Clinical Context
Heart failure with preserved ejection fraction (HFpEF) represents one of the most challenging conditions in cardiovascular medicine. Unlike heart failure with reduced ejection fraction (HFrEF), which has numerous proven therapies, HFpEF has historically lacked effective treatments. This syndrome disproportionately affects older adults, women, and those with obesity—a patient population that has been underrepresented in cardiovascular trials.
The obesity-HFpEF phenotype is increasingly recognized as a distinct entity characterized by excessive epicardial and systemic adiposity, volume overload, systemic inflammation, and impaired cardiac reserve. Weight gain exacerbates symptoms, while weight loss through bariatric surgery has shown dramatic improvements in HFpEF parameters. The question of whether pharmacological weight loss could similarly benefit these patients led to the STEP-HFpEF trial program.
Sex differences in heart failure are well-documented: women are more likely to develop HFpEF than HFrEF, present with different symptoms, and may respond differently to therapies. This analysis specifically examines whether semaglutide’s benefits in obesity-related HFpEF are consistent between men and women—a critical question for clinical application given the female predominance of this condition.
Study Summary (PICO Framework)
Summary:
In adults with obesity-related HFpEF (EF ≥45%, BMI ≥30 kg/m²), weekly semaglutide 2.4 mg for 52 weeks significantly improved HFpEF symptoms, physical function, and exercise capacity in both sexes, with greater weight loss in women (-9.6%) than men (-7.2%) compared to placebo with standard care, and was associated with fewer serious adverse events than placebo.
| PICO | Description |
|---|---|
| Population | Adults with obesity-related HFpEF (EF ≥45%, BMI ≥30 kg/m²), including both men and women, from the STEP-HFpEF trials. |
| Intervention | Semaglutide 2.4 mg subcutaneously once weekly for 52 weeks. |
| Comparison | Matching placebo weekly plus standard heart failure care. |
| Outcome | KCCQ-CSS improvement: +7.6 points (women), +7.5 points (men). Weight loss: -9.6% (women), -7.2% (men). Exercise capacity improved. Fewer serious adverse events with semaglutide. |
Clinical Pearls
1. Benefits are consistent across both sexes—an important finding for a female-predominant condition. The similar improvements in KCCQ clinical summary scores (+7.6 points for women, +7.5 for men) demonstrate that semaglutide’s symptomatic benefits are not sex-dependent. This is reassuring given that HFpEF predominantly affects women, who have historically been underrepresented in heart failure trials.
2. Women achieve greater weight loss than men. The 9.6% weight reduction in women versus 7.2% in men is clinically meaningful. This sex difference in weight loss response to GLP-1 RAs has been observed in obesity trials as well and may reflect hormonal or body composition differences. For women with obesity-related HFpEF, semaglutide may be particularly effective.
3. Semaglutide had fewer serious adverse events than placebo. This counterintuitive finding—an active drug being safer than placebo—likely reflects the disease-modifying effects of weight loss in HFpEF. Obesity contributes to hospitalizations, thromboembolic events, and other complications that weight loss may prevent. It reinforces that semaglutide’s benefits extend beyond symptom improvement.
4. The KCCQ improvement exceeds clinically meaningful thresholds. A 5-point improvement in KCCQ is considered clinically meaningful; the 7.5+ point improvements observed represent substantial quality-of-life gains. Patients report feeling better, having less dyspnea, greater exercise tolerance, and improved daily functioning.
Practical Application
Patient selection: Semaglutide is now a evidence-based treatment option for patients with HFpEF and BMI ≥30 kg/m², regardless of sex. Ideal candidates have symptomatic heart failure (NYHA II-IV), obesity contributing to their symptoms, and no contraindications to GLP-1 RA therapy. The presence of type 2 diabetes is not required.
Setting expectations by sex: Counsel women that they may experience greater weight loss (~10%) compared to men (~7%), though both groups can expect similar improvements in heart failure symptoms and quality of life. Symptom improvement typically begins within the first few months and continues to improve over the full year of treatment.
Integration with guideline-directed HFpEF therapy: Semaglutide should be considered additive to, not a replacement for, other HFpEF therapies. SGLT2 inhibitors (empagliflozin, dapagliflozin) are now guideline-recommended for HFpEF regardless of diabetes status. The combination of SGLT2i plus GLP-1 RA may offer complementary benefits through different mechanisms, though this combination in HFpEF has not been specifically studied.
Monitoring and follow-up: Use the KCCQ or similar patient-reported outcome measures to track symptomatic response. Monitor weight, 6-minute walk distance (if available), and functional status at regular intervals. Gastrointestinal side effects are the main tolerability concern; gradual dose titration helps minimize these.
How This Study Fits Into the Broader Evidence
The STEP-HFpEF program (STEP-HFpEF and STEP-HFpEF DM for those with diabetes) represents the first dedicated trials of a GLP-1 RA for heart failure. The primary results showed significant improvements in the dual primary endpoint of KCCQ-CSS and body weight, establishing semaglutide as the first pharmacotherapy specifically proven effective for obesity-related HFpEF.
This sex-based analysis adds important information for clinical practice. Previous HFpEF trials (EMPEROR-Preserved, DELIVER with SGLT2i) showed consistent benefits across sexes, and these findings confirm the same for semaglutide. The FDA approved semaglutide 2.4 mg (Wegovy) for adults with obesity-related HFpEF based on these trials.
The findings complement SELECT (cardiovascular outcomes in obesity without HF) and FLOW (kidney outcomes in diabetes), positioning semaglutide as an agent with broad cardiometabolic benefits across multiple patient populations.
Limitations to Consider
This is a post-hoc sex-stratified analysis, not a pre-specified subgroup analysis, limiting the strength of conclusions about sex differences. The 52-week trial duration doesn’t capture very long-term outcomes or durability of benefit. Patients with more severe heart failure (NYHA IV, recent hospitalization) were underrepresented. The trials did not assess hard cardiovascular outcomes like hospitalization or mortality.
Bottom Line
Semaglutide 2.4 mg weekly produces clinically meaningful improvements in symptoms, quality of life, and exercise capacity in both men and women with obesity-related HFpEF. Women may experience greater weight loss than men, though symptomatic benefits are similar. For the many women with this challenging condition, semaglutide represents a welcome evidence-based treatment option that addresses the root cause of their obesity-related heart failure.
Source: Subodh Verma, et al. “Efficacy of Semaglutide by Sex in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Trials.” Journal of the American College of Cardiology, 2024 Aug 27; 84(9):773-785. Read article here.
