ActRII blockade a novel pharmacologic approach for weight loss?

ActRII* pathway inhibition with bimagrumab led to weight loss and metabolic improvements in overweight/obese individuals with type 2 diabetes, a phase II trial suggests.

Although effective, long-term effects of lifestyle modifications outside specialized centres remain limited. [Prog Cardiovasc Dis 2018;61:246-252; Obesity 2020;28:529-536] “Combining lifestyle management with pharmacotherapy is increasingly recognized as an effective and safe treatment option for many patients with obesity,” said the researchers.

“[Our] results suggest that there may be a novel mechanism for achieving weight loss with a profound loss of body fat and an increase in lean mass (LM), along with other metabolic benefits,” said study author Professor Steve Heymsfield from the Pennington Biomedical Research Center, Baton Rouge, Louisiana, US.

The team randomized 75 adults (mean age 60.4 years, mean BMI 32.9, mean HbA_1c 7.8 percent) 1:1 to receive 30-minute IV infusions of bimagrumab 10 mg/kg (up to 1,200 mg in 5% dextrose solution) or placebo every 4 weeks for 48 weeks. All participants received diet and exercise counselling. Except for metformin and/or a DPP4** inhibitor, participants should not be on any other antidiabetic drug. [JAMA Network Open 2021;doi:10.1001/jamanetworkopen.2020.33457]

Bimagrumab slashed total fat mass (FM) at week 48 vs placebo (least squares mean [LSM] change from baseline, −20.5 percent vs −0.5 percent), translating to a significant drop in weight (–7.49 kg vs –0.18 kg; p<0.001).

Gain in the face of loss?

Conversely, LM increased with bimagrumab vs placebo (LSM change from baseline, 3.6 percent [1.7 kg] vs −0.8 percent [–0.4 kg]; p<0.001) which, according to the researchers, may have been driven by fluid rather than muscle build-up. “[O]ur LM estimates [may represent] normally hydrated skeletal muscle.”

This is a novel finding, they said, as loss, rather than gain, in lean tissues is more likely with certain diet/exercise protocols. [Clin Nutr 2019;38:372-382; Nutrients 2018;10:1876] However, extreme programmes lead to substantial losses of lean components that might trigger serious functional deficits and even death. [Int J Obes (Lond) 2019;43:2536-2544]

“[As such,] an important goal of obesity treatment is there should be minimal loss of lean tissues and their associated functions,” they said. “Uniquely, ActRII blockade with bimagrumab not only limited LM loss but also increased the mass of this compartment by ~4 percent after four monthly doses.”

Fat loss + muscle gain = weight loss?

The combined FM loss and LM gain led to a significant net reduction in total body weight with bimagrumab vs placebo (LSM change from baseline, −6.5 percent [−5.9 kg] vs –0.8 percent [–0.8 kg]; p<0.001).

These effects were supplemented by LSM reductions from baseline waist circumference (−9.0 vs 0.5 cm; p<0.001), waist-to-hip ratio (−0.05 vs 0.01; p<0.001), adipose tissue (−1.71 vs −0.52 L; p=0.07 [subcutaneous] and −1.52 vs −0.01 L; p=0.08 [visceral]), hepatic fat fraction (−7.00 percent vs −2.33 percent; p=0.01), BMI (−2.19 vs −0.28; p<0.001), and HbA_1c (−0.76 vs 0.04 percentage points; p=0.005). “These highlight the importance of moving away from body weight as a primary efficacy marker of drugs to more metabolically relevant endpoints, such as total body FM,” they explained.

A different pattern in humans

More than 80 percent of participants experienced adverse events (AEs), the most frequent being mild diarrhoea and muscle spasms (bimagrumab arm). Six patients reported nine serious AEs, four of which occurring in the bimagrumab arm (ie, pancreatitis, pneumonia, epigastric pain, and elevated lipase). Five bimagrumab recipients withdrew from the study owing to AEs.

As opposed to animal models showing only skeletal muscle mass gains with ActRII blockade, this study reflected a different pattern in humans. “[ActRII] inhibition … in humans leads not only to increases in LM but profound decreases in body fat, along with improvements in glycaemic control,” said the researchers.

“[As such, ActRII inhibition] may provide a novel pathway for the pharmacologic management of excess adiposity and accompanying metabolic disturbances,” they concluded.

The researchers called for further exploration in larger and more diverse cohorts to ascertain the drug’s efficacy, safety, and potential mechanisms that could explain for the effects of ActRII blockade on weight loss.