HU6 Cuts Fat-Specific Body Weight in Obesity-Related HFpEF

HU6, a novel controlled metabolic accelerator, achieved modest, but statistically significant, reductions in fat-specific body weight without notably impacting skeletal muscle mass among individuals with obesity-related heart failure with preserved ejection fraction (HFpEF).1

The HuMAIN-HFpEF randomized clinical trial randomized 66 patients to short-term oral administration HU6 or placebo, for 19 weeks, beginning at 150 mg per day, with the potential for titration up to the therapeutic dose of 450 mg based on safety and tolerability outcomes.

“The weight loss achieved by HU6 over 19 weeks was smaller in magnitude than that observed with semaglutide over the same period. However, it was primarily driven by significant loss of fat mass and visceral adiposity with preservation of lean mass,” wrote the investigative team, led by Ambarish Pandey, MD, University of Texas Southwestern Medical Center. “This is particularly relevant as loss of lean mass may be detrimental in the long-term among older patients with HFpEF and could worsen sarcopenia and lead to worse frailty and disability.”

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) significantly impact body weight and patient-reported and clinical outcomes, but notably lower lean muscle mass, representing up to 40% of the total weight loss. Given the burden of sarcopenia and frailty in older patients with HFpEF, investigators highlighted the need for weight loss therapy to reduce adiposity and maintain skeletal muscle mass.2

In Phase 2 data, HU6, a novel agent metabolized to enhance mitochondrial uncoupling, demonstrated significant fat-specific weight loss and preservation of lean mass for patients with steatotic liver disease. Efficacy and safety of HU6 to reduce body weight, boost peak volume oxygen consumption (VO2), and improve fat-specific weight loss in obesity-related HFpEF was investigated in the HuMAIN-HFpEF trial.3

Participants aged ≥30 years with chronic HFpEF and obesity were enrolled in the dose-escalation trial to undergo standardized weight and body composition assessment and cardiopulmonary exercise tests. The primary efficacy endpoint was the change in body weight from baseline to Day 134, with a key secondary endpoint of the change in peak VO2.1

Among 66 individuals randomized to the study, with a mean age of 64.5 years and 38 (58%) females, 56 finished the trial. Most participants self-reported their race and ethnicity as White (80.3%) or Black/African American (16.7%).

At 19 weeks, compared with placebo, HU6 demonstrated significant reductions in weight (between-group difference, –2.86 kg [95% CI, –4.68 to –1.04 kg]; P = .003) and percentage body weight (between-group difference, –2.72% [95% CI, –4.49 to –0.95]; P = .003). Total lean body mass and dry lean mass did not significantly change with HU6 treatment versus placebo.

However, further analysis showed that HU6 significantly lowered total fat mass (between-group difference, –2.96 kg; 95% CI, –4.50 to –1.42 kg; P <.001), percentage of fat mass (between-group difference, –1.77% [95% CI, –2.71 to –0.84]; P <.001), and percentage visceral fat (between-group difference, –1.3% [95% CI, –2.1 to –0.5]; P =.003), compared with placebo.

Notably, HU6 was not linked to a significant benefit for peak VO2, exercise time, 6-minute walk distance, or quality of life measured by the Kansas City Cardiomyopathy Questionnaire (KCCQ) score. Among biomarkers, it led to no significant change in NT-pro-BNP level, troponin level, hs-CRP levels, or other glycemic or lipid parameters. Serious adverse events were identified in 4 individuals treated with HU6, and 1 with placebo, but all were determined to be unrelated to treatment.

Based on these findings, Pandey and colleagues noted the study provided both the rationale and clinical preliminary data to design and conduct further studies involving longer-term HU6 treatment and larger quantities of patients with HFpEF.1

“Future studies with longer-term treatment in larger cohorts of patients are needed to evaluate the efficacy of HU6 to improve functional outcomes and quality of life and assess the clinical relevance of its effects on body composition, cardiac function, and blood pressure,” Pandey and colleagues added.

References

1. Pandey A, Lewis GD, Borlaug BA, et al. Novel Controlled Metabolic Accelerator for Obesity-Related HFpEF: The HuMAIN-HFpEF Randomized Clinical Trial. JAMA Cardiol. Published online March 12, 2025. doi:10.1001/jamacardio.2025.0103

2. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384(11):989-1002. doi:10.1056/NEJMoa2032183

3. Noureddin M, Khan S, Portell F, et al. Safety and efficacy of once-daily HU6 versus placebo in people with non-alcoholic fatty liver disease and high BMI: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet Gastroenterol Hepatol. 2023;8(12):1094-1105. doi:10.1016/S2468-1253(23)00198-X