Liver resection remains the mainstay of curative treatment for early-stage HCC with preserved liver function; however, the 5-year cumulative recurrence rates after resection are higher than 50%. Certain medications, including statins, aspirin, NSAIDs and metformin, have been reported to alter the risk of developing HCC[14, 17, 26–28]. However, the effects of these medications on HCC recurrence have not yet been examined. In this population-based, propensity score-matched study, we confirmed that statin use may lower the risk of HCC recurrence in patients with HCC after curative resection. This association remained consistent regardless of age, sex, cause of hepatitis, diabetic status or the presence or absence of cirrhosis, which suggests statins could be beneficially employed as a chemopreventive agent to reduce the risk of recurrence after resection in patients with HCC. These results emphasize the need for large-scale RCTs to validate the potential chemopreventive effect of statins on the recurrence of HCC.
Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are used worldwide as a treatment for dyslipidemia and can prevent cardiovascular events and mortality[16, 29]. In addition to their cholesterol-lowering capability, increasing evidence indicates statins also exert anti-oncogenic effects. Kim et al. reported that statin use decreased the risk of developing HCC among patients with new-onset type 2 diabetes mellitus in a nested case-control, longitudinal study. Tsan et al. demonstrated that statins may dose-dependently reduce the risk of HCC among individuals with HBV or HCV infection[17, 19]. Furthermore, a recent meta-analysis of 25 studies that included 1,925,964 patients concluded statins exert a beneficial chemopreventive effect against the development of HCC.
However, most of these studies focused on the ability of statins to protect against the development of HCC; only a few studies have assessed the potential of statins to protect against recurrence after curative resection. A retrospective study in Japan by Kawaguchi et al. showed that statins may protect against HCC recurrence. Similarly, we found statin use was associated with a significantly lower risk of recurrence after resection (HR: 0.34; p = 0.005). However, OS, including liver- and non-liver-related mortality, were not significantly different between the statin and non-statin groups in this study (Supplementary Fig. 2). The differences between the study by Kawaguchi et al. and our findings may be related to the varied proportions of patients with HBV and HCV infection. In the study by Kawaguchi et al., significantly fewer patients in the statin group had hepatitis B surface antigen (HBsAg) positivity and hepatitis C virus antibody (HCVAb) positivity compared to the non-statin group (HBsAg: 6.5% vs. 22.8%, p = 0.032; HCVAb: 19.4% vs. 45.0%, p = 0.005). In the present study, there was no difference in the proportions of HBV- and HCV-positive patients between the statin and non-statin groups. More importantly, we also compared various potential chemopreventive agents, including statins, aspirin, metformin and NSAIDs. To the best of our knowledge, this study represents the largest analysis of the relationship between chemopreventive agents and HCC recurrence in a country where HBV and HCV are endemic.
The mechanisms underlying the ability of statins to protect against HCC development are not well understood; some potential mechanisms have been suggested. First, statin-mediated reduction of downstream metabolites of the mevalonate pathway—including geranyl pyrophosphate, farnesyl pyrophosphate and geranylgeranyl pyrophosphate—interferes with cancer cell proliferation and differentiation, which promotes apoptosis[33, 34]. Secondly, statins can suppress proteasomal degradation, which limits breakdown of the cyclin-dependent kinase (CDK) inhibitors p21 and p27 and reduces CDK2 expression, and thus disrupts mitosis in malignant cells[35, 36]. Third, statins may inhibit tumor cell migration and invasion by attenuating angiogenesis via downregulating VEGF production. Fourth, statins exert anti-inflammatory and immunomodulatory effects by decreasing TNF-α and IL-6 expression, downregulating the activity of metalloproteinases, and inducing a shift towards the TH2 cytokine anti-inflammatory response, which may reduce hepatic inflammation.[38, 39] Chronic hepatic inflammation plays an important role in hepatocarcinogenesis. Moreover, statins activate AMP-activated protein kinase, which enhances p21 expression and the endoplasmic reticulum stress response, and thus induces higher levels of autophagy.
Statins are generally classified into hydrophilic and lipophilic groups based on tissue selectivity. Lipophilic statins, including atorvastatin, simvastatin, lovastatin, fluvastatin and pitavastatin, distribute widely throughout various tissues. Hydrophilic statins, such as pravastatin and rosuvastatin, have lower levels of tissue absorption—except in the liver—and exert fewer side effects as they are not metabolized by cytochrome P450 enzymes. Although a previous meta-analysis showed lipophilic statins, but not hydrophilic statins, were associated with a lower risk of developing HCC, we did not observe a significant difference in RFS between the subgroups of patients taking lipophilic and hydrophilic statins (Supplementary Fig. 1). However, this analysis may be affected by the limited number of patients. Furthermore, the mechanisms that explain the varied anticancer efficacies of lipophilic and hydrophilic statins remain to be determined.
A recent cohort study by Young et al. indicated aspirin use—but, interestingly, not statin use—reduced the risk of HCC recurrence. In contrast, aspirin use was not significantly associated with HCC recurrence in our cohort (p = 0.864). These discrepancies may be related to differences between the design of each study. Firstly, Young et al. only examined exposure to chemopreventive agents in the 30 days before tumor recurrence. However, we defined exposure as more than 90 days, as generally adopted by previous studies.[32, 44] Secondly, Young et al. enrolled patients with BCLC stage A/B/C HCC who underwent resection. In contrast, we only assessed patients with BCLC stage 0/A, so called early-stage HCC, for which surgical resection is the widely accepted standard treatment. Moreover, Young et al. focused on HