Are statins protective against HCC?

In a study presented at EASL 2025, the use of statins appears to be associated with a reduced risk of hepatocellular carcinoma (HCC) and slower progression of liver fibrosis in individuals with chronic liver disease (CLD).

“Statin use, particularly lipophilic statins and longer durations of statin therapy, is associated with reduced risks of HCC and hepatic decompensation in patients with CLD,” according to a group of researchers from Harvard Medical School, Boston, Massachusetts, US.

Compared with non-statin users, statin users had significantly lower 10-year cumulative incidence of HCC (3.8 percent vs 8 percent; adjusted hazard ratio [aHR], 0.67, 95 percent confidence interval [CI], 0.59–0.76; p<0.001). [EASL 2025, abstract WED-116]

Statin type did not appear to influence the treatment effect, but the effect was more profound among those taking lipophilic (3.7 percent vs 8 percent; aHR, 0.64, 95 percent CI, 0.55–0.73; p<0.001) vs hydrophilic (4.1 percent vs 8 percent; aHR, 0.79, 95 percent CI, 0.63–0.99; p<0.001) statins.

A longer duration of statin use (≥600 cDDD*; 3.5 percent vs 8 percent; aHR, 0.60, 95 percent CI, 0.52–0.70; p<0.001) seems to be more favourable than a shorter one (30–599 cDDD; 3.8 percent vs 8 percent; aHR, 0.79, 95 percent CI, 0.67–0.93; p<0.001) to reduce the risk of HCC.

There were also similar patterns favouring statin use over nonuse for hepatic decompensation in the overall cohort and when stratifying by statin type and duration of use (p<0.001 for all).

FIB-4 group transitions at 3 years

Moreover, in patients with intermediate-to-high baseline FIB-4** scores, statin use was associated with more stable fibrosis trajectories and lower transition rates to higher fibrosis risk than nonuse, the investigators noted.

This was evidenced by the fewer statin users who had high FIB-4 scores at year 3, be it among those with baseline intermediate (14.7 percent vs 20 percent; p<0.001) or high (61.1 percent vs 76.9 percent; p<0.001) FIB-4 scores in the overall cohort. A similar effect was observed in the propensity-score matched population (p<0.001 for all).

“Statin users with high baseline FIB-4 scores were more likely to improve or remain stable, compared with nonusers,” the investigators said.

Potential chemopreventive role

The burden of HCC is increasing worldwide, with metabolic and alcohol-related liver diseases now emerging as leading causes, the researchers noted. “Statins may protect against HCC by reducing liver inflammation and fibrosis.”

Statins demonstrate a direct chemopreventive effect by blocking oncogenic pathways, including Ras-MAPK and PI3K/Akt pathways. Statins also block Myc phosphorylation, leading to the suppression of cancer proliferation. [World J Gastroenterol 2016;22:6201-6213; Semin Liver Dis 2019;39:141-152; Cancer Res 2011;71:2286-2297]

A review also noted that statin therapy should be actively considered in patients with CLD or cirrhosis who are statin therapy candidates due to other conditions (eg, cardiovascular disease prevention). [Clin Mol Hepatol 2022;28:380-395]

However, the evidence on the impact of statins on fibrosis progression over time remains insufficient, the investigators pointed out.

The team conducted this historical cohort study using data from a large-scale hospital registry database. The final study sample comprised 16,501 patients with baseline FIB-4 scores ≥1.3. Of these, 3,610 were statin users (mean age 63.7 years, 61.8 percent men, 4.8 percent Asian). Statin use was defined as ≥30 cDDD. Among statin users, the most common aetiology of CLD was metabolic dysfunction-associated steatotic liver disease (30.5 percent) and hepatitis C virus infection (20.9 percent). A third of statin users had cirrhosis.

“[Taken together,] these findings support the potential chemopreventive role of statins in reducing HCC risk by mitigating liver fibrosis progression in at-risk CLD populations,” the investigators concluded.