based therapy.
b
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.
Summary
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
(SAVOR-TIMI 53).
B27
B28
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.
Acknowledgements
O. Mosenzon and I. Raz
10.
11.
12.
The authors take full responsibility for the content of this publication and confirm that it reflects their viewpoint and medical
expertise.
13.
Funding
14.
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.
16.
17.
18.
19.
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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.
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