Eli Lilly and Company’s next-generation obesity treatment, retatrutide, reduced body weight by up to 22.6% in Phase 3 clinical trials, though it did not definitively confirm the anticipated benefit of preventing cardiovascular disease. While significant improvements were observed in weight, blood lipids, and inflammatory markers, reductions in major adverse cardiovascular events—such as heart attack and stroke—did not reach statistical significance.
Lilly announced on July 23 (local time) that its Phase 3 trials evaluating retatrutide in patients with obesity or overweight, designated TRIUMPH-2 and TRIUMPH-3, successfully met their primary weight-loss endpoints.
Retatrutide is an investigational once-weekly subcutaneous injection functioning as a "triple agonist." It simultaneously activates three distinct hormone receptors: glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. This mechanism regulates appetite and blood glucose via GLP-1 and GIP activity, while adding glucagon receptor activity to increase energy expenditure and metabolic function.
In the TRIUMPH-2 trial, which enrolled 1,152 patients with type 2 diabetes who also had obesity or overweight, the 12 mg dose group achieved an average 20.8% reduction in body weight over 80 weeks, compared with a 4.0% reduction in the placebo group. Glycated hemoglobin (HbA1c) levels fell by an average of 1.4 to 1.6 percentage points depending on the dose. Patients with obesity and type 2 diabetes generally tend to lose less weight than patients without diabetes.
In the TRIUMPH-3 trial involving 1,949 patients with severe obesity and pre-existing cardiovascular disease, the 12 mg group posted an average 22.6% reduction in body weight over 80 weeks, while the placebo group saw a 3.2% reduction.
Despite substantial weight reduction, the cardiovascular prevention benefit remained unconfirmed. Major adverse cardiovascular events (MACE-5)—a composite endpoint including cardiovascular death, myocardial infarction, stroke, heart failure, and coronary revascularization—occurred in 44 cases across the combined retatrutide 9 mg and 12 mg groups, compared with 52 cases in the placebo group. Although retatrutide groups showed a numerical trend toward fewer events, the difference was not statistically meaningful. Lilly explained that cardiovascular events occurred less frequently than anticipated in both cohorts, making it difficult to establish a definitive treatment effect.
Even so, key risk markers linked to cardiovascular health showed notable improvements. In the TRIUMPH-3 12 mg group, triglycerides dropped by an average of 37%, non-HDL cholesterol fell by 16.5%, and high-sensitivity C-reactive protein (hs-CRP), a key indicator of systemic inflammation, decreased by 51.2%. Common adverse events consisted of gastrointestinal symptoms such as nausea, diarrhea, and constipation. Discontinuation rates due to adverse events were 7.7% in the TRIUMPH-2 12 mg group and 13.5% in the TRIUMPH-3 12 mg group.
Building on these clinical results, Lilly is preparing global regulatory submissions for retatrutide as a treatment for obesity, knee osteoarthritis pain, and obstructive sleep apnea. The company plans to submit a biologics license application (BLA) to the U.S. Food and Drug Administration (FDA) in the first quarter of 2027.
