TRIUMPH-1 vs TRIUMPH-4: How Retatrutide's Two Phase 3 Trials Differ

Introduction

Retatrutide has completed two Phase 3 obesity trials. Both tested the same drug. Both showed similar headline weight loss numbers. And yet the two trials produced meaningfully different results on safety, secondary outcomes, and what they tell us about who retatrutide works best for.

TRIUMPH-4 enrolled patients with obesity and knee osteoarthritis and asked two questions simultaneously: does retatrutide produce significant weight loss, and does it reduce joint pain? TRIUMPH-1 enrolled a much larger population of adults with general obesity — without requiring a joint condition — and had the longest follow-up data of any retatrutide trial to date.

Together they form the core of the NDA package expected in Q4 2026. Separately, they answer different questions. This article breaks down how the two trials differ, why the differences matter, and what they mean for patients considering retatrutide when it becomes available.

Quick Reference

Who Was in Each Trial

The single most important difference between TRIUMPH-4 and TRIUMPH-1 is the population.

TRIUMPH-4 enrolled adults with two simultaneous conditions: obesity or overweight, and confirmed knee osteoarthritis (Kellgren-Lawrence grade 2 or 3). Type 2 diabetes was an exclusion criterion. With a mean baseline BMI of 40.4, 84% of participants had a BMI ≥35. This is a more comorbid population than the general obesity population — older on average, dealing with joint pain that limits mobility, and carrying a higher total disease burden alongside their obesity.

TRIUMPH-1 enrolled adults with obesity or overweight without requiring any additional comorbidity. With 2,339 participants — more than five times the size of TRIUMPH-4 — it provides the broader and more statistically robust dataset for understanding retatrutide in the general obesity population. Three dose arms (4mg, 9mg, 12mg) versus TRIUMPH-4's two (9mg, 12mg) provide a more complete dose-response picture.

This population difference is the primary explanation for most of the differences seen between the two trials.

Study Design: What Each Trial Was Built to Test

The titration schedule is identical in both trials — confirming that 2mg → 4mg → 6mg → 9mg → 12mg is the confirmed protocol for reaching the highest dose. This consistency is important for patients and prescribers planning treatment timelines.

Weight Loss: Similar Headlines, Different Context

The 12mg weight loss results were strikingly similar across both trials:

The consistency of the 12mg result — 28.7% in TRIUMPH-4 and 28.3% in TRIUMPH-1, in different populations, different durations — is exactly what a robust efficacy signal looks like. This is what regulators mean by replication across populations.

The TRIUMPH-1 104-week extension is the most significant weight loss data point that TRIUMPH-4 does not have. In the BMI ≥35 subgroup who continued to 104 weeks, weight loss reached 30.3% — with no plateau observed. TRIUMPH-4's follow-up ended at 68 weeks, so equivalent long-term data does not exist for that trial.

A note on estimands: TRIUMPH-1's 28.3% at 12mg is reported using the efficacy estimand (participants who remained on treatment). The treatment-regimen estimand for TRIUMPH-1 at 12mg is 25.0% (including participants who discontinued). Both are valid ways to report the same trial. The 28.7% from TRIUMPH-4 used the same efficacy estimand approach.

Safety: Why the Numbers Diverged

The most practically significant difference between the two trials is in tolerability — and it has a clear explanation.

GI side effects were nearly identical between the two trials — nausea, diarrhea, and vomiting rates are within a few percentage points at the 12mg dose, which is what you expect when the pharmacology is the same.

The differences that stand out are dysesthesia and discontinuation:

TRIUMPH-4: dysesthesia 20.9% vs TRIUMPH-1: 12.5% at 12mg

TRIUMPH-4's population was older on average and carried knee osteoarthritis as a confirmed comorbidity. Patients with pre-existing joint and nerve-related conditions may have heightened sensitivity to the peripheral neural effects that produce dysesthesia. The lower rate in TRIUMPH-1's general obesity population is more likely to reflect what most retatrutide patients — without OA — would experience.

TRIUMPH-4: 18.2% discontinuation vs TRIUMPH-1: 11.3% at 12mg

The same logic applies. A more comorbid, potentially older population with more competing health concerns discontinued at a higher rate. TRIUMPH-1's 11.3%, while still higher than tirzepatide's 6.2%, gives a more representative picture of discontinuation in the target population.

New safety signal from TRIUMPH-1 (not seen in TRIUMPH-4):TRIUMPH-1 identified a urinary tract infection signal not observed in TRIUMPH-4: 7.5% (4mg), 8.8% (9mg), and 8.4% (12mg) vs 5.3% placebo. This was identified at the ADA June 6, 2026 presentation as a new finding. The mechanism is not yet understood. TRIUMPH-4's shorter follow-up and smaller population may explain why this signal wasn't detected there.

Secondary Outcomes: What Each Trial Added Beyond Weight Loss

TRIUMPH-4 uniquely provided:

Joint pain: WOMAC pain subscale reduction of 75.8% at 9mg and 73.3% at 12mg (efficacy estimand). Approximately 1 in 8 participants became completely free of knee pain. Six-minute walk test improved by 63 meters vs 12 meters for placebo. These are data no other retatrutide trial provides.

TRIUMPH-1 uniquely provided:

OSA outcomes: The nested OSA basket confirmed 60.6% AHI reduction from a baseline of 58.6 events/hour — directly supporting a potential FDA sleep apnea co-indication.

Cardiovascular outcomes: -12.3 mmHg systolic BP at 80 weeks; triglycerides -41.0%; non-HDL cholesterol -24.2%. These longer-duration cardiovascular markers are among the most comprehensive secondary outcome data in any retatrutide trial to date.

104-week extension: Weight loss continuing to 30.3% in the BMI ≥35 subgroup with no plateau — establishing that retatrutide's efficacy extends well beyond the 68–80-week primary endpoint windows.

4mg dose arm: The only Phase 3 data on the 4mg maintenance dose (~17.6% weight loss), which matters for patients who cannot tolerate higher doses or for potential maintenance dosing strategies.

What Each Trial Means for the FDA Label

When Eli Lilly submits the NDA — expected Q4 2026 — both trials contribute to different parts of the application:

TRIUMPH-4 supports:

• Retatrutide's obesity indication (weight loss endpoint met)
• A potential separate OA indication or OA-specific labeling language
• Evidence that the drug benefits the musculoskeletal system beyond weight loss alone

TRIUMPH-1 supports:

• The primary obesity indication with a much larger, more representative dataset
• A potential OSA co-indication through the nested basket
• Long-term durability data through the 104-week extension
• The broadest available safety dataset for the general obesity population
• The 4mg dose data needed for labeling across the full dose range

The two trials are designed to work together. TRIUMPH-1 establishes the breadth of retatrutide's efficacy in the largest, most representative obesity population. TRIUMPH-4 establishes depth — specifically, what the drug does in a population where obesity-related joint damage is already present.

For the eligibility guide on who qualifies for retatrutide when it becomes available, see our eligibility guide.

Conclusion

TRIUMPH-4 and TRIUMPH-1 asked different questions about retatrutide — and each one answered them.

TRIUMPH-4 was a proof of concept for something clinically significant: a weight loss drug that simultaneously reduces knee pain by 75%, improves functional mobility, and produces surgical-level weight loss in a comorbid population. Its smaller size and specific OA focus are features, not limitations.

TRIUMPH-1 is the confirmatory dataset. 2,339 participants, 80 weeks, three dose arms, nested OSA data, 104-week extension, and a safety profile more representative of the patients who will actually receive retatrutide — without the complicating variable of pre-existing joint disease.

The headline numbers are nearly identical (28.7% vs 28.3% at 12mg). The context around them tells two different stories that together make a stronger regulatory and clinical case than either could alone.

Sources

• Eli Lilly press release: TRIUMPH-4 Phase 3 topline results. December 11, 2025.
• Eli Lilly press release: TRIUMPH-1 Phase 3 topline results. May 21, 2026.
• Eli Lilly press release: TRIUMPH-1 and TRANSCEND-T2D-1 results at ADA 86th Scientific Sessions. June 6, 2026.
• Giblin K, Kaplan LM, Somers VK, et al. "Retatrutide for the treatment of obesity, obstructive sleep apnea and knee osteoarthritis: Rationale and design of the TRIUMPH registrational clinical trials." Diabetes, Obesity and Metabolism, 2026;28(1):83-93.
• Jastreboff AM, et al. "Triple-Hormone-Receptor Agonist Retatrutide for Obesity — A Phase 2 Trial." New England Journal of Medicine, 2023;389:514–526.