From Cure to Complexity: Post-SVR Liver and Metabolic Trajectories in Diabetic Patients

ABSTRACT Background and Aims: The long-term impact of HCV cure on hepatic and metabolic outcomes in patients with type 2 diabetes (T2D) remains insufficiently defined. This study evaluated T2D-related vascular complications, liver disease progression and overall survival over 9 years of follow-up, also exploring genetic variability contribution. Methods: Consecutive T2D patients with HCV-related chronic liver disease or cirrhosis treated with direct-acting antivi- rals (DAAs) between 2015 and 2018 at the University Hospital of Messina were prospectively followed until September 2024. Demographic, biochemical, and clinical data were collected at baseline and throughout follow-up. Regression models were ap- plied to identify predictors of metabolic and hepatic outcomes. Genetic variants—PNPLA3 rs738409, TM6SF2 rs58542926 and rs641738 at the MBOAT7/TMC4 locus—were also assessed. Results: A total of 183 patients (52% males, median age 67 years; 56% cirrhotic) were followed for a median of 48 months (range 24–84). Despite significant improvements in HbA1c (p = 0.006), liver-stiffness (p < 0.001), gamma-globulins (p < 0.001), and ami- notransferases (p < 0.001), only 27.3% maintained clinical stability. Liver disease progression occurred in 20.8% of patients and was related to cirrhosis (p = 0.021), prior decompensation (p = 0.07), and the MBOAT7 variant (p = 0.025). Macrovascular and mi- crovascular complications developed in 50.8% and 33.9% of patients, respectively, mostly within 2 years after SVR. In multivariate models, higher TyG index (p = 0.038) predicted the composite progression endpoint, while elevated LDL cholesterol (p = 0.048), mortality.