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.
Level 2 - randomized trial
Individual randomized controlled trial
PubMed 42250575 · doi:10.1016/S0140-6736(26)00967-0
What was done
In a 40-week, multicentre, randomized, double-blind, placebo-controlled phase 3 trial at 48 sites in the USA, Mexico, and India, adults (aged ≥18 years) with type 2 diabetes inadequately controlled by diet and exercise alone (HbA1c 7.0–9.5% [53–80 mmol/mol], BMI ≥23 kg/m²) were randomized (1:1:1:1) to receive once-weekly subcutaneous retatrutide (4 mg, 9 mg, or 12 mg) or placebo. 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.
What was found
537 participants were randomly assigned (134 to retatrutide 4 mg, 133 to 9 mg, 136 to 12 mg, and 134 to placebo; mean baseline age 48.8 years, HbA1c 7.9%, BMI 35.8 kg/m²). At week 40, the 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, yielding estimated treatment differences versus placebo of -0.88% (95% CI -1.18 to -0.59), -1.04% (-1.32 to -0.76), and -1.12% (-1.39 to -0.85), respectively (all p<0.0001). Mean bodyweight change 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. Adverse events were predominantly mild-to-moderate gastrointestinal symptoms that subsided over time. Discontinuations due to adverse events occurred in 2–5% with retatrutide and 0% with placebo, with no severe hypoglycaemia reported.
Why it matters
Retatrutide monotherapy demonstrates substantial, dose-dependent reductions in HbA1c and bodyweight in people with early type 2 diabetes inadequately controlled by lifestyle changes alone.
Limits
The trial duration was limited to 40 weeks and did not measure long-term cardiovascular or microvascular outcomes. The study population was restricted to patients not on background glucose-lowering drugs with a relatively short mean diabetes duration (2.5 years), limiting generalizability to advanced disease. An active comparator was not included.
Cited by
- supports Retatrutide is a multi-agonist targeting GLP-1, GIP, and glucagon receptor pathways.
- contradicts Retatrutide has fewer gastrointestinal side effects compared to earlier GLP-1 agonists.