What Recent Trials Show About Retatrutide (LY3437943)

Retatrutide — the investigational compound assigned the development code LY3437943by Eli Lilly — has accumulated more published trial data in the past three years than most peptides receive in a decade. It is also one of our most searched-for products. This article is a structured reading list of the major retatrutide studies in the literature: what each was designed to ask, how it was run, what it reported, and where the open questions still sit.

Nothing here is a recommendation. Retatrutide is an investigational research compound; it is not approved by FDA, EMA, or any other regulator for human or veterinary use, and the product PepMax sells under the designation PM-3RT is supplied for laboratory research use only. The studies summarized below are the published scientific record — the same record any researcher evaluating the molecule should be working from.

What retatrutide is

Retatrutide is a 39-residue synthetic peptide engineered to activate three distinct G-protein-coupled receptors at once: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). The molecule carries Aib (α-aminoisobutyric acid) substitutions at positions 2 and 20 to resist DPP-4 cleavage and a C20 fatty diacid tethered through a γ-glutamate-PEG2 linker at Lys-17 to enable albumin binding and a once-weekly pharmacokinetic profile^[1].

In transfected-cell receptor assays from the discovery paper, retatrutide’s reported in vitro EC₅₀ values were approximately 0.064 nM at GIPR, 0.78 nM at GLP-1R, and 5.79 nM at GCGR, giving the molecule a deliberately asymmetric receptor activation profile rather than balanced triple agonism^[1]. The interest in adding glucagon-receptor activity to a GLP-1/GIP backbone is a hypothesis about energy expenditure and hepatic lipid handling: the Phase 2 trials below are the first place that hypothesis was tested at scale in humans.

Discovery and Phase 1 (Coskun & Urva, 2022)

The molecule was first described in two companion papers in 2022. Coskun and colleagues reported the discovery, structure–activity relationship, and preclinical pharmacology in Cell Metabolism^[1]. Urva and colleagues reported the first multiple-ascending-dose human study in The Lancet^[2].

The discovery paper’s contribution is the molecule itself — the SAR work that produced the GIPR-dominant agonism profile, the rationale for Aib stabilization, and the diacid linker design — together with rodent and non-human-primate metabolic data. The Phase 1b paper’s contribution is the first signal that the molecule’s pharmacology in humans matched the preclinical model: weekly dosing was feasible, the adverse-event profile was qualitatively similar to other incretin agonists, and a dose–response on HbA1c and body weight was visible within twelve weeks.

Phase 2 in obesity (Jastreboff, 2023)

The most-cited retatrutide paper to date is the Phase 2 obesity trial published by Jastreboff and colleagues in the New England Journal of Medicine in 2023^[3]. It is the largest published retatrutide dataset and the one that produced the weight-change figures that have anchored most subsequent reporting on the molecule.

The headline weight-change results at 48 weeks (least-squares mean, intent-to-treat):

Adverse events were predominantly gastrointestinal (nausea, diarrhoea, vomiting, constipation), dose-related, and concentrated during the dose-escalation period. The trial used a stepwise escalation schedule rather than initiating at target dose. The proportion of participants discontinuing study drug because of adverse events was numerically higher in the 12 mg arm than in lower-dose arms but did not exceed levels reported in comparable trials of other incretin-class agents. The authors flagged a small but measurable increase in heart rate that attenuated by the end of the trial.

Why this study matters

The 48-week LS-mean weight change at the 12 mg dose — −24.2% — is the largest reported in any blinded, placebo-controlled Phase 2 pharmacotherapy trial in obesity at the time of publication. It is also incomplete: the 48-week endpoint appeared to still be on the descending portion of the weight curve in higher-dose arms, meaning the asymptote was not yet reached. The TRIUMPH-1 Phase 3 trial is the study designed to answer how much further the curve continues, and how durable the loss is once the molecule is discontinued.

Phase 2 in type 2 diabetes (Rosenstock, 2023)

Published in The Lancetthe same summer, the Phase 2 type 2 diabetes trial by Rosenstock and colleagues asked whether retatrutide’s glycemic effect held up against an active comparator and across a longer dosing window^[4].

