From Cure to Complexity: Post‐ <scp>SVR</scp> Liver and Metabolic Trajectories in Diabetic Patients

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 antivirals (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 applied 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 aminotransferases (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 microvascular 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. CONCLUSIONS: Although DAAs lead to metabolic and hepatic improvements, long-term prognosis in T2D patients remains largely determined by baseline liver disease severity, insulin resistance, and genetic background. These findings emphasize the importance of early antiviral treatment and optimized metabolic management in this high-risk population.