In a prespecified pooled analysis of STEP-HFpEF and STEP-HFpEF DM among 1145 patients with obesity-related HFpEF and with or with no T2D, semaglutide improved HF outcomes and reduced body weight compared with placebo.

This summary is based on the publication of Butler J, Shah SJ, Petrie MC, et al. - Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet. 2024 Apr 4:S0140-6736(24)00469-0 [Online ahead of print]. doi: 10.1016/S0140-6736(24)00469-0

Introduction and methods

Background

In the STEP-HFpEF trial, semaglutide reduced HF symptoms, physical limitations, and body weight and improved exercise function compared with placebo in patients with obesity-related HFpEF but no T2D [1]. The GLP-1RA also improved HF outcomes in patients with obesity-related HFpEF and T2D, although they lost less weight, as shown by the subsequent STEP-HFpEF DM trial [2].

Aim of the study

In a prespecified pooled analysis of individual patient-level data from the STEP-HFpEF and STEP-HFpEF DM trials, the authors aimed to provide a more definitive assessment of the effects of semaglutide in patients with obesity-related HFpEF and with or with no T2D across a broad range of outcomes and examine whether these effects were consistent across key patient subgroups.

Methods

The STEP-HFpEF (Research Study to Investigate How Well Semaglutide Works in People Living With Heart Failure and Obesity; n=529) and STEP-HFpEF DM (Effect of Semaglutide 2.4 mg Once-weekly on Function and Symptoms in Subjects With Obesity-related Heart Failure With Preserved Ejection Fraction, and Type 2 Diabetes; n=616) trials were international, multicenter, double-blind, placebo-controlled, phase 3 RCTs. In both trials, patients with LVEF ≥45%, NYHA class II–IV HF symptoms, KCCQ – Clinical Summary Score (CSS) <90 points, and BMI ≥30 kg/m² were randomized to subcutaneous semaglutide 2.4 mg once weekly or placebo for 52 weeks. Median follow-up duration was 401 days (IQR: 400–404).

In the STEP-HFpEF trial, patients with diabetes or HbA1c ≥6.5% were excluded, whereas inclusion criteria for the STEP-HFpEF DM trial were a T2D diagnosis ≥90 days before screening and HbA1c ≤10%. In addition to the study drug, participants in the STEP-HFpEF DM trial received background glucose-lowering medication.

The effects of semaglutide on the dual primary endpoints were examined across 14 prespecified subgroups stratified by, among others, age (<64 years vs. ≥65 to <75 years vs. ≥75 years), sex, geographical region (North America vs. Europe vs. other), BMI (<35 kg/m² vs. ≥35 kg/m² to <40 kg/m² vs. ≥40 kg/m²), and LVEF (45–49% vs. 50–59% vs. ≥60%).

Outcomes

The dual primary endpoints were the change in the KCCQ-CSS and percent change in body weight from baseline to 52 weeks. Confirmatory secondary endpoints included the change in 6-minute walk distance (6MWD) from baseline to 52 weeks; a hierarchical composite endpoint comprising all-cause mortality, HF events (adjudicated hospitalization or urgent hospital visit requiring intravenous therapy), differences in KCCQ-CSS change from baseline to 52 weeks of ≥15, ≥10, or ≥5 points, and difference in 6MWD change from baseline to 52 weeks of ≥30 m; and change in CRP level from baseline to 52 weeks.

Safety endpoints included serious adverse events and adverse events of special interest, such as adverse events leading to permanent treatment discontinuation, and clinically significant episodes of hypoglycemia and new or worsening diabetic retinopathy (STEP-HFpEF DM only).

Main results

Dual primary endpoints

• In the pooled study population, the mean change in the KCCQ-CSS from baseline to 52 weeks was larger in patients treated with semaglutide (n=573) than in those receiving placebo (n=572) (15.0 vs. 7.5 points; difference: 7.5 points; 95%CI: 5.3–9.8; P<0.0001).
• The mean percent change in body weight was also greater in the semaglutide group than in the placebo group (–11.4% vs. –3.0%; difference: –8.4%; 95%CI: –9.2% to –7.5%; P<0.0001).

Confirmatory secondary endpoints

• A larger improvement in the 6MWD from baseline to 52 weeks was observed in the semaglutide group compared with the placebo group (16.7 vs. –0.3 m; difference: 17.1 m; 95%CI: 9.2–25.0; P<0.0001).
• Treatment with semaglutide versus placebo led to more wins for the hierarchical composite endpoint (win ratio: 1.65; 95%CI: 1.42–1.91; P<0.0001).
• The semaglutide group also showed a larger CRP reduction than the placebo group (estimated treatment ratio: 0.64; 95%CI: 0.56–0.72; P<0.0001).

Subgroup analysis

• Subgroup analysis demonstrated significant interactions for the treatment effect of semaglutide versus placebo on the KCCQ-CSS by median NT-proBNP level, use of loop diuretics, use of RAASi therapy, and history of AF (all P for interaction<0.05). For weight change, significant interactions by sex and race were observed, although the numbers of non-White participants were small.
• For both primary endpoints, the efficacy of semaglutide was largely consistent across subgroups stratified by age, geographical region, baseline BMI, LVEF, systolic blood pressure, CRP level, or heart rate.

Safety assessment

• The frequency of serious adverse events was 161 in the semaglutide group (28.7 per 100 patient-years) and 301 in the placebo group (52.7 per 100 patient-years), most of which were cardiac disorders or infections and infestations.
• The number of adverse events leading to discontinuation of the study drug was higher in the semaglutide group than in the placebo group (92 (16.4 per 100 patient-years) vs. 51 (8.9 per 100 patient-years)), most of which were gastrointestinal disorders.

Conclusion

In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials among 1145 patients with obesity-related HFpEF and with or with no T2D, 52-week treatment with semaglutide reduced HF-related symptoms, physical limitations, and body weight and improved exercise function compared with placebo. The beneficial effects of semaglutide were largely consistent across various demographic and clinical characteristics of the study participants. The drug was well tolerated, with fewer serious adverse events in the semaglutide group than in the placebo group.

The authors point out that “obesity, diabetes, and heart failure result in pro-inflammatory states, and each are risk factors for infectious disease complications. [...] Thus, the reduced frequency of [these] complications in the semaglutide group compared with the placebo group in our pooled analysis further adds to the overall favorable risk–benefit balance for the use of semaglutide in people with heart failure with preserved ejection fraction, particularly given the high risk for non-cardiac morbidity and mortality in this patient population.”

Find this article online at Lancet.

References

1. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in patients with heart failure with preserved ejection fraction and obesity. N Engl J Med 2023; 389: 1069–84.
2. Kosiborod MN, Petrie MC, Borlaug BA, et al. Semaglutide in patients with obesity-related heart failure and type 2 diabetes. N Engl J Med 2024; 390: 1394–407.