‘Metabolic Accelerator’ Cuts Weight, Not Muscle in HFpEF: HuMAIN-HF

A drug designed to increase the body’s resting metabolic rate significantly reduces excess weight in patients with obesity-related heart failure with preserved ejection (HFpEF) and does so by preferentially targeting adipose tissue and sparing lean muscle mass, results of the small HuMAIN-HF study show.

Known as HU6 (Rivus Pharmaceuticals), the drug is a mitochondrial uncoupling agent—also known as a controlled metabolic accelerator—that promotes weight loss by increasing mitochondrial energy use rather than by reducing caloric intake.

The GLP-1 receptor agonist semaglutide (Wegovy; Novo Nordisk) has been shown to significantly cut body weight in the pivotal STEP-HFpEF trial, but a concern has been that treatment reduces skeletal muscle mass in addition to body fat, said lead investigator Amarish Pandey, MD (University of Texas Southwestern Medical Center, Dallas, TX). This is problematic for HFpEF patients, who often have sarcopenia and impaired skeletal muscle function.

“The whole premise of testing a novel weight-loss therapy that promotes differential loss of fat, and that keeps lean muscle mass, is predicated on the fact that patients with HFpEF have sarcopenic obesity—they’re obese and have lower lean muscle mass to begin with,” Pandey told TCTMD. “They have a high burden of frailty and physical dysfunction. With GLP-1 [receptor agonists], you lose a good amount of weight, but a good proportion of the weight you lose is actually muscle mass. When the drug gets discontinued, you gain back the fat mass but not necessarily the muscle mass.”

HU6 was previously shown to be effective for weight loss—with the preservation of skeletal muscle mass—in patients with metabolic dysfunction-associated steatotic liver disease, said Pandey.

Muscle Kept, Fat Mass Reduced

In HuMAIN-HF, which was presented online after the Heart Failure Society of America (HFSA) 2024 scientific sessions were canceled due to Hurricane Helene, investigators randomized 66 adults with obesity-related HFpEF to placebo or escalating doses of HU6: 150 mg for 3 weeks, 300 mg for 3 weeks, and 450 mg for 3 months. In the active treatment arm, mean age was 63.8 years, body mass index was 38.8 kg/m², and body weight was 110 kg. More than 42% of patients had diabetes. Baseline characteristics were consistent with other studies of HFpEF patients, with no clinically meaningful differences between the two study groups, said Pandey.  

At 19 weeks, there was a 2.9 kg difference in body weight favoring HU6, with weight declining steadily over the follow-up period while it remained unchanged in the placebo group. Regarding body composition, which was assessed using the InBody scale (InBody USA), there was no significant difference in lean body mass between the two treatments. However, loss of fat mass was significantly greater in those treated with HU6 (-6.9% vs placebo; P = 0.0001). Visceral body fat loss also was greater with active treatment (-6.6% vs placebo; P = 0.001).

“The absolute weight loss is modest, but you have to interpret it in the context of what are we losing?” said Pandey. “If you compare it to a 20-week treatment with semaglutide in STEP-HFpEF, patients lose like 8% of their body weight or more, but around 40% to 50% of that is muscle mass. The fat mass loss is comparable.”

There were no significant improvements in peak VO2, exercise time, 6-minute walk distance, or Kansas City Cardiomyopathy Questionnaire scores with the controlled metabolic accelerator. Various cardiac biomarkers, including NT-proBNP, troponin, and C-reactive protein, also didn’t significantly improve. There was evidence of positive changes in echocardiographic measures of left ventricular systolic function, including increased LVEF and decreased LV end-systolic volume. Right ventricular systolic function also appeared to improve with treatment.  

Pandey said HuMAIN-HF is a proof-of-concept study that focuses on weight loss and body composition rather these other secondary endpoints. “We need a larger study, something similar to the STEP program studies [with semaglutide] to see whether or not we can accomplish the kind of benefits you would expect from selective loss of fat mass and visceral deposits,” he said.

The drug was safe in this small study, said Pandey, but larger trials are needed to confirm an acceptable risk-benefit profile. Adverse events were numerically higher with HU6, the most common being diarrhea and dyspnea. 

Amanda Vest, MBBS, MPH (Cleveland Clinic, OH), the discussant following Pandey’s presentation, said she is excited for the development of a novel metabolic intervention for HFpEF. Safety, she pointed out, is paramount with the development of new therapeutics, and metabolic accelerators have historically been associated with certain side effects, including tachypnea and hyperthermia.

“So, the numerically higher [risk of] dyspnea in the HU6 does require careful attention in future trials,” she said.

Vest said it remains to be determined what degree of weight loss is needed to result in functional gains and improved clinical outcomes in the HFpEF population. The selective loss of adipose tissue, particularly visceral adiposity, with HU6 is “intriguing,” she added, noting that optimal means of measuring body composition in HF patients still needs to be clarified.