TRANSCEND-T2D-2: Retatrutide Beats Semaglutide 2 mg on A1C, Weight Loss

Retatrutide reduced A1C more and produced more than double the weight loss of semaglutide 2 mg (Ozempic) at 80 weeks in adults with type 2 diabetes in the phase 3 TRANSCEND-T2D-2 trial, according to topline results from Eli Lilly.¹

TRANSCEND-T2D-2 is the sixth phase 3 trial of retatrutide to report positive results, according to Lilly.¹ Retatrutide is an investigational once-weekly single molecule activating receptors for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1), and glucagon.¹ Lilly is also comparing retatrutide with tirzepatide in TRIUMPH-5, an ongoing phase 3 trial in adults with obesity with or without type 2 diabetes.¹

“In TRANSCEND-T2D-2, the first Phase 3 trial comparing retatrutide with another incretin medicine, retatrutide delivered greater A1C reduction and more than double the weight loss of the highest approved dose of Ozempic for type 2 diabetes,” said Kenneth Custer, PhD, executive vice president and president, Lilly Cardiometabolic Health. “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.”¹

Retatrutide vs Semaglutide: TRANSCEND-T2D-2 Design and A1C Results

The randomized, open-label trial (NCT06260722) enrolled 1,298 adults with type 2 diabetes inadequately controlled on metformin, with or without an SGLT2 inhibitor, and a baseline A1C of 7.0% to 10.5%.^1,2 Participants were randomized 2:2:1 to once-weekly retatrutide 9 mg, retatrutide 12 mg, or semaglutide 2 mg. Retatrutide was started at 2 mg and escalated every 4 weeks to the target dose.¹

The primary objective was to show noninferiority of retatrutide 12 mg vs semaglutide 2 mg for A1C reduction at 80 weeks.¹ From a mean baseline A1C of 8.3%, both retatrutide doses lowered A1C by 2.2% at 80 weeks, compared with 1.8% with semaglutide.¹

Superiority of retatrutide 12 mg was significant with family-wise type 1 error control (P < .001). The 9 mg dose met noninferiority as a key secondary end point and showed nominal superiority (P < .001).¹ All results reflect the efficacy estimand, which assumes participants remained on treatment without additional glucose-lowering medication.¹

Retatrutide Weight Loss and Safety in Type 2 Diabetes

Mean baseline body weight was 102.4 kg, with a mean BMI of 36.8 kg/m².¹ At 80 weeks, body weight fell 19.5% (20.1 kg) with retatrutide 9 mg and 20.9% (21.5 kg) with retatrutide 12 mg, vs 9.4% (9.5 kg) with semaglutide (P < .001 for both doses).¹ Retatrutide also produced greater improvements in non-HDL cholesterol, triglycerides, and systolic blood pressure, according to Lilly.¹

Gastrointestinal events were the most common adverse events (AEs). Diarrhea occurred in 28.3% and 32.7% of participants receiving retatrutide 9 mg and 12 mg vs 26.4% with semaglutide, and nausea occurred in 21.2% and 23.8% vs 21.3%.¹ Vomiting rates were 10.2% and 15.0% vs 13.2%, while constipation was less frequent with retatrutide (14.2% and 13.1% vs 19.8%).¹

Dysesthesia occurred in 4.8% and 6.5% of retatrutide recipients vs 2.7% with semaglutide.¹ Discontinuation due to AEs was 4.8% and 7.9% with retatrutide 9 mg and 12 mg, respectively, vs 2.7% with semaglutide.¹ Lilly reported most events were mild to moderate and typically resolved during treatment.¹

In the phase 3 TRIUMPH-2 trial in adults with obesity and type 2 diabetes, the highest retatrutide dose produced mean weight loss of 20.8%.^1,3 Detailed TRANSCEND-T2D-2 results will be presented at a future medical meeting and published in a peer-reviewed journal.¹

An extension period will follow approximately 650 participants on retatrutide for an additional 24 weeks.¹ Retatrutide remains investigational and is under phase 3 study in obesity, knee osteoarthritis pain, obstructive sleep apnea, cardiovascular outcomes, and metabolic dysfunction-associated steatotic liver disease.¹

References

1. Eli Lilly and Company. 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. Published 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. 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 identifier: NCT06260722. Accessed October 28, 2026. https://clinicaltrials.gov/study/NCT06260722

3. HCPLive. TRIUMPH-2: Retatrutide reduces weight, A1C in patients with obesity. https://www.hcplive.com/view/triumph-2-retatrutide-reduces-weight-a1c-in-patients-with-obesity. Published August 5, 2026. Accessed October 28, 2026.