ACC.24 – In patients with obesity-related HFpEF and T2D, semaglutide resulted in larger reductions in HF-related symptoms and physical limitations, greater weight loss, and greater improvement in exercise function at 52 weeks compared with placebo.

This summary is based on the presentation of Mikhail Kosiborod, MD (Kansas City, MO, USA) at the ACC.24 Scientific Session - Once-weekly Semaglutide In Patients With Heart Failure With Preserved Ejection Fraction, Obesity And Type 2 Diabetes: Main Results From The Step-hfpef Dm Trial.

Introduction and methods

HFpEF patients who also have obesity and T2D have a high burden of symptoms. In fact, excess body fat plays an important role in the development and progression of both HFpEF and T2D. Previously, in the STEP-HFpEF trial, it was shown that semaglutide reduced HF-related symptoms, physical limitations, and body weight in HFpEF patients with obesity but with no diabetes.

The 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) trial was an international, multicenter, double-blind, placebo-controlled, phase 3 RCT in which 616 patients with HFpEF (LVEF ≥45%, NYHA class II–IV HF symptoms), BMI ≥30 kg/m², and T2D were randomized to subcutaneous semaglutide 2.4 mg once weekly or placebo for 52 weeks, in addition to standard of care.

The coprimary endpoints were changes from baseline to 52 weeks in the KCCQ – Clinical Summary Score (CSS) and body weight. Confirmatory secondary endpoints were change from baseline to 52 weeks in 6-minute walk distance (6MWD); a hierarchical composite outcome comprising all-cause mortality, HF events, and differences in the changes in KCCQ-CSS and 6MWD; and change from baseline to 52 weeks in CRP level.

Main results

• At 52 weeks, the mean change in the KCCQ-CSS from baseline was 13.7 points in the semaglutide group (n=310) and 6.4 points in the placebo group (n=306) (estimated treatment difference: 7.3 points; 95%CI: 4.1–10.4; P<0.001).
• The mean percentage change in body weight from baseline to 52 weeks was −9.8% with semaglutide and −3.4% with placebo (estimated treatment difference: −6.4 percentage points; 95%CI: −7.6 to −5.2; P<0.001).
• The results for the confirmatory secondary endpoints also favored semaglutide over placebo: The estimated between-group difference in 6MWD change was 14.3 m (95%CI: 3.7–24.9; P=0.008), the stratified win ratio for the hierarchical composite endpoint was 1.58 (95%CI: 1.29–1.94; P<0.001), and the estimated treatment ratio for CRP change was 0.67 (95%CI: 0.55–0.80; P<0.001).
• Subgroup analysis showed that background SGLT2 inhibitor use did not influence the difference in change in KCCQ-CSS between the treatment groups (P for interaction=0.35), but the magnitude of weight loss was slightly more pronounced in patients not taking SGLT2 inhibitors at baseline (P for interaction=0.04).
• The frequency of serious adverse events was 17.7% in the semaglutide group and 28.8% in the placebo group (P=0.002), of which cardiac disorders were the most frequently reported (6.1% vs. 13.1%; P=0.004).

Conclusion

In patients with obesity-related HFpEF and T2D, semaglutide treatment resulted in larger reductions in HF-related symptoms and physical limitations, greater weight loss, and greater improvement in exercise function at 52 weeks compared with placebo. The drug was well tolerated.

- Our reporting is based on the information provided at the ACC.24 Scientific Session -

The findings of this study were simultaneously published in N Engl J Med.