The TRIUMPH Phase 3 Program: Everything We Know

What Is the TRIUMPH Program?

TRIUMPH is Eli Lilly’s full Phase 3 clinical development program for retatrutide (LY3437943). Its name is an acronym reflecting its goals. The program is made up of several pivotal trials testing retatrutide across a range of metabolic conditions. It began after the striking Phase 2 results published in the New England Journal of Medicine, which showed up to 24.2% mean body weight reduction at 48 weeks and a large drop in liver fat.

TRIUMPH is one of the largest Phase 3 efforts in metabolic medicine, with trials covering obesity, obesity with type 2 diabetes, cardiovascular disease, knee osteoarthritis and sleep apnea. Liver disease (MASLD/MASH) is studied in separate trials. In total, the program is expected to enroll thousands of participants at sites around the world.

Individual Trials Within TRIUMPH

The program includes several separate trials, each aimed at a specific patient group and use:

TRIUMPH-1 focuses on adults with obesity or overweight with at least one weight-related comorbidity, without type 2 diabetes. This is the core obesity trial and is expected to be the primary basis for a weight management indication. The trial ran for 80 weeks of treatment, addressing a Phase 2 limitation: weight loss had not leveled off at 48 weeks. It enrolled 2,339 participants; topline results on May 21, 2026 showed 28.3% mean weight loss at 12 mg (efficacy estimand), and the full results were published in the New England Journal of Medicine on September 29, 2026.

TRIUMPH-2 enrolls adults with obesity or overweight (BMI ≥27) who also have type 2 diabetes, with a nested obstructive sleep apnea (OSA) basket. The primary endpoint is percent change in body weight, with AHI change measured in the OSA subset. Doses are 4 mg, 9 mg, and 12 mg in 1,152 participants over 80 weeks. Topline results on July 23, 2026 showed 20.8% mean weight loss at 12 mg (efficacy estimand); the trial was published in The Lancet on September 29, 2026.

TRIUMPH-3 evaluates retatrutide in adults with Class II/III obesity (BMI ≥35) and established cardiovascular disease, with and without type 2 diabetes. Doses are 9 mg and 12 mg. It focuses on a high-risk group with both severe obesity and CVD. It enrolled 1,949 participants; topline results on July 23, 2026 showed 22.6% mean weight loss at 12 mg over 80 weeks. No paper has been published yet.

TRIUMPH-4 enrolled 445 participants with obesity and knee osteoarthritis over 68 weeks of treatment. Results announced in December 2025 showed 28.7% mean weight loss at the 12 mg dose and 26.4% at 9 mg, compared to 2.1% with placebo. The pain results were striking: WOMAC pain scores improved by 74.3-75.8%, with 12-14% of participants becoming completely pain-free versus 4.2% on placebo. Systolic blood pressure decreased by 14.0 mmHg at 12 mg. The trial used a five-step dose escalation (2mg to 4mg to 6mg to 9mg to 12mg at four-week intervals). Notable safety findings included dysesthesia (abnormal skin sensation) in 20.9% of the 12 mg group versus 0.7% on placebo, a new signal that had not stood out in Phase 2. Gastrointestinal events remained consistent with the class: nausea 43.2%, diarrhea 33.1%, and vomiting 20.9% at 12 mg. Discontinuation rates were 18.2% at 12 mg, 12.2% at 9 mg, and 4.0% on placebo. TRIUMPH-4 was the first Phase 3 result from the TRIUMPH program and the first confirmation of retatrutide’s efficacy in a large, controlled Phase 3 trial.

In addition to these four numbered trials, TRIUMPH-Outcomes is a separate 10,000-patient cardiovascular outcomes trial (CVOT) evaluating major adverse cardiovascular events. The MASLD/MASH indication is being pursued through the separate SYNERGY and MACELD programs, not through TRIUMPH.

Enrollment and Study Design

Across the TRIUMPH program, Eli Lilly is enrolling participants at sites in North America, Europe, Asia, and other regions. This global reach addresses a key limitation of the Phase 2 trial, which ran only at U.S. sites. Total enrollment across all TRIUMPH trials is expected to exceed 10,000 participants.

The pivotal obesity and diabetes trials use randomized, double-blind, placebo-controlled designs with dose escalation protocols informed by Phase 2 tolerability data. Phase 2 showed that this escalation approach (starting low and increasing gradually) improves tolerability and reduces gastrointestinal side effects compared with starting at a fixed dose.

Primary Endpoints

Each trial has endpoints aligned with its target indication:

• Obesity trials: Percent change in body weight from baseline and the proportion of participants achieving ≥5%, ≥10%, and ≥15% weight loss thresholds at 80 weeks (68 weeks in TRIUMPH-4)
• Diabetes trials: Change in HbA1c from baseline, with weight loss and other glycemic parameters as key secondary endpoints
• Liver trials (separate SYNERGY-OUTCOMES and MACELD programs): major adverse liver outcomes in SYNERGY-OUTCOMES, and liver tissue and fibrosis in MACELD (see the liver program explained)

Expected Timelines

The first Phase 3 readout from TRIUMPH arrived in December 2025, when Eli Lilly announced topline results from TRIUMPH-4. Further pivotal readouts followed in 2026: TRANSCEND-T2D-1 (March 19), TRIUMPH-1 (May 21), TRIUMPH-2 and TRIUMPH-3 (July 23), and TRANSCEND-T2D-2, the head-to-head comparison with semaglutide in type 2 diabetes (October 28). TRIUMPH-5, against tirzepatide, and TRIUMPH-Outcomes are still running.

Based on these timelines and Lilly’s guidance, the company plans to file for FDA approval no later than the first quarter of 2027, with parallel regulatory filings expected in the EU, Japan, and other markets. On October 2, 2026 the FDA ruled that retatrutide is a drug, not a biologic, so the application must be a New Drug Application (NDA); Lilly is contesting the FDA ruling in court and has not said which pathway it will use. By our estimate, an FDA decision could come around the first quarter of 2028 with standard review, or in late 2027 with priority review.

What This Means for Approval

The TRIUMPH program is built to support several regulatory submissions. Obesity will probably come first, given the strong Phase 2 weight loss signal and the commercial path already set by semaglutide and tirzepatide. A diabetes indication could follow soon after or be filed at the same time.

MASLD could be a transformative opportunity. With very few approved drugs for metabolic liver disease and more than 25% of adults worldwide affected, the separate SYNERGY and MACELD liver disease programs could give retatrutide a place in an area with almost no treatments.

Perspective

The TRIUMPH program is ambitious, and its first Phase 3 result beat expectations. TRIUMPH-4’s 28.7% weight loss at 12 mg did more than confirm the Phase 2 signal; it surpassed it. That is unusual in drug development, where effects usually shrink from Phase 2 to Phase 3. The longer treatment duration (68 weeks versus 48 weeks in Phase 2) and the five-step dose escalation protocol likely contributed to this result.

However, important questions remain. Dysesthesia, a dose-dependent side effect (20.9% at 12 mg), is a new safety signal that needs watching across the rest of the program. Discontinuation rates of 18.2% at 12 mg are notable. The later trials have since reported lower rates at 12 mg, both for discontinuation due to adverse events (11.3% in TRIUMPH-1, 7.7% in TRIUMPH-2, 13.5% in TRIUMPH-3) and for dysesthesia (12.5%, 7.3% and 6.4%).