Liver international : official journal of the International Association for the Study of the LiverAug 11, 2026

Changes in Liver Fat in Type 2 Diabetes Patients With or Without Genetic Fatty Liver

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗OA ↗

Updated Aug 12, 2026

Abstract

Tirzepatide treatment resulted in significant reductions in liver fat content (LFC) and other cardiometabolic parameters in patients with type 2 diabetes.

The PNPLA3 I148M genetic variant is associated with steatotic liver disease.
Tirzepatide reduced LFC, weight, HbA1c, and improved lipid and liver enzyme levels after 52 weeks of treatment.
Improvements in LFC and cardiometabolic parameters occurred regardless of the presence of the PNPLA3 I148M allele.
Findings were consistent across different genotype subgroups (GG, CG, CC).
The presence of the PNPLA3 I148M allele did not appear to influence the effectiveness of tirzepatide.

Simplified

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, HbA_1c, 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.