Age-specific protective effects of statins against cirrhosis in patients with chronic liver enzyme elevation associated with metabolic dysfunction: a retrospective cohort study of electronic health records

Background: The hepatoprotective effects of statins in chronic liver diseases are well-documented; however, variation by age, sex, and formulation remains unclear. The optimal regimen for cirrhosis prevention has yet to be defined. We aimed to address this knowledge gap. Methods: In this retrospective cohort study using Veterans Affairs (VA) electronic health records, we defined a cohort of patients with chronic liver enzyme elevation primarily associated with metabolic dysfunction, between Jan 1, 2007, and Dec 31, 2009. Patients were followed-up for incident cirrhosis for a 10-year period until 2019. Time to cirrhosis was analysed using Cox proportional hazards models, with and without adjustment for demographics, relevant comorbidities, and co-medications. Hazard ratio (HR) estimates were used to compare event rates between groups. We also assessed potential effect modification by age and sex and evaluated differences across statin formulations. Findings: In adjusted models, baseline statin use was significantly associated with a reduced risk of cirrhosis over 10 years (HR 0.74 [95% confidence interval 0.70-0.78], p < 0.0001). Cumulative statin dose, standardised by low-density lipoprotein (LDL)-lowering intensity as simvastatin-equivalent units, and duration were dose-dependently associated with cirrhosis risk reduction (p < 0.05). The protective effect of statin use, at baseline and during follow-up, demonstrated a significant effect modification with age (p ≤ 0.01), with greater protection in older individuals. No sex disparities were observed. Borderline to significant protection against cirrhosis was achieved with a daily dose of ≥6961 mg simvastatin-equivalent for at least 245 days per year among individuals aged ≥54 years. Those younger than 54 years required a higher dose (>15,561 mg annually) to achieve comparative protection. No significant differences in effectiveness were observed among different formulations. Interpretation: Statins reduce cirrhosis risk in a dose- and age-dependent manner. A daily dose equivalent to ≥20 mg simvastatin (or >40 mg for <54 years) appears effective, regardless of formulation. Independent validation in a cohort with a higher proportion of women is warranted.