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Journalism of Courage
Ever since the arrival of Semaglutide, the weight loss drug that is helping people battle both obesity and diabetes, one thought the peak had been reached — First single receptor, then dual receptor agonists. But now there’s a triple receptor agonist that can help you reduce your weight by 25 per cent in a year. This was revealed at the annual meeting of the American Diabetes Association (ADA) in San Diego, the world’s most important diabetes congress.
The quest for further improvements led scientists like German Matthias Tschop and his brilliant collaborators to develop a triple receptor agonist (GLP1, GIP and Glucagon). The one molecule that acts via three different receptors and pathways is Retatrutide. Clinical results were presented and showed that full doses of the drug produced weight loss by approximately 25 per cent in 48 weeks. There were no “non responders” as 100 per cent participants lost at least five per cent of their body weight in the same period. Something that seemed unimaginable even a few years ago has become a reality.
Retatrutide is an investigational molecule suitable for once-weekly injection with the potential to treat obesity and Type 2 diabetes, according to the ADA release. The results indicate that Retatrutide has an overall safety and tolerability profile similar to other nutrient-stimulated hormone-based therapies, such as GLP-1 receptor agonists approved for obesity treatment. “It is striking that on average, participants with obesity taking the highest dose of Retatrutide lost nearly a quarter of their body weight during 11 months of treatment – on average losing nearly 60 pounds,” said Ania M. Jastreboff, MD, PhD, Associate Professor of Medicine, Director of the Yale Obesity Research Center (Y-Weight) and co-Director of the Yale Center for Weight Management, Yale School of Medicine and lead author of the publication. “We need to treat obesity as we would any other chronic, treatable, disease with therapies that target underlying disease mechanisms. These results are an important next step in moving this new agent forward from phase 2 into phase 3 trials to assess its efficacy and safety as a potential new treatment option for patients with obesity,” she was quoted as saying.
Incretins are a family of hormones that are released from the gut in response to food intake and control various aspects of carbohydrate and fat metabolism. They belong to the glucagon family, examples being GLP1 and GIP. Glucagon administration enhances energy expenditure and suppresses food intake.
Most research has focussed on activation of the GLP1 receptor, leading to better glucose control and significant weight loss as seen with Semaglutide. Tirzepatide acts on both GLP1 and GIP receptors and, therefore, produces somewhat greater weight loss and glucose lowering. Retratrutide acts via glucagon receptor in addition to GIP and GLP1, producing profound effects not seen with the single or dual receptor agonists. Acting via the glucagon receptor induces satiety and enhances energy expenditure. Much of the action of all these molecules is via the brain. Also, adding glucagon activity increases liver fat clearance in a way not seen before, and potentially could turn out to be a powerful drug for fatty liver.
It will take at least two years for Retratutide to become commercially available, provided phase 3 trials do not show any unexpected adverse signal.
A study on Semaglutide was presented at the meeting too. It revealed how a much higher oral dose of the drug, 25 or 50 mg, showed weight loss similar to the injection. Another interesting, novel approach has been to combine Semaglutide with another new molecule – Cagrinitide (Cagri- Sema) – which produces greater weight loss than Semaglutide alone, typically around 15 per cent.
Scientists have been trying to develop dual agonists — drugs that act through more than one receptor — that is GLP 1 plus GIP. Tirzepatide (Mounjaro) was the first such agent to be approved in 2022 for those with diabetes plus obesity. It was the first drug to demonstrate weight reduction of >20% in those without diabetes. Approval for obesity without diabetes is expected soon. Semaglutide and Tirzepatide are the most popular anti-obesity drugs at present. Another dual receptor agonist called “Survedutide”, which targets GLP1 and glucagon (rather than GIP) receptors, has been developed. The weight loss achieved with this new agent was 18.7 per cent at 46 weeks, and it had not plateaued yet. About 40 per cent of participants lost more than 20 per cent of their body weight.
However, the 2023 story of anti-obesity drugs does not end there. One of the main challenges in this field is the limited efficacy of oral preparations, although Semaglutide has partially surmounted that barrier. Orforglipron is an orally administered partial GLP1 agonist that produced weight loss of 14.7 per cent or 15 kg at 36 weeks. Unlike Semaglutide, it is not a peptide, so is much less sensitive to breakdown in the gut and can be administered once daily without regard to timing or food intake. Yet another remarkable development is the monoclonal antibody Bimagrumab, which causes fat loss while helping increase muscle mass.
ADA is the meeting ground of diabetes and endocrine specialists from across the world. This year’s meeting was particularly exciting because of a series of presentations highlighting new discoveries in the field of obesity, which is one of the biggest medical challenges facing the modern world. The epidemic of non-communicable diseases that we are facing is largely fuelled by obesity. Diabetes, heart disease, fatty liver disease, stroke, cancer, gallbladder disease, osteoarthritis and many other conditions can be linked to obesity. It is fair to say that obesity is the mother of modern non-communicable diseases.
For endocrinologists, treating obesity is a big challenge. Our advice emphasises dietary changes like calorie restriction (through a variety of diet plans) coupled with increase in physical activity as the mainstay of weight reduction. Extreme cases are offered bariatric or weight loss surgery, which most patients are reluctant to accept. This “lifestyle” approach fails frequently and can be exceedingly frustrating both for the patient and the physician. Unfortunately drugs to treat obesity have been few and far between, and their track record has been dismal. Almost all have fallen by wayside, most often because of side effects. The cupboard of anti-obesity medication has been bare for too long.
All that started changing with the advent of newer molecules that act through the incretin pathway – the GLP1 receptor agonists. Popular anti-diabetic medications that belong to this group include Liraglutide (Victoza, Saxenda) and Dulaglutide (Trulicity). These antidiabetic molecules have the additional advantage of producing weight loss, which led to Liraglutide being approved for weight reduction even in the absence of diabetes, as a pure anti-obesity agent. The weight loss with Liraglutide, however, is typically 3 to 5 kg, which, although helpful, usually falls short of what is needed.
Moving further down the Liraglutide track is another anti diabetic agent that acts through the GLP1 pathway — Semaglutide. Approved in 2021 for obesity, weekly injections of Semaglutide are more powerful than Liraglutide, and produce weight loss of 10-15 per cent. Oral Semaglutide, which is available in India as 3, 7 and 14 mg tablets, also produces weight loss but to a lesser degree than the injectable version.
The landscape of obesity treatment is changing, and changing rapidly. These drugs, however, will remain “treatments” for “patients” at present, and should not be regarded as cosmetic agents to be used at will. They cannot be the answer to the obesity pandemic, which can only be controlled by preventing weight gain and its consequences by lifestyle measures. With all these agents, there are issues about cost and gut-related side effects like nausea and vomiting which can limit their use. Besides, there are unanswered questions: What happens when we discontinue the medication? How will muscle loss (albeit small) that accompanies fat loss impact Indians, who tend to have lower muscle mass anyway? Regardless of these concerns, treatment of obesity has changed. Irreversibly.
(Dr Mithal was at the annual meeting of the American Diabetes Association (ADA) in San Diego, US, the world’s most important diabetes congress)
