Changes in Liver Fat in Patients with Type 2 Diabetes by Presence of Genetic Hepatic Steatosis in the SURPASS-3 MRI Substudy

Patatin-like phospholipase 3 (PNPLA3) I148 genetic variant is highly associated with nonalcoholic fatty liver disease. Tirzepatide (TZP), a novel GIP/GLP-1 receptor agonist, significantly reduced liver fat content (LFC) vs insulin degludec (IDeg) in a subpopulation of patients in the SURPASS-3 phase 3 trial. This post-hoc analysis evaluated changes from baseline to Week 52 in LFC and cardiometabolic parameters by presence of PNPLA3 I148 allele (yes [genotype CG/GG] or no [genotype CC]). Insulin-naïve patients with type 2 diabetes inadequately controlled on metformin with/without SGLT-2i and fatty liver index ≥60 at baseline had an MRI scan performed prior to randomization (1:1:1:1) to once-weekly TZP (5, 10, 15 mg) or IDeg. LFC was assessed with MRI. Patients (mean baseline age, 56.2 years; diabetes duration, 8.3 years; HbA1c, 8.2%; weight, 94.4 kg; BMI, 33.5 kg/m2; 30% on SGLT-2i) experienced greater reductions in LFC, weight, HbA1c, and overall greater improvement in lipids profile and liver enzymes with all doses of TZP than with IDeg regardless of the presence of PNPLA3 I148 allele (Table). Findings with TZP were consistent in both subgroups. In summary, TZP led to clinically meaningful improvements in several cardiometabolic parameters in patients with type 2 diabetes regardless of the presence of PNPLA3 I148 allele. Disclosure K. Cusi: Research Support; Echosens, Inventiva. Consultant; Poxel SA. Research Support; LabCorp, Zydus. Consultant; Altimmune, Arrowhead Pharmaceuticals, Inc., AstraZeneca, 89bio, Inc., Bristol-Myers Squibb Company, Lilly, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Medscape, Myovant, Novo Nordisk, ProSciento, Quest Diagnostics, Sagimet, Sonic Incytes, Terns. A. Gastaldelli: Consultant; Boehringer Ingelheim International GmbH, Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Pfizer Inc. Consultant; Fractyl Health, Inc. Advisory Panel; Novo Nordisk, Merck Sharp & Dohme Corp., Boehringer Ingelheim International GmbH. Other Relationship; Pfizer Inc. Consultant; Merck Sharp & Dohme Corp. L. Fernandez Lando: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. M. Liu: Consultant; Eli Lilly and Company. A. Torcello-Gomez: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Á. Rodríguez: Employee; Eli Lilly and Company. Stock/Shareholder; Eli Lilly and Company. Funding Eli Lilly and Company