Retatrutide

A single-molecule triple agonist of the GIP, GLP-1 and glucagon receptors, and one of the most potent metabolic research compounds studied to date.

What it is

Retatrutide, known in the development literature as LY3437943, is a synthetic 39-amino-acid peptide engineered by Eli Lilly to activate three metabolic receptors from a single molecule: the glucose-dependent insulinotropic polypeptide receptor (GIPR), the glucagon-like peptide-1 receptor (GLP-1R), and the glucagon receptor (GCGR). Its backbone is derived from the GIP sequence and carries a C20 fatty-diacid moiety that binds albumin, extending the circulating half-life to support once-weekly research dosing.

It belongs to the incretin and glucagon co-agonist class, extending the dual-agonist work behind tirzepatide by adding a third arm, glucagon-receptor activity, to the GIP and GLP-1 pathways. Supplied strictly for laboratory research use only, not for human or veterinary use.

How it works

Retatrutide is a balanced agonist across its three targets, with reported in-vitro potencies (EC50) of 0.0643 nM at GIPR, 0.775 nM at GLP-1R and 5.79 nM at GCGR. The GLP-1 and GIP arms drive incretin signalling, which in research models is associated with enhanced glucose-dependent insulin secretion and reduced food intake, mechanisms shared with the established single and dual incretin agonists.

The distinguishing feature is the added glucagon-receptor agonism. Glucagon signalling is studied for its effect on energy expenditure and hepatic lipid handling, and the working hypothesis in the literature is that pairing glucagon activity with the appetite and glycemic effects of GIP and GLP-1 amplifies weight loss beyond what either incretin pathway achieves alone, while the glucagon-driven rise in energy expenditure and lipid mobilisation is thought to underlie the compound's marked effects on liver fat.

What the research shows

Retatrutide has been evaluated in randomised phase 2 trials in obesity, type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD). In the 338-participant phase 2 obesity trial published in the New England Journal of Medicine, once-weekly subcutaneous retatrutide produced dose-dependent, placebo-adjusted weight loss reaching a mean of 24.2% at the 12 mg dose over 48 weeks, among the largest reductions reported for any pharmacological agent. Parallel trials showed strong glycemic effects in type 2 diabetes and near-normalisation of liver fat in MASLD.

Liver Fat

Excess fat stored inside the liver is the defining feature of metabolic dysfunction-associated steatotic liver disease (MASLD, previously called NAFLD), and it sits upstream of the more serious steatohepatitis, fibrosis and cirrhosis. This is the arena where retatrutide's third receptor arm sets it apart from every compound in the pure GLP-1 or dual GIP/GLP-1 class. Glucagon-receptor agonism acts directly on hepatocytes to raise fat oxidation and lipid export, so on top of the appetite and glucose effects it shares with the incretins, retatrutide mobilises hepatic fat through a pathway those other agents never engage. In the dedicated MASLD trial the result was one of the most striking reported for any drug studied for the liver: at the higher doses liver fat fell by more than 80% and returned to the normal range in the large majority of participants.

The MASLD trial (Sanyal, 2024)

The liver-fat data come from a randomised, double-blind, placebo-controlled phase 2a sub-study of Eli Lilly's phase 2 obesity programme, published in Nature Medicine by Sanyal and colleagues. It followed 98 adults who had obesity and MASLD with at least 10% liver fat at baseline (group mean baselines ranged from roughly 16% to 21%), none of whom had type 2 diabetes. Participants received once-weekly subcutaneous retatrutide at 1, 4, 8 or 12 mg, or placebo, and liver fat was quantified non-invasively by MRI-PDFF (proton density fat fraction), the standard imaging readout for liver fat, at weeks 24 and 48.

The effect was steeply dose-dependent and largely established by week 24, then held or deepened through week 48. At 8 mg and 12 mg the relative reduction passed 80%, approaching the floor of what MRI-PDFF can still resolve, while placebo barely moved: a slight 0.3% rise at 24 weeks and a 4.6% reduction at 48 weeks. Both timepoints are plotted so the trajectory of each dose is visible, and the near-flat placebo bars make the size of the drug effect hard to miss.

Reaching normal liver fat

A relative-reduction percentage matters most when it crosses a clinical line, and here it did. Bringing liver fat back below the 5% normal threshold is the outcome that reflects a healthy liver, and retatrutide reached it in most treated participants. By week 24, liver fat had already normalised in 79% of the 8 mg group and 86% of the 12 mg group, rising to 89% and 93% by week 48. The lower doses moved a meaningful share too, bringing roughly a quarter of the 1 mg group and about half of the 4 mg group into the normal range by week 24. Across the retatrutide arms, between 63% and 100% of participants achieved at least a 30% relative reduction in liver fat by 48 weeks, compared with 21% on placebo.

Values are least-squares mean relative change in liver fat from baseline by MRI-PDFF, drawn from Sanyal et al., Nature Medicine 2024. A negative figure is a reduction; placebo shows a small 0.3% rise at 24 weeks before a 4.6% reduction at 48 weeks.

Safety signals in the literature

Across the phase 2 programme the most common adverse events were gastrointestinal (nausea, diarrhoea, vomiting and constipation), which were dose-related and mostly mild to moderate in severity, consistent with the incretin class. The obesity trial also reported dose-dependent increases in heart rate that peaked around 24 weeks and then declined. These are third-party clinical observations reported for context only and do not constitute safety guidance for any non-research setting.

Side Effects

Retatrutide (LY3437943) is an investigational triple GLP-1, GIP, and glucagon receptor agonist that is not yet approved by the FDA. Its tolerability profile comes mainly from Eli Lilly's Phase 2 trials: the obesity trial reported by Jastreboff and colleagues in the New England Journal of Medicine (2023) and the type 2 diabetes trial reported by Rosenstock and colleagues in The Lancet (2023), plus a later meta-analysis pooling the randomized data. Across these studies the side-effect picture looks like other incretin-based drugs: mostly gastrointestinal, dose-related, and concentrated during dose escalation.

In these trials the gastrointestinal effects were largely transient, dose-related, and manageable by slower dose escalation, and the heart-rate increase reversed over time. Because retatrutide remains investigational, its long-term safety, rare adverse events, and cardiovascular outcomes are still being evaluated in ongoing Phase 3 studies.

At a glance

Dosing

Retatrutide (LY3437943) is an investigational triple GLP-1/GIP/glucagon receptor agonist from Eli Lilly, and it is not approved by the FDA. The dose figures below come from two phase 2 trials published in 2023: an obesity trial in the New England Journal of Medicine (Jastreboff et al.) and a type 2 diabetes trial in The Lancet (Rosenstock et al.). In both studies the drug was given by weekly subcutaneous injection starting at a low dose, then titrated upward over several weeks to reach the assigned maintenance dose. Lower starting doses were used specifically because gastrointestinal side effects were dose related and were partly reduced by starting low.

These are doses used in clinical studies, not dosing instructions. The trials used gradual titration from a low starting dose, and the lower maintenance doses (for example 1 mg and 4 mg) still produced measurable effects, so effective doses were not limited to the 12 mg maximum. Retatrutide remains investigational and is described here for laboratory research use only.

Preparing it

Reconstitute the lyophilized powder with bacteriostatic or sterile water, drawn slowly down the side of the vial and swirled gently, never shaken, until fully dissolved. The volume of water you add sets the concentration of the solution.

For the full procedure see reconstitution, and to work out concentration per unit see concentration & math.

Where to go next

Last updated on July 6, 2026