# Retatrutide research record — Phase 2 and Phase 3 trial summaries > Trial-by-trial summary of the published retatrutide evidence: Phase 1b pharmacokinetics, Phase 2 obesity (Jastreboff 2023 NEJM), Phase 2 T2D, Phase 2a MASLD, and the TRIUMPH Phase 3 program. Phase 1b through Phase 3 — what each study measured, who it enrolled, and what it found. ## The short version The retatrutide trial program spans Phase 1b pharmacokinetics through the ongoing Phase 3 TRIUMPH series. The short version: Phase 1b established a ~6-day half-life and once-weekly dosing. Phase 2 obesity (NEJM 2023) randomised 338 adults and found dose-dependent weight loss up to 24.2% at 48 weeks. Phase 2 type 2 diabetes (Lancet 2023) showed HbA1c reductions up to 2.02%. A Phase 2a substudy (Nature Medicine 2024) found the largest pharmacological liver-fat reductions reported for any agent to date. Phase 3 TRIUMPH-4 (Dec 2025) and TRIUMPH-1 (2026) have reported toplines; TRIUMPH-3 — the cardiovascular outcomes trial — remains active and unreported. Three safety signals run through the record: GI events (dose-dependent, escalation-clustered), a heart-rate increase (~5-10 bpm), and dysesthesia (20.9% on 12 mg in TRIUMPH-4). The sections below go trial by trial. ## Mechanism and pharmacology Retatrutide is a 39-amino-acid synthetic peptide derived from a glucagon backbone, lipid-modified with a C20 fatty di-acid via a gamma-glutamic acid linker at lysine 17. The lipidation enables albumin binding and extends circulating half-life to approximately six days, supporting once-weekly subcutaneous dosing [6]. In vitro the molecule activates all three target receptors with biased potency toward GIPR: EC50 0.064 nM (GIPR), 0.775 nM (GLP-1R), 5.79 nM (GCGR) [8]. Cryo-EM structural analysis published in 2024 showed retatrutide adopting a continuous helix that penetrates the transmembrane core of all three class-B G-protein-coupled receptors with distinct conformations at each [8]. Functionally, GLP-1R and GIPR activation drive glucose-dependent insulin secretion, slowed gastric emptying, and central appetite suppression. Glucagon receptor agonism adds hepatic fatty-acid oxidation and an increase in resting energy expenditure — a thermogenic component absent from pure GLP-1 agonists and from dual GLP-1/GIP agonists [16]. ## Phase 1b multiple ascending dose (Urva 2022) The first multiple-ascending-dose study enrolled 72 adults with type 2 diabetes for 12 weeks of weekly subcutaneous dosing from 0.5 mg up to 12 mg [6]. Pharmacokinetics were linear and dose-proportional, with an apparent terminal half-life of approximately six days. Placebo-adjusted body-weight reduction reached 8.96 kg at the highest dose by week 12 — an early efficacy signal at a duration shorter than any later trial [6]. This study set the once-weekly dosing schedule, the 12 mg ceiling explored in subsequent Phase 2 work, and the expectation that steady state would require several weeks of repeated dosing. ## Phase 2 obesity (Jastreboff 2023, NEJM) The pivotal Phase 2 obesity trial randomised 338 adults with obesity (without diabetes) to placebo or weekly retatrutide at 1, 4, 8, or 12 mg with stepwise dose escalation [1]. The primary endpoint was percentage body-weight change at 24 and 48 weeks. At 24 weeks the dose-response was clean: -7.2% (1 mg), -12.9% (combined 4 mg arms), -17.3% (combined 8 mg arms), -17.5% (12 mg), versus -1.6% on placebo [2]. At 48 weeks the 12 mg arm reached -24.2% versus -2.1% placebo; 83% of 12 mg participants had lost at least 15% of body weight by week 48 [1]. The trial also produced the broadest cardiometabolic biomarker profile in the program. At 48 weeks on 12 mg, systolic blood pressure fell approximately 10.2 mmHg, diastolic 4.5 mmHg, triglycerides 40.6%, non-HDL cholesterol 26.9%, and apoB 24.2%, with an increase in HDL particle size [14]. Hard cardiovascular outcomes are the remit of TRIUMPH-3, not Phase 2. ## Phase 2 type 2 diabetes (Rosenstock 2023, Lancet) A parallel Phase 2 trial in adults with type 2 diabetes evaluated 0.5, 4, 8, and 12 mg weekly with fast or slow escalation arms over 36 weeks, with dulaglutide 1.5 mg as the active comparator [5]. HbA1c reductions were dose-dependent up to -2.02% at the 12 mg escalation arm, compared with -1.41% for dulaglutide. Body-weight reduction reached approximately 16.94% at the highest dose. A 2025 body-composition substudy of the same trial reported that weight loss was predominantly fat mass — 15.2% fat-mass reduction (4 mg), 26.1% (8 mg), 23.2% (12 mg) — versus 4.5% on placebo and 2.6% on dulaglutide [9]. The proportion of weight loss attributable to lean mass was comparable to other obesity therapies. ## Phase 2a MASLD substudy (Sanyal 2024, Nature Medicine) A prespecified substudy of the Phase 2 obesity trial measured liver-fat content by MRI-PDFF in adults with obesity and metabolic dysfunction-associated steatotic liver disease [7]. At 48 weeks, mean liver-fat reduction was -81.7% on 8 mg and -86.0% on 12 mg, versus +4.6% on placebo. Normalisation of liver fat (below 5%) occurred in 89% of 8 mg participants and 93% of 12 mg participants, versus 0% on placebo [7]. These are the largest pharmacological reductions in hepatic steatosis reported for any agent to date. The Phase 3 program includes a dedicated MASLD study (TRIUMPH-MASLD); definitive histological data are pending. ## Phase 3 TRIUMPH program The TRIUMPH program is the sponsor's umbrella name for the Phase 3 evidence base, totalling more than 5,800 participants across studies in obesity, type 2 diabetes, MASLD, cardiovascular disease, knee osteoarthritis, and chronic kidney disease [17]. Three trials have read out so far. **TRIUMPH-4** (445 adults with obesity and knee osteoarthritis) reported in December 2025. At 68 weeks the 12 mg arm produced a 28.7% body-weight reduction and the 9 mg arm 26.4%, versus 2.1% placebo. The WOMAC pain subscale dropped 4.4-4.5 points (approximately 75.8% relative reduction), and roughly one in eight retatrutide-treated participants reported being completely free of knee pain at week 68 [12]. Systolic blood pressure decreased by 14 mmHg on 12 mg [13]. **TRIUMPH-1** (2,339 adults with obesity without diabetes) reported topline in 2026. Mean 80-week weight reductions were 19.0% (4 mg), 25.9% (9 mg), and 28.3% (12 mg), versus 2.2% placebo. 45.3% of the 12 mg arm achieved at least 30% weight loss [10]. In a prespecified extension to 104 weeks for participants with baseline BMI ≥35, the 12 mg arm lost on average 30.3% of body weight without a clear plateau through two years [11]. **TRIUMPH-3** (NCT05882045) is the dedicated cardiovascular outcomes trial in adults with obesity and established cardiovascular disease. It is the trial that will provide the first prospective MACE data for retatrutide. As of 2026 it remains active and unblinded outcomes have not been reported [15]. Until TRIUMPH-3 reads out, the cardiovascular benefit-risk profile is anchored on Phase 2 biomarker data and the safety findings summarised below. ## Safety signals Three signals run through the trial record. **Gastrointestinal events** are the most common, are dose-dependent, mostly mild-to-moderate, and cluster during dose escalation. In Phase 2, adverse-event-driven discontinuation ranged from 6% (1 mg) to 16% (12 mg) versus 0% on placebo [3]. In TRIUMPH-4 the rates were 12.2% (9 mg), 18.2% (12 mg), and 4.0% placebo [13]. Slow-escalation arms in the Phase 2 type 2 diabetes trial improved tolerability versus fast-escalation arms at the same final dose [5]. **Heart rate** increased by approximately 5-10 bpm in Phase 2 in a dose-dependent fashion, peaked around week 24, and partially declined thereafter. One severe cardiac arrhythmia event (prolonged QT syndrome) was reported. There was no MACE signal versus placebo in Phase 2, but the trial was not powered for cardiovascular outcomes [4]. **Dysesthesia** — abnormal cutaneous sensation such as tingling, burning, or prickling — was reported in 20.9% of the TRIUMPH-4 12 mg group versus 0.7% on placebo, mostly mild [13]. The signal magnitude exceeds what has been reported with other approved incretin therapies and is under further evaluation. No retatrutide data exist in pregnancy, breastfeeding, or pediatric populations [17]. Long-term safety beyond approximately two years is unknown. --- A primary-literature monitor for an investigational compound — not a clinic, not a vendor, not a clinical recommendation.