Eli Lilly has announced compelling top‑line results from the first Phase III clinical trial of its triple-hormone receptor agonist retatrutide in patients with diabetes.
Retatrutide is an investigational, once‑weekly therapy that simultaneously targets the GLP-1, glucose‑dependent insulinotropic polypeptide (GIP) and glucagon receptors.
Results from the TRANSCEND‑T2D‑1 study showed that retatrutide delivered significant reductions in both blood sugar (A1C) and body weight in adults with type 2 diabetes.
In the trial, participants treated with retatrutide for 40 weeks achieved A1C reductions ranging from approximately 1.7% to 2.0% compared with baseline, a level of glycemic control that may help many patients approach or meet treatment targets.
At the same time, those on the investigational therapy experienced substantial weight loss, with average reductions of up to about 15% to 17% of body weight, roughly equivalent to 35 pounds to 36 pounds over the study period, and no obvious plateau in weight loss by study end.
The weight loss results are a bit lower than the ones Lilly shared from the trial in December. That data showed an estimated weight loss of 28.7% in the Triumph-4 Phase III trial. There was also a 75.8% reduction in pain scores in patients with both obesity and knee osteoarthritis in the trial.
Nevertheless, there are high hopes and a lot of bets being placed on retatrutide, as it’s a step up from traditional GLP‑1 receptor agonists with its triple targeting action intended to enhance metabolic effects across glycemic and weight outcomes.
“For many people with type 2 diabetes, it is a struggle to achieve both A1C control and weight loss, since obesity has historically been harder to treat for those with type 2 diabetes,” said Kenneth Custer, PhD, Executive Vice President and President, Lilly Cardiometabolic Health.
“With triple agonist retatrutide, we set out to make a molecule that could help patients achieve substantial A1C reduction and weight loss. These results support the remarkable potential of this novel molecule for people living with type 2 diabetes, with up to 2% A1C improvement and nearly 17% weight loss in 40 weeks of treatment.”
The Phase III Transcend‑T2D‑1 trial program includes three global registrational trials. Lilly said the program, launched in 2024, has enrolled more than 2,050 participants. The latest read-out from one of the trials included 537 individuals with type 2 diabetes.
In addition to assessing A1C and weight loss, the study evaluated changes in triglycerides, fasting serum glucose, non-HDL cholesterol and systolic blood pressure. It also examined the proportion of patients achieving specific A1C reduction and weight loss milestones.
Lilly said it will share detailed results from the trial at the American Diabetes Association Scientific Sessions in June, which will also be published in a peer-reviewed journal.
Additional Phase III readouts are expected later this year, with investors in particular keeping a close watch on the next-gen GLP-1 hopeful.
Retatrutide initially made headlines in December for its impressive obesity trial results, but that strong efficacy was tempered by a higher-than-expected discontinuation rate of 18.2%.
The latest Phase III diabetes data paints a more favorable picture. At the 12‑mg dose, discontinuation due to adverse events was just 5.1%, with the most common side effects being nausea (26.5%), diarrhea (22.8%) and vomiting (17.6%), which are all typical for this class of medications.
Notably, while 21% of patients in the 12‑mg obesity trial experienced dysesthesia (an unpleasant skin sensation), this rate dropped to 4.4% in the current diabetes study.
Lilly is hoping for a regulatory submission in the obesity indication by the end of this year, followed by a diabetes filing in 2027.
GLP-1 rival Novo Nordisk is also busy with its next-gen GLP-1 CagriSema, a combo featuring semaglutide (the active ingredient in its blockbusters Ozempic and Wegovy) and experimental amylin receptor agonist cagrilintide. In a Phase III trial, the drug has shown an average weight loss of 14.2% after 68 weeks and lowered A1C levels by an average of 1.9%, highlighting its potential as a dual-action approach for diabetes and weight management.
But in the Phase III REDEFINE 4 head‑to‑head trial, CagriSema failed to match the weight‑loss performance of Zepbound (tirzepatide). After 84 weeks, patients taking CagriSema achieved about 23% body weight loss compared with 25.5% for Zepbound.
Meanwhile, China-based Sciwind Biosciences and commercial partner Pfizer recently received approval for their new GLP‑1 therapy, ecnoglutide, in China, branded as Xianyida (diabetes) and Xianweiying (obesity). Phase III data for ecnoglutide show A1C reductions of 2.2% to 2.6% at the highest 1.2‑mg dose, compared with 0.6% to 1.09% for placebo, along with an average weight loss of about 7 pounds or 15.1% of total body weight.
Lilly’s diabetes GLP-1 Mounjaro currently carries an FDA label showing an average A1C reduction of 1.8% over 40 weeks, with patients losing 14 pounds to 17 pounds on average.
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