Abstract 11812: Heterogeneity in Treatment Benefits of Oral Semaglutide in People with Heart Failure with Preserved Ejection Fraction

Abstract

Importance: Heart failure with preserved ejection fraction (HFpEF) is common among people with visceral adiposity and type 2 diabetes, yet evidence regarding the benefits of oral formulations of semaglutide in clinical practice and the patients most likely to benefit remains limited. Objective: To evaluate the effectiveness of oral semaglutide among people with adiposity-related HFpEF and type 2 diabetes in clinical practice. Design, Setting, and Participants: Active-comparator, new-user cohort study using a design, data, and analytic approach benchmarked against randomized trials. Data were obtained from 3 nationwide US healthcare claims databases. Adults with adiposity-related HFpEF and type 2 diabetes newly initiating oral semaglutide or sitagliptin were followed for up to 52 weeks. Exposures: Initiation of oral semaglutide or sitagliptin. Main Outcomes and Measures: Primary end points were worsening heart failure events requiring hospitalization or intravenous diuretics, with or without all-cause mortality. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models after propensity score overlap weighting. Results: Benchmarking against a reference trial showed close alignment in effect estimates. Among 5,945 oral semaglutide and 18,163sitagliptin initiators (mean age, 66 years; 49% women), the 1-year risk of heart failure events or death was 6.1% vs 8.9% (risk difference [RD], 2.8%; number needed to treat [NNT], 36; HR, 0.64 [95% CI, 0.53-0.77]). Risks of worsening heart failure events alone were 4.3% and 6.6%, respectively (NNT, 42; HR, 0.61 [0.49-0.75]). Relative treatment effects were generally consistent across clinically relevant HFpEF phenotypes, but absolute benefits varied substantially. For the composite end point, NNTs ranged from 18 among individuals with prior myocardial infarction or stroke and those with atrial fibrillation (RDs, 5.5%) to 135 among those receiving baseline SGLT2 inhibitors (RD, 0.7%) and 357 among those with CKD stage 1-2 (RD, 0.3%). Similar patterns were observed for worsening heart failure events. Individual components of the primary composite showed consistent reductions. No increased risks were observed for serious infections or gastrointestinal adverse events. Sensitivity analyses and negative control outcomes yielded consistent findings. Conclusions and Relevance: Oral semaglutide led to lower risks of worsening heart failure events among people with adiposity-related HFpEF and type 2 diabetes, with clinically meaningful heterogeneity in absolute treatment effects across clinically relevant patient subgroups. Trial Registration: ClinicalTrials.gov Identifier: NCT07390110