GLP-1RA Effective in Obesity Phenotype of HFpEF, Regardless of Obesity Class

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Introduction and methods


The obesity phenotype of HFpEF is a pathophysiologically distinct form of HFpEF that is characterized by more severe symptoms, poorer exercise capacity, more adverse hemodynamics, and greater risk of HF hospitalization compared with HFpEF patients without obesity [1-8]. Recently, the STEP-HFpEF (Semaglutide Treatment Effect in People with obesity and HFpEF) trial showed that semaglutide reduced symptoms, physical limitations, inflammation, and body weight and improved exercise function in patients with the obesity phenotype of HFpEF compared with placebo [9,10]. However, it is unclear whether these treatment effects vary by obesity class and whether they are related to the magnitude of body weight reduction.

Aim of the study

In a prespecified analysis of the STEP-HFpEF trial, the authors investigated the efficacy of semaglutide versus placebo in HFpEF patients across different obesity categories and whether the degree of body weight reduction achieved with semaglutide was related to the improvements in the key trial endpoints.


The STEP-HFpEF trial was an international, double-blind, placebo-controlled RCT in which 529 patients with the obesity phenotype of HFpEF (LVEF ≥45%; NYHA class II–IV HF symptoms; BMI ≥30 kg/m²) without diabetes were randomized to subcutaneous semaglutide 2.4 mg once weekly or placebo for 52 weeks, in addition to standard of care [10].


The dual primary endpoints of the STEP-HFpEF trial were change in Kansas City Cardiomyopathy Questionnaire-Clinical Summary Score (KCCQ-CSS) and percent change in body weight from baseline to 52 weeks. Confirmatory secondary endpoints included change in 6-minute walk distance (6MWD), overall clinical benefit assessed using a hierarchical composite outcome (all-cause death, HF events, and several thresholds of change in KCCQ-CSS from baseline to 52 weeks and change in 6MWD ≥30 m), and change in CRP level from baseline to 52 weeks.

Safety and tolerability were assessed by reported serious adverse events and adverse events leading to premature treatment discontinuation.

Main results

Treatment effects by baseline obesity category

  • In the intention-to-treat analysis, semaglutide improved the KCCQ-CSS from baseline to 52 weeks compared with placebo in patients with BMI 30–34 kg/m² (estimated treatment difference (ETD): 8.5; 95%CI: 3.2–13.8; P=0.0018) and BMI ≥40 kg/m² (ETD: 10.8; 95%CI: 5.5–16.1; P<0.0001) but not BMI 35–39 kg/m² (ETD: 4.1; 95%CI: –1.2 to 9.4; P=0.1331) (P for interaction=0.2122). Comparable results were seen in the on-treatment analysis (P for interaction=0.5505).
  • Semaglutide reduced body weight across 52 weeks in all obesity categories compared with placebo in the intention-to-treat analysis (ETD for BMI 30–34 kg/m²: –9.6; 95%CI: –11.8 to –7.4; P<0.0001; ETD for BMI 35–39 kg/m²: –11.3; 95%CI: –13.5 to –9.0; P<0.0001; ETD for BMI ≥40 kg/m²; ETD: –11.3; 95%CI: –13.4 to –9.1; P<0.0001; P for interaction=0.4902). The on-treatment analysis showed similar results (P for interaction=0.9371).
  • With regard to the confirmatory secondary endpoints, semaglutide improved the 6MWD compared with placebo, resulted in a greater number of wins in the composite hierarchical endpoint, and reduced CRP levels in all 3 obesity categories (all P for interaction>0.05).
  • There was no evidence of heterogeneity in the effects of semaglutide versus placebo.

Association between semaglutide effects and weight change

  • Among semaglutide-treated patients, greater improvements in KCCQ-CSS and 6MWD and a larger CRP reduction were significantly associated with a larger body weight reduction, both when body weight change was analyzed as an ordinal and as a continuous variable.
  • For example, after adjustment for baseline body weight, endpoint value, age, sex, history of AF, history of coronary artery disease, NYHA class, CRP level (log-transformed), and NT-proBNP level (log-transformed), each 10% reduction in body weight with semaglutide was associated with an increase in KCCQ-CSS of 6.4 points (95%CI: 4.1–8.8; P<0.0001), an increase in 6MWD of 14.4 m (95%CI: 5.5–23.3; P=0.0016), and a decrease in CRP level of 28% (95%CI: 16%–37%; P<0.0001).

Adverse events

  • In each obesity category, fewer serious adverse events were reported in semaglutide-treated patients compared with placebo-treated patients, with no evidence of heterogeneity in the safety or tolerability outcomes.
  • The number of patients who discontinued study medication due to serious adverse events was low in both the semaglutide and placebo groups, for all obesity categories.


In this prespecified analysis of the STEP-HFpEF trial among patients with the obesity phenotype of HFpEF, 52-week treatment with semaglutide versus placebo reduced body weight, HF-related symptoms, physical limitations, and systemic inflammation and improved exercise function, across all 3 obesity categories . In semaglutide-treated patients, the magnitude of benefit was associated with the degree of weight loss. According to the authors, “these data support semaglutide-mediated weight loss as a key treatment strategy in patients with the obesity phenotype of HFpEF” and “indicate that [those with only mild obesity] benefit just as much as patients with more severe obesity.”


Show references

1. Morgen, C. S. et al. Obesity, cardiorenal comorbidities and risk of hospitalization in patients with heart failure with preserved ejection fraction. Mayo Clin. Proc. (2023).

2. Dalos, D. et al. Functional status, pulmonary artery pressure, and clinical outcomes in heart failure with preserved ejection fraction. J. Am. Coll. Cardiol. 68, 189–199 (2016).

3. Kitzman, D. W. & Shah, S. J. The HFpEF obesity phenotype: the elephant in the room. J. Am. Coll. Cardiol. 68, 200–203 (2016).

4. Obokata, M., Reddy, Y. N. V., Pislaru, S. V., Melenovsky, V. & Borlaug, B. A. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 136, 6–19 (2017).

5. Reddy, Y. N. V. et al. Characterization of the obese phenotype of heart failure with preserved ejection fraction: a RELAX trial ancillary study. Mayo Clin. Proc. 94, 1199–1209 (2019).

6. Reddy, Y. N. V. et al. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur. J. Heart Fail. 22, 1009–1018 (2020).

7. Adamson, C. et al. Dapagliflozin for heart failure according to body mass index: the DELIVER trial. Eur. Heart J. 43, 4406–4417 (2022).

8. Borlaug, B. A. et al. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc. Res. 118, 3434–3450 (2023).

9. Kosiborod, M. N. et al. Once weekly semaglutide in heart failure with preserved ejection fraction and obesity. N. Engl. J. Med. (in the press).

10. Kosiborod, M. N. et al. Design and baseline characteristics of STEP-HFpEF program evaluating semaglutide in patients with obesity HFpEF phenotype. JACC Heart Fail. 11, 1000–1010 (2023).

Find this article online at Nat Med.

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