Kitzman, Dalane W

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.

Importance Excess body fat plays a pivotal role in the pathogenesis of heart failure with preserved ejection fraction (HFpEF). HU6 is a novel, controlled metabolic accelerator that enhances mitochondrial uncoupling resulting in increased metabolism and fat-specific weight loss. Objective To assess efficacy and safety of HU6 in reducing body weight, improving peak volume of oxygen consumption (VO 2 ) and body composition among patients with obesity-related HFpEF. Design, Setting, and Participants The Exploratory Phase 2A, Double-Blind, Placebo-Controlled Dose Escalation Study of Safety, Tolerability, Pharmacodynamics, and Pharmacokinetics of HU6 for Subjects With Obese HFpEF (HuMAIN-HFpEF) trial was a multicenter, dose-escalation randomized clinical trial among patients with chronic stable HFpEF and obesity. Data were analyzed from July to October 2024. Intervention HU6 treatment for 19 weeks, starting at 150 mg per day and potentially up titrated to 450 mg per day based on safety and tolerability vs placebo. Main Outcomes and Measures The primary end point was change in body weight. Results Of 66 participants randomized (mean [SD] age, 64.5 [12] years; 38 female [58%]; mean [SD] weight, 110.9 [22.4] kg), 56 completed the trial. HU6 (vs placebo) significantly decreased weight (between-group difference, −2.86 kg; 95% CI, −4.68 to −1.04 kg; P = .003), total fat mass (between-group difference, −2.96 kg; 95% CI, −4.50 to −1.42 kg; P < .001), and percentage visceral fat (between-group difference,−1.3%; 95% CI, −2.1 to −0.5%; P = .003), with no significant loss of muscle mass. There were no statistically significant changes in peak VO 2 , 6-minute walk distance, Kansas City Cardiomyopathy Questionnaire score, high-sensitivity C-reactive protein level, N-terminal pro–brain natriuretic peptide level, or diastolic function. Serious adverse events were noted in 5 participants (4 in the HU6 group; 1 in the placebo group), including 1 death, all judged unrelated to treatment. Conclusions and Relevance Among patients with obesity-related HFpEF, treatment with HU6 for 19 weeks led to modest but statistically significant weight loss without significant changes in peak VO 2 . Larger trials of longer duration are warranted to determine whether longer-term administration of HU6 can improve exercise function, quality of life, and cardiovascular outcomes in this increasingly common disorder. Trial Registration ClinicalTrials.gov Identifier: NCT05284617

Abstract Aims Sodium–glucose co-transporter-2 (SGLT2) inhibitors improve health status and outcomes in the setting of heart failure (HF) across the range of ejection fraction (EF). Baseline kidney disease is common in HF, complicates HF management and is strongly linked to worse health status. This study aimed to assess whether the treatment effects of dapagliflozin on health status vary based on estimated glomerular filtration rate (eGFR). Methods and Results We conducted a pooled participant-level analysis of two double-blind, randomized trials, DEFINE-HF (n = 236) and PRESERVED-HF (n = 324), which evaluated dapagliflozin versus placebo. Both multicentre studies enrolled adults with HF, New York Heart Association Class II or higher, elevated natriuretic peptides, and an EF < 40% in DEFINE-HF or >45% in PRESERVED-HF. The primary exposure was eGFR. The main outcome was the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) at 12 weeks. Across both trials, there were 583 (99.3%) participants with a baseline eGFR. The median (25th, 75th) eGFR was 59 (46, 77) mL/min/1.73 m2. Dapagliflozin improved KCCQ-CSS at 12 weeks [placebo-adjusted difference, +5.0 points, 95% confidence interval (CI) 2.6–7.5; P < 0.001], and this was consistent in participants with an eGFR ≥ 60 (+6.0 points, 95% CI 2.4–9.7; P = 0.001) and eGFR < 60 (+4.1 points, 95% CI 0.5–7.7; P = 0.025) (P interaction = 0.46). The benefits of dapagliflozin on KCCQ-CSS remained robust across eGFR when modelled as a continuous variable (P interaction = 0.48). Conclusions Dapagliflozin led to early and clinically meaningful improvements in health status in HF patients, regardless of EF or baseline eGFR.