Novel HU6 reduces weight without muscle loss in patients with obesity-related HFpEF

Treatment with HU6, a novel, first-in-class controlled metabolic accelerator, significantly reduces body weight while preserving lean body mass in patients with obesity-related heart failure with preserved ejection fraction (HFpEF), according to the HuMAIN-HFpEF* trial presented at HFSA 2024.

From baseline to week 19, patients treated with HU6 achieved a significant weight loss of 2.9 kg (p=0.003), with a mean percentage change in body weight of -2.7 percent (p=0.003), compared with placebo. [HFSA 2024, Late Breaking Clinical Research Session II]

In terms of changes in body composition between baseline and week 19, using the InBody Scale, HU6-treated patients also showed a significant reduction of 6.9 percent in total body fat (p=0.0001) than placebo-treated patients.

In particular, visceral fat decreased by 6.6 percent (p=0.001) in the HU6 arm, but no significant difference in lean body mass was observed between the treatment arms (difference of 0.8 percent; p=0.30).

Taken together, “the weight loss effect of HU6 [also led to] favourable changes in body composition, including significant reductions in overall fat mass and visceral adiposity and preservation of lean body mass,” said lead author Dr Ambarish Pandey from the Department of Internal Medicine, Division of Cardiology and Geriatrics at the University of Texas Southwestern Medical Center in Dallas, Texas, US.

In previous studies, “the GLP-1 agonist semaglutide significantly reduced body weight … However, concerns have been raised about loss of muscle mass with GLP-1 receptor agonists in older patients with HFpEF who have sarcopenic obesity and significant skeletal muscle dysfunction,” Pandey noted.

Based on the current findings of the HuMAIN-HFpEF study, it was demonstrated that HU6 therapy selectively reduced body fat while simultaneously preserving skeletal muscle mass in older patients with obesity-related HFpEF, thus meeting the need for novel weight loss interventions.

This multicentre, double-blind, dose-escalation, phase IIa HuMAIN-HFpEF trial analysed 66 patients (mean age 64 years) with obesity-related HFpEF who were randomized in a 1:1 ratio to receive either HU6 (150, 300, or 450 mg) or placebo for 19 weeks. Majority of the participants were female with a mean BMI of 39 kg/m² and a peak V0₂ of 13.4 mL/kg/minute.

In terms of safety, the most common adverse events (AEs) reported in the HU6 and placebo arms were diarrhoea (18.2 percent vs 6.3 percent), COVID-19 (15.2 percent vs 3.1 percent), and dyspnoea (12.1 percent vs 0 percent).

Although more serious AEs occurred in the HU6 group than the placebo group (12.1 percent vs 3.1 percent), they were all deemed unrelated to the study drug as per the blinded investigator team, said Pandey.

“HU6 appeared safe and well tolerated [in this patient population],” he added.

“Overall, the phase IIa HuMAIN results showing significant reductions in body fat and visceral fat in patients with obesity-related HFpEF, who typically have excess fat throughout their cardiovascular system and systemic inflammation, are extremely promising given that the study participants had obesity, were older, and with multiple medical conditions,” Pandey said in a press release. “We were also encouraged to see the preservation of lean muscle mass, which is particularly important for older patients with HFpEF, who are often frail and have low muscle mass.”

However, as the HuMAIN-HFpEF trial was considered a small study with a short study duration, “future larger trials with longer-term follow-up are needed to evaluate whether HU6 can improve functional status and clinical outcomes in the growing population of patients with obesity-related HFpEF,” he noted.