New Delhi: Blockbuster drugs like semaglutide, sold as Ozempic and Wegovy, and tirzepatide, marketed as Mounjaro, have taken the world by storm for their impressive weight loss and blood glucose-reducing effects. But amid the excitement, a critical concern has emerged: the potential loss of muscle mass alongside fat. Now, a promising solution seems to be on the horizon.
A new molecule called HS235, developed by the Canadian biopharmaceutical company 35Pharma, has grabbed the attention of diabetologists and endocrinologists around the world, including in India.
Preclinical studies of HS235 presented at the Obesity Week 2023 conference in Texas last week showed that the drug can help increase muscle mass while also aiding in the loss of fat mass.
A statement issued by 35Pharma on October 16 said that mice treated with tirzepatide alone lost 46 percent of their fat mass, while those receiving a combination of tirzepatide and HS235 lost 64 percent of their fat mass.
Additionally, the statement said that HS235 completely rescued the lean mass lost by tirzepatide — all weight loss in the HS235 and tirzepatide combination was exclusively due to fat loss.
“It is perhaps the most important news in obesity research after the discovery of dual or triple receptor agonists,” said Dr Ambrish Mithal, chairman & head, endocrinology and diabetes with Max Super Speciality Hospital in Delhi, speaking to ThePrint.
“There is a molecule on the horizon that preserves or increases muscle mass while decreasing fat,” he stressed.
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‘Encouraging’ results
There’s a growing buzz in India surrounding Novo Nordisk’s semaglutide, available as Rybelsus oral pills, although Eli Lilly’s tirzepatide isn’t on the market here yet.
Both drugs operate by binding to gut hormone receptors. These hormones regulate pancreatic hormones and gut function, and their malfunctioning contributes to type 2 diabetes and obesity.
Semaglutide targets the GLP-1 receptor, while tirzepatide targets both the GLP-1 and GIP receptors. Both drugs work by mimicking the hormone incretin, which is released in the gut in response to a meal. This creates a feeling of fullness for longer, which reduces appetite.
Another promising drug by Eli Lilly, retatrutide, is currently in Phase 3 clinical trials. It works on three receptors: GLP-1, GIP, and glucagon.
However, one of the problems with people trying to shed weight with the aid of these medicines or other weight loss programme is that crucial lean or muscle mass may also be lost, said Dr Rajeev Jayadevan, a gastroenterologist and researcher from Kerala.
“Apart from physical weakness, muscle loss also upsets our metabolic balance. Good muscle mass is vital for resting metabolic rate, which, simply put, means the ability of the body to burn calories even while resting. Thus, loss of lean weight is not desirable in the long run,” he pointed out.
Jayadevan emphasises that those who are attempting to drop kilos must take steps to minimise muscle loss.
“Effective strategies include maintaining adequate protein intake in the diet, regular exercise, and avoiding massive weight loss over a short period of time. Less muscle is lost with less aggressive weight loss programmes,” he said.
However, according to Mithal, in the case of these new obesity drugs, the loss of muscle can range from 20-40 percent. In other words, if a person loses 10 kg in weight with these medicines, they may also lose 2-4 kg of muscle mass.
Mithal told ThePrint that the initial results of HS235 in tackling this issue look “encouraging”.
The new drug under development, Mithal said, acts through the activin pathway.
“Activin and myostatin (proteins in the muscle) act through their receptors to ultimately promote muscle breakdown,” he explained.
HS235, Mithal said, interferes with the activin pathway and may reduce muscle breakdown.
“The studies so far have shown that the molecule in itself does not cause significant weight loss, but combining it with drugs like tirzepatide may be fascinating,” said the endocrinologist.
Mithal suggested that such a drug, if proven safe and effective, could have particular significance for Indians in the future, given their typically lower muscle weight.
‘May see a drastic decline in bariatric surgery’
Weight loss drugs are getting better and better with each passing year, said Chennai diabetologist V Mohan, calling the latest discovery “exciting”.
First, he said, there were the GLP-1 receptor agonists like liraglutide, dulaglutide, and semaglutide, which proved to be “very effective” for controlling diabetes as well as promoting weight loss.
“Next came tirzepatide, a dual agonist, which offered even better results for managing diabetes and losing weight. And then there was retatrutide, which showed the most profound weight loss and far superior diabetes control,” he added.
Mohan said that the new agent HS235, when used in combination with tirzepatide, showed even better results.
“It is possible that if these drugs stand the test of time and in the long term are shown to be safe and effective, we may be seeing a drastic decline in bariatric or metabolic surgeries,” he said.
However, Mohan reinforced the need for further studies, including clinical trials in various ethnic groups, including Indians, to comprehensively evaluate the safety and effectiveness of these drugs.
Jayadevan also stressed the importance of validating, peer-reviewing, publishing, replicating, and monitoring HS235 for any undesirable outcomes, as is standard practice for all new therapies.
(Edited by Asavari Singh)
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