Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial
Authors' conclusion
In this secondary analysis of the SOUL randomized clinical trial, among individuals with T2D, atherosclerotic CV disease, and/or chronic kidney disease, a reduction of HF events was observed with use of oral semaglutide compared with placebo in those with a history of HF, without increasing the risk of serious adverse events. These data support the potential benefit of oral semaglutide in reducing HF events in people with T2D and HF.
Study context
- Population
- T2D with atherosclerotic CVD and/or CKD, stratified by heart failure (HF) history at baseline; 444 centers in 33 countries; 2229 (23.1%) with HF historyrandomized
- Participants
- 9,650 participants
- Comparison
- Oral semaglutide vs placebo, by HF history at baseline
- Primary endpoint
- Prespecified composite HF outcome:
- Time to first HF hospitalization
- Urgent HF visit
- Cardiovascular (CV) death
- Follow-up
- Mean (SD) 47.5 (10.9) months
Methodological detailsdouble-blind, placebo-controlled, event-driven, phase 3b, multicentre, Enrolled June 17, 2019 to March 24, 2021; analyzed December 2024 to August 2025
- Double-blind
- Placebo-controlled
- Event-driven
- Phase 3b
- Multicentre
- Enrolled June 17, 2019 to March 24, 2021; analyzed December 2024 to August 2025
Primary result
As reported in the abstract
Composite HF outcome by HF history at baseline
Oral semaglutide vs PlaceboHazard ratio (95% CI)P value
With HF at baseline
0.78(0.63–0.96)
Without HF at baseline
1.01(0.84–1.20)
P = 0.06for interactionFurther findings
| Outcome | HR (95% CI) | P value | |
|---|---|---|---|
| Composite HF outcome by HF subtype, among participants with HFOral semaglutidevs PlaceboPreserved ejection fraction | 0.59 (0.39–0.86) | ||
| Composite HF outcome by HF subtype, among participants with HFOral semaglutidevs PlaceboReduced ejection fraction | 0.98 (0.70–1.38) | ||
| MACE by HF historyOral semaglutidevs PlaceboWith HF history | 0.83 (0.68–1.01) | ||
| MACE by HF historyOral semaglutidevs PlaceboWithout HF history | 0.86 (0.75–0.98) | P for interaction = 0.77 | |
| 0.20.5125Hazard ratio (log scale) |
MACE by HF history
- No heterogeneity in MACE risk reduction by HF history
Safety
Serious adverse events among participants with HF
Serious adverse events among participants with HF
- Similar with oral semaglutide and placebo
Original publication
Oral Semaglutide and Heart Failure Outcomes in Persons With Type 2 Diabetes: A Secondary Analysis of the SOUL Randomized Clinical Trial. JAMA Intern Med. Published 1 April 2026. doi:10.
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