TRIPLE AGONIST / LY3437943 / RESEARCH RECORD
What the trials say about retatrutide safety
A monitor for the investigational once-weekly triple agonist of GLP-1R, GIPR, and GCGR. Phase 2 and Phase 3 safety signals, side by side. Investigational; not FDA-approved.
The short version
Retatrutide (LY3437943) is an investigational drug — not approved anywhere, not available by prescription. It is being studied by Eli Lilly in Phase 3 trials under the TRIUMPH program. The basic idea: a single molecule activates three hormone receptors at once — GLP-1 (appetite suppression), GIP (insulin enhancement), and glucagon (energy expenditure). No approved drug does all three simultaneously.
Phase 2 trials showed large weight-loss numbers: up to 24.2% mean body-weight reduction at 48 weeks on the highest dose. Phase 3 TRIUMPH-1 has since reported 28.3% at 80 weeks. The most common adverse events were gastrointestinal — nausea, vomiting, diarrhea — and a dose-dependent heart-rate increase was also documented.
This site catalogues the published trial evidence with safety as the organising lens. For what the research community reports from personal use — and for cited safety cautions from the trial data — see effects and safety.
What retatrutide is
Retatrutide (development code LY3437943) is a 39-amino-acid synthetic peptide engineered to engage three receptors simultaneously: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR) [1]. It is administered once weekly by subcutaneous injection, with an apparent terminal half-life of approximately six days [6].
As of 2026 retatrutide is investigational. It is not approved by the FDA, the EMA, or any other regulator, and it is not legally prescribable outside an enrolled clinical trial [15]. The Phase 3 TRIUMPH program is ongoing; topline results from TRIUMPH-4 (knee osteoarthritis with obesity) were announced in December 2025, with TRIUMPH-1 (obesity without diabetes) following in 2026 [10][12]. The cardiovascular outcomes trial, TRIUMPH-3, has not yet read out [15].
This site catalogues the published and preliminary evidence with safety as the organising lens. The headline numbers — 24.2% mean weight loss at 48 weeks in Phase 2, 28.3% at 80 weeks in Phase 3 — are well attested [1][10]. The safety questions that surround them are not yet fully answered.
Why a triple agonist
Single-receptor GLP-1 agonists slow gastric emptying, enhance glucose-dependent insulin release, and reduce appetite through hypothalamic signalling. Dual GLP-1/GIP agonists add an additional incretin arm with effects on insulin secretion and adipose-tissue energy handling [8].
Retatrutide adds a third arm: glucagon receptor agonism. In the published mechanism literature this is the component believed to drive the molecule's marked hepatic-fat reduction and to partially offset the drop in resting energy expenditure that typically accompanies rapid weight loss, via hepatic fatty-acid oxidation and brown-adipose mitochondrial uncoupling [16].
In vitro receptor potency is biased toward GIPR: the published EC50 values are 0.064 nM at GIPR, 0.775 nM at GLP-1R, and 5.79 nM at GCGR [8]. Cryo-EM structural work in 2024 showed how a single peptide ribbon engages all three class-B GPCRs with distinct conformations [8].
What the Phase 2 data showed
The pivotal Phase 2 obesity trial, published in the New England Journal of Medicine in 2023, randomised 338 adults to placebo or weekly retatrutide at 1, 4, 8, or 12 mg with stepwise dose escalation [1]. At 48 weeks, the 12 mg arm produced a least-squares mean body-weight reduction of 24.2% versus 2.1% with placebo; 83% of participants on 12 mg lost at least 15% of body weight [1].
Dose-response was clean. At 24 weeks the body-weight reductions were -7.2% (1 mg), -12.9% (combined 4 mg), -17.3% (combined 8 mg), and -17.5% (12 mg) versus -1.6% placebo [2]. A parallel Phase 2 trial in adults with type 2 diabetes reported HbA1c reductions up to -2.02% at the 12 mg escalation arm versus -1.41% for the active comparator dulaglutide 1.5 mg [5].
The Phase 2a substudy in adults with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) reported the largest pharmacological reductions in liver fat seen to date: 48-week MRI-PDFF was -86.0% on 12 mg versus +4.6% on placebo, with 93% of 12 mg participants achieving liver fat below 5% [7].
What the Phase 3 readouts have added so far
TRIUMPH-4 (445 adults with obesity and knee osteoarthritis) was the first Phase 3 retatrutide trial to read out, in December 2025 [12]. At 68 weeks the 12 mg arm produced a mean body-weight reduction of 28.7% and the 9 mg arm 26.4%, versus 2.1% with placebo. The WOMAC pain subscale dropped by 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].
The TRIUMPH-1 obesity topline followed in 2026: in 2,339 adults without diabetes, 80-week mean weight reductions were 19.0% (4 mg), 25.9% (9 mg), and 28.3% (12 mg) versus 2.2% placebo, with 45.3% of the 12 mg arm achieving at least 30% weight loss [10]. In a prespecified extension to 104 weeks for participants with baseline BMI of 35 or higher, the 12 mg arm lost on average 30.3% of body weight — roughly 85 lbs — without an obvious plateau [11].
TRIUMPH-1 and TRIUMPH-4 topline data have been released by the sponsor but had not yet been peer-reviewed at the time of writing. Final published numbers may differ from the press-release figures.
The safety questions that remain
Three signals are under active investigation.
Gastrointestinal events are the most common adverse events, are dose-dependent, mostly mild-to-moderate, and cluster during dose escalation. In Phase 2, adverse-event-driven discontinuation ranged from 6% at 1 mg to 16% at 12 mg, versus 0% placebo [3]. In TRIUMPH-4, discontinuation was 12.2% (9 mg), 18.2% (12 mg), and 4.0% placebo [13].
Heart rate increased by approximately 5-10 bpm in Phase 2, peaking around week 24 and partially declining thereafter; one severe arrhythmia event (prolonged QT syndrome) was reported [4]. The TRIUMPH-3 cardiovascular outcomes trial in adults with obesity and established cardiovascular disease is the trial that will provide prospective MACE (major adverse cardiovascular events) data; as of 2026 it is still active and has not yet read out [15].
Dysesthesia — abnormal cutaneous sensation such as tingling or burning — was reported in 20.9% of the 12 mg group in TRIUMPH-4 versus 0.7% on placebo, mostly mild [13]. This signal is not seen at the same magnitude with other approved incretin therapies and is under further evaluation.
No data exist in pregnancy, breastfeeding, or pediatric populations. Long-term safety beyond approximately two years is unknown [17].
How this site is organised
/research catalogues each trial — Phase 1b pharmacokinetics, Phase 2 obesity (NEJM), Phase 2 T2D (Lancet), Phase 2a MASLD (Nature Medicine), the body-composition substudy (Lancet D&E), and the TRIUMPH program — with dose, duration, population, primary outcome, and safety findings.
/effects presents two layers: effects reported by the research-use community (labeled anecdotal) and cited safety cautions from the Phase 2 trial data.
/dosage summarises the doses studied across the trial program and the titration schedules used. Because retatrutide is investigational, all dosing information is research-context only.
/faq answers the questions readers send. /references is the citation table, sortable and searchable. /about describes the editorial standards and what this site is and is not.