Next-generation drug from Eli Lilly boosts weight loss to 24%, highest yet seen in trials

By Meg Tirrell, CNN

(CNN) — An experimental drug from Eli Lilly helped patients with obesity lose an average of 24% of their body weight over 48 weeks on the highest dose in a mid-stage study, the most weight loss seen yet in a new class of drugs that’s revolutionizing the field.

The medicine, called retatrutide, had similar side effects – mainly gastrointestinal in nature – as approved drugs in the class, including Ozempic, Wegovy and Mounjaro, researchers reported in a study, funded by Lilly, published Monday in the New England Journal of Medicine. The results were also presented at the American Diabetes Association conference in San Diego.

These drugs mimic gut hormones to curb appetite and slow stomach emptying, and are administered as once-weekly injections, although pill versions are in development as well. Novo Nordisk’s Ozempic, approved for type 2 diabetes, and Wegovy, cleared for weight loss, mimic just one hormone, called GLP-1, and have shown up to 15% weight loss in trials. Eli Lilly’s Mounjaro, cleared for type 2 diabetes and awaiting FDA approval for weight loss, targets both GLP-1 and a hormone called GIP, and has produced weight loss of 21 to 23%.

Retatrutide adds yet a third target, glucagon, giving it the moniker “triple G.” In this mid-stage trial, Lilly enrolled about 340 adults with obesity, who had a body mass index of at least 30. The trial also included about 4% of patients with a BMI of between 27 and 30, in the overweight category, with at least one weight-related health condition.

In addition to the 24% average weight loss on the highest dose in the trial – about 58 pounds over 11 months – a quarter of patients on that dose experienced weight loss of at least 30%.

“This is an unusually high magnitude of efficacy” compared with other weight-loss medicines, researchers led by Dr. Ania Jastreboff at the Yale School of Medicine wrote in the NEJM paper. They noted it’s a degree of weight loss that’s been observed with bariatric-metabolic surgery.

Patients on the medicine had side effects like nausea, diarrhea, vomiting and constipation, which got worse at higher doses, the study showed. The researchers described them as generally “mild to moderate” in severity, and said they could be improved if patients started on lower doses before moving to higher ones.

About 7% of patients on the drug experienced skin tingling, the researchers reported, compared with 1% on placebo. One patient had elevated liver enzymes, and one had a case of acute pancreatitis, or inflammation of the pancreas. Increases in heart rate were seen up until 24 weeks in patients on the medicine, and then decreased, the study showed, although one patient had a severe adverse heart event known as prolonged QT syndrome.

Patients taking the medicine experienced benefits beyond weight loss, the researchers reported, including lowered blood pressure – some patients were able to stop taking a blood pressure medication. Almost three quarters of patients who started the trial with prediabetes had reached normal blood sugar levels by 48 weeks.

The average weight loss appeared not to be slowing down by the 48-week mark, the researchers said, suggesting a longer study could show even more. Lilly is currently recruiting patients for a Phase 3 trial.

The medicine was just one of many with updates at the diabetes conference that started Friday. Other results showed that pill forms of drugs targeting GLP-1 produce similar weight loss – about 15% – as Wegovy. Novo Nordisk presented results from a Phase 3 study, while Lilly shared Phase 2 data. Pfizer also said Monday morning it had selected a GLP-1 pill to take forward in trials, though it’s currently a twice-daily pill, compared with once-daily for Lilly’s and Novo Nordisk’s.

Many of these drugs are also being tested for diabetes and other conditions. Retatrutide showed in additional results presented at the diabetes conference that it helped lower blood sugar as well as or better than an approved treatment, and led to more weight loss in these patients. An additional set of results suggest the drug may have promise for treating nonalcoholic fatty liver disease, a condition in which excess fat builds up in the liver and can lead to liver complications. An estimated 24% of American adults have the condition.

“This study raises the possibility that in the early stages of liver disease, it is possible to ‘de-fat’ the liver, which could in turn help to reduce the long-term cardiac, metabolic, renal, and liver-related harm from obesity,” Dr. Arun Sanyal, a professor of Medicine, Physiology and Molecular Pathology at Virginia Commonwealth University, said in a news release from the American Diabetes Association. “We are encouraged by these results and how they can potentially help tackle a disease that is currently without any approved therapies.”

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