Examining EXAMINE for an Interaction With Angiotensin-Converting Enzyme Inhibition
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See related article, pp 606–613
Incretin-based therapies for type 2 diabetes mellitus increase glucose-dependent insulin secretion, reducing the risk of fasting hypoglycemia, and suppress glucagon secretion. Whereas stable glucagon-like peptide (GLP)-1 analogs require injection, dipeptidyl peptidase 4 (DPP4) inhibitors are orally bioavailable. DPP4 inhibitor use has grown rapidly in the United States because sitagliptin was approved in 2006. In April 2016, however, the Food and Drug Administration (FDA) added warnings to the labels of saxagliptin and alogliptin, indicating that these DPP4 inhibitors may increase the risk of heart failure.
The FDA warnings resulted from a review of 3 major randomized, placebo-controlled clinical trials investigating the cardiovascular effects of DPP4 inhibitors that yielded disparate results with respect to the association between DPP4 inhibitor use and risk of heart failure. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Thrombolysis in Mycoardial Infarction (SAVOR-TIMI) 53 trial enrolled 16 492 patients with a history of cardiovascular disease or risk factors for cardiovascular disease.1 There were no differences between the saxagliptin and placebo groups in the primary combined end point of cardiovascular death, myocardial infarction or ischemic stroke or the major secondary combined end point of cardiovascular death, myocardial infarction, ischemic stroke, hospitalization for unstable angina, coronary revascularization, or heart failure. Unexpectedly, however, saxagliptin was associated with a significantly increased risk of hospitalization for heart failure compared with placebo (hazard ratio, 1.27; 95% confidence interval [CI], 1.07–1.51; P=0.007).1
The Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care (EXAMINE) trial enrolled 5380 patients with type 2 diabetes mellitus and a recent acute coronary event; there was no effect of drug on the primary composite end point of cardiovascular death, myocardial infarction, and …