Every Published Retatrutide Trial (2026): the 24.2% Drug

The trial the reputation rests on: 338 adults with obesity and no diabetes, on four doses or placebo for 48 weeks. At 12 mg the result was −24.2% against −2.1% — past tirzepatide's 20.9% ceiling, and the largest weight reduction any drug has produced in a randomized trial. Essentially everyone on the top dose lost at least 5%, 83% lost at least 15%, and 26% lost more than 30%. ⚠ 338 people over 48 weeks is a phase 2 trial, and the confidence you can place in it is phase 2 confidence.

PMID 37366315 ↗NCT04881760 ↗DOI 10.1056/NEJMoa2301972 ↗

281 adults with type 2 diabetes across four doses, against dulaglutide and against placebo, over 36 weeks. The top dose cut A1C by 2.02 points where dulaglutide managed 1.41, and took off 16.9% of body weight. The design matters more than the numbers: it included an active comparator, so this is the first evidence that triple agonism beats a GLP-1 alone on both fronts rather than just looking impressive against placebo.

PMID 37385280 ↗NCT04867785 ↗DOI 10.1016/S0140-6736(23)01053-X ↗

The liver substudy: 98 participants with at least 10% liver fat on imaging. The two top doses cleared roughly 82% of it against essentially no change on placebo, and 86 to 93% of those participants ended below the 5% threshold that counts as a normal liver. ⚠ This is measured by scan rather than biopsy, so it demonstrates fat leaving — not that inflammation or scarring resolved, which is the question the phase 3 liver program has to answer.

PMID 38858523 ↗NCT04881760 ↗DOI 10.1038/s41591-024-03018-2 ↗

The substudy that addresses the obvious worry. Glucagon agonism drives energy expenditure, and there was a legitimate concern that a triple agonist would burn muscle along with fat. DXA scanning of 99 participants found roughly 81% of the weight lost was fat and 19% lean — comparable to what semaglutide and tirzepatide substudies report — with visceral fat down 36%. It is the finding that let phase 3 proceed without a body-composition cloud over it.

PMID 40609566 ↗NCT04867785 ↗DOI 10.1016/S2213-8587(25)00092-0 ↗

A pooled post-hoc look at kidney measures across both phase 2 trials. Urinary protein fell 30 to 40% at the top doses, most in those who started with the most, while kidney function showed the small dose-dependent dip familiar from the rest of the class. ⚠ Post-hoc and pooled, which is the weakest design on this page — but it was enough to justify a dedicated kidney trial, which is the honest measure of a hypothesis-generating result.

PMID 40630318 ↗DOI 10.1016/j.ekir.2025.03.049 ↗

Not a result — a design paper, describing the first dedicated kidney-outcomes trial for a triple agonist. Around 2,000 adults whose type 2 diabetes has already reached their kidneys, randomized on top of standard protective therapy, with a combined endpoint modeled on the trial that won Ozempic its kidney label. Included here because it tells you what Lilly intends to claim, and because knowing a trial is running is useful when someone quotes you its result early.

PMID 41160422 ↗NCT06602557 ↗DOI 10.1093/ndt/gfaf230 ↗

The founding chemistry paper, plus first-in-human work. Lilly engineered a single peptide agonizing all three receptors at a deliberately chosen potency balance, and in obese mice it outperformed both the GIP/GLP-1 and the GLP-1/glucagon combinations. A phase 1a study in 72 healthy adults then established that weekly dosing was viable. Everything downstream on this list depends on the design choices documented here.

PMID 35985340 ↗DOI 10.1016/j.cmet.2022.07.013 ↗

The phase 1b dose-ranging study: 72 patients with type 2 diabetes over 12 weeks, establishing the maximum tolerated dose and the escalation schedule that every later trial used. By week 12 the top dose had produced about 9 kg of loss and 1.6 points of A1C. Gastrointestinal side effects followed the pattern the whole class shows. Both phase 2 trials started within six months of this reading out.

PMID 36354040 ↗NCT04143958 ↗DOI 10.1016/S0140-6736(22)02033-5 ↗

A mechanistic substudy measuring how much retatrutide slows the stomach, using paracetamol absorption as the probe. The delay was dose-dependent but modest at therapeutic doses — closer to tirzepatide's behavior than to the pronounced slowing short-acting GLP-1s produce. That finding shaped the escalation schedules, and it is also relevant to anyone weighing sedation or surgery risk on these drugs.

PMID 37311727 ↗DOI 10.1111/dom.15167 ↗

A patient-reported substudy using validated appetite and eating-behavior instruments, and the most interesting mechanistic result here. Hunger, cravings and disinhibited eating all fell dose-dependently, with the largest changes at 8 and 12 mg — and by margins larger than semaglutide or tirzepatide substudies typically report. ⚠ Self-reported instruments across different trials are not directly comparable, so read it as consistent with the glucagon hypothesis rather than as proof of it.

PMID 40916752 ↗NCT04867785 ↗DOI 10.1111/dom.70097 ↗