Beneficial Effects of Dipeptidyl Peptidase-4 Inhibitors on Heart Failure With Preserved Ejection Fraction and Diabetes

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to exert pleiotropic effects on heart failure (HF) in animal experiments. This study sought to investigate the impact of DPP-4 inhibitors on HF patients with diabetes mellitus (DM). We analyzed hospitalized patients with HF and DM enrolled in the JROADHF (Japanese Registry Of Acute Decompensated Heart Failure) registry, a nationwide registry of acute decompensated HF. Primary exposure was the use of a DPP-4 inhibitor. The primary outcome was a composite of cardiovascular death or HF hospitalization during the median follow-up of 3.6 years according to left ventricular ejection fraction. Out of 2,999 eligible patients, 1,130 had heart failure with preserved ejection fraction (HFpEF), 572 had heart failure with midrange ejection fraction (HFmrEF), and 1,297 had heart failure with reduced ejection fraction (HFrEF). In each cohort, 444, 232, and 574 patients received a DPP-4 inhibitor, respectively. A multivariable Cox regression model showed that DPP-4 inhibitor use was associated with a lower composite of cardiovascular death or HF hospitalization in HFpEF (HR: 0.69; 95% CI: 0.55-0.87; P = 0.002) but not in HFmrEF and HFrEF. Restricted cubic spline analysis demonstrated that DPP-4 inhibitors were beneficial in patients with higher left ventricular ejection fraction. In HFpEF cohort, propensity score matching yielded 263 pairs. DPP-4 inhibitor use was associated with a lower incidence rate of the composite of cardiovascular death or HF hospitalization (19.2 vs 25.9 events per 100 patient-years; rate ratio: 0.74; 95% CI: 0.57-0.97; P = 0.027) in matched patients. DPP-4 inhibitor use was associated with better long-term outcomes in HFpEF patients with DM.