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.
All five pivotal Phase 3 readouts are in hand as of September 2026: TRIUMPH-4, TRANSCEND-T2D-1, TRIUMPH-1, and, on July 23, 2026, TRIUMPH-2 (obesity + T2D, -20.8% at 12 mg) and TRIUMPH-3 (severe obesity + cardiovascular disease, -22.6%). Eli Lilly plans a Biologics License Application in Q1 2027. The TRIUMPH-Outcomes ~10,000-patient cardiovascular outcomes trial runs as a longer-term post-approval study.
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-1
TRIUMPH-1: Phase 3 Pivotal Obesity Trial of Retatrutide (Results-Published)
The pivotal Phase 3 obesity trial of retatrutide. Topline results announced May 21, 2026: 28.3% mean weight loss at 12 mg over 80 weeks (n=2,339 adults with obesity or overweight + at least one weight-related comorbidity, no diabetes). All three doses met primary and key secondary endpoints. The largest pivotal weight-loss readout in the retatrutide program to date.
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: Retatrutide in Severe Obesity With Cardiovascular Disease
Phase 3, 1,949 adults with BMI 35+ and CVD, 80 weeks: -22.6% weight loss at 12 mg vs -3.2%, triglycerides -37%, hsCRP -51%; MACE-5 HR 0.82, not significant.
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: Retatrutide in Obesity With Type 2 Diabetes (Results)
Phase 3, 1,152 adults, 80 weeks. Topline July 23, 2026: -20.8% weight loss and A1C -1.5 points at 12 mg vs -4.0% and -0.2 on placebo; dysesthesia 7.3%.
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: Phase 3 Type 2 Diabetes Trial (Results-Published)
Pivotal Phase 3 trial of retatrutide in adults with type 2 diabetes (n=537, 40 weeks). Full results published in The Lancet on June 6, 2026 and presented at ADA 2026: HbA1c reductions up to 1.94 percentage points and weight loss up to 15.3% at 12 mg — glycemic control comparable to tirzepatide with substantially greater 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
- Q1 2027: Biologics License Application to the U.S. FDA planned (Lilly guidance of July 23, 2026), with an EU marketing authorisation application expected to follow
- 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