Dysmetabolism, Diabetes and Clinical Outcomes in Patients Cured of Chronic Hepatitis C: A Real-Life Cohort Study

Abstract

The aim of this study was to examine the impact of features of dysmetabolism on liver disease severity, evolution, and clinical outcomes in a real-life cohort of patients treated with direct acting antivirals for chronic hepatitis C virus (HCV) infection. To this end, we considered 7,007 patients treated between 2014 and 2018, 65.3% with advanced fibrosis, of whom 97.7% achieved viral eradication (NAVIGATORE-Lombardia registry). In a subset (n = 748), liver stiffness measurement (LSM) was available at baseline and follow-up. Higher body mass index (BMI; odds ratio [OR] 1.06 per kg/m² , 1.03-1.09) and diabetes (OR 2.01 [1.65-2.46]) were independently associated with advanced fibrosis at baseline, whereas statin use was protective (OR 0.46 [0.35-0.60]; P < 0.0001 for all). The impact of BMI was greater in those without diabetes (P = 0.003). Diabetes was independently associated with less pronounced LSM improvement after viral eradication (P = 0.001) and in patients with advanced fibrosis was an independent predictor of the most frequent clinical events, namely de novo hepatocellular carcinoma (HCC; hazard ratio [HR] 2.09 [1.20-3.63]; P = 0.009) and cardiovascular events (HR 2.73 [1.16-6.43]; P = 0.021). Metformin showed a protective association against HCC (HR 0.32 [0.11-0.96]; P = 0.043), which was confirmed after adjustment for propensity score (P = 0.038). Diabetes diagnosis further refined HCC prediction in patients with compensated advanced chronic liver disease at high baseline risk (P = 0.024). Conclusion: Metabolic comorbidities were associated with advanced liver fibrosis at baseline, whereas statins were protective. In patients with advanced fibrosis, diabetes increased the risk of de novo HCC and of cardiovascular events. Optimization of metabolic comorbidities treatment by a multi-disciplinary management approach may improve cardiovascular and possibly liver-related outcomes.

FIG. 1

Study flow chart.

FIG. 2

Prevalence of obesity in patients stratified by fibrosis stage and diabetes diagnosis. Data are shown as % and SEM. P < 0.0001 for increased prevalence of obesity with fibrosis stage severity in the overall cohort and patients without diabetes (age and sex adjusted); P = NS in patients with diabetes; and P < 0.05 for the higher prevalence of obesity in diabetes versus without diabetes across fibrosis stages F0‐F4 (age and sex adjusted).

FIG. 3

Impact of diabetes and metformin therapy on the incidence of de novo HCC in 2,442 patients with cirrhosis. P values are shown at log‐rank test.

FIG. 4

Impact of diabetes on the reclassification of HCC risk in 536 patients with cACLD. We considered patients with LSM > 10 kPa at baseline, who achieved viral eradication, with compensated liver disease, no previous history of HCC, and re‐evaluation of LSM and serum albumin at follow‐up. HCC risk was evaluated according to Pons et al.^{( 12 )} Patients with LSM ≥ 20 kPa at follow‐up and those with LSM = 10‐20 kPa and albumin levels < 4.4 g/dL at follow‐up were classified as at higher risk. P values are shown at log‐rank test.