In the STEP-HFpEF DM trial, semaglutide 2.4 mg weekly improved heart failure symptoms by 7.3 points more than placebo, produced 9.8% weight loss, and increased walking distance by 14.3 meters in 616 obese diabetic patients with HFpEF.
7.3-point symptom improvement over placeboSemaglutide 2.4 mg weekly also produced 9.8% weight loss, improved walking distance by 14.3 meters, and reduced inflammation by 33% in 616 obese diabetic HFpEF patients over 1 year
What the researchers found
In 616 randomized patients with HFpEF, obesity (BMI ≥30), and type 2 diabetes over 52 weeks:
Primary endpoints:
- KCCQ-CSS (symptoms/function): +13.7 vs +6.4 points; difference 7.3 points (95% CI: 4.1–10.4; P < 0.001)
- Body weight: -9.8% vs -3.4%; difference -6.4 percentage points (95% CI: -7.6 to -5.2; P < 0.001)
Confirmatory secondary endpoints:
- 6-minute walk distance: +14.3 m difference (95% CI: 3.7–24.9; P = 0.008)
- Hierarchical composite (death, HF events, KCCQ-CSS, walk distance): win ratio 1.58 (P < 0.001)
- CRP level: treatment ratio 0.67 (P < 0.001) — 33% greater reduction in inflammation
- Serious adverse events: 17.7% semaglutide vs 28.8% placebo — fewer with semaglutide
Why it matters
Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure and has had very few effective treatments. This trial shows that semaglutide addresses a key driver — obesity — while simultaneously improving heart failure symptoms, exercise capacity, and inflammation. Published in the New England Journal of Medicine, it establishes a new treatment paradigm for this previously undertreated patient population.
How the study worked
Randomized, double-blind, placebo-controlled trial (STEP-HFpEF DM, NCT04916470) in patients with heart failure with preserved ejection fraction, BMI ≥30, and type 2 diabetes. Patients received once-weekly subcutaneous semaglutide 2.4 mg or placebo for 52 weeks. Co-primary endpoints were change in KCCQ-CSS (symptom score) and body weight. Confirmatory secondary endpoints included 6-minute walk distance, a hierarchical composite endpoint, and CRP levels.
What this study cannot tell us
The trial duration was 52 weeks — longer-term outcomes including mortality benefits are unknown. Patients were specifically obese with type 2 diabetes and HFpEF, so results may not apply to all heart failure patients. The weight loss itself could account for some of the symptom improvement, making it difficult to isolate direct cardiac effects of semaglutide. The trial was funded by Novo Nordisk, the manufacturer of semaglutide.
How to read the evidence
This is a large, well-designed, double-blind, randomized, placebo-controlled trial published in the New England Journal of Medicine — the gold standard of clinical evidence. All primary and confirmatory secondary endpoints were statistically significant with pre-specified testing hierarchies.
When this study was published
Published in 2024 in NEJM, this is a landmark trial that has already influenced clinical guidelines and led to expanded FDA approval of semaglutide for heart failure indications.
The bigger picture
This trial, along with the companion STEP-HFpEF trial (in patients without diabetes), fundamentally changes the treatment of obesity-related heart failure. It validates the hypothesis that targeting obesity with GLP-1 drugs directly improves heart failure outcomes — not just weight and blood sugar. The surprisingly lower serious adverse event rate with semaglutide suggests these patients may have been hospitalized less for heart failure events. This has led to FDA approval of semaglutide for this indication.
Questions still open
- Does semaglutide reduce heart failure hospitalizations and mortality in longer follow-up periods?
- How much of the symptom improvement is due to weight loss versus direct cardiac effects of GLP-1 activation?
- Should semaglutide be considered first-line therapy for all obese patients with HFpEF?
Common questions
Can semaglutide treat heart failure?
Is semaglutide safe for heart failure patients?
Read the original research
Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.
The New England journal of medicine, 390(15), 1394-1407
Citation
Kosiborod, Mikhail N; Petrie, Mark C; Borlaug, Barry A; Butler, Javed; Davies, Melanie J; Hovingh, G Kees; Kitzman, Dalane W; Møller, Daniél V; Treppendahl, Marianne B; Verma, Subodh; Jensen, Thomas J; Liisberg, Karoline; Lindegaard, Marie L; Abhayaratna, Walter; Ahmed, Fozia Z; Ben-Gal, Tuvia; Chopra, Vijay; Ezekowitz, Justin A; Fu, Michael; Ito, Hiroshi; Lelonek, Małgorzata; Melenovský, Vojtěch; Merkely, Bela; Núñez, Julio; Perna, Eduardo; Schou, Morten; Senni, Michele; Sharma, Kavita; van der Meer, Peter; Von Lewinski, Dirk; Wolf, Dennis; Shah, Sanjiv J. (2024). Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.. The New England journal of medicine, 390(15), 1394-1407. https://doi.org/10.1056/NEJMoa2313917