Retatrutide Improves Glycemic Control, Reduces Bodyweight in Phase 3

Retatrutide is a triple-hormone receptor agonist acting on glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon. According to results from the phase 3 TRANSCEND-T2D-1 trial published in The Lancet, it was associated with improved glycemic control and bodyweight reduction in adults with type 2 diabetes inadequately controlled with diet and exercise alone. Retatrutide is under clinical development (Eli Lilly and Company) for type 2 diabetes, obesity, and related complications.

The 40-week, randomized, double-blind, placebo-controlled trial evaluated retatrutide as monotherapy in adults with type 2 diabetes. The study was conducted at 48 sites in the United States, Mexico, and India. Eligible participants were aged 18 years or older, had type 2 diabetes inadequately controlled by diet and exercise alone, had glycated hemoglobin (HbA1c) of 7.0% to 9.5%, and had a body mass index of at least 23kg/m2.

Investigators screened 930 participants and randomly assigned 537 participants in a 1:1:1:1 ratio to once-weekly subcutaneous retatrutide 4mg, 9mg, or 12mg, or placebo. The primary endpoint was change in HbA1c from baseline to week 40, and a key secondary endpoint was percentage change in bodyweight from baseline to week 40.

For the treatment regimen estimand, mean HbA1c decreased by 1.69% with retatrutide 4mg, 1.86% with 9mg, and 1.94% with 12mg, compared with 0.81% with placebo. Estimated treatment differences versus placebo were −0.88%, −1.04%, and −1.12%, respectively, with all comparisons reaching p<0.0001. Mean bodyweight decreased by 11.5%, 13.9%, and 15.3% with retatrutide 4mg, 9mg, and 12mg, respectively, compared with 2.6% with placebo.

The most frequent adverse events with retatrutide were generally mild to moderate gastrointestinal events that subsided over time. Discontinuations due to adverse events occurred in 2% to 5% of retatrutide-treated participants and 0% of placebo-treated participants. No severe hypoglycemia was reported. The authors concluded that the findings support retatrutide’s potential as an effective treatment for type 2 diabetes.

Sources: Bajaj HS, Welch M, Shah P, et al. Efficacy and safety of retatrutide, a GIP, GLP-1, and glucagon receptor agonist, in people with type 2 diabetes and inadequate glycaemic control with diet and exercise (TRANSCEND-T2D-1): a double-blind, randomised, phase 3 trial. Lancet. 2026;407(10546):2402-2413. doi:10.1016/S0140-6736(26)00967-0