Retatrutide Lowers A1C and Weight in Phase 3 Type 2 Diabetes Trial

Key Takeaways

• Retatrutide was associated with larger HbA1c reductions than placebo at all evaluated doses over 40 weeks.
• Body weight decreased more with retatrutide than with placebo during the same 40-week period.
• Gastrointestinal events were the most common adverse events and were usually mild to moderate.

In the TRANSCEND-T2D-1 phase 3 trial, adults with type 2 diabetes inadequately controlled by diet and exercise had placebo-adjusted HbA1c reductions of up to 1.12 percentage points with once-weekly retatrutide. Body weight also declined more with retatrutide than with placebo across the tested dose range during the 40-week placebo-controlled phase.

In this 40-week, randomized, double-blind, placebo-controlled phase 3 trial at 48 sites in the USA, Mexico, and India, eligible participants were adults aged 18 years or older with type 2 diabetes inadequately controlled by diet and exercise alone, HbA1c 7.0% to 9.5%, and BMI at least 23 kg/m2. Between April 10, 2024, and April 21, 2025, 930 people were screened and 537 were randomly assigned 1:1:1:1 to retatrutide 4 mg, 9 mg, 12 mg, or placebo. The cohort included 296 women and 241 men, with mean age 48.8 years, mean HbA1c 7.9%, diabetes duration 2.5 years, and mean BMI 35.8 kg/m2. The primary endpoint was change in HbA1c from baseline to week 40, and the key secondary endpoint was percentage change in body weight over the same period.

At week 40, mean HbA1c changes under the treatment-regimen estimand were -1.69% with retatrutide 4 mg, -1.86% with 9 mg, -1.94% with 12 mg, and -0.81% with placebo. Estimated HbA1c treatment differences versus placebo were -0.88 percentage points, -1.04 points, and -1.12 points, with 95% CIs of -1.18 to -0.59, -1.32 to -0.76, and -1.39 to -0.85. All reported HbA1c treatment differences versus placebo met p<0.0001. Mean percentage body-weight changes were -11.5% with retatrutide 4 mg, -13.9% with 9 mg, -15.3% with 12 mg, and -2.6% with placebo. Reductions increased across the retatrutide dose range, and both glycaemic and weight changes were larger than those seen with placebo at week 40.

The most frequent adverse events with retatrutide were generally mild to moderate gastrointestinal events that subsided over time. Discontinuations due to adverse events ranged from 2% to 5% with retatrutide and were 0% with placebo. No severe hypoglycaemia was reported, and two deaths occurred in the 4 mg group, with both considered unrelated to study drug.