Liver Fat Changes in Patients With Type 2 Diabetes by Presence of Genetic Hepatic Steatosis: A Post Hoc Analysis of SURPASS-3 MRI
In brief
Tirzepatide lowers liver fat by similar amount in diabetics
In a 52-week MRI substudy of insulin-naïve type 2 diabetes patients, tirzepatide produced significant reductions in liver fat, weight, HbA1c, lipids and liver enzymes, and these improvements were comparable in participants carrying the PNPLA3 I148M variant (genotypes GG or CG) and those without it (CC). The analysis suggests the drug's liver-fat benefits are not limited by this common genetic risk factor, though longer-term outcomes remain to be studied.
- Journal
- Liver international : official journal of the International Association for the Study of the Liver (Q1)
- Published
- 1 September 2026
- Study design
- Randomized controlled trial
- Evidence level
- Level 1, High (CEBM 1b)
- Authors
- Kenneth Cusi, Amalia Gastaldelli, Laura Fernández Landó, Palash Sharma, Amelia Torcello-Gómez, Ángel Rodríguez
- PMID
- 42576670
- DOI
- 10.1111/liv.70837
Why clinicians should know about it
- Picked for Radiology, Radiation Oncology, Nuclear Medicine, Medical Physics and Imaging (top studies of the week, 16 August 2026): Tirzepatide liver fat changes, metabolic trial
Abstract
The patatin-like phospholipase 3 (PNPLA3) I148M genetic variant is highly associated with steatotic liver disease. In the SURPASS-3 MRI substudy, tirzepatide significantly reduced liver fat content (LFC) versus insulin degludec in insulin-naïve patients with type 2 diabetes with metabolic dysfunction-associated steatotic liver disease. The influence of PNPLA3 I148M allele on changes in LFC in response to tirzepatide is unknown. This post hoc analysis evaluated changes in MRI-assessed LFC and cardiometabolic parameters by presence (genotypes GG and CG) or absence (genotype CC) of the PNPLA3 I148M allele after 52-week treatment. Tirzepatide-treated participants experienced significant reductions in LFC, weight, HbA1c, and overall greater improvement in lipids and liver enzymes regardless of the presence of PNPLA3 I148M allele. Findings were consistent across genotype subgroups. In this exploratory analysis, the presence of PNPLA3 I148M allele did not seem to affect tirzepatide-induced improvement in LFC and several cardiometabolic parameters in patients with type 2 diabetes. Trial Registration: ClinicalTrials.gov identifier: NCT03882970.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.