Eli Lilly's TRIUMPH Program: All the Retatrutide Phase 3 Trials in One Place
Eli Lilly's triple agonist retatrutide (LY3437943) generated enormous excitement after Phase 2 data showed unprecedented weight loss of up to 24.2% at 48 weeks. Now the company has launched one of the most ambitious obesity and metabolic disease clinical programs in pharmaceutical history — the TRIUMPH trial suite — designed to evaluate retatrutide across a sweeping range of indications. Here's everything researchers need to know about each trial, what's being measured, and when results are expected.
What Makes Retatrutide Unique
Retatrutide is a single-molecule triple agonist targeting three incretin-related receptors simultaneously: GLP-1 (glucagon-like peptide-1), GIP (glucose-dependent insulinotropic polypeptide), and glucagon receptors. This triple mechanism differentiates it from dual agonists like tirzepatide (GLP-1/GIP) and single agonists like semaglutide (GLP-1 only).
The glucagon receptor component is the key differentiator. Glucagon signaling increases energy expenditure, promotes hepatic fat oxidation, and may contribute to the dramatic reductions in liver fat observed in early trials. Coskun et al., 2022 demonstrated in preclinical models that this triple agonism produced superior metabolic outcomes compared to dual or single receptor engagement.
Phase 2 results published by Jastreboff et al., 2023 in the New England Journal of Medicine showed dose-dependent weight loss reaching -24.2% at the highest dose (12 mg) over 48 weeks — numbers that rivaled or exceeded bariatric surgery benchmarks. Equally striking were the metabolic improvements: reductions in HbA1c, triglycerides, and liver fat markers across virtually all dose groups.
The TRIUMPH Program Overview
Eli Lilly's TRIUMPH program encompasses multiple Phase 3 trials spanning obesity, type 2 diabetes, metabolic dysfunction-associated steatohepatitis (MASH), obstructive sleep apnea, and cardiovascular outcomes. The naming convention follows a numbered system (TRIUMPH-1 through TRIUMPH-5 and beyond), with each trial addressing a distinct population or indication.
Collectively, these trials are expected to enroll tens of thousands of participants across dozens of countries. The program represents Lilly's bet that retatrutide's triple mechanism can address metabolic disease more comprehensively than any existing therapy.
TRIUMPH-1: Obesity Without Diabetes
TRIUMPH-1 is the foundational obesity trial, enrolling adults with BMI ≥30 kg/m² (or ≥27 with at least one weight-related comorbidity) without type 2 diabetes. This is the trial most directly comparable to semaglutide's STEP program and tirzepatide's SURMOUNT program.
The study is a randomized, double-blind, placebo-controlled trial evaluating multiple retatrutide doses administered via subcutaneous injection. Co-primary endpoints include percent change in body weight and the proportion of participants achieving ≥5% weight loss at the primary time point. Given Phase 2 results, expectations are extraordinarily high — researchers are watching closely to see whether the >20% mean weight loss observed in Phase 2 is replicated at scale.
TRIUMPH-2: Obesity With Type 2 Diabetes
TRIUMPH-2 targets adults living with both obesity and type 2 diabetes, a population that historically achieves less weight loss with GLP-1 receptor agonists compared to people without diabetes. Phase 2 data from Rosenstock et al., 2023 showed retatrutide produced HbA1c reductions of up to -2.16% and significant weight loss even in participants with established T2D.
This trial will be critical for positioning retatrutide against tirzepatide (Mounjaro) in the diabetes space. Endpoints include both glycemic control and body weight change, reflecting the dual burden these patients carry.
TRIUMPH-3: Metabolic Dysfunction-Associated Steatohepatitis (MASH)
Perhaps the most scientifically intriguing trial in the program, TRIUMPH-3 evaluates retatrutide in participants with biopsy-confirmed MASH (formerly called NASH). This indication plays to retatrutide's unique glucagon receptor activity, which directly promotes hepatic lipid metabolism.
Early evidence supporting this approach was striking. In Phase 2 substudies, retatrutide reduced liver fat by up to ~86% as measured by MRI-proton density fat fraction, with a large proportion of participants achieving complete normalization of liver fat content (Sanyal et al., 2024). These reductions far exceeded what has been observed with GLP-1-only or GLP-1/GIP dual agonists.
The Phase 3 MASH trial uses histological endpoints — specifically, resolution of steatohepatitis without worsening of fibrosis, and/or improvement in fibrosis without worsening of steatohepatitis. These are the gold-standard regulatory endpoints that the FDA requires for MASH drug approval, making this trial's design highly significant.
TRIUMPH-4: Obstructive Sleep Apnea
TRIUMPH-4 investigates retatrutide in adults with obesity and moderate-to-severe obstructive sleep apnea (OSA). This follows the regulatory pathway established by tirzepatide, which demonstrated significant reductions in the apnea-hypopnea index (AHI) in the SURMOUNT-OSA trial published by Malhotra et al., 2024.
The primary endpoint is expected to be change in AHI, the standard measure of sleep apnea severity. With retatrutide's greater weight loss potential, researchers speculate it could produce even larger AHI reductions than those seen with tirzepatide — potentially making CPAP therapy unnecessary for a meaningful subset of patients.
TRIUMPH-5: Cardiovascular Outcomes
The TRIUMPH cardiovascular outcomes trial (CVOT) is the largest and longest study in the program, designed to determine whether retatrutide reduces the risk of major adverse cardiovascular events (MACE) — typically defined as cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke.
This trial follows the landmark SELECT trial, in which Lincoff et al., 2023 demonstrated that semaglutide 2.4 mg reduced MACE by 20% in adults with overweight/obesity and established cardiovascular disease. A positive CVOT for retatrutide would be transformative for its commercial and clinical positioning. These trials typically require thousands of participants followed over 3-5 years, meaning results are the furthest out on the horizon.
Expected Timelines and Regulatory Path
Most TRIUMPH trials began enrollment in late 2024 or early 2025. Based on typical Phase 3 timelines:
Eli Lilly has indicated it plans to pursue regulatory submissions on a rolling basis, potentially seeking initial approval for obesity and/or T2D while longer trials continue. This strategy mirrors the approach Novo Nordisk used with semaglutide, building the label over time.
How TRIUMPH Compares to Competing Programs
The breadth of the TRIUMPH program reflects the competitive intensity of the obesity drug landscape:
Lilly is effectively racing against both its own tirzepatide franchise and Novo Nordisk's semaglutide/CagriSema pipeline. The company appears to be betting that retatrutide's superior efficacy profile — driven by triple receptor agonism — will justify the investment even if it partially cannibalizes tirzepatide sales.
Open Questions for Researchers
Several critical unknowns remain: