Retatrutide Tops Semaglutide on A1C, Weight in Head-to-Head Trial

Once-weekly retatrutide produced greater reductions in glycated hemoglobin A_1c (HbA_1c) and more than twice the weight loss of the highest approved dose of semaglutide for type 2 diabetes (T2D), according to topline phase 3 results announced by Eli Lilly.¹

"Head-to-head trials show patients and physicians how a potential new medicine compares with treatments that are available and reimbursed today,” said Kenneth Custer, PhD, executive vice president and president of Lilly Cardiometabolic Health, in a statement. In TRANSCEND-T2D-2, the first phase 3 trial comparing retatrutide with another incretin medicine, retatrutide delivered greater A_1c reduction and more than double the weight loss of the highest approved dose of Ozempic for type 2 diabetes. Based on these results and those from across our phase 3 program, we believe retatrutide, if approved, could shift the treatment paradigm for people living with type 2 diabetes, obesity, and related cardiometabolic conditions."

TRANSCEND-T2D-2 (NCT06260722) is the first phase 3 trial to compare retatrutide, an investigational agonist of the glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon receptors, with another incretin-based therapy. The randomized, open-label trial enrolled 1298 adults with T2D inadequately controlled on metformin with or without a sodium-glucose cotransporter-2 (SGLT2) inhibitor and a baseline HbA_1C of 7.0% to 10.5%. Participants were randomized 2:2:1 to once-weekly retatrutide 9 mg, retatrutide 12 mg, or semaglutide 2 mg (Ozempic; Novo Nordisk). Retatrutide was started at 2 mg and escalated every 4 weeks.

Both Retatrutide Doses Lowered HbA1c by 2.2 Points

At 80 weeks, both retatrutide doses lowered HbA_1c by an average of 2.2 percentage points from a mean baseline of 8.3%, compared with 1.8 points with semaglutide. The primary objective was to show that retatrutide 12 mg was noninferior to semaglutide on HbA_1c reduction; the 12-mg dose also demonstrated superiority (P < .001). Noninferiority of the 9-mg dose was met as a key secondary end point, while its superiority over semaglutide on HbA_1c reached nominal significance (P < .001) as a prespecified secondary end point outside the trial's family-wise type 1 error control.

Retatrutide also produced greater improvements than semaglutide in non-high-density lipoprotein cholesterol, triglycerides, and systolic blood pressure, although Eli Lilly did not report the size of those differences, and the systolic blood pressure advantage with the 9-mg dose reached only nominal significance. All results reflect the efficacy estimand, which assumes participants remained on treatment for 80 weeks without starting additional glucose-lowering medication.

Weight Loss Reached 20.9% With Retatrutide 12 mg

From a mean baseline weight of 225.8 lb (BMI, 36.8), participants lost 19.5% (44.3 lb) of body weight with retatrutide 9 mg and 20.9% (47.4 lb) with retatrutide 12 mg, compared with 9.4% (20.9 lb) with semaglutide (P < .001 for both doses).

The results fall in line with the weight reductions reported in TRIUMPH-2, in which adults with T2D and obesity taking the highest retatrutide dose lost an average of 20.8%. In TRIUMPH-1, which enrolled adults with obesity or overweight but without diabetes, the 12-mg dose produced a mean weight loss of 28.3% at 80 weeks.²

Discontinuations Due to Adverse Events Were Higher With Retatrutide

Gastrointestinal events were the most common adverse events across all arms. Diarrhea occurred in 28.3% and 32.7% of participants taking retatrutide 9 mg and 12 mg, respectively, vs 26.4% with semaglutide; nausea in 21.2% and 23.8% vs 21.3%; and vomiting in 10.2% and 15.0% vs 13.2%.¹ Constipation (14.2% and 13.1% vs 19.8%) and dyspepsia (10.4% and 8.5% vs 11.6%) were less frequent with retatrutide.

Dysesthesia, an abnormal or unpleasant skin sensation, was reported in 4.8% and 6.5% of retatrutide recipients vs 2.7% with semaglutide, and urinary tract infections in 5.8% and 4.2% vs 5.8%. Most events were mild to moderate and typically resolved during treatment. Treatment discontinuation due to adverse events occurred in 4.8% and 7.9% of participants taking retatrutide 9 mg and 12 mg, respectively, vs 2.7% with semaglutide.

Detailed results will be presented at a future medical meeting and published in a peer-reviewed journal. Eli Lilly is also comparing retatrutide head-to-head with tirzepatide in TRIUMPH-5, an ongoing phase 3 trial in adults with obesity with or without T2D.

References

1. 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. News release. Eli Lilly and Company. October 28, 2026. Accessed October 28, 2026. https://investor.lilly.com/news-releases/news-release-details/lillys-retatrutide-delivered-greater-a1c-reduction-and-more
2. Grossi G. Retatrutide achieves up to 30.3% average weight loss in phase 3 TRIUMPH-1 trial. AJMC^®. May 21, 2026. Accessed October 28, 2026. https://www.ajmc.com/view/retatrutide-achieves-up-to-30-3-average-weight-loss-in-phase-3-triumph-1-trial