Retatrutide tops Ozempic on A1C and weight in Phase 3

Eli Lilly said on October 28, 2026 that its investigational triple agonist retatrutide beat injectable Ozempic on blood sugar and more than doubled average weight loss in TRANSCEND-T2D-2, a head-to-head Phase 3 trial in adults with type 2 diabetes. The figures are company-reported topline results under an efficacy estimand. Full data are not yet in a peer-reviewed journal. Retatrutide is not approved for any use.

Kenneth Custer, Ph.D., president of Lilly Cardiometabolic Health, called TRANSCEND-T2D-2 “the first Phase 3 trial comparing retatrutide with another incretin medicine” in the company’s release. Lilly also described the readout as the sixth Phase 3 trial in which retatrutide “has delivered powerful efficacy.”

What the trial tested

TRANSCEND-T2D-2 is registered on ClinicalTrials.gov as NCT06260722. Lilly’s release and the registry both describe a Phase 3, randomized, open-label comparison of once-weekly retatrutide with once-weekly Ozempic in adults with type 2 diabetes inadequately controlled on metformin, with or without an SGLT2 inhibitor. The registry lists allocation as randomized, parallel assignment, and masking as none, matching the open-label design.

Lilly says 1,298 adults were randomized 2:2:1 to a lower retatrutide target dose (the release’s "9 mg"), a higher retatrutide target dose ("12 mg"), or Ozempic at its highest approved dose for type 2 diabetes (the release’s "2 mg"). Average baseline A1C was 8.3%, average weight 102.4 kg (225.8 lbs), and average BMI 36.8. The primary analysis was at 80 weeks. Lilly says the primary objective was to show the higher retatrutide dose was noninferior to Ozempic on A1C change at week 80. ClinicalTrials.gov still lists enrollment as an estimated 1,250 and status as active, not recruiting; the 1,298 figure is from Lilly’s Oct 28 release.

Blood sugar and weight

Under the efficacy estimand at 80 weeks, Lilly reported:

• A1C: −2.2% on both retatrutide arms versus −1.8% on Ozempic, from the 8.3% baseline.
• Weight: −19.5% (−20.1 kg; −44.3 lbs) on the lower retatrutide arm and −20.9% (−21.5 kg; −47.4 lbs) on the higher arm, versus −9.4% (−9.5 kg; −20.9 lbs) on Ozempic.

Lilly said retatrutide also improved non-HDL cholesterol, triglycerides and systolic blood pressure more than Ozempic. Exact deltas for those lab and blood-pressure measures were not in the topline release.

How to read the p-values

Lilly’s footnotes matter. Weight-loss superiority for both retatrutide arms, and A1C superiority for the higher retatrutide arm, were reported as p under 0.001 with family-wise type 1 error controlled. For the lower retatrutide arm on A1C, the release marks p under 0.001 as nominal; the key secondary under error control for that arm was noninferiority of A1C versus Ozempic, which Lilly said was met. An endnote says all comparisons versus Ozempic were family-wise controlled except superiority of the lower retatrutide dose on A1C and on systolic blood pressure, which were prespecified secondary endpoints with only nominal significance.

In short: do not treat the lower-dose A1C gap as a controlled superiority claim. The higher-dose A1C superiority and both weight comparisons are the controlled ones Lilly highlighted.

Lilly said the trial met its primary endpoint and all key secondary endpoints.

Safety

The most common adverse events with retatrutide (lower dose, higher dose versus Ozempic) were diarrhea (28.3%, 32.7% vs 26.4%), nausea (21.2%, 23.8% vs 21.3%), constipation (14.2%, 13.1% vs 19.8%), vomiting (10.2%, 15.0% vs 13.2%) and dyspepsia (10.4%, 8.5% vs 11.6%). Dysesthesia was 4.8%, 6.5% vs 2.7%. Treatment discontinuation because of adverse events was 4.8% and 7.9% on the two retatrutide arms versus 2.7% on Ozempic. Lilly said most of these events were mild to moderate and typically resolved during treatment.

What is not known

• Peer-reviewed detail. These are topline numbers. Lilly says detailed results will be presented at a future medical meeting and published in a journal.
• Treatment-regimen estimand. The release presents the efficacy estimand (what would have been seen if participants stayed on assigned treatment without adding other antihyperglycemic drugs for more than 14 days). Other analysis sets were not shown here.
• How it compares with tirzepatide. This trial used Ozempic, not Mounjaro. Lilly notes a separate ongoing head-to-head with tirzepatide in TRIUMPH-5.
• Approval. Retatrutide remains investigational. Lilly states it has not been approved by the FDA or any other regulator and “cannot be legally sold or marketed for human use.”

Retatrutide is the same investigational GIP/GLP-1/glucagon triple agonist that recently showed large reductions in sleep-apnea events in two Phase 3 trials reported in the New England Journal of Medicine (Amino Wire coverage). TRANSCEND-T2D-2 is a diabetes head-to-head, not a sleep-apnea study.

Amino Wire does not give medical advice.