STEP-HFpEF: semaglutide in heart failure with preserved ejection fraction and obesity

STEP-HFpEF is a weight-management trial with a cardiology endpoint welded on. It is the first of the STEP programme to make a symptom score coprimary with weight.

What the trial asked

Whether semaglutide 2.4 mg reduces symptoms and physical limitations, and reduces body weight, in people who have both heart failure with preserved ejection fraction (HFpEF) and obesity.

Design

Randomised, placebo-controlled, once-weekly semaglutide 2.4 mg versus placebo for 52 weeks. Dual primary endpoints: change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS, 0 to 100, higher means fewer symptoms and limitations), and change in body weight.

Who was enrolled

529 patients with HFpEF and a BMI of 30 or higher. The abstract does not give age, sex or baseline weight.

Primary endpoint and result

P less than 0.001 for both.

Key secondary results

Confirmatory secondary endpoints, all P less than 0.001:

• 6-minute walk distance: +21.5 m versus +1.2 m; difference 20.3 m (95% CI 8.6 to 32.1).
• Hierarchical composite (death, heart-failure events, KCCQ-CSS and walk distance): win ratio 1.72 (95% CI 1.37 to 2.15) in favour of semaglutide.
• C-reactive protein: -43.5 percent versus -7.3 percent; estimated treatment ratio 0.61 (95% CI 0.51 to 0.72).

Adverse events and discontinuation

Serious adverse events were reported in 35 participants (13.3 percent) on semaglutide and 71 (26.7 percent) on placebo. The abstract does not give discontinuation rates or itemise gastrointestinal events.

Funding and registration

Novo Nordisk. ClinicalTrials.gov NCT04788511.

What this trial does not show

• It was not powered for death or hospitalisation. The hierarchical composite includes those events but is dominated by the symptom and walk-distance components.
• Everyone had obesity. It says nothing about HFpEF in people of normal weight.
• 52 weeks. Durability of the symptom benefit beyond that is not addressed.
• It does not disentangle how much of the symptom improvement came through weight loss rather than another mechanism.

Where the numbers come from

PubMed abstract of the primary paper (PubMed 37622681), fetched 4 September 2026. For the hard-outcome cardiovascular trial in obesity without diabetes, see SELECT.