Activation of the sympathetic nervous system when there is
dipeptidyl peptidase 4 inhibition in the presence of high-dose
angiotensin-converting enzyme (ACE) inhibition has led to concerns of potential increases in cardiovascular events when the 2 classes of drugs are coadministered. We evaluated cardiovascular outcomes from the EXAMINE (Examination of Cardiovascular Outcomes With
Alogliptin versus Standard of Care) trial according to
ACE inhibitor use. Patients with
type 2 diabetes mellitus and a recent
acute coronary syndrome were randomly assigned to receive the
dipeptidyl peptidase 4 inhibitor alogliptin or placebo added to existing
antihyperglycemic and cardiovascular prophylactic
therapies. Risks of adjudicated cardiovascular death, nonfatal
myocardial infarction and
stroke, and hospitalized
heart failure were analyzed using a Cox proportional hazards model in patients according to
ACE inhibitor use and dose. There were 3323 (62%) EXAMINE patients treated with an
ACE inhibitor (1681 on
alogliptin and 1642 on placebo). The composite rates of cardiovascular death, nonfatal
myocardial infarction, and nonfatal
stroke were comparable for
alogliptin and placebo with
ACE inhibitor (11.4% versus 11.8%; hazard ratio, 0.97; 95% confidence interval, 0.79-1.19; P=0.76) and without
ACE inhibitor use (11.2% versus 11.9%; hazard ratio, 0.94; 95% confidence interval, 0.73-1.21; P=0.62). Composite rates for cardiovascular death and
heart failure in patients on
ACE inhibitor occurred in 6.8% of patients on
alogliptin versus 7.2% on placebo (hazard ratio, 0.93; 95% confidence interval, 0.72-1.2; P=0.57). There were no differences for these end points nor for blood pressure or heart rate in patients on higher doses of
ACE inhibitor. Cardiovascular outcomes were similar for
alogliptin and placebo in patients with
type 2 diabetes mellitus and
coronary disease treated with
ACE inhibitors.