MINNEAPOLIS — The GLP-1 receptor agonist tirzepatide confers the same benefit in women as it does in men with obesity-related heart failure with preserved ejection fraction (HFpEF), according to a new analysis from the SUMMIT trial.

Results from the randomized study also showed that women with obesity-related HFpEF had higher risk factors for worse outcomes than men with HFpEF, including greater adiposity, more severe symptoms, and poorer exercise capacity. The same trial found that women also had reduced risk with lower left ventricular mass and paracardiac fat deposition than men.

“We know that there are important sex differences in the heart and the vasculature in patients with HFpEF,” investigator Barry Borlaug, MD, a cardiologist at Mayo Clinic in Rochester, Minnesota, said during a late-breaking clinical research session at the Heart Failure Society of America (HFSA) 2025 Annual Scientific Meeting.

In general, women have smaller, stiffer hearts than men. For example, women tend to have greater age-related increases in diastolic chamber stiffness; higher levels of leptin, a proinflammatory adipokine released by visceral adipocytes; and more severe systemic inflammation. Women with HFpEF also have “a bigger problem with abdominal visceral adipose tissue,” according to Borlaug.

“Despite these differences, tirzepatide resulted in consistent benefits across multiple domains of heart failure severity, including similar benefits in terms of reduction in heart failure hospitalization or cardiovascular death” in both women and men compared with placebo, Borlaug added.

Secondary Analysis of SUMMIT Trial

In the original randomized SUMMIT trial, researchers compared tirzepatide with placebo in 731 patients with HFpEF classified as New York Heart Association (NYHA) class II to IV and a BMI ≥ 30. Tirzepatide reduced the composite primary endpoint of heart failure hospitalization or cardiovascular death by 38%. In addition, treatment was associated with a statistically significant 7-point improvement of scores on the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks.

Secondary outcomes also improved with tirzepatide, including changes in 6-minute walk distance, C-reactive protein levels, and BMI during the same period.

For the current, prespecified secondary analysis of SUMMIT, Borlaug and colleagues compared 338 men (mean age, 65 years; mean BMI, 37) and 393 women (mean age, 66 years; mean BMI, 39) with obesity-related HFpEF who were randomly assigned tirzepatide or placebo. They assessed baseline characteristics and the effectiveness of treatment on the same primary and secondary outcomes by sex.

Effective in Both Men and Women

In addition to having higher BMI, higher NYHA class, and lower KCCQ-CSS scores than men, women had a greater waist-to-height ratio and lower 6-minute walk distance measures.

Both men and women with greater baseline waist-to-height ratios had lower KCCQ-CSS and 6-minute walk distance results. Greater waist-to-height ratio was also associated with poorer kidney function, but only in women (P for interaction = .043).

The analysis linked tirzepatide with a lower risk of worsening heart failure or cardiovascular death, a result that did not differ significantly between women and men (hazard ratio [HR], 0.66 and 0.61, respectively; P for interaction = .81). The researchers also reported no differences in effect on KCCQ-CSS at 52 weeks (8.1- and 5.5-point placebo-corrected improvement; P for interaction = .43) or 6-minute walk distance (18-m and 15-m placebo-corrected improvement; P for interaction = .76).

A subpopulation of participants underwent cardiac MRIs, which revealed higher left ventricular mass and paracardiac fat volumes in men than in women.

The Takeaway

Women and men respond differently across ranges of left ventricular ejection fractions to some heart failure medications, such as angiotensin receptor-neprilysin inhibitors, said session Co-moderator Jennifer Thibodeau, MD, Medical Director of Heart Failure at UT Southwestern Medical Center in Dallas. “With any new therapeutic, it is important to understand the population characteristics that best respond to treatment.”

Asked if the study is clinically relevant, Thibodeau, who was not affiliated with the study, replied by email, “It informs us that tirzepatide is effective in both men and women!”

Borlaug disclosed having relationships with Amgen; Boehringer Ingelheim; Edwards LifeSciences; Merck; Novo Nordisk; Eli Lilly and Company; Aria; AstraZeneca; Corvia Medical; National Institutes of Health/National Heart, Lung, and Blood Institute; Tenax Therapeutics; GlaxoSmithKline; Medtronic; Mesoblast; Janssen; NGM Bio; ShouTi; VADovations; DoD; Axon; and Rivus Pharmaceuticals. Thibodeau reported having no relevant financial disclosures.

Damian McNamara is a freelance writer for Medscape Medical News. He uses what he learned in school — he holds a BA in chemistry and an MA in science, health, and environmental reporting/journalism. He works out of his home office in Miami, with a 100-lb chocolate lab known to snore under his desk during work hours.