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.

All three doses of retatrutide produced statistically significant reductions in HbA1c compared to placebo at 40 weeks.

• Mean change from baseline in HbA1c was -1.69% (SE 0.11) with 4 mg, -1.86% (0.10) with 9 mg, and -1.94% (0.08) with 12 mg, versus -0.81% (0.12) with placebo.
• Estimated treatment differences versus placebo were -0.88% (95% CI -1.18 to -0.59) with 4 mg, -1.04% (-1.32 to -0.76) with 9 mg, and -1.12% (-1.39 to -0.85) with 12 mg.
• All treatment differences versus placebo were statistically significant (all p<0.0001).
• Baseline mean HbA1c was 7.9% (SD 1.1) across participants.
• The trial used a treatment regimen estimand for the primary endpoint.

Retatrutide produced substantial bodyweight reductions across all doses compared to placebo at 40 weeks.

• Mean percentage change from baseline in bodyweight was -11.5% (SE 0.7) with 4 mg, -13.9% (0.8) with 9 mg, and -15.3% (0.8) with 12 mg, versus -2.6% (0.5) with placebo.
• Bodyweight reduction was a key secondary endpoint.
• Baseline mean BMI was 35.8 kg/m2 (SD 7.0), indicating a predominantly obese population.
• Weight loss appeared dose-dependent, with the 12 mg dose producing the greatest reduction.

The most frequent adverse events with retatrutide were gastrointestinal events that were generally mild to moderate and subsided over time.

• The adverse event profile was described as consistent with molecules with GLP-1 agonist activity.
• Study intervention discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo.
• No severe hypoglycaemia was reported in any treatment group.
• Two deaths occurred during the study, both in the retatrutide 4 mg group and assessed as unrelated to the study drug.

The trial enrolled 537 adults with type 2 diabetes inadequately controlled by diet and exercise, with participants randomly assigned equally to four treatment arms.

• 930 participants were screened between April 10, 2024, and April 21, 2025; 537 were randomly assigned 1:1:1:1.
• 134 were assigned to retatrutide 4 mg, 133 to 9 mg, 136 to 12 mg, and 134 to placebo.
• 296 (55%) participants were female and 241 (45%) were male.
• Baseline mean age was 48.8 years (SD 12.1) and mean duration of diabetes was 2.5 years (SD 4.4).
• Eligibility required HbA1c between 7.0% and 9.5% and BMI of at least 23 kg/m2.

Trial completion rates were high, with 490 (91%) participants completing the treatment period on study drug and 504 (94%) completing the study.

• The trial was a 40-week, double-blind, placebo-controlled phase 3 study conducted at 48 sites in the USA, Mexico, and India.
• Retatrutide was administered as once-weekly subcutaneous injections.
• The study is registered with ClinicalTrials.gov as NCT06354660 and is completed.