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.

BACKGROUND: Retatrutide is a GIP, GLP-1, and glucagon triple hormone receptor agonist, under clinical development for type 2 diabetes, obesity, and related complications. We aimed to assess the efficacy and safety of retatrutide as a monotherapy in people with type 2 diabetes that is inadequately controlled by diet and exercise alone.

METHODS: In this 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India, we recruited adults (aged ≥18 years) with type 2 diabetes that is inadequately controlled by diet and exercise alone, glycated haemoglobin (HbA1c) between 7·0% and 9·5% (53-80 mmol/mol), and BMI of at least 23 kg/m2. Participants were randomly assigned (1:1:1:1) to receive retatrutide (4 mg, 9 mg, or 12 mg) or placebo by once-weekly subcutaneous injection. The primary endpoint was the change in HbA1c concentration from baseline to week 40. A key secondary endpoint was the percentage change in bodyweight from baseline to week 40. This trial is registered with ClinicalTrials.gov, NCT06354660, and is completed.

FINDINGS: Between April 10, 2024, and April 21, 2025, 930 participants were screened and 537 (296 [55%] female and 241 [45%] male) were randomly assigned: 134 to retatrutide 4 mg, 133 to retatrutide 9 mg, 136 to retatrutide 12 mg, and 134 to placebo. Baseline mean age was 48&#xb7;8 years (SD 12&#xb7;1), mean HbA1c concentration was 7&#xb7;9% (SD 1&#xb7;1), mean duration of diabetes was 2&#xb7;5 years (SD 4&#xb7;4), and mean BMI was 35&#xb7;8 kg/m2 (SD 7&#xb7;0). 490 (91%) participants completed the treatment period on study drug and 504 (94%) completed the study. For the treatment regimen estimand, the mean change from baseline in HbA1c concentration was -1&#xb7;69% (SE 0&#xb7;11) with retatrutide 4 mg, -1&#xb7;86% (0&#xb7;10) with 9 mg, and -1&#xb7;94% (0&#xb7;08) with 12 mg, versus -0&#xb7;81% (0&#xb7;12) with placebo, resulting in estimated treatment differences versus placebo of -0&#xb7;88% (95% CI -1&#xb7;18 to -0&#xb7;59) with retatrutide 4 mg, -1&#xb7;04% (-1&#xb7;32 to -0&#xb7;76) with 9 mg, and -1&#xb7;12% (-1&#xb7;39 to -0&#xb7;85) with 12 mg (all p<0&#xb7;0001). The mean percentage change from baseline in bodyweight was -11&#xb7;5% (SE 0&#xb7;7) with retatrutide 4 mg, -13&#xb7;9% (0&#xb7;8) with 9 mg, and -15&#xb7;3% (0&#xb7;8) with 12 mg, versus -2&#xb7;6% (0&#xb7;5) with placebo. The most frequent adverse events with retatrutide were generally mild to moderate gastrointestinal events, which subsided over time. Study intervention discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo. No severe hypoglycaemia was reported. Two deaths occurred during the study, both in the retatrutide 4 mg group and unrelated to the study drug.

INTERPRETATION: Retatrutide showed significant improvements in glycaemic control and bodyweight reduction as a monotherapy in adults with type 2 diabetes that is inadequately controlled with diet and exercise alone, with an adverse event profile consistent with molecules with GLP-1 agonist activity, supporting its potential as an effective treatment for type 2 diabetes.

FUNDING: Eli Lilly and Company.