Diabetes Dialogue: Retatrutide Tops Semaglutide on A1C, Weight in T2D

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Triple agonism is reshaping expectations for weight loss in type 2 diabetes, a population historically less responsive to incretin-based therapy. New head-to-head phase 3 data show retatrutide more than doubled the weight reduction achieved with the highest approved dose of semaglutide (Ozempic).

On a recent episode of Diabetes Dialogue, hosts Diana Isaacs, PharmD, and Natalie Bellini, DNP, reviewed topline results from the TRANSCEND-T2D-2 trial. Retatrutide is an investigational once-weekly agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors.

The open-label trial randomized 1298 adults with type 2 diabetes to retatrutide 9 mg, retatrutide 12 mg, or semaglutide 2 mg. From a mean baseline A1C of 8.3%, both retatrutide doses lowered A1C by 2.2 percentage points at 80 weeks vs 1.8 points with semaglutide. From a mean baseline weight of 102.4 kg, weight fell 19.5% with retatrutide 9 mg and 20.9% with 12 mg vs 9.4% with semaglutide.

With both agents producing substantial glycemic reductions, individual weight goals may increasingly guide agent selection. Patients needing A1C lowering without large weight loss, such as frail older adults at risk for falls and fractures, may be better suited to semaglutide.

Gastrointestinal events were common across all arms, with more diarrhea on retatrutide, slightly more constipation on semaglutide, and comparable rates of nausea. Discontinuation due to adverse events, however, reached 4.8% with retatrutide 9 mg and 7.9% with 12 mg vs 2.7% with semaglutide. Slower titration in practice, and use of the 9 mg dose, may help preserve tolerability without sacrificing much efficacy.

Cardiovascular outcomes remain the largest open question. Semaglutide and tirzepatide (Mounjaro) both carry cardiovascular indications, while the cardiovascular effects of adding glucagon receptor agonism to GIP and GLP-1 activity are unknown. For patients with type 2 diabetes and established cardiovascular disease, agents with proven outcome benefit remain the preferred choice.

Retatrutide is not FDA-approved, and compounded products of uncertain composition should be avoided. Full TRANSCEND-T2D-2 results are expected at a future medical meeting, and a placebo-controlled trial in roughly 320 adults inadequately managed with basal insulin should report in 2027.

Collectively, the findings position retatrutide as a potential option for patients with type 2 diabetes who need substantial weight reduction. Tolerability at higher doses and forthcoming cardiovascular data will likely determine its place alongside established incretin therapies.

Editors’ Note: Isaacs reports disclosures with Dexcom, Abbott, Lilly, Novo Nordisk, Medtronic, Insulet, and others. Bellini reports disclosures with Abbott Diabetes Care, MannKind, Povention Bio, and others.

References

1. Eli Lilly. Lilly's retatrutide delivered greater A1C reduction and more than double the weight loss of Ozempic's highest approved dose in head-to-head trial. October 28, 2026. Accessed November 12, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-retatrutide-delivered-greater-a1c-reduction-and-more