Lilly reports greater mean weight loss with retatrutide than semaglutide 2 mg at 80 weeks in TRANSCEND-T2D-2, with dose-specific A1C and safety findings.
Written By: Aasritha Thippavajjala, PharmD
Reviewed By: Pharmacally Editorial Team
Eli Lilly and Company reported topline results from TRANSCEND-T2D-2 (NCT06260722), a Phase 3 trial comparing investigational retatrutide with injectable semaglutide (Ozempic) 2 mg in adults with type 2 diabetes inadequately controlled with metformin, with or without an SGLT2 inhibitor. At week 80, both retatrutide doses reduced mean A1C by 2.2 percentage points, compared with 1.8 percentage points with semaglutide. Mean weight loss was also greater with retatrutide. Detailed findings have not yet been published in a peer-reviewed journal.
Randomized Trial Compared Two Retatrutide Doses with Semaglutide
The randomized, open-label trial enrolled 1,298 adults with baseline A1C levels of 7.0% to 10.5%. Participants were assigned in a 2:2:1 ratio to once-weekly retatrutide 9 mg, retatrutide 12 mg or semaglutide 2 mg. Retatrutide treatment began at 2 mg, with dose increases every four weeks until the assigned target dose was reached.
The primary assessment was conducted at week 80. An extension involving approximately 650 participants will continue retatrutide treatment for another 24 weeks to assess longer-term efficacy and safety.
A1C Results Require Dose-Specific Interpretation
Mean baseline A1C was 8.3%. At week 80, mean A1C decreased by 2.2 percentage points with both retatrutide doses and by 1.8 percentage points with semaglutide.
The primary objective was to establish noninferiority of retatrutide 12 mg to semaglutide for A1C reduction. Lilly also reported superiority for the 12 mg dose under family-wise type I error control. For retatrutide 9 mg, A1C superiority was nominally significant (p<0.001), rather than controlled for family-wise error. The 9 mg dose separately met the key secondary noninferiority endpoint under family-wise error control.
These distinctions matter because the similar numerical A1C reductions across the two retatrutide doses do not mean that both doses demonstrated controlled statistical superiority over semaglutide.
Retatrutide Produced Greater Mean Weight Loss
Mean baseline body weight was 102.4 kg. At week 80, mean body weight decreased by 19.5% with retatrutide 9 mg and 20.9% with 12 mg, compared with 9.4% with semaglutide. Absolute mean changes were −20.1 kg, −21.5 kg and −9.5 kg, respectively.
Both retatrutide doses were superior to semaglutide for body-weight change, with family-wise type I error control. The 12 mg group had the largest mean reduction, although the difference between the two retatrutide doses was comparatively modest.
These findings use the efficacy estimand, which estimates outcomes assuming participants remained on their assigned study intervention for 80 weeks, allowing possible dose interruptions or modifications, without initiating additional antihyperglycemic medication for more than 14 days of use. The results therefore should not be interpreted as treatment-policy estimates or as outcomes that every randomized participant would necessarily experience.
Adverse Event Data
Adverse event (%) | Retatrutide 9 mg | Retatrutide 12 mg | Semaglutide 2 mg |
Diarrhea | 28.3% | 32.7% | 26.4% |
Nausea | 21.2% | 23.8% | 21.3% |
Constipation | 14.2% | 13.1% | 19.8% |
Vomiting | 10.2% | 15.0% | 13.2% |
Dyspepsia | 10.4% | 8.5% | 11.6% |
Dysesthesia | 4.8% | 6.5% | 2.7% |
Urinary tract infection | 5.8% | 4.2% | 5.8% |
Discontinuation due to adverse events | 4.8% | 7.9% | 2.7% |
Diarrhea was the most frequently reported adverse event across all three treatment groups. The retatrutide 12 mg group had higher reported rates of diarrhea, nausea and vomiting than the 9 mg group, while adverse-event-related treatment discontinuation was also more frequent with the 12 mg dose (7.9%) than with the 9 mg dose (4.8%) or semaglutide (2.7%). These selected topline data provide a comparative view of reported events but are insufficient to establish overall safety equivalence or superiority.
Retatrutide Remains Investigational
Retatrutide is an investigational, once-weekly triple hormone receptor agonist that activates receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon. Lilly states that retatrutide has not been approved by the US Food and Drug Administration or any other regulatory authority and cannot be marketed for human use.
Clinical Interpretation
TRANSCEND-T2D-2 provides a direct comparison with semaglutide 2 mg in adults with inadequately controlled type 2 diabetes. The principal finding is the difference in mean weight reduction at 80 weeks, accompanied by greater mean A1C reduction with retatrutide. However, the A1C superiority finding requires dose-specific interpretation, and the reported efficacy-estimand results do not necessarily represent outcomes under routine clinical use.
Lilly also reported greater improvements in non-HDL cholesterol, triglycerides and systolic blood pressure, without providing numerical effect sizes in the topline announcement. These changes may be relevant to cardiometabolic risk, but they do not demonstrate reductions in cardiovascular events, diabetes complications or mortality. Full trial results, including confidence intervals, detailed statistical methods and comprehensive safety data, will be needed to assess the magnitude and clinical significance of the findings independently.
References
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, Lilly, 28 October 2026
Effect of Retatrutide Compared with Semaglutide in Adult Participants with Type 2 Diabetes and Inadequate Glycemic Control with Metformin with or Without SGLT2 Inhibitor (TRANSCEND-T2D-2), ClinicalTrials.gov ID NCT06260722
About the Writer
Aasritha Thippavajjala (Linkedin) is a pharm D student and aspiring medical writer with medical writing, clinical training experience and a strong interest in clinical research and patient safety She has hands-on exposure to clinical pharmacy activities including medication profile assessment, clinical case review, identification of potential drug-related problems, ADR awareness, patient counselling, and clinical documentation. She has also gained experience in medical literature review, evidence synthesis, and scientific communication through her published review article on digital twin-based patient simulation and her poster presentation at the 74th Indian Pharmaceutical Congress. Certified in ICH Good Clinical Practice (E6(R3)) and Scientific Writing in Health Research, she is passionate about applying her clinical knowledge and research skills to medical writing ,clinical research and contributing to accurate, evidence-based healthcare.