Early and Chronic Dipeptidyl-Peptidase-IV Inhibition and Cardiovascular Events in Patients With Type 2 Diabetes Mellitus After an Acute Coronary Syndrome: A Landmark Analysis of the EXAMINE Trial

Abhinav Sharma, Christopher P Cannon, William B White, Yuyin Liu, George L Bakris, William C Cushman, Faiez Zannad, Abhinav Sharma, Christopher P Cannon, William B White, Yuyin Liu, George L Bakris, William C Cushman, Faiez Zannad

Abstract

Background: Antihyperglycemic therapies may increase the risk of cardiovascular events including hospitalization for heart failure. There is a paucity of data evaluating the cardiovascular safety of antihyperglycemic therapies in the high-risk period following an acute coronary syndrome (ACS).

Methods and results: The EXAMINE (Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial randomized 5380 patients who were 15 to 90 days post ACS to the dipeptidyl dipeptidase-IV (DPP-IV) inhibitor alogliptin versus placebo; mean follow-up was 18 months. Using a landmark analysis, we assessed the (1) burden of cardiovascular events from randomization to 6 months (early period) and from 6 months to the end of follow-up (late period) and (2) the risk of cardiovascular events associated with early (up to 6 months) and chronic (6 months to end of follow-up) DPP-IV inhibition with alogliptin. Patients with early versus late events had similar baseline demographic profiles. Overall, 42.1% of the composite of cardiovascular death/myocardial infarction/stroke and 47.5% of hospitalization for heart failure occurred in the early period. Early DPP-IV inhibition did not increase the risk of early cardiovascular death/myocardial infarction/stroke (hazard ratio 0.96, 95% confidence interval, 0.76-1.21) or hospitalization for heart failure (1.23, 95% confidence interval, 0.84-1.82). Similarly, chronic DPP-IV inhibition did not increase the risk of late cardiovascular death/myocardial infarction/stroke (hazard ratio 1.03, 95% confidence interval, 0.89-1.26) or hospitalization for heart failure (hazard ratio 1.02, 95% confidence interval, 0.85-1.22).

Conclusions: Early after an ACS, patients with type 2 diabetes mellitus experience a significant burden of HF events and recurrent ACS. DPP-IV inhibition with alogliptin appears to be safe even in the high-risk period following an ACS.

Trial registration: ClinicalTrials.gov NCT00968708.

Keywords: acute coronary syndrome; alogliptin; diabetes mellitus; dipeptidyl dipeptidase‐4 inhibitor; medical therapy; medication.

© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.

Figures

Figure 1
Figure 1
A, Risk of cardiovascular events associated with early DPP‐IV inhibition with alogliptin. B, Risk of cardiovascular events associated with late DPP‐IV inhibition. CI indicates confidence interval; CV, cardiovascular; DPP‐IV, dipeptidyl dipeptidase‐IV; HR, hazard ratio; MI, myocardial infarction.
Figure 2
Figure 2
Kaplan–Meier curves for landmark analysis of cardiovascular events. CV indicates cardiovascular; HR, hazard ratio; MI, myocardial infarction.
Figure 3
Figure 3
A, Risk of HF heart failure events associated with early DPP‐IV inhibition with alogliptin. B, Risk of HF events associated with late DPP‐IV inhibition with alogliptin. CI indicates confidence interval; CV, cardiovascular; DPP‐IV, dipeptidyl‐dipeptidase‐IV; HF, heart failure; HHF, hospitalization for heart failure; HR, hazard ratio; MI, myocardial infarction; UAH, unstable angina hospitalization.
Figure 4
Figure 4
Kaplan–Meier curves for landmark analysis of cardiovascular events including HF. CI indicates confidence interval; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
Figure 5
Figure 5
Kaplan–Meier curve for landmark analysis of HF hospitalization. CI indicates confidence interval; HF, heart failure; HR, hazard ratio.

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