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

In a phase 3 trial, retatrutide significantly improved glycaemic control and reduced bodyweight in adults with type 2 diabetes inadequately controlled by diet and exercise. All doses (4 mg, 9 mg, 12 mg) produced greater reductions in HbA1c than placebo, and weight loss reached up to 15.3%. Adverse events were mostly mild-to-moderate gastrointestinal effects that subsided over time.

Late-phase clinical trial — double-blind, randomised, phase 3 trial. Population: adults with type 2 diabetes inadequately controlled by diet and exercise alone. Sample size: 537 adults. Follow-up: 40 weeks. Interventions: retatrutide 4 mg; retatrutide 9 mg; retatrutide 12 mg. Cited by 1 other paper.

The mean change in HbA1c from baseline was -1.69% with retatrutide 4 mg, -1.86% with 9 mg, and -1.94% with 12 mg, versus -0.81% with placebo, giving treatment differences of -0.88%, -1.04%, and -1.12% (all p<0.0001). Mean bodyweight decreased by 11.5%, 13.9%, and 15.3% with the three doses, compared with 2.6% for placebo. Gastrointestinal adverse events were the most common, generally mild to moderate and subsiding over time. Discontinuations due to adverse events were 2-5% with retatrutide but 0% with placebo, with no severe hypoglycaemia; two deaths occurred in the 4 mg group and were judged unrelated.

This phase 3 trial provides pivotal evidence that retatrutide monotherapy improves glycaemic control and reduces bodyweight in type 2 diabetes, supporting its development as a treatment. For researchers working on retatrutide, this paper establishes short-term efficacy and a safety profile consistent with GLP-1 receptor agonists. It does not establish long-term outcomes, effects versus other active drugs, or use in people with more advanced diabetes.

Key findings

• Retatrutide 4 mg, 9 mg, and 12 mg reduced HbA1c by 1.69%, 1.86%, and 1.94% respectively, compared with 0.81% for placebo (all p<0.0001).
• Bodyweight fell by 11.5%, 13.9%, and 15.3% with retatrutide 4, 9, and 12 mg versus 2.6% with placebo.
• Estimated HbA1c treatment differences versus placebo ranged from -0.88% to -1.12%.
• Discontinuations due to adverse events were 2-5% with retatrutide and 0% with placebo.
• No severe hypoglycaemia was reported.
• Two deaths occurred in the retatrutide 4 mg group and were unrelated to study drug.

Limitations

• Follow-up limited to 40 weeks; longer-term efficacy and safety not assessed in this trial.
• Placebo-controlled design, so comparative effectiveness against other glucose-lowering agents is not established.
• Results apply to people with type 2 diabetes on diet and exercise alone, not to those on background therapy.

The record

• Journal: Lancet (London, England) 407(10546): 2402-2413
• Published: 2026-06-06
• PMID: 42250575 — DOI: 10.1016/s0140-6736(26)00967-0
• MeSH terms: Humans, Diabetes Mellitus, Type 2, Blood Glucose, Fatty Acids, Peptides, Hypoglycemic Agents, Treatment Outcome, Exercise, Double-Blind Method, Adult, Aged, Middle Aged, Female, Male, Glycemic Control, Glycated Hemoglobin, Glucagon-Like Peptide-1 Receptor Agonists
• Funding: Eli Lilly and Company
• Author countries: Canada, India, USA

Peptide profiles: Retatrutide.

All indexed evidence: Retatrutide trials & papers.

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