Novel Controlled Metabolic Accelerator for Obesity-Related HFpEF

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 (VO2) 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 VO2, 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 VO2. 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.