Verma, Subodh

Abstract Background The prevalence of heart failure with preserved ejection fraction (HFpEF) increases with age, and older adults with HFpEF have worse physical function, quality of life, and clinical outcomes. Semaglutide demonstrated efficacy in the treatment of obesity-related HFpEF in the STEP-HFpEF trials. Some have speculated that older patients may have less to gain from incretin therapies (and perhaps more to lose) than younger patients. Aims In this pre-specified pooled subanalysis of the STEP-HFpEF trials, we evaluated the efficacy of semaglutide across the age spectrum. Methods The STEP-HFpEF and STEP-HFpEF DM trials enrolled participants with obesity-related HFpEF and randomized them to semaglutide 2.4 mg once weekly (n = 573) or placebo (n = 572) for 52 weeks. Dual primary outcomes (change in Kansas City Cardiomyopathy Questionnaire clinical summary score [KCCQ-CSS] and change in body weight) and secondary outcome measures (6-minute walk distance [6MWD], C-reactive protein, hierarchical composite endpoint containing all-cause death, heart failure events, changes in KCCQ-CSS and 6MWD) were compared across specific age groups; <55 years, 55–64 years, 65–74 years and ≥75 years. Results Among 1145 randomized participants, 8.8% (N = 101) were <55, 23.3% (N = 267) were aged between 55–64, 42.4% (N = 485) were between 65–74, and 25.5% (N = 292) were 75 years or over. The efficacy of semaglutide on the dual primary endpoints was consistent across the age spectrum, KCCQ-CSS (p-interaction = 0.80), and body weight (p-interaction = 0.41). Similar benefits were observed for the key secondary endpoints, with no treatment effect heterogeneity across age groups. Moreover, the safety of semaglutide was consistent across age groups. Conclusion In patients with HFpEF enrolled across the STEP-HFpEF and STEP-HFpEF DM trials, treatment with semaglutide improved disease-specific symptoms, physical function and reduced body weight across the age spectrum. The safety profile of semaglutide was consistent in older and younger patients.

Abstract Background and Aims In the STEP-HFpEF trial programme, treatment with semaglutide resulted in multiple beneficial effects in patients with obesity-related heart failure with preserved ejection fraction (HFpEF). Efficacy may vary according to baseline diuretic use, and semaglutide treatment could modify diuretic dose. Methods In this pre-specified analysis of pooled data from the STEP-HFpEF and STEP-HFpEF-DM trials (n = 1145), which randomized participants with HFpEF and body mass index ≥ 30 kg/m2 to once weekly semaglutide 2.4 mg or placebo for 52 weeks, we examined whether efficacy and safety endpoints differed by baseline diuretic use, as well as the effect of semaglutide on loop diuretic use and dose changes over the 52-week treatment period. Results At baseline, across no diuretic (n = 220), non-loop diuretic only (n = 223), and loop diuretic [<40 (n = 219), 40 (n = 309), and >40 (n = 174) mg/day furosemide equivalents] groups, there was progressively higher prevalence of hypertension and atrial fibrillation; and greater severity of obesity and heart failure. Over 52 weeks of treatment, semaglutide had a consistent beneficial effect on change in body weight across diuretic use categories (adjusted mean difference vs. placebo ranged from −8.8% [95% confidence interval (CI) −10.3, −6.3] to −6.9% [95% CI −9.1, −4.7] from no diuretics to the highest loop diuretic dose category; interaction P = .39). Kansas City Cardiomyopathy Questionnaire clinical summary score improvement was greater in patients on loop diuretics compared to those not on loop diuretics (adjusted mean difference vs. placebo: +9.3 [6.5; 12.1] vs. +4.7 points [1.3, 8.2]; P = .042). Semaglutide had consistent beneficial effects on all secondary efficacy endpoints (including 6 min walk distance) across diuretic subgroups (interaction P = .24–.92). Safety also favoured semaglutide vs. placebo across the diuretic subgroups. From baseline to 52 weeks, loop diuretic dose decreased by 17% in the semaglutide group vs. a 2.4% increase in the placebo group (P < .0001). Semaglutide (vs. placebo) was more likely to result in loop diuretic dose reduction (odds ratio [OR] 2.67 [95% CI 1.70, 4.18]) and less likely dose increase (OR 0.35 [95% CI 0.23, 0.53]; P < .001 for both) from baseline to 52 weeks. Conclusions In patients with obesity-related HFpEF, semaglutide improved heart failure-related symptoms and physical limitations across diuretic use subgroups, with more pronounced benefits among patients receiving loop diuretics at baseline. Reductions in weight and improvements in exercise function with semaglutide vs. placebo were consistent in all diuretic use categories. Semaglutide also led to a reduction in loop diuretic use and dose between baseline and 52 weeks. Clinical Trial Registration NCT04788511 and NCT04916470.