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 .