Retatrutide and fatty liver: what the phase 2 MASLD substudy found
Retatrutide's glucagon receptor activity gives it an unusual effect on the liver. In the MASLD substudy of the phase 2 obesity trial, published in Nature Medicine in 2024, relative liver fat fell by 81.4% on 8 mg and 82.4% on 12 mg at 24 weeks, versus a 0.3% increase on placebo, and more than 80% of participants on those doses reached a normal liver fat level. No histology or outcomes data exist yet.
Key facts
- The substudy enrolled 98 participants from the phase 2 obesity trial who had at least 10% liver fat on MRI-PDFF at baseline.
- At 24 weeks, relative change in liver fat was −42.9% (1 mg), −57.0% (4 mg), −81.4% (8 mg) and −82.4% (12 mg), against +0.3% on placebo.
- Normal liver fat (below 5%) was reached by 27%, 52%, 86% and 82% of participants on 1, 4, 8 and 12 mg respectively, and by none on placebo.
- The liver fat reduction outpaced body weight loss, which was about 17 to 18% on the higher doses at the same time point; glucagon receptor activity is the likely reason.
Photograph: editorial illustration for this article. It does not show retatrutide.
On this page
What is MASLD and why does it matter here?
Metabolic dysfunction-associated steatotic liver disease is the accumulation of fat in the liver in people with a metabolic risk factor such as obesity or type 2 diabetes. It is the most common chronic liver condition worldwide, it progresses in a minority of people to inflammation (MASH), fibrosis and cirrhosis, and until recently it had no approved drug treatment. Any obesity drug that clears liver fat quickly is therefore of interest to hepatologists as well as to obesity specialists.
Retatrutide is of particular interest because one of its three targets, the glucagon receptor, acts directly on the liver to increase fatty acid oxidation, as described in the discovery paper[3]. Our mechanism article explains the receptor pharmacology; this page is about what that produced in people.
What was the substudy?
The phase 2 obesity trial (NCT04881760) enrolled 338 adults with obesity or overweight and followed them for 48 weeks on placebo or retatrutide 1, 4, 8 or 12 mg weekly[4][2]. Within that trial, 98 participants who had a liver fat fraction of at least 10% on MRI-PDFF at baseline formed a pre-specified substudy, published by Sanyal and colleagues in Nature Medicine in 2024. The primary endpoint of the substudy was the relative change in liver fat at 24 weeks[1].
What were the results at 24 weeks?
The relative reductions in liver fat at 24 weeks were 42.9%, 57.0%, 81.4% and 82.4% for the 1, 4, 8 and 12 mg groups, against a 0.3% increase on placebo. The proportion of participants whose liver fat fell below 5%, the conventional threshold for normal, was 27%, 52%, 86% and 82% respectively, and zero on placebo[1]. The paper also reports improvements in markers of insulin sensitivity and lipid metabolism consistent with the liver changes.
| Dose | Liver fat, relative change | Normal liver fat reached | Body weight change (main trial) |
|---|---|---|---|
| Placebo | +0.3% | 0% | −1.6% |
| 1 mg | −42.9% | 27% | −7.2% |
| 4 mg | −57.0% | 52% | −12.9% |
| 8 mg | −81.4% | 86% | −17.3% |
| 12 mg | −82.4% | 82% | −17.5% |
Body weight figures are the 24-week values from the main trial publication[2]; the substudy participants were a subset of those groups.
Why does the liver respond faster than body weight?
Because two mechanisms act on it at once. Weight loss of any kind reduces liver fat, and at 17% weight loss most people show a substantial decline. On top of that, glucagon receptor activation in hepatocytes increases fatty acid oxidation and reduces lipogenesis directly, independent of how much weight has been lost[3]. The result in the substudy is a liver fat reduction of more than 80% while body weight had fallen by less than 20%[1], a ratio that single and dual incretin agonists have not matched at similar time points in their own trials.
What are the limits of this evidence?
- Size and length. 98 people, 24-week primary endpoint, inside a trial that ended at 48 weeks.
- Imaging, not histology. MRI-PDFF measures fat. It does not measure inflammation or fibrosis, which are what determine liver outcomes. No biopsy data for retatrutide have been published.
- No outcomes. Nobody knows yet whether the liver fat reduction prevents cirrhosis, liver cancer or death; those endpoints take years.
- Selection. Participants had obesity and at least 10% liver fat; the effect in lean MASLD or in advanced disease is untested.
What comes next for retatrutide and the liver?
The phase 3 TRIUMPH program was designed around body weight, not the liver, and Lilly has not announced a dedicated MASH trial with histological endpoints for retatrutide as of September 2026. The natural next step in the literature would be a biopsy-based phase 2 or 3 study of the kind other incretin-based drugs have run. Until then, the Nature Medicine substudy is the liver evidence, and it is strong on fat and silent on everything after fat. The rest of the program is on our clinical trials page.
Frequently asked questions
Does retatrutide treat fatty liver disease?
It reduced liver fat by more than 80% in 24 weeks at the 8 mg and 12 mg doses in a phase 2a substudy of 98 people. That is a change in liver fat on imaging, not a demonstrated improvement in inflammation, fibrosis or clinical outcomes, and retatrutide is not approved for any indication.
What is MASLD?
Metabolic dysfunction-associated steatotic liver disease, the current name for what was called non-alcoholic fatty liver disease (NAFLD). It is defined by excess liver fat together with a metabolic risk factor such as obesity or type 2 diabetes.
How was liver fat measured?
By MRI proton density fat fraction (MRI-PDFF), a non-invasive imaging method that quantifies the percentage of fat in the liver. A value below 5% is considered normal.
Is the liver effect bigger than with tirzepatide or semaglutide?
The retatrutide figures are larger than those published for dual or single agonists at similar time points, but the studies are not comparable in design and there is no head-to-head liver trial.
Sources
- Sanyal AJ, Kaplan LM, Frias JP, et al. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nature Medicine. 2024;30:2037-2048. DOI 10.1038/s41591-024-03018-2
- Jastreboff AM, Kaplan LM, Frías JP, et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity: A Phase 2 Trial. New England Journal of Medicine. 2023;389(6):514-526. DOI 10.1056/NEJMoa2301972
- Coskun T, Urva S, Roell WC, et al. LY3437943, a novel triple glucagon, GIP, and GLP-1 receptor agonist for glycemic control and weight loss: From discovery to clinical proof of concept. Cell Metabolism. 2022;34(9):1234-1247. DOI 10.1016/j.cmet.2022.07.013
- ClinicalTrials.gov. A Phase 2 Study of Once-Weekly LY3437943 Compared With Placebo in Participants Who Have Obesity or Are Overweight With Weight-Related Comorbidities. Phase 2, 338 participants, started 20 May 2021, completed 22 November 2022. NCT04881760
DOIs were checked against the CrossRef API and trial identifiers against the ClinicalTrials.gov API v2 on 2026-09-21. Press releases are cited by URL because topline results are not yet in a peer-reviewed journal.