Diabetes does not influence effects of tirzepatide in HFpEF patients with obesity

Patients with heart failure (HF) with preserved ejection fraction (HFpEF), obesity, and type 2 diabetes (T2D) show a favourable response to tirzepatide despite less pronounced weight loss, reports a study.

“This favourable response was reflected by a reduced risk of adverse HF 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,” the investigators said.

This double-blind trial included 731 patients with HFpEF with a BMI of ≥30 kg/m². They were randomized to receive tirzepatide (up to 15 mg subcutaneously weekly) or placebo for a median of 104 weeks. The primary outcomes were time to first cardiovascular death or worsening HF event and change in the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks.

Furthermore, the investigators assessed changes in left ventricular mass and paracardiac fat at week 52 using paired cardiac magnetic resonance imaging.

Overall, patients who received tirzepatide had a lower risk of cardiovascular death or worsening HF (hazard ratio [HR], 0.62, 95 percent confidence interval [CI], 0.41‒0.95; p=0.026), which was mainly driven by fewer worsening HF events. [J Am Coll Cardiol 2025;86:696-707]

The effect was comparable between patients with (HR, 0.64, 95 percent CI, 0.35‒1.15) or without T2D (HR, 0.61, 95 percent CI, 0.33‒1.10; p=0.95 for interaction).

Furthermore, tirzepatide significantly improved KCCQ-CSS, 6-min walk distance, quality of life scores, and NYHA functional class, and these improvements did not differ in patients with and without T2D.

At 52 weeks, patients with T2D exhibited less noticeable weight loss. They lost 10.4 percent (95 percent CI, 8.7‒12.2) of body weight compared with 12.9 percent (95 percent CI, 11.2‒14.6) in those without diabetes (p=0.04 for interaction).

Nevertheless, reductions in visceral adiposity (as reflected by the decline in paracardiac fat) and in left ventricular mass were similar in patients with or without T2D.

“These observations are consistent with the hypothesis that treatment-related changes in body weight may not represent a faithful estimate of the HF benefits of these drugs,” the investigators said.

Diabetes influence

The current findings of similar clinical benefits with tirzepatide in patients with or without diabetes support observations that diabetes did not influence the effect of tirzepatide to reduce both left ventricular mass and visceral fat surrounding the heart, according to the investigators.

In previous studies, the adverse cardiovascular effects of obesity are mediated through an expansion of visceral fat depots, specifically in an increase in epicardial or paracardiac adipose tissue. [J Am Coll Cardiol 2018;71:2360-2372]

“The hypertrophy and biological transformation of adipocytes adjacent to the myocardium can result in the transmission of proinflammatory adipocytokines that may lead to myocardial fibrosis, resulting in HFpEF,” the investigators said. [Eur J Heart Fail 2020;22:1551-1567; JACC Adv 2023;2:9:100657]

“Epicardial adipose tissue mass is increased in HFpEF, and its expansion is associated with increases in left ventricular mass, abnormalities of left atrial and right ventricular function, and impairment in exercise capacity,” they added. [Cardiovasc Diabetol 2023;22:23; Int J Cardiol Heart Vasc 2024;54:101485]

“Drugs that signal through the GLP-1 receptor have been shown to shrink visceral adipose tissue depots surrounding the heart, and this effect may represent the key mediators of their favourable impacts in patients with HFpEF,” according to the investigators. [J Am Coll Cardiol 2024;84:865-867]