The TRIUMPH Phase 3 Program: Everything We Know

What Is the TRIUMPH Program?

TRIUMPH is Eli Lilly’s comprehensive Phase 3 clinical development program for retatrutide (LY3437943). Named as an acronym reflecting its therapeutic ambitions, the program comprises multiple pivotal trials designed to evaluate retatrutide across several metabolic indications. The program was initiated following the striking Phase 2 results published in the New England Journal of Medicine, which demonstrated up to 24.2% mean body weight reduction at 48 weeks and significant liver fat reduction.

The TRIUMPH program represents one of the largest Phase 3 efforts in metabolic medicine, with trials spanning obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD). Collectively, the program is expected to enroll thousands of participants across global sites.

Individual Trials Within TRIUMPH

The program includes several distinct trials, each targeting a specific patient population and indication:

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 duration extends to 72 weeks of treatment, addressing one of the Phase 2 limitations where weight loss had not plateaued at 48 weeks.

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 approximately 1,000 participants.

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. This trial addresses a high-risk population where severe obesity and CVD intersect.

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. Pain outcomes 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) occurring in 20.9% of the 12 mg group versus 0.7% on placebo — a new signal not prominent 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 is the first Phase 3 readout from the TRIUMPH program and represents the first confirmation of retatrutide efficacy in a large, controlled Phase 3 setting.

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 scope addresses a key limitation of the Phase 2 trial, which was conducted exclusively 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. The escalation approach — starting at lower doses and gradually increasing — was shown in Phase 2 to improve tolerability and reduce gastrointestinal adverse events compared to fixed-dose initiation.

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 72 weeks
• Diabetes trials: Change in HbA1c from baseline, with weight loss and other glycemic parameters as key secondary endpoints
• MASLD trials (separate SYNERGY/MACELD programs): Change in hepatic fat content measured by MRI-PDFF, with histological endpoints (liver biopsy) in a subset of participants

Expected Timelines

The first Phase 3 readout from TRIUMPH arrived in December 2025, when Eli Lilly announced topline results from TRIUMPH-4. Six additional Phase 3 readouts are expected in 2026, with data from the core obesity (TRIUMPH-1) and diabetes (TRIUMPH-2) trials anticipated to follow.

Based on these timelines and Lilly’s Q4 2025 earnings call, the company plans to file a New Drug Application (NDA) with the FDA in late 2026, with parallel regulatory filings expected in the EU, Japan, and other markets. This places potential FDA approval in the mid-2027 to early 2028 timeframe, assuming a standard 10-12 month review period.

What This Means for Approval

The TRIUMPH program is designed to support multiple regulatory submissions. The obesity indication is likely to be the first pursued, given the robust Phase 2 weight loss signal and the commercial precedent set by semaglutide and tirzepatide in this space. A diabetes indication could follow closely behind or be submitted concurrently.

The MASLD indication represents a potentially transformative opportunity. With very few approved therapies for metabolic liver disease and a global prevalence exceeding 25% of adults, the separate SYNERGY and MACELD liver disease programs could establish retatrutide in a largely unaddressed therapeutic area.

Perspective

The TRIUMPH program is ambitious in scope, and the first Phase 3 readout has exceeded expectations. TRIUMPH-4’s 28.7% weight loss at 12 mg not only confirmed the Phase 2 signal but surpassed it — an uncommon outcome in drug development, where Phase 3 effect sizes typically attenuate relative to Phase 2. 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. The emergence of dysesthesia as a dose-dependent adverse event (20.9% at 12 mg) is a new safety signal that warrants monitoring across the broader program. Discontinuation rates of 18.2% at 12 mg are notable and will need to be assessed in the context of the core obesity and diabetes trials. Six more Phase 3 readouts in 2026 will fill in the picture across different patient populations and indications.