Oral semaglutide and survival in heart failure with preserved ejection fraction and type 2 diabetes.
This retrospective, multi-centre observational study used the TriNetX global healthcare research network to compare outcomes of oral semaglutide versus sitagliptin in patients with heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D). From a pool of over 800,000 patients with both conditions, 3,470 initiated oral semaglutide and 22,840 initiated sitagliptin between October 2019 and December 2023. After propensity score matching (3,452 patients per group), the study found that the oral semaglutide group had a significantly lower 1-year all-cause mortality rate (4.3% vs. 7.0%, log-rank p < 0.001) and lower rates of hospitalisation compared with the sitagliptin group. Important limitations include the observational, non-randomised design, which introduces potential for residual confounding despite propensity score matching; the reliance on administrative/claims data from the TriNetX platform; and the inability to confirm medication adherence or establish causality. The authors note that prior evidence for semaglutide in HFpEF comes from injectable formulations, and these findings for the oral route remain hypothesis-generating pending randomised controlled trial confirmation.
Why this grade: Although the study involves a large human cohort with propensity score matching, its retrospective observational design using administrative data precludes causal inference and is susceptible to residual confounding, warranting only a limited-human evidence grade.
Aims Heart failure with preserved ejection fraction (HFpEF) and type 2 diabetes (T2D) commonly coexist and are associated with poor outcomes. Although injectable semaglutide has demonstrated benefits in HFpEF, the effectiveness of oral semaglutide in this setting remains uncertain. This study compared all-cause death and hospitalisation between oral semaglutide and sitagliptin in patients with HFpEF and T2D. Materials and methods Using a global healthcare data and analytics platform, the TriNetX research network, we conducted a retrospective multi-centre observational study. We identified patients aged ≥18 years with HFpEF diagnosed before December 31, 2023 (N = 1 731 548), of whom 812 259 had concomitant T2D. Among them, 3470 initiated oral semaglutide and 22 840 initiated sitagliptin between October 1, 2019, and December 31, 2023. After propensity score matching, each group included 3452 patients. The primary outcome was all-cause death; the secondary outcome was hospitalisation. Results Over 1 year, the risk for all-cause death in patients who received oral semaglutide relative to those who received sitagliptin was significantly lower (4.3% [145/3452] vs. 7.0% [229/3452]; log-rank p Conclusions Oral semaglutide appeared to be associated with a lower 1-year risk of all-cause death compared with sitagliptin in patients with HFpEF and T2D.
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