Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes

The STEP-HFpEF DM trial was an international, randomized, double-blind, placebo-controlled study evaluating whether weekly semaglutide 2.4 mg could improve symptoms and function in patients with heart failure with preserved ejection fraction (HFpEF) associated with obesity and type 2 diabetes — a phenotype with very high prevalence and morbidity. 616 patients with BMI >=30, EF >=45%, and HbA1c <=10% were randomized to semaglutide or placebo over 52 weeks.

The dual primary endpoint was: (1) change in KCCQ-CSS score (symptoms and quality of life) and (2) percentage weight loss at 52 weeks:

• KCCQ-CSS: improvement of +13.7 points with semaglutide vs. +6.4 with placebo (estimated difference +7.3 points; P<0.001)
• Weight loss: -9.8% with semaglutide vs. -3.4% with placebo (difference -6.4 points; P<0.001)
• 6-minute walk distance: +14 m with semaglutide vs. -1 m with placebo (P=0.008)
• hsCRP: 41% reduction with semaglutide (P<0.001)
• NT-proBNP: reduction with semaglutide vs. placebo

The safety profile was favorable, with fewer serious adverse events in the semaglutide group than placebo (17.7% vs. 28.8%), reflecting reduced cardiovascular hospitalizations. Mild gastrointestinal events were more common with active treatment.

STEP-HFpEF DM, together with the original STEP-HFpEF (without diabetes), established semaglutide as effective treatment for HFpEF associated with obesity in patients with and without type 2 diabetes. The magnitude of symptomatic and functional improvement exceeded what is normally observed with any other pharmacological treatment for HFpEF, positioning GLP-1 agonists as an emerging therapeutic pillar in this HF phenotype, alongside SGLT2 inhibitors.