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.

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.

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 (HbA 1c ) between 7·0% and 9·5% (53-80 mmol/mol), and BMI of at least 23 kg/m 2 .

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 HbA 1c 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.

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 48·8 years (SD 12·1), mean HbA 1c concentration was 7·9% (SD 1·1), mean duration of diabetes was 2·5 years (SD 4·4), and mean BMI was 35·8 kg/m 2 (SD 7·0).

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 HbA 1c 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.

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.

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