DPP-4 Inhibitors and Heart Failure: Some Reassurance, Some Uncertainty.

Abstract

The American Diabetes Association’s Standards of Medical Care in Diabetes—2016 recommends the use of dipeptidyl peptidase 4 (DPP-4) inhibitors in combination with metformin as a second- or third-line treatment for type 2 diabetes (1). Owing to their relatively high costs, many jurisdictions restrict their use to patients whose glycemia remains poorly controlled on metformin–sulfonylurea combination therapy. By inhibiting DPP-4 activity, these agents increase postprandial incretin concentrations, thereby increasing insulin secretion and decreasing glucagon secretion (1). With intermediate efficacy, a low risk of hypoglycemia, neutral effects on body weight, and relatively rare adverse effects (1), their use has increased considerably since their 2006 entry into the U.S. market (2). Nevertheless, concerns remain regarding their potential association with serious adverse effects including acute pancreatitis (3), pancreatic cancer (3), and heart failure (HF) (4). The potential increased risk of HF with DPP-4 inhibitors was reported in the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus–Thrombolysis in Myocardial Infarction 53 (SAVOR-TIMI 53) trial, which randomized 16,492 patients with type 2 diabetes and either a history of cardiovascular disease (CVD) or multiple CVD risk factors to saxagliptin (Onglyza) or placebo (5) (Table 1). Patients randomly assigned to saxagliptin unexpectedly had a significantly higher risk of hospitalization for HF (hazard ratio [HR] 1.27 [95% CI 1.07–1.51]), a prespecified component of the secondary composite end point. This increased risk was clustered in the first year of follow-up (HR 1.46 [95% CI 1.15–1.88]) with no increase thereafter (6). View this table: Table 1 Data from randomized placebo-controlled trials of DPP-4 inhibitors and the risk of HF The increased HF risk in SAVOR-TIMI 53 was not observed in subsequent trials (Table 1). In the Examination …