Top 10 PubMed Studies on Retatrutide (Triple Agonist GLP-1/GIP/Glucagon) 2026

The pivotal phase 2 obesity trial randomized 338 adults with obesity (BMI ≥30, or ≥27 with weight-related complication, no diabetes) to retatrutide 1, 4, 8, or 12 mg weekly or placebo for 48 weeks. Retatrutide 12 mg produced −24.2% body weight versus −2.1% on placebo — the largest weight reduction ever reported for an obesity pharmacotherapy at the time, exceeding tirzepatide's SURMOUNT-1 ceiling of −20.9%. About 100% of the 12 mg arm lost ≥5%, 83% lost ≥15%, and 26% lost ≥30% at 48 weeks. Drove the launch of the phase 3 TRIUMPH-1 program and reset expectations for what triple agonism can deliver.

PMID 37366315 ↗NCT04881760 ↗DOI 10.1056/NEJMoa2301972 ↗

The phase 2 T2D trial randomized 281 adults with type 2 diabetes (HbA1c 7-10.5%, BMI 25-50) to retatrutide 0.5, 4, 8, or 12 mg weekly, dulaglutide 1.5 mg, or placebo for 36 weeks. Retatrutide 12 mg reduced HbA1c by −2.02% (vs −0.01% placebo, −1.41% dulaglutide) and body weight by −16.9% — substantially more weight loss than any GLP-1-class agent at comparable A1C reduction. The trial provided the first head-to-head signal that triple agonism outperforms GLP-1 monotherapy for both glycemia and weight in T2D, supporting the phase 3 TRIUMPH-2 design.

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

This pre-specified MASLD substudy of the phase 2 obesity trial enrolled 98 participants with ≥10% MRI-PDFF liver fat at baseline and assigned them to retatrutide 1/4/8/12 mg or placebo for 48 weeks. Liver fat content fell by 81.4-82.4% in the 8 and 12 mg arms versus +0.3% on placebo. Roughly 86-93% of high-dose participants achieved normalization (liver fat <5%). The magnitude exceeded any prior pharmacotherapy for steatosis and supported the phase 3 TRIUMPH-4 MASH program, positioning retatrutide as a potential dual obesity-hepatology agent.

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

This body-composition substudy of the phase 2 T2D trial used DXA on 99 participants to quantify the partitioning of retatrutide's weight loss between fat mass and lean mass. Of total weight lost on retatrutide 12 mg (~17%), approximately 81% was fat mass and 19% was lean mass — a ratio comparable to or favorable versus tirzepatide and semaglutide substudies. Visceral adipose tissue fell 36%. The data addressed the key safety question for triple agonists with glucagon activity and supported continued phase 3 development despite glucagon-driven catabolic concerns.

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

This pooled post-hoc analysis combined the two retatrutide phase 2 trials (obesity n=338, T2D n=281) to evaluate kidney effects across 48-week and 36-week timepoints. Retatrutide reduced UACR by 30-40% at the highest doses versus placebo, with the largest reductions in participants with baseline albuminuria. eGFR showed a small dose-dependent decline consistent with on-target hemodynamic effects seen with other incretin agents. The signal mirrored the FLOW kidney benefit established for semaglutide and motivated the dedicated phase 3 TRANSCEND-CKD trial in chronic kidney disease.

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

The TRANSCEND-CKD design paper describes the first dedicated phase 3 kidney-outcomes trial of a triple agonist. The trial will randomize ~2,000 adults with type 2 diabetes and CKD (eGFR 20-75, UACR 200-5000) to retatrutide or placebo on top of standard kidney-protective therapy (RAAS blockade plus SGLT2 inhibitor where appropriate). Primary composite endpoint mirrors the FLOW design that established the Ozempic CKD label in 2025. The baseline characteristics paper signals Lilly's intent to seek a dedicated kidney indication for retatrutide alongside its obesity, T2D, and MASH phase 3 programs.

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

The founding molecular paper for retatrutide. The Lilly chemistry team engineered LY3437943 as a single peptide with balanced GIP, GLP-1, and glucagon receptor agonism (potency ratio favoring GIP and GLP-1). Preclinical work in diet-induced obese mice produced dose-dependent weight loss exceeding the GIP/GLP-1 dual agonist tirzepatide and the GLP-1/glucagon dual agonist controls. A first-in-human phase 1a study in 72 healthy adults established safety, pharmacokinetics supporting weekly dosing, and dose-dependent weight reduction in a 12-week proof-of-concept cohort. Established the rationale for the obesity and T2D phase 2 programs.

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

The phase 1b multiple-ascending-dose trial randomized 72 type 2 diabetes patients to weekly retatrutide (0.5-12 mg) or placebo for 12 weeks. The trial established the maximum tolerated dose schedule and the dose-titration pattern carried forward into phase 2 and phase 3. At week 12, retatrutide 12 mg produced approximately −9 kg body weight and −1.6% HbA1c reduction. GI tolerability (nausea, diarrhea) followed the typical incretin pattern. The trial cleared the safety/PK hurdle for the larger phase 2 obesity (Jastreboff) and T2D (Rosenstock) trials, both initiated within 6 months of phase 1b readout.

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

This mechanistic substudy used acetaminophen pharmacokinetics to quantify retatrutide's effect on gastric emptying — the GLP-1-mediated mechanism that mediates much of the appetite-suppression and early-satiety signal across the incretin class. Retatrutide produced dose-dependent delay in gastric emptying that was modest at therapeutic doses and consistent with tirzepatide-class kinetics rather than the more pronounced delay seen with short-acting GLP-1s. The paper informed phase 2/3 dose escalation schedules and clinical guidance on GI tolerability management, important for the high-dose 12 mg regimen used in obesity trials.

PMID 37311727 ↗DOI 10.1111/dom.15167 ↗

This patient-reported-outcome substudy of the phase 2 T2D trial used validated instruments (Eating Behaviour Questionnaire, Three-Factor Eating Questionnaire, hunger/satiety VAS scales) to characterize how retatrutide changes appetite and eating behaviour. Retatrutide produced dose-dependent reductions in hunger, food cravings, and disinhibited eating, with the largest changes in the 8 and 12 mg arms — and the magnitude exceeded what is typically reported with semaglutide or tirzepatide phase-2 substudies. The data support the hypothesis that glucagon-receptor agonism layers an additional appetite-suppressive signal on top of the GIP+GLP-1 mechanism.

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