Does dipeptidyl peptidase IV inhibitor increase the risk of heart failure? A cardiologist's paradox

Diabetes patients have a higher burden of cardiovascular disease compared with the general population. In addition, type 2 diabetes portends a very high risk for major adverse cardiovascular events. The SAVOR trial showed that patients with documented type 2 diabetes and a previous history of, or risk factors for, cardiovascular disease had a 1-year cardiovascular event rate of 2-3%. Whereas in the EXAMINE trial, type 2 diabetes patients with acute coronary syndrome had a 1-year event rate between 6 and 7% after revascularization. Both of these prospective trials used new dipeptidyl peptidase IV (DPP-4) inhibitors as the treatment modality. Clinically, this class of compounds is extremely well tolerated by patients. The new DPP-4 inhibitors were promising from previous meta-analyses at reducing cardiovascular outcomes. In this article, we review literature on the cardiovascular outcomes with oral hypoglycemic agents, focusing on the two recent, large prospective trials on DDP-4 inhibitors. It is important to recognize that these trials enrolled different patients. The SAVOR trial had type 2 diabetes patients (>40 years old) with established cardiovascular disease or multiple cardiovascular risk factors, whereas EXAMINE trial had type 2 diabetes patients (>18 years old) 15-90 days postrevascularization for acute coronary syndrome. The primary cardiovascular endpoint was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. Neither trial showed a significant cardiovascular benefit. However, neither trial showed increased cardiovascular mortality.