Influence of Type 2 Diabetes on the Effects of Tirzepatide in Patients With Heart Failure and a Preserved Ejection Fraction With Obesity: A Prespecified Stratification-Based Analysis.

BACKGROUND: Incretin-based therapies are used to treat type 2 diabetes and obesity, but the presence of diabetes diminishes the magnitude of weight loss produced by these drugs in people with obesity. It is not known whether this attenuated weight change is relevant to the clinical benefits of these drugs in heart failure. OBJECTIVES: The goal of this study was to assess the influence of diabetes on the efficacy and safety of tirzepatide in the SUMMIT trial. METHODS: In a double-blind trial, 731 patients with heart failure and a preserved ejection fraction (HFpEF) with a body mass index ≥30 kg/mwere randomly assigned in a 1:1 ratio to receive tirzepatide (up to 15 mg subcutaneously weekly) or placebo for a median of 104 weeks. History of diabetes was a stratification variable for randomization. The 2 primary outcomes were: 1) time to first cardiovascular death or worsening heart failure event; and 2) change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score at 52 weeks. Paired cardiac magnetic resonance imaging was used to assess changes in left ventricular mass and paracardiac fat at 52 weeks. RESULTS: Overall, cardiovascular death or worsening heart failure events occurred less frequently in the tirzepatide group (HR: 0.62; 95% CI: 0.41-0.95; P = 0.026), primarily related to fewer worsening heart failure events. The effect in patients with or without diabetes was similar: HR of 0.64 (95% CI: 0.35-1.15) in patients with diabetes and 0.61 (95% CI: 0.33-1.10) in patients without diabetes (P= 0.95). The magnitude of the improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score, 6-minute walk distance, quality-of-life scores, and NYHA functional class with tirzepatide was statistically significant and did not differ in patients with and without type 2 diabetes. At 52 weeks, weight loss was less pronounced in patients with type 2 diabetes; patients with diabetes lost 10.4% (95% CI: 8.7%-12.2%) of body weight, compared with 12.9% (95% CI: 11.2%-14.6%) in patients without diabetes (P= 0.04). However, patients with or without diabetes showed similar decreases in visceral adiposity (as reflected by the decline in paracardiac fat) and in left ventricular mass. CONCLUSIONS: Despite less pronounced weight loss, patients with HFpEF, obesity, and type 2 diabetes responded favorably to tirzepatide. This favorable response was reflected by a reduced risk of adverse heart failure outcomes and improved health status, quality of life, and functional capacity, as well as a decrease in left ventricular mass and paracardiac fat, to a degree that was similar to that in patients without diabetes. These observations raise the possibility that the heart failure benefits of incretin-based drugs may not be faithfully estimated by measuring the magnitude of the change in body weight. (SUMMIT [A Study of Tirzepatide (LY3298176) in Participants With Heart Failure With Preserved Ejection Fraction (HFpEF) and Obesity]; NCT04847557).