Phase 3 TRIUMPH-2: once-weekly retatrutide cut bodyweight up to 18.8% over 80 weeks in adults with obesity and type 2 diabetes

The Lancet published the phase 3 TRIUMPH-2 trial of retatrutide, an Eli Lilly triple agonist of GIP, GLP-1, and glucagon receptors, in adults with obesity and type 2 diabetes. The double-blind, parallel-group, placebo-controlled trial ran at 92 medical and research centers across eight countries and enrolled adults with a BMI of 27 kg/m2 or higher, type 2 diabetes with glycated hemoglobin of 6.5% to 10.5%, stable diabetes treatment for at least 90 days, and at least one prior unsuccessful dietary weight-loss effort.

Between July 11, 2023 and November 1, 2024, investigators screened 2,047 people and randomly assigned 1,152 (mean age 55.1 years, 48% female, mean baseline BMI 38.2 kg/m2, mean HbA1c 7.71%) to once-weekly self-administered subcutaneous retatrutide 4 mg (n=292), 9 mg (n=284), or 12 mg (n=287), or placebo (n=289). The primary endpoint was the percentage change in bodyweight from baseline to week 80 for the 9 mg and 12 mg doses versus placebo; 84% of participants completed the study drug.

At week 80, average bodyweight change was -11.9% with 4 mg, -16.8% with 9 mg, and -18.8% with 12 mg, versus -5.1% with placebo. Estimated differences against placebo were -6.9, -11.8, and -13.8 percentage points respectively (p<0.0001 for all). The authors report the treatment was also associated with improvements in glycemic control.

The most frequent adverse events were gastrointestinal and dose-related: diarrhea in 27%, 34%, and 34% of the retatrutide groups versus 13% on placebo, and nausea in 14%, 21%, and 28% versus 8%. Hypotension (up to 6% vs <1%) and dysesthesia (up to 7% vs 1%) were also more common on retatrutide. Permanent discontinuation for adverse events or death was more frequent at 9 mg (12%) and 12 mg (8%) than at 4 mg (4%) or placebo (5%). Seven participants died during the trial (two on 4 mg, three on 9 mg, one on 12 mg, one on placebo); investigators deemed all deaths unrelated to the study drug.

The authors conclude that retatrutide produced substantial weight reduction with a safety profile generally consistent with other GLP-1-based medicines, and that it might be effective for treating obesity in people with type 2 diabetes. Eli Lilly and Company funded the trial. Retatrutide remains investigational; it is not FDA-approved for any use, and trial results do not establish approval, availability, or any dosing recommendation. This brief summarizes a peer-reviewed trial publication and is not medical advice or a source for obtaining any drug.