Retatrutide

Retatrutide (LY3437943) is an investigational once-weekly injectable developed by Eli Lilly. It's a first-in-class triple hormone receptor agonist — a single peptide that activates GLP-1, GIP, and glucagon receptors simultaneously. In Phase 2 trials it produced 24.2% weight loss at 48 weeks, and in the first Phase 3 readout (TRIUMPH-4, December 2025) 28.7% at 68 weeks — the largest weight loss ever reported for a single-agent pharmacotherapy. It is not yet FDA-approved; Lilly is targeting regulatory submission in 2026–2027.

Lilly is targeting regulatory submission in 2026–2027. Seven additional Phase 3 trials are expected to read out throughout 2026 (TRIUMPH-1 obesity, TRIUMPH-2 diabetes, TRIUMPH-3 cardiovascular, plus sleep apnea, low back pain, MASLD, and cardio-renal outcomes). Assuming the remaining readouts are positive and submission proceeds on schedule, FDA approval for the first indication (likely obesity) could come in 2027–2028. Until then, retatrutide is available only through clinical trials.

Both are made by Lilly and share a similar molecular framework, but retatrutide adds a third receptor target: glucagon. That glucagon component drives direct hepatic fat oxidation and increases resting energy expenditure, adding a thermogenic effect on top of tirzepatide's appetite suppression. In head-to-head context (cross-trial comparison, not direct), retatrutide 12 mg produced 28.7% weight loss at 68 weeks vs tirzepatide's ~20.9% at 72 weeks — roughly 40% greater relative effect. The tradeoff is a higher discontinuation rate and a retatrutide-specific side effect (dysesthesia) not seen with tirzepatide.

Phase 2 and Phase 3 trials used weekly subcutaneous doses ranging from 0.5 mg to 12 mg, titrated over 12–16 weeks. The clinical efficacy doses are 8 mg and 12 mg. A lower 4 mg maintenance dose is being tested in 2026 readouts. There is no FDA-approved dosing label because retatrutide is not approved — the protocols here are research regimens, not prescription guidance.

The main side effects mirror other incretin agonists: nausea (most common during titration), diarrhea, constipation, vomiting, and fatigue. Two distinctive features: (1) a retatrutide-specific side effect called dysesthesia — unusual skin sensations — occurring in roughly 20% of patients at the 12 mg dose, not seen with tirzepatide or semaglutide; (2) a small heart rate increase (3–5 bpm) attributed to the glucagon component. Discontinuation rates in Phase 2/3 were 16–18% at 12 mg, higher than tirzepatide's ~2–3% at comparable efficacy.

Dysesthesia is an unusual skin sensation — participants in retatrutide trials describe it as tingling, prickling, or mild burning, typically in the extremities. It occurred in about 20% of patients at the 12 mg dose in Phase 2 and was typically mild and self-limited. The mechanism is not fully understood. It has not been reported with tirzepatide or semaglutide, suggesting it's related to the glucagon or GIP component specifically. If retatrutide is approved, dosing and titration guidance will be designed partly around managing this effect.

Across the 12 mg dose: 24.2% at 48 weeks in Phase 2 (Jastreboff 2023, no diabetes), and 28.7% at 68 weeks in the first Phase 3 trial (TRIUMPH-4, December 2025, obesity + knee osteoarthritis). A distinctive feature is that no weight loss plateau was observed at 48 weeks — participants were still losing weight when the Phase 2 endpoint was reached. Longer-duration data from TRIUMPH-1 (Phase 3 obesity) is expected in 2026.

Phase 2 data are extraordinarily positive. A MASLD substudy (Sanyal et al., Nature Medicine 2024) found that retatrutide 12 mg reduced liver fat by 82.4% at 24 weeks, with 86% of participants achieving normal liver fat levels — the largest pharmacological liver fat reduction ever reported. This prompted Lilly to add MASH (the inflammatory form of MASLD) as a Phase 3 target. The Phase 3 MASLD trial is expected to read out in 2026 and will assess not just liver fat but also histological resolution of steatohepatitis and fibrosis — the regulatory bar for a liver-disease indication.

Not lawfully for human use. Retatrutide is investigational and available only through Eli Lilly's clinical trials. Many peptide vendors sell 'research use only' retatrutide, but these products are not FDA-regulated, have variable purity and potency, and are not legal to administer to humans. Compounding pharmacies cannot compound retatrutide because it is not on the FDA's Drug Shortage list and has no reference listed drug. Waiting for approval is the only safe path.

The leading hypothesis is the glucagon receptor component. GLP-1 and GIP both suppress appetite and improve insulin response, but glucagon receptor agonism adds a distinct action: direct hepatic lipid oxidation and a modest increase in resting energy expenditure (roughly 5–10% in clinical measurements). This stacks with appetite suppression rather than overlapping it. The liver fat data — 82% reduction vs ~30% with tirzepatide — is the clearest mechanistic evidence that the third receptor is doing distinct work, not just amplifying what the other two do.