Abstract

Background:

Statins reduce the risk of hepatic fibrosis in patients with chronic liver diseases. Since age, sex, and menopausal status modulate NAFLD pathogenesis and fibrosis risk, the effects of statins on hepatic fibrosis may vary by age and sex. We aimed to assess age-/sex-disparities in the association between statin use and the incidence of cirrhosis in patients with NAFLD.

Methods:

We developed a cohort of NAFLD patients between 2007 and 2009 (baseline period), applying the validated algorithm (PMID: 30144434) to the VA electronic health records. We created baseline variables including demographics, BMI, statin use, comorbidities, relevant co-medications, such as beta-blockers and metformin, and FIB-4 scores. The cohort was then followed for incident cirrhosis defined by ICD codes for up to ten years. We also captured cumulative standardized dose and duration of statins, BMI, and co-medication use during the follow-up and analyzed them as time-dependent covariates. Patients were censored at the diagnosis of other chronic liver diseases, alcohol use disorder, death unrelated to cirrhosis, or loss to follow-up. Cox proportional hazards regression models without and with time-dependent covariates were used to associate incident cirrhosis with statin use at baseline and during follow-up, respectively. Disparities were assessed in subgroup analyses by age (using a cut-off of 51 years, the average age at menopause in the US) and sex as well as in a model with an interaction term.

Results:

A total of 335,991 patients (median age of 62 years, male 91%, White 78%, median BMI of 31 kg/m2, DM 39%, and statin use 65% at baseline) were analyzed after excluding prevalent cirrhosis, incident cirrhosis within one-year follow-up, and no follow-up data after the index date from 346,818 NAFLD patients identified at the baseline. Cumulative incidence of cirrhosis was 2.96% (median follow-up of 117 [50, 121] months), which differed by sex and age group (≤ or > 50 years). After adjusting for potential confounders and baseline FIB-4 score, baseline statin use was associated with a reduced risk of developing cirrhosis (HR and 95% CI = 0.77 [0.65, 0.91]). In the models with time-dependent covariates, both cumulative standardized dose and duration during follow-up showed significant protective effects against cirrhosis development (HR and 95%CI = 0.72 [0.68, 0.76]) and 0.67 [0.63, 0.72], respectively). The effect of cumulative standardized statin dose and duration showed a significant interaction with age (interaction: p=0.0005 and p<0.0001, respectively), associated with stronger protection from cirrhosis development in older vs. younger subjects.

Conclusion: Statins are more protective against cirrhosis in older subjects, and this effect is not influenced by sex.