Use of metabolic accelerator HU6 in Obesity-Related HFpEF tied to Modest Weight Loss Without VO2 Change: JAMA

Obesity-related HFpEF is an increasing health concern, leading to impaired cardiac function and reduced quality of life. With limited treatment options available, there is a need for therapies that address both metabolic and cardiovascular factors. Excess body fat plays a key role in HFpEF development, making targeted weight reduction a crucial aspect of management.

HU6, a novel controlled metabolic accelerator, has emerged as a potential solution. By promoting mitochondrial uncoupling, it boosts metabolism and facilitates fat-specific weight loss, offering a promising approach to improving outcomes in patients with obesity-related HFpEF. To further explore this, Ambarish Pandey, Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, and colleagues aimed to evaluate the effectiveness and safety of HU6 in reducing body weight, enhancing peak oxygen consumption (VO2), and improving body composition in patients with obesity-related HFpEF.

For this purpose, the researchers conducted the HuMAIN-HFpEF trial, a multicenter, double-blind, placebo-controlled, dose-escalation study to evaluate the safety, tolerability, and effects of HU6 in patients with chronic stable HFpEF and obesity. The randomized clinical trial assessed HU6 treatment over 19 weeks, beginning at 150 mg per day, with the possibility of increasing the dose to 450 mg per day based on safety and tolerability. Data were analyzed from July to October 2024.

The primary focus of the study was to measure changes in body weight, providing insights into HU6's potential as a targeted treatment for obesity-related HFpEF.

Based on the study, the researchers reported the following findings:

• The study included 66 participants with an average age of 64.5 years, of whom 58% were female, and the mean weight was 110.9 kg. A total of 56 participants completed the trial.
• HU6 led to significant weight loss compared to placebo, with an average reduction of 2.86 kg.
• Total fat mass decreased by 2.96 kg, and visceral fat percentage reduced by 1.3% without significant muscle loss.
• There were no significant improvements in peak VO2, 6-minute walk distance, heart failure symptoms, inflammation markers, or diastolic function.
• Serious adverse events occurred in five participants, including one death, but none were linked to treatment.

The findings suggest that HU6 led to modest but significant fat-specific weight loss in patients with obesity-related HFpEF over 19 weeks without notable improvements in peak VO2. The treatment demonstrated a favorable safety profile with low rates of serious adverse events and discontinuation.

"Given the increasing prevalence of obesity-related HFpEF, larger and longer trials are needed to evaluate whether extended HU6 therapy can enhance functional status, quality of life, and cardiovascular outcomes," the authors concluded.

Reference:

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