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
Ayako Suzuki, Georgia Sofia Karachaliou, Amy M. Perkins, Chad Dorn, Ruth Reeves, Timothy Arnold, Mustafa R. Bashir, Jimmy T. Efird, Manal F. Abdelmalek, Anna Mae Diehl
Abstract
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. Funding: The Department of Defence, Translational Team Science Award.