New research has revealed that statin therapy may lower the risk of hepatocellular carcinoma and hepatic decompensation while improving fibrosis outcomes in patients with chronic liver disease with elevated Fibrosis-4 scores.
In a large-scale cohort study, published in in JAMA Internal Medicine, investigators from Massachusetts General Hospital and Asan Medical Center analyzed data from 16,501 patients with chronic liver disease (CLD) and baseline Fibrosis-4 (FIB-4) scores ≥ 1.3, including 3,610 statin users and 12,891 nonusers. The 10-year cumulative incidence of hepatocellular carcinoma (HCC) was substantially lower among statin users compared with nonusers (3.8% vs 8.0%, absolute risk difference = –4.2%, 95% confidence interval [CI] = –5.3 to –3.1%), with an adjusted subhazard ratio (SHR) of 0.67 (95% CI = 0.59–0.76).
"This cohort study found that statin use was associated with a reduced risk of HCC and hepatic decompensation in patients with CLD as well as improved FIB-4 group transitions over time," the study authors wrote. "These findings provide support for the potential role of statins in prevention of HCC and liver disease progression," they added.
Hepatic decompensation also occurred less frequently in statin users, with a 10-year cumulative incidence of 10.6% compared with 19.5% in nonusers (risk difference = –9.0%, 95% CI = –10.6 to –7.3), corresponding to an adjusted SHR of 0.78 (95% CI = 0.67–0.91).
The investigators revealed several important nuances in the relationship between statins and liver outcomes. Lipophilic statins (atorvastatin, fluvastatin, lovastatin, pitavastatin, and simvastatin) appeared to confer greater protection against HCC (adjusted SHR = 0.64, 95% CI = 0.55–0.73) compared with hydrophilic statins (rosuvastatin and pravastatin; adjusted SHR = 0.79, 95% CI = 0.63–0.99). Additionally, longer statin exposure (≥ 600 cumulative defined daily doses) was associated with greater risk reductions for both HCC (adjusted SHR = 0.60, 95% CI = 0.52–0.70) and hepatic decompensation (adjusted SHR = 0.64, 95% CI = 0.51–0.80).
The investigators also analyzed FIB-4 score transitions in a subset of 7,038 patients with serial data. Among the patients with intermediate baseline FIB-4 scores, 14.7% of the statin users progressed to the high-risk group compared with 20.0% of the nonusers (P < .001). Among patients with high baseline FIB-4 scores, 31.8% of statin users improved to the intermediate group and 7.0% to the low-risk group compared with just 18.8% and 4.3% of nonusers, respectively (P < .001).
The inverse association between statin use and HCC risk remained consistent across various subgroups, including patients with and without cirrhosis, those with and without dyslipidemia, and those with metabolic dysfunction–associated steatotic liver disease and other CLD etiologies.
The investigators posited that statins may reduce HCC risk by mitigating liver fibrosis progression. Experimental studies have shown that statins, particularly atorvastatin, may exert antifibrotic effects by reducing the expression of profibrotic cytokines, improving liver microcirculation, and decreasing levels of procollagen I and alpha-smooth muscle actin.
The study employed rigorous methodological approaches, including inverse probability of treatment weighting to balance baseline characteristics, accounting for competing risks, and conducting multiple sensitivity analyses, all of which yielded consistent results.
Despite these promising findings, the investigators several limitations, including potential unmeasured confounders, the inability to account for postindex treatments, and reliance on FIB-4 as a surrogate marker for liver fibrosis rather than more direct measures such as liver biopsy.
The study authors concluded: "statin use, particularly lipophilic statin use and longer duration of therapy, was associated with reduced HCC risk and slower fibrosis progression in patients with CLD and intermediate to high fibrosis risk."
Disclosures can be found in the study.