A triple agonist's first phase 3 readout: 28.7% weight loss, knee pain down three quarters

Eli Lilly reported topline results on 11 December from TRIUMPH-4, the first phase 3 trial of retatrutide to read out [s1]. Retatrutide is a triple agonist — it acts at the GIP, GLP-1, and glucagon receptors, the third of which distinguishes it from the dual agonists already on the market. The trial enrolled a heavier population than most obesity trials and paired weight outcomes with a joint-pain endpoint.

These are company-reported topline results. The full dataset has not been peer-reviewed or presented in detail, and retatrutide is not approved by any regulator.

The design

TRIUMPH-4 (NCT05869903) randomised 445 adults 1:1:1 to retatrutide 9 mg, retatrutide 12 mg, or placebo for 68 weeks [s1]. Participants had obesity or overweight (baseline BMI ≥27.0 kg/m²) plus knee osteoarthritis. The enrolled population was heavy: mean baseline weight 112.7 kg (248.5 lbs), mean BMI 40.4 kg/m², with 84% at BMI ≥35 [s1].

The weight results

Lilly reported two sets of numbers, and the difference between them is the most instructive thing in the release.

On the efficacy estimand — what happens in people who stay on the drug as directed — mean weight change at 68 weeks was −26.4% on 9 mg (−29.1 kg; −64.2 lbs), −28.7% on 12 mg (−32.3 kg; −71.2 lbs), and −2.1% on placebo (−2.1 kg; −4.6 lbs) [s1].

On the treatment-regimen estimand — which includes people who stopped the drug or started something else, and is closer to what a population of real patients would experience — the figures were −20.0% on 9 mg (−22.9 kg; −50.5 lbs), −23.7% on 12 mg (−27.2 kg; −60.0 lbs), and −4.6% on placebo (−5.3 kg; −11.7 lbs) [s1].

The gap between the two estimands is roughly five to six percentage points of body weight. That gap is discontinuation, and it is the number to hold onto when comparing this trial against others, because trials do not all headline the same estimand.

The joint-pain results

Knee pain was measured with the WOMAC pain subscale, from a mean baseline score of 6.0. On the efficacy estimand, scores fell 4.5 points (−75.8%) on 9 mg and 4.4 points (−74.3%) on 12 mg, against 2.4 points (−40.3%) on placebo [s1]. The WOMAC physical function subscale, from a baseline of 5.8, fell 4.1 points (−71.8%) on 9 mg and 4.2 points (−73.7%) on 12 mg, against 2.1 points (−35.6%) on placebo [s1].

In a post-hoc analysis, 14.1% of the 9 mg group and 12.0% of the 12 mg group reported complete freedom from knee pain, against 4.2% on placebo [s1].

Two things to note. The placebo response was large — a 40% reduction in pain score in the placebo arm [s1] — which is characteristic of osteoarthritis trials and is why the between-group comparison matters more than the within-group change. And the complete-pain-freedom figure is post-hoc [s1], meaning it was not a pre-specified endpoint and should be read as description rather than as a tested result.

Tolerability, which is where the trade-off lives

Adverse events were common and dose-dependent. Comparing 9 mg, 12 mg, and placebo [s1]:

• Nausea: 38.1% / 43.2% / 10.7%
• Diarrhoea: 34.7% / 33.1% / 13.4%
• Constipation: 21.8% / 25.0% / 8.7%
• Vomiting: 20.4% / 20.9% / 0.0%
• Dysesthesia: 8.8% / 20.9% / 0.7%

Discontinuation due to adverse events was 12.2% on 9 mg and 18.2% on 12 mg, against 4.0% on placebo [s1]. Among participants with baseline BMI ≥35, the discontinuation figures were lower: 8.8%, 12.1%, and 4.8% respectively [s1].

The dysesthesia signal is worth flagging specifically — an abnormal, often unpleasant sensation, reported by roughly one in five participants at the higher dose against under 1% on placebo [s1]. It is not a class effect familiar from GLP-1 and GIP/GLP-1 drugs, and what it reflects is not established by a topline release.

How to read this

The efficacy-estimand figure of −28.7% [s1] sits at the top of the range that phase 3 obesity trials have produced, and it came from a heavier-than-typical population — mean BMI 40.4, with 84% at BMI ≥35 [s1] — where percentage weight loss is generally harder to achieve. That combination is genuinely notable. Cross-trial comparisons, though, are not head-to-head evidence: different trials use different estimands, populations, and durations, and no trial has yet compared retatrutide against an approved incretin drug.

But this is one trial, in 445 people, over 68 weeks, in a population selected for having knee osteoarthritis — which means participants had a reason to want mobility that other trial populations may not share, and which limits how far the results generalise. Nothing here speaks to durability past 68 weeks, to cardiovascular outcomes, or to what happens when the drug stops.

Lilly said seven additional phase 3 trials of retatrutide in obesity and type 2 diabetes are expected to complete in 2026 [s1].

What to watch

The full TRIUMPH-4 publication, including how the dysesthesia cases were characterised. Whether the remaining TRIUMPH trials reproduce both the efficacy and the discontinuation rates in populations without osteoarthritis. And whether the dose that ends up in front of regulators is 12 mg — which produced the larger effect and nearly a fifth of participants discontinuing — or the more tolerable 9 mg.

This article describes trial results for an investigational drug that is not approved. It is not medical advice.

Sources

1. Lilly's triple agonist, retatrutide, delivered weight loss of up to an average of 71.2 lbs along with substantial relief from osteoarthritis pain in first successful Phase 3 trial — Eli Lilly and Company, 11 December 2025