Higher BMI, Bigger Gains: Tirzepatide’s Effects on HFpEF

TOPLINE:

In patients with obesity-related heart failure with preserved ejection fraction (HFpEF), tirzepatide reduced the risk for worsening heart failure or cardiovascular death regardless of their baseline BMI or fat distribution, with larger gains observed among those with higher BMI. Those who lost more weight with tirzepatide showed greater improvements in exercise capacity and symptom severity.

METHODOLOGY:

• The SUMMIT trial previously showed significant benefits of tirzepatide, a long-acting glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, in patients with obesity-related HFpEF.
• In this secondary analysis, researchers looked at whether the effects of tirzepatide varied with the severity and distribution of a patient’s obesity or by the extent of weight loss achieved after treatment.
• The trial included 731 patients aged 40 years or older (mean age, 65.2 years; 53.8% women) with obesity-related HFpEF (defined by the New York Heart Association’s functional classes II-IV) and a BMI of 30 or higher.
• Participants were randomly assigned to subcutaneously receive either 2.5 mg/wk of tirzepatide (n = 364) or a placebo (n = 367).
• Patients were categorized into tertiles of their baseline BMI and waist to height ratio.
• Primary endpoints were the time to first adjudicated cardiovascular death or an event of worsening HF and a change in the symptom status measured using the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 52 weeks. Secondary endpoints included changes in exercise capacity (measured using the 6-minute walk distance), body weight, and blood pressure.

TAKEAWAY:

• Patients in the highest tertile of BMI were younger and most likely to be women and had more severe HF, a greater volume overload, and more severe inflammation. Those with a higher waist to height ratio showed similar patterns, as well as shorter 6-minute walk distances and more severe kidney disease.
• Use of tirzepatide vs placebo reduced the risk for cardiovascular death or worsening HF across all BMI ranges and waist to height ratios.
• Tirzepatide was associated with greater improvement in the 6-minute walk distance in patients in the highest range for BMI (37.5 m) than in those in the middle (26.3 m) and lower (9.9 m) ranges (P for trend = .025); improvements in weight loss and systolic blood pressure followed similar patterns.
• After 52 weeks on tirzepatide, those who lost more weight had bigger gains in their 6-minute walk distance and changes in the KCCQ-CSS (P < .0001 for both). The same benefits were seen in those with larger drops in waist circumference.

IN PRACTICE:

“These data provide further evidence supporting the importance of excess body fat, particularly visceral fat, as driving HF severity in patients with the obesity phenotype of HFpEF,” the researchers reported.

“While these findings reinforce the role of incretin therapies in HFpEF management, these data, perhaps more importantly, highlight the urgent need for precision strategies to define obesity and direct therapy to those who will benefit most,” experts wrote in an editorial accompanying the journal article.

SOURCE:

This study was led by Barry A. Borlaug, MD, of Mayo Clinic in Rochester, Minnesota. It was published online on July 21, 2025, in the Journal of the American College of Cardiology. The researchers presented the findings at the American College of Cardiology (ACC) Scientific Session 2025.

LIMITATIONS:

Categorizing patients into tertiles of their BMI or waist to height ratio may have masked some trends. The trial included a higher proportion of women and participants from Latin America, limiting generalizability. Imaging-based methods could possibly offer more precise measurements of obesity. 

DISCLOSURES:

The original trial was funded by Eli Lilly and Company. The lead author reported receiving grants from the National Heart, Lung, and Blood Institute and US Department of Defense, receiving research grants from and consulting for several pharmaceutical companies, and being a named inventor for tools and approach for procedure to treat HF. Several other authors reported being employees of or consultants for Eli Lilly and Company and several other companies.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.