medwireNews: Short-term treatment with the metabolic accelerator HU6 in adults who have obesity and heart failure with preserved ejection fraction (HFpEF) leads to modest but significant weight loss, suggests the HuMAIN-HFpEF trial.
The 33 patients randomly assigned to receive oral HU6, at a starting dose of 150 mg/day and titrated up to 450 mg/day if tolerated, had a least squares mean (LSM) reduction in body weight that was a significant 2.86 kg greater on average than that for the 33 patients given placebo.
From a mean starting weight of 110 kg, the LSM reduction in body weight with HU6 treatment was 3.10 kg versus 0.23 kg with placebo.
HU6 increases metabolism by enhancing mitochondrial uncoupling, explain study author Ambarish Pandey (University of Texas Southwestern Medical Center, Dallas, USA) and colleagues in JAMA Cardiology.
And while the weight loss achieved with its use was smaller than that reported in previous studies of similar length with semaglutide, they note that it was “primarily driven by significant loss of fat mass and visceral adiposity with preservation of lean mass.”
Specifically, mean reductions in total fat mass and percentage visceral fat were a significant 2.96 kg and 1.3% greater, respectively, among patients in the HU6 group than those in the placebo group at study end. The investigators say HU6 may therefore “be advantageous, as it directly targets the key pathophysiologic mechanisms pivotal to the progression of HFpEF.”
By contrast, the LSM change in lean body mass after 18 weeks was 0.34 kg in the HU6 group and 0.29 kg in the placebo group, giving a nonsignificant 0.8% treatment difference in the percentage change from baseline.
The investigators say that this finding “is particularly relevant,” as losing lean mass “could worsen sarcopenia and lead to worse frailty and disability.”
They suggest: “Preserving lean muscle mass may be a more desirable and safer strategy for weight loss among older patients with obesity-related HFpEF.”
However, Pandey et al also found that “[d]espite favorable effects on bodyweight and composition, HU6 did not significantly improve exercise capacity or HF-specific quality of life.”
The study participants were aged over 30 years, had a mean age of 64.5 years, and 58% were women. The two treatment groups were well matched for baseline characteristics, except that the HU6-treated patients had numerically higher rates of diabetes than those treated with placebo (42.5 vs 24.2%) and lower median levels of troponin I (5.08 vs 6.42 ng/L).
At least one on-treatment adverse event (AE) was reported in 69% of participants, with no significant between-group difference in the rate. The most common AEs were diarrhea, COVID-19, dyspnea, and headache. Four participants in the HU6 group and one in the placebo group had a serious AE deemed unrelated to the study drug, and one person in the HU6 group died, also deemed unrelated to the treatment.
Given the totality of the findings, Pandey et al say that “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 addition to reducing weight in patients with obesity-related HFpEF.
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JAMA Cardiol 2025; doi:10.1001/jamacardio.2025.0103
