Results of the phase III trial of the new anti-obesity drug, Retatrutide, have shown it to be more effective than current treatments. At the highest 12 mg dose, trial participants lost 28.3% of their body weight on average in 80 weeks, according to results announced by its maker Eli Lilly on Thursday.

To compare, the company’s own therapy Tirzepatide — marketed as Mounjaro and Zepbound — demonstrated an average loss of 20.9% of body weight in trial participants at 72 weeks. The findings will allow the company to seek regulatory approval and potentially launch the next-generation drug next year. This could make Retatrutide the most powerful weight-loss drug in the obesity therapy market, where Lilly is competing with Danish pharmaceutical major Novo Nordisk.

“It was impressive to see that every dose of Retatrutide resulted in clinically meaningful weight reduction for nearly all participants, and people with severe obesity on the highest dose lost on average 30% of their body weight over two years. Importantly, treatment with Retatrutide not only resulted in robust weight reduction but also in clear improvements in assessed cardio-metabolic health measures,” said Dr Ania Jastreboff, lead investigator and professor of medicine and paediatrics (endocrinology) at Yale School of Medicine.

What did the trial results show?

The Triumph-1 trial — where 2,399 people either received one of the three doses of the medicine or placebo — demonstrated remarkable weight-loss by participants. At the 80-week mark, participants on the lowest 4 mg dose lost 19% of their body weight, those on 9 mg lost 25.9%, and those on the highest 12mg dose lost 28.3% of their body weight. Participants on placebo, in comparison, lost only 2.2% of their body weight. The weight-reductions witnessed increased further at the 104 week mark, when those on 4mg lost 27.9% of their body weight on average, those on 9 mg lost 29.5%, and those on 12mg lost 30.3%.

The waist circumference — an indicator of abdominal obesity that increases the risk of hypertension and heart attacks — reduced by 16.3 cm on average in those receiving the lowest 4 mg dose, 21.8 cm in those receiving 9 mg, and 24.1cm in those receiving the highest 12 mg dose.

Remarkably, 62.5% of the participants on the highest 12 mg dose lost more than 25% of their body weight, 45.3% lost more than 30% of their body weight, and 27.2% lost even more than 35% of their body weight. To compare, the phase III trials of tirzepatide had shown that 36.2% of the participants on the highest 15 mg dose had lost more than 25% of their body weight. The proportion of participants who lost more than 30% of their body weight was never calculated in the trial.

When it comes to the lowest 4 mg dose of Retatrutide, the trial shows that 27.8% of the participants lost more than 25% of their body weight, 15.3% lost more than 30%, and 5.9% of the participants lost more than 35% of their body weight. With Tirzepatide, only 15.3% of the participants on the lowest 5 mg dose lost more than 25% of their body weight.

What about side effects?

Analysts had previously raised concerns about the drug’s side effects after earlier trial data showed patients had experienced dysesthesia, a rare abnormal skin sensation. The latest data appeared to ease some of those worries, with fewer patients ⁠reporting dysesthesia.

How does Retatrutide differ from existing therapies like semaglutide and tirzepatide?

All three belong to the same class of medicines called incretin mimetics — drugs that mimic the action of certain gut hormones to improve secretion of insulin, inhibit secretion of glucagon that stimulates glucose production in the liver and reduce appetite by slowing down digestion. All of these actions come together to reduce blood glucose levels as well as body weight.

The difference in the weight-loss impact of these medicines, however, lies in the number of target hormones. While semaglutide only targets one incretin called GLP-1, Tirzepatide uses two GLP-1 along with GIP. When it comes to Retatrutide, it uses three targets GLP-1, GIP and glucagon.

Why is this significant?

With these drugs resulting in weight-loss comparable to bariatric procedures, they have already changed the way obesity is viewed and treated. These drugs, in large part, were behind the change in view that obesity is a chronic, relapsing disease and not a cosmetic issue.

When the World Health Organisation (WHO) released guidelines on the use of these drugs last year, WHO director-general Dr Tedros Adhanom Ghebreyesus said: “These new medicines are a powerful clinical tool, offering hope to millions. But let me be clear: medication alone will not solve the obesity crisis. Obesity is a complex disease that requires comprehensive, lifelong care. And it has many social, commercial and environmental determinants, requiring action in many sectors – not only in the clinic. This guideline is about integration. These therapies are part of a holistic strategy.”