The Safety of Dipeptidyl Peptidase 4 Inhibitors and the Risk for Heart Failure.

In 2008, the Food and Drug Administration proposed a 2-step process for the approval of oral glucose-lowering therapies for type 2 diabetes that included an initial approval contingent on effective hemoglobin A1c reduction and then a postmarketing cardiovascular outcomes trial with predefined end points, longer follow-up, and a higher risk population to demonstrate “noninferiority” to placebo. Incretin-based therapies were the first drugs to be evaluated under the new guidance policy. Glucagon-like peptide (GLP)–1 and glucose-dependent insulinotropic polypeptide are incretin hormones secreted from the small intestine after meals and lower glucose levels by increasing β-cell insulin secretion, decreasing glucagon release, improving satiety, and slowing gut motility. Glucagon-like peptide–1 is rapidly deactivated by the enzyme dipeptidyl peptidase 4 (DPP4). The incretin axis can be pharmacologically enhanced either through injections of GLP-1 mimetics to achieve supraphysiologic levels or by inhibition of DPP4, which prolongs the half-life of physiologic levels of GLP-1, thus prolonging its action, although to a lesser extent than exogenous GLP-1 agonist. In preclinical experiments, both GLP-1 agonists and DPP4 inhibitors promoted nonglycemic-mediated cardioprotective actions.1 There were no signals of any cardiovascular harm in any of the incretin-based clinical development programs and, in fact, there were data to suggest direct cardioprotective and vasculoprotective benefits.2 To date, 3 DPP4 inhibitors (saxagliptin,3 alogliptin,4 and sitagliptin5) and 1 GLP-1 agonist (lixisenatide6) have published the primary results of their cardiovascular outcomes trials. On balance, the studies were more similar than different. Two studies enrolled patients following an acute coronary syndrome,4,6 while the other 2 enrolled stable patients of whom most had established cardiovascular disease.3,5 The primary results of the trials were also similar. Each easily met the noninferiority boundary with an upper bound of the 95% CI well below 1.3 for their primary and secondary composite end points. In fact, the event curves of each trial seemed to intertwine and the hazard ratios all fell within a few hundredths of a decimal point of 1.00. These safety data alone in almost 43 000 patients with type 2 diabetes are an important advance in understanding the cardiovascular risk profile of drugs to treat diabetes. Among the different trial results, the most unexpected finding was a 27% increased relative risk of hospitalization for heart failure in patients assigned to saxagliptin compared with placebo in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) Study (N = 289; 3.5% vs 228; 2.8% over 2 years; P = .007). 3 Despite extensive analysis, no mechanism of action to explain this observation could be found.7 The results from the Examination of Cardiovascular Outcomes With Alogliptin vs Standard of Care (EXAMINE) Study, where there was a numerically but not statistically higher rate of hospitalizations for heart failure in patients treated with alogliptin compared with placebo (n = 106, 3.9% vs n = 89, 3.3%; hazard ratio, 1.19; 95% CI, 0.90-1.58; P = .22),8 further raised the suspicion of a possible class effect of the DPP4 inhibitors on the risk of hospitalization for heart failure. The Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS) Study, which compared sitagliptin vs placebo in 14 671 stable patients with type 2 diabetes and established cardiovascular disease, was the third DPP4 study to report results and provides valuable, although discordant, data regarding the risk for heart failure. In contrast to the SAVOR-TIMI 53 and EXAMINE trials, the rates of hospitalization for heart failure in TECOS were exactly the same between sitagliptin and placebo (3.1% vs 3.1%; hazard ratio, 1.00; 95% CI, 0.83-1.20; P = .98). 5 This report by McGuire et al9 in JAMA Cardiology provides a detailed assessment of the hospitalization for heart failure end point in TECOS. Regardless of how it was analyzed and using similar analytic methods to SAVOR-TIMI 53 and EXAMINE, there was no signal of any increased risk of hospitalization for heart failure or the total hospitalizations for heart failure, nor evidence of any heterogeneity in the risk of hospitalization for heart failure by time or in different subgroups. This contrasts to saxagliptin, where the greatest risk of hospitalization for heart failure was observed just during the first year after randomization.7 Overall, this is very reassuring data for sitagliptin. There are several potential explanations for the discordant findings. The patient populations in the 3 trials were more similar than different, but there were some distinctions. The EXAMINE Study enrolled patients following acute coronary syndromes. Most patients in SAVOR-TIMI 53 had established cardiovascular disease, but a significant proportion of patients did not have manifest cardiovascular disease. More than 15% of patients in SAVOR-TIMI 53 had an estimated glomerular filtration rate less than 50 mL/min/1.73 m2 compared with 9.3% in TECOS. However, the subtle differences in patient population are unlikely to explain the differences in Author Audio Interview at jamacardiology.com