Tirzepatide Affects Men and Women with HFpEF Equally, With Barry Borlaug, MD

Tirzepatide achieves consistent benefits across multiple domains of heart failure (HF) severity in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), irrespective of sex, according to a secondary analysis of the phase 3 SUMMIT trial.1

Presented at the Heart Failure Society of America (HFSA) Annual Scientific Meeting 2025 by Barry Borlaug, MD, associate professor of medicine at Mayo Clinic, this analysis aimed to determine potential variance in treatment response among women with obesity-related HFpEF. The disease is famously represented differently between both sexes, with women exhibiting greater severity in several disease aspects.1

The editorial team at HCPLive sat down with Borlaug to discuss the findings of the study, how they may implement HFpEF treatment, and whether this method should be explicated to other medications.

“We know that women tend to have more severe obesity and a higher percent body fat,” Borlaug told HCPLive. “There are some important differences: they have smaller, stiffer hearts, and they have more abdominal visceral fat relative to women without HFpEF. There are lots of reasons why [tirzepatide] should behave a little bit differently.”

The original SUMMIT trial included both men and women ≥40 years old with chronic HF defined as New York Heart Association class II to IV, left ventricular ejection fraction of ≥50%, and a body mass index (BMI) of ≥30. Enrolled patients also had a 6-minute walk distance between 100 and 425 m and a Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) of ≤80.2

Eligible patients were randomly assigned in a 1:1 ratio to either tirzepatide subcutaneously at 2.5 mg/week or placebo, in addition to usual therapy. Patients were stratified according to HF decompensation occurrence within 12 months before baseline, a history of type 2 diabetes (T2D), and BMI over or under 35.2

Ultimately, SUMMIT screened 1494 patients, 731 of whom were assigned to either tirzepatide (n = 364) or placebo (n = 367). Cardiovascular or HF-related death occurred in 36 patients in the tirzepatide group versus 56 in the placebo group. Mean KCCQ-CSS increase was 19.5 points in the tirzepatide group and 12.7 in placebo.2

This secondary analysis included 393 female and 338 male patients from the initial SUMMIT group. Average BMI was 39 kg/m2 among women and 37.3 kg/m2 among men. Baseline waist circumference was 116.9 cm in the female group versus 123 cm in the male group. Investigators saw more severe baseline HF in women with HFpEF, noting an inverse relation between eGFR and waist-to-height ratio in women (P = 0.043). However, men displayed more cardiac remodeling and paracardiac fat.1

Despite these differences, investigators found similar benefits with tirzepatide versus placebo between both sexes. Men experienced a 10.6% reduction in body weight (95% CI, -12.2 to -8.9) compared to a 12.5% reduction in women (95% CI, -14.2 to -10.8). Time to worsening HF or cardiovascular disease was 0.66 in women (95% CI, 0.38 to 1.18) versus 0.61 in men (95% CI, 0.33 to 1.13).1

Borlaug also spoke on the importance of using similar study methods to analyze potential sex differences in other medications, outside of both HFpEF and cardiology in general.

“I think this is something we should be looking at in basically all trials,” Borlaug said. “It’s a very straightforward analysis. We know that women and men are different in many ways, so we want to make sure that benefits are similar in both sexes. We pre-specify them, obviously, and plan for them in the statistical analysis plan. But yes, I think this is something that should routinely be done to better understand sex differences in response to treatment.”

References

1. Borlaug B. Effects of Tirzepatide in Obesity-Related HFpEF by Sex: A Prespecified Secondary Analysis from the SUMMIT Trial. Presented at the Heart Failure Society of America Annual Scientific Meeting 2025. Minneapolis, MN. September 26-29, 2025.

2. Packer M, Zile MR, Kramer CM, et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med. 2025;392(5):427-437. doi:10.1056/NEJMoa2410027