SURPASS-3 MRI sub-study reports a large drop in liver fat with tirzepatide

A sub-study of the phase 3 SURPASS-3 trial found that tirzepatide, sold as Mounjaro and Zepbound, reduced liver fat content much more than insulin degludec in adults with type 2 diabetes who also had signs of fatty liver disease ^[1]. The findings, published in The Lancet Diabetes & Endocrinology, add to evidence that this dual GIP and GLP-1 receptor agonist affects fat stored in the liver and abdomen, not just blood sugar ^[1].

The sub-study enrolled 296 participants from the larger SURPASS-3 trial who had a fatty liver index of at least 60, a marker suggesting fatty liver disease ^[1]. All had type 2 diabetes, a body mass index of at least 25, and were being treated with metformin alone or with an SGLT2 inhibitor before joining the study ^[1]. Participants were randomly assigned to weekly tirzepatide at 5 mg, 10 mg, or 15 mg, or daily insulin degludec, and researchers measured liver fat using MRI-based proton density fat fraction at the start of the study and after 52 weeks ^[1].

At baseline, average liver fat content across the group was 15.71%, with a standard deviation of 8.93 ^[1]. After a year, participants on pooled tirzepatide 10 mg and 15 mg doses saw liver fat drop by 8.09 percentage points, compared with a 3.38 percentage point drop for those on insulin degludec ^[1]. The estimated difference between groups was -4.71 percentage points, with a 95% confidence interval of -6.72 to -2.70, a statistically significant result (p<0.0001) ^[1]. The trial also tracked visceral and abdominal subcutaneous fat, and researchers found the reduction in liver fat was correlated with baseline liver fat levels, reductions in these other fat measures, and reductions in body weight, though the strength of these correlations varied ^[1].

The study was funded by Eli Lilly and Company, the maker of tirzepatide, and several authors disclosed financial ties to the company, including two who are Lilly employees and shareholders ^[1]. The trial was open-label, meaning participants and researchers knew which treatment was being given, which can affect how results are interpreted ^[1].

Why it matters for patients

Fatty liver disease is common in people with type 2 diabetes, and liver fat buildup can progress to more serious liver damage over time. This sub-study suggests tirzepatide may reduce liver fat more effectively than a standard insulin treatment in this population, based on MRI measurements taken over one year ^[1]. That is a different kind of outcome than blood sugar control or weight loss numbers reported elsewhere in the main SURPASS-3 trial, and it may be relevant to patients managing both diabetes and fatty liver disease.

However, this was a sub-study of 296 people, not the full SURPASS-3 trial population, and it measured liver fat by imaging rather than clinical outcomes like liver scarring or disease progression ^[1]. The study also did not test tirzepatide specifically for a fatty liver disease diagnosis, nor did it compare tirzepatide against no treatment or a placebo, only against insulin degludec ^[1]. What this means for long-term liver health, or whether it applies to people without diabetes, is not addressed in this study.

What happens next

The SURPASS-3 MRI sub-study was completed and its results published in 2022, registered under ClinicalTrials.gov number NCT03882970 ^[1]. The sources provided do not describe any specific follow-up trials designed to test tirzepatide as a treatment for fatty liver disease on its own, so further clinical evidence on that question is not yet available in these materials.