Retatrutide Phase 3 Clinical Development Programs
Eli Lilly's retatrutide (LY3437943) is being evaluated in three comprehensive Phase 3 programs spanning obesity, type 2 diabetes, and liver disease — representing one of the largest clinical development initiatives in metabolic medicine history.
First Phase 3 Results: TRIUMPH-4 (December 2025)
TRIUMPH-4 evaluated retatrutide in 445 adults with obesity and knee osteoarthritis. The 28.7% mean weight loss at 12 mg over 68 weeks is the highest ever reported for any obesity drug in Phase 3, exceeding both the Phase 2 result (-24.2% at 48 weeks) and tirzepatide's SURMOUNT-1 result (-22.5%). A new safety signal — dysesthesia (abnormal sensation) — was observed in 20.9% of participants at 12 mg vs. 0.7% on placebo.
Three Clinical Programs
TRIUMPH
Triple Receptor Agonist Intervention Utilizing Metabolic Pathways in Health
4 trials evaluating retatrutide for obesity and weight management: TRIUMPH-1 (obesity/overweight without T2D), TRIUMPH-2 (obesity/overweight with T2D), TRIUMPH-3 (Class II/III obesity with CVD), and TRIUMPH-4 (obesity with knee OA, completed Dec 2025). Plus the 10,000-patient TRIUMPH-Outcomes CVOT.
TRANSCEND
Triple Receptor Agonist for Normalization of Sustained Cardiometabolic Endpoints in Diabetes
3 trials evaluating retatrutide for glycemic control in type 2 diabetes — as add-on to metformin, as add-on to basal insulin, and in combination with other diabetes therapies. Phase 2 showed HbA1c reductions up to -2.02%.
SYNERGY
Liver Outcomes Program
Dedicated MASLD/MASH program with a 4,500-participant outcomes trial using liver biopsy endpoints. Based on Phase 2 data showing 82% liver fat reduction — far exceeding all competitors. Targets MASH resolution and fibrosis improvement.
TRIUMPH Program Trials (Obesity & Weight)
TRIUMPH-4
TRIUMPH-4: Obesity with Knee Osteoarthritis (First Phase 3 Readout)
The first Phase 3 trial of retatrutide to report results, evaluating weight loss and knee osteoarthritis pain reduction in adults with obesity and knee OA. Demonstrated 28.7% weight loss and 75% pain reduction at 12 mg/68 weeks.
TRIUMPH-3
TRIUMPH-3: Phase 3 Weight Management in Cardiovascular Disease
Phase 3 trial evaluating retatrutide for weight management in adults with Class II/III obesity (BMI ≥35) and established cardiovascular disease, with and without type 2 diabetes.
TRIUMPH-Outcomes
TRIUMPH-Outcomes: Cardiovascular Outcomes Trial (CVOT)
Large-scale cardiovascular outcomes trial evaluating whether retatrutide reduces major adverse cardiovascular events (MACE) in adults with overweight/obesity and established cardiovascular disease.
TRIUMPH-2
TRIUMPH-2: Phase 3 Weight Management in Type 2 Diabetes
Phase 3 trial evaluating retatrutide for weight management in adults with obesity or overweight (BMI ≥27) AND type 2 diabetes, with a nested obstructive sleep apnea (OSA) basket. Part of the TRIUMPH development program.
TRIUMPH-1
TRIUMPH-1: Phase 3 Pivotal Obesity Trial of Retatrutide
The pivotal Phase 3 trial evaluating retatrutide for the treatment of obesity and overweight in adults, part of the TRIUMPH (Triple Receptor Agonist Intervention Utilizing Metabolic Pathways in Health) program.
TRANSCEND Program Trials (Type 2 Diabetes)
TRANSCEND-T2D-2
TRANSCEND-T2D-2: Retatrutide vs Semaglutide
Head-to-head comparison of retatrutide vs semaglutide in adults with T2D inadequately controlled on metformin +/- SGLT2 inhibitor.
TRANSCEND-T2D-1
TRANSCEND-T2D-1: Type 2 Diabetes Glycemic Control Trial
Pivotal Phase 3 trial evaluating retatrutide for glycemic control in adults with type 2 diabetes inadequately controlled on metformin, assessing HbA1c reduction and weight loss.
SYNERGY Program Trial (MASLD/MASH)
Timeline and Regulatory Pathway
The Phase 3 program launched in late 2023. Based on current timelines:
- December 2025: TRIUMPH-4 became the first Phase 3 trial to report results, with 28.7% weight loss at 12 mg
- 2026: At least 6 additional Phase 3 readouts expected across TRIUMPH and TRANSCEND programs
- 2026: Regulatory submissions planned — NDA to U.S. FDA and MAA to the EMA, pending positive Phase 3 results
- 2026-2027: Regulatory review and potential approval decisions
- 2028-2029: Long-term CVOT (TRIUMPH-Outcomes) and liver outcomes (SYNERGY-Outcomes) results expected
The EMA agreed on a Pediatric Investigation Plan (PIP) for retatrutide in September 2024, requiring evaluation in adolescents aged 12-17. Eli Lilly has committed $3.5 billion to manufacturing capacity expansion in anticipation of potential approval.
How the Programs Build on Phase 1-2 Data
The three Phase 3 programs build on a strong foundation of earlier clinical evidence:
- Phase 1 (3 trials): Established safety, PK (~6-day half-life, 12-72h Tmax), and tolerability in healthy volunteers, T2D patients, and Japanese subjects
- Phase 2 Obesity (NCT04881706): 24.2% weight loss at 12 mg/48 weeks, 82% liver fat reduction, favorable body composition (75:25 fat-to-lean ratio)
- Phase 2 T2D (NCT04867785): HbA1c reduction of -2.02% at 12 mg/36 weeks, with 16.9% concurrent weight loss
- Phase 2 CKD (NCT05936151): Ongoing evaluation in chronic kidney disease with obesity