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. — VialBase Research
TRANSCEND-T2D-1 is the first phase 3 trial of retatrutide monotherapy, showing dose-dependent HbA1c reductions up to -1.94% and bodyweight loss up to -15.3% in type 2 diabetes inadequately controlled by diet and exercise.
- At week 40, mean HbA1c fell -1.69% (4 mg), -1.86% (9 mg), and -1.94% (12 mg) with retatrutide vs -0.81% with placebo; treatment differences vs placebo were -0.88%, -1.04%, and -1.12% (all p<0.0001)
- Mean bodyweight change was -11.5% (4 mg), -13.9% (9 mg), and -15.3% (12 mg) with retatrutide vs -2.6% with placebo at week 40
- 537 adults with type 2 diabetes inadequately controlled by diet and exercise were randomised 1:1:1:1; baseline mean HbA1c 7.9%, mean BMI 35.8 kg/m2, mean diabetes duration 2.5 years
- Most frequent adverse events were mild-to-moderate gastrointestinal events that subsided over time; discontinuations due to adverse events were 2-5% with retatrutide vs 0% with placebo, and no severe hypoglycaemia was reported
- 490 (91%) participants completed treatment on study drug and 504 (94%) completed the study; two deaths occurred, both in the 4 mg group and unrelated to study drug
Summary
TRANSCEND-T2D-1 was a 40-week, phase 3, randomised, double-blind, placebo-controlled trial at 48 sites in the USA, Mexico, and India testing retatrutide — a GIP, GLP-1, and glucagon triple receptor agonist — as monotherapy in adults with type 2 diabetes inadequately controlled by diet and exercise alone. 537 participants were randomly assigned 1:1:1:1 to once-weekly subcutaneous retatrutide (4 mg, 9 mg, or 12 mg) or placebo. Retatrutide produced significant, dose-dependent reductions in both HbA1c (the primary endpoint) and bodyweight (a key secondary endpoint) versus placebo.
Key Findings
- Change in HbA1c from baseline to week 40: -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 vs placebo: -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 p<0.0001)
- Percentage change in bodyweight at week 40: -11.5% (4 mg), -13.9% (9 mg), and -15.3% (12 mg) versus -2.6% with placebo
- Baseline cohort: 296 (55%) female and 241 (45%) male; mean age 48.8 years, mean HbA1c 7.9%, mean diabetes duration 2.5 years, mean BMI 35.8 kg/m2
- Safety: mostly mild-to-moderate gastrointestinal events that subsided over time; adverse-event discontinuations 2-5% (retatrutide) vs 0% (placebo); no severe hypoglycaemia; two deaths, both in the 4 mg group, unrelated to study drug
Relevance to Retatrutide
This is the first phase 3 evidence for retatrutide as a standalone therapy in type 2 diabetes, moving it beyond the earlier phase 2 obesity and diabetes programmes. The dose-dependent HbA1c reductions (up to -1.12% versus placebo) combined with substantial bodyweight loss (up to -15.3%) in a population with early, diet-and-exercise-managed diabetes suggest the triple GIP/GLP-1/glucagon mechanism can deliver glycaemic and weight benefits together. The gastrointestinal-predominant safety profile is consistent with other GLP-1-based agents such as Semaglutide and Tirzepatide, and the results provide a benchmark for positioning retatrutide against approved incretin therapies as its phase 3 programme matures.
Citation
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 (London, England). 2026. doi:10.1016/S0140-6736(26)00967-0.
See Also
- Parent compound: Retatrutide
- Semaglutide
- Tirzepatide
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