The retatrutide Phase 2 data (TRIUMPH trial) published by Jastreboff et al. in the NEJM are, frankly, jaw-dropping.[1] This is a GIP/GLP-1/glucagon triple agonist — the first of its kind to report clinical data — and the weight loss numbers exceed anything we've seen before.
Design: Phase 2, randomized, double-blind, placebo-controlled, dose-finding. N = 338 adults with BMI >= 30 (or >= 27 with comorbidity), without diabetes. Multiple dose cohorts (1, 4, 8, 12 mg). 48-week treatment period.
Key weight loss results (treatment-estimand, 48 weeks):
- Placebo: -2.1%
- 1 mg: -8.7%
- 4 mg (starting dose 2mg): -17.1%
- 4 mg (starting dose 4mg): -22.1%
- 8 mg (starting dose 2mg): -22.8%
- 8 mg (starting dose 4mg): -24.2%
- 12 mg (starting dose 2mg): -24.0%
- 12 mg (starting dose 4mg): -26.2% (though this cohort was small, n=11)
At the 12 mg dose, mean weight loss was approaching 25% at 48 weeks, and the curves were still descending with no clear plateau. For reference, STEP 1 (semaglutide 2.4 mg) showed 14.9% at 68 weeks[2], and SURMOUNT-1 (tirzepatide 15 mg) showed 20.9% at 72 weeks[3].
The triple agonism adds glucagon receptor activity. Glucagon increases energy expenditure and hepatic lipid oxidation. The theoretical concern is glucagon-mediated hyperglycemia, but this wasn't seen — HbA1c actually decreased, suggesting GLP-1/GIP activity adequately counters the glycemic effect.
[1] Jastreboff AM, et al. N Engl J Med. 2023;389(6):514-526.
[2] Wilding JPH, et al. N Engl J Med. 2021;384(11):989-1002.
[3] Jastreboff AM, et al. N Engl J Med. 2022;387(4):327-337.
The numbers are impressive but let's apply some healthy skepticism to Phase 2 data.
Cautions:
- Small sample size: N = 338 total across 8 treatment arms. Some cohorts had fewer than 40 participants. Phase 2 weight loss results almost always attenuate in Phase 3 due to larger, more heterogeneous populations.
- Treatment-estimand vs. trial-product-estimand: The headline 24.2% figure uses the treatment estimand (what happens if you stay on drug). The trial-product estimand (ITT-like, including all randomized regardless of adherence) was lower — around 22.1% for the 8 mg group. In real-world practice, adherence will be lower still.
- 48 weeks ≠ 72 weeks: STEP 1 and SURMOUNT-1 were 68-72 week trials. Retatrutide at 48 weeks hadn't plateaued, which could mean even more weight loss... or it could mean the plateau just hadn't arrived yet. We need 72-week data from Phase 3.
- GI tolerability: Nausea (43% at 12 mg), diarrhea (35%), vomiting (24%). These rates are higher than semaglutide or tirzepatide. The slow titration schedule helped, but GI side effects are a real barrier to adherence.
That said, even if Phase 3 shows "only" 20-22% weight loss at 72 weeks, that would still be best-in-class.
I want to highlight the liver data from TRIUMPH because it's potentially as important as the weight loss numbers. At 48 weeks in the 8-12 mg groups:
- Liver fat content (by MRI-PDFF) decreased by ~82-86% relative change
- ALT normalized in essentially all patients with elevated baseline ALT
- These changes exceeded what's been seen with semaglutide or tirzepatide monotherapy in comparable timeframes
The glucagon component likely drives much of the hepatic benefit. Glucagon promotes hepatic lipid oxidation, ketogenesis, and reduced de novo lipogenesis. This is why survodutide (GLP-1/glucagon dual) and retatrutide are both being developed for MASH — the glucagon receptor activation may be specifically important for liver disease.
Lilly is running the Phase 3 TRIUMPH-3 trial for obesity and a separate MASH trial. If the liver histology data confirms what MRI-PDFF suggests, retatrutide could be the most effective pharmacological treatment for MASH ever studied.
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Shop Reference StandardsFrom a body composition standpoint, did TRIUMPH report lean mass vs fat mass data? With 24% total weight loss, the absolute amount of lean mass lost could be substantial. At what point does the lean mass loss start to become a clinical problem — particularly in older adults who are already at risk for sarcopenia?
I recall that in STEP 1, DEXA subsets showed approximately 39% of weight lost was lean mass[4]. If that ratio holds with retatrutide, a 24% total weight loss on a 100 kg person means ~9.4 kg of lean mass lost. That's a lot of muscle.
[4] Wilding JPH, et al. Supplementary Appendix. N Engl J Med. 2021;384(11).
Critical question. TRIUMPH Phase 2 did not include DEXA body composition as a pre-specified endpoint. We do have some signals from the glucagon receptor component though.
Theoretically, glucagon receptor agonism should improve the lean-to-fat mass loss ratio compared to pure GLP-1 agonism. Glucagon stimulates energy expenditure partly through increased protein turnover but also through thermogenesis and lipid oxidation. Preclinical data in GLP-1/glucagon co-agonist models showed preferential fat loss vs lean mass loss compared to GLP-1 agonism alone[5].
Whether this translates to humans at clinically relevant doses is unproven. Phase 3 should include DEXA substudy data. In the meantime, resistance training should be considered a co-intervention for any patient losing >15% body weight, regardless of the pharmacological agent used.
[5] Day JW, et al. Nat Chem Biol. 2009;5(10):749-757.