At 36 weeks, retatrutide produced HbA1c reductions of up to −2.02 percentage points at the highest dose, compared with −1.41for dulaglutide 1.5 mg and −0.01 for placebo. Body-weight reduction at 36 weeks reached approximately −16.9% in the highest-dose retatrutide arm, against −2.0% for dulaglutide and −3.0%for placebo. The adverse-event profile was again dominated by transient gastrointestinal events, with no unexpected safety signals identified at the trial’s 36-week horizon.

Phase 2 MASLD substudy (Sanyal, 2024)

A pre-specified substudy of the Phase 2 obesity trial, published by Sanyal and colleagues in Nature Medicine in 2024, used MRI proton-density fat fraction (MRI-PDFF) to quantify liver-fat changes in participants who had ≥5% hepatic steatosis at baseline^[5]. The substudy was designed to ask whether the molecule’s glucagon-receptor activity translated into the hepatic-steatosis reduction the preclinical program had predicted.

The proportion of participants achieving normal liver-fat content (MRI-PDFF ≤5%) at 48 weeks was approximately 86–93% in the highest-dose retatrutide arms, compared with 0% in the placebo group. The authors framed the result as evidence that the glucagon-receptor component of the molecule’s pharmacology contributes meaningfully to hepatic-fat reduction, beyond what would be expected from weight loss alone — though the substudy was not designed to disentangle weight-mediated from weight-independent effects, and a dedicated MASH histology trial (TRIUMPH-5) is required to test the histological endpoints regulators care about.

The TRIUMPH Phase 3 program

Eli Lilly initiated retatrutide’s Phase 3 program under the TRIUMPH umbrella beginning in 2024^[6]. As of this article’s publication, the program comprises five large registration-grade trials. None has reported a primary completion at the time of writing.

These trials are the studies that will determine whether the Phase 2 effect sizes survive contact with a registration-grade endpoint set, larger and more diverse populations, and the longer dosing horizons under which durability and rare adverse events become visible. Anyone using the Phase 2 numbers as a stand-in for “what retatrutide does” should treat them as preliminary until TRIUMPH topline data is available and peer-reviewed.

What this body of evidence does and does not show

Read together, the published trials establish a consistent set of claims and a consistent set of unanswered questions.

What the evidence supports

• A coherent pharmacological identity: a long-acting, weekly-dosed synthetic peptide whose triple-receptor agonism is reproducible across the discovery, Phase 1, and Phase 2 datasets.
• A dose–response on body weight and HbA1c visible from 12 weeks and extending through 48 weeks, with no clear plateau in higher-dose arms by the end of the published trials.
• A liver-fat signal larger than what weight loss alone has historically produced in incretin-class trials, consistent with the glucagon-receptor mechanism.
• An adverse-event profile in line with the incretin class over the published horizons: predominantly gastrointestinal, dose-related, attenuating after escalation.

What remains open

• Long-term durability.Phase 2 trials end at 36–48 weeks. Whether weight-loss and metabolic effects persist at 80+ weeks, and how the body responds to discontinuation, will not be answered until TRIUMPH-1 reads out.
• Cardiovascular outcomes. A weight-loss number is not a MACE number. TRIUMPH-3 is the trial that determines whether retatrutide reduces hard cardiovascular endpoints in adults with established disease.
• Histological MASH endpoints. MRI-PDFF is a quantitative imaging biomarker; biopsy-confirmed resolution of steatohepatitis without fibrosis worsening is a different and harder endpoint, scheduled for TRIUMPH-5.
• Comparative effectiveness.No published head-to-head trial exists yet against tirzepatide or semaglutide 2.4 mg in obesity; cross-trial comparisons of weight-change percentages are not the same as randomised comparisons.
• Population breadth. The Phase 2 datasets are predominantly middle-aged adults from a limited set of geographies, without major medical comorbidities outside the studied indication. Generalization beyond those populations awaits Phase 3.

Further reading

Each of the citations below links to the source paper or registry record. For research contextualizing what an HPLC purity number means for any peptide — including retatrutide — see our companion methods articles on what ≥99% purity actually means and how we verify peptide purity.