Lilly Retatrutide Beats Ozempic on A1C and Weight Loss in Phase 3 Trial

Eli Lilly and Company (LLY ), the maker of Mounjaro (tirzepatide) and Foundayo (orforglipron), on October 28, 2026, announced positive topline results from TRANSCEND-T2D-2, a head-to-head Phase 3 trial comparing retatrutide with injectable Ozempic 2 mg in adults with type 2 diabetes. At 80 weeks, retatrutide met the primary and all key secondary endpoints, with both retatrutide doses lowering A1C by an average of 2.2% compared with 1.8% for Ozempic, the company reported.

Participants taking retatrutide lost an average of 44.3 lbs (19.5%) at the 9 mg dose and 47.4 lbs (20.9%) at the 12 mg dose, compared with 20.9 lbs (9.4%) for participants on Ozempic. Lilly said retatrutide also delivered greater improvements than Ozempic across certain cardiovascular risk factors, including non-HDL cholesterol, triglycerides and systolic blood pressure. The company described TRANSCEND-T2D-2 as the sixth Phase 3 trial in which retatrutide has delivered powerful efficacy.

Efficacy and Safety Results

The A1C reduction was measured from an average baseline of 8.3%, and the percent change in body weight from an average baseline of 102.4 kg (225.8 lbs) with a body mass index of 36.8 kg/m², according to the release’s efficacy table. In absolute terms, weight change was -20.1 kg (-44.3 lbs) at 9 mg and -21.5 kg (-47.4 lbs) at 12 mg, versus -9.5 kg (-20.9 lbs) with Ozempic 2 mg.

For the 12 mg dose, the A1C comparison reached p<0.001 versus Ozempic with family-wise type 1 error controlled for superiority. The 9 mg A1C comparison showed nominal p<0.001, and A1C noninferiority for the 9 mg dose versus Ozempic was met under family-wise type 1 error control as a key secondary endpoint, according to the release’s endnotes. Superiority of retatrutide 9 mg versus Ozempic in change in A1C and in systolic blood pressure were prespecified secondary endpoints that showed nominal statistical significance. All data in the release are for the efficacy estimand, which represents efficacy had all randomized participants remained on study intervention, with possible dose interruptions and modifications, for 80 weeks without initiating additional antihyperglycemic medication for more than 14 days.

The most common adverse events with retatrutide at the 9 mg and 12 mg doses versus Ozempic were diarrhea (28.3% and 32.7% versus 26.4%), nausea (21.2% and 23.8% versus 21.3%), constipation (14.2% and 13.1% versus 19.8%), vomiting (10.2% and 15.0% versus 13.2%) and dyspepsia (10.4% and 8.5% versus 11.6%). Dysesthesia occurred in 4.8% and 6.5% of participants on retatrutide 9 mg and 12 mg, versus 2.7% on Ozempic, while urinary tract infections occurred in 5.8% and 4.2% versus 5.8%. The majority of these events were mild-to-moderate and typically resolved during treatment, the company said. Treatment discontinuation rates due to adverse events were 4.8% for retatrutide 9 mg and 7.9% for retatrutide 12 mg, versus 2.7% for Ozempic.

Trial Design and Retatrutide Program

TRANSCEND-T2D-2 (NCT06260722) is a randomized, open-label trial that enrolled 1,298 adults with type 2 diabetes inadequately controlled with metformin, with or without an SGLT2 inhibitor. Participants with a baseline A1C of 7.0% to 10.5% were randomized 2:2:1 to once-weekly retatrutide 9 mg, once-weekly retatrutide 12 mg or once-weekly Ozempic 2 mg. The primary objective was to demonstrate that retatrutide 12 mg is noninferior to Ozempic 2 mg in A1C reduction at 80 weeks. Retatrutide was initiated at 2 mg and increased every four weeks to the 9 mg or 12 mg target dose. An extension period has approximately 650 participants continuing retatrutide for an additional 24 weeks to evaluate long-term efficacy and safety.

The broader TRANSCEND-T2D Phase 3 program is evaluating the safety and efficacy of retatrutide in adults with type 2 diabetes across three global registrational trials and has enrolled more than 2,050 participants since it began in 2024. Lilly said it compared retatrutide with injectable Ozempic 2 mg because that is the highest approved dose, making it a meaningful point of comparison.

Retatrutide is an investigational, once-weekly triple hormone receptor agonist, a single molecule that activates the body’s receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon. It has not been approved by the U.S. Food and Drug Administration or any regulatory organization anywhere in the world. Lilly is studying retatrutide in Phase 3 trials across obesity and overweight with at least one weight-related medical problem, type 2 diabetes, knee osteoarthritis pain, moderate-to-severe obstructive sleep apnea, chronic low back pain, cardiovascular outcomes and metabolic dysfunction-associated steatotic liver disease.

Kenneth Custer, executive vice president and president of Lilly Cardiometabolic Health, said TRANSCEND-T2D-2 is the first Phase 3 trial comparing retatrutide with another incretin medicine. “Head-to-head trials show patients and physicians how a potential new medicine compares with treatments that are available and reimbursed today,” Custer said. He added that based on these results and those from across the Phase 3 program, Lilly believes retatrutide, if approved, could shift the treatment paradigm for people living with type 2 diabetes, obesity and related cardiometabolic conditions.

Lilly is separately comparing retatrutide head-to-head with tirzepatide in TRIUMPH-5, an ongoing Phase 3 trial in adults with obesity with or without type 2 diabetes. In TRIUMPH-2, people with type 2 diabetes and obesity taking the highest retatrutide dose lost an average of 49.6 lbs (20.8%), according to the company, which added that weight loss has historically been more difficult for people living with type 2 diabetes.

Detailed results from TRANSCEND-T2D-2 will be presented at a future medical meeting and published in a peer-reviewed journal, Lilly said.