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Oral Semaglutide Reduces Heart Failure Events in Type 2 Diabetes Patients With Established HF
Among people with type 2 diabetes and a prior history of heart failure, once-daily oral semaglutide reduced the composite heart failure outcome by approximately 22% compared with placebo (HR 0.78, 95% CI 0.63–0.96), with a particularly pronounced benefit observed in those with preserved ejection fraction. No comparable reduction was seen in participants who had no heart failure history at enrollment, suggesting the benefit may be concentrated in those with pre-existing disease.
What Was Studied
This secondary analysis examined whether once-daily oral semaglutide reduces heart failure events — specifically the composite of heart failure hospitalization, urgent heart failure visits, or cardiovascular death — in people with type 2 diabetes who either had or did not have a documented heart failure history at the time of enrollment. The analysis also assessed whether oral semaglutide’s previously established benefit in reducing major adverse cardiovascular events (MACE) differed according to heart failure status at baseline.
How It Was Studied
This was a prespecified secondary analysis of the SOUL trial, a double-blind, placebo-controlled, event-driven phase 3b randomized clinical trial conducted across 444 centers in 33 countries. A total of 9,650 adults with type 2 diabetes and established atherosclerotic cardiovascular disease and/or chronic kidney disease were randomized to once-daily oral semaglutide or placebo added to standard care, with participants stratified at enrollment by presence or absence of heart failure history. Mean follow-up was 47.5 months (approximately four years), providing substantial duration for event accrual. Of all participants, 2,229 (23.1%) had a documented heart failure history, including those with preserved ejection fraction, reduced ejection fraction, and an unknown subtype.
What Was Observed
- Among participants with established heart failure at baseline, oral semaglutide was associated with about a 22% lower risk of the composite heart failure outcome compared with placebo (HR 0.78, 95% CI 0.63–0.96). This represents a statistically significant reduction in the combined endpoint of heart failure hospitalization, urgent heart failure visit, or cardiovascular death.
- In the heart failure with preserved ejection fraction subgroup, the risk reduction was substantially larger — approximately 41% lower risk with oral semaglutide versus placebo (HR 0.59, 95% CI 0.39–0.86). By contrast, in those with reduced ejection fraction, there was essentially no difference between treatment arms (HR 0.98, 95% CI 0.70–1.38), suggesting potential heterogeneity by ejection fraction phenotype.
- In participants without heart failure history, oral semaglutide showed no reduction in the composite heart failure outcome (HR 1.01, 95% CI 0.84–1.20). The interaction p-value between the heart failure and no-heart-failure subgroups was 0.06, which falls just short of conventional statistical significance, leaving some uncertainty about whether the difference between subgroups is real.
- MACE reduction with oral semaglutide was consistent regardless of heart failure history — roughly 17% lower risk in those with heart failure (HR 0.83, 95% CI 0.68–1.01) and about 14% lower in those without (HR 0.86, 95% CI 0.75–0.98), with no statistically significant interaction (P for interaction = .77). Serious adverse events were similarly distributed between semaglutide and placebo arms in participants with heart failure.
Why This Matters
Heart failure is a common and serious complication of type 2 diabetes, and identifying therapies that reduce heart failure events in this population addresses a significant clinical need acknowledged within the SOUL trial itself. These findings indicate that oral semaglutide, already shown to reduce MACE in the parent trial, may extend its cardiovascular benefit to include heart failure endpoints — particularly in people with preserved ejection fraction. This ejection-fraction-dependent pattern of benefit warrants dedicated prospective investigation in heart failure populations.
How to Read This Result
While derived from a large, well-conducted randomized trial with long follow-up, these are secondary exploratory findings not powered for heart failure outcomes, and the subgroup interaction just missed conventional significance (P = .06), so the apparent restriction of benefit to those with pre-existing heart failure should be interpreted cautiously pending confirmatory evidence.
Limitations
This analysis was not the primary prespecified objective of the SOUL trial, making all heart failure subgroup findings exploratory rather than confirmatory. The trial was not powered to detect differences in heart failure outcomes, which affects the precision of the estimates. The interaction p-value of 0.06 does not meet the conventional threshold of 0.05, leaving genuine uncertainty about whether the observed benefit is truly limited to those with established heart failure. Additionally, ejection fraction subtype was unknown in 6.7% of participants with heart failure, limiting the completeness of the ejection-fraction-stratified analysis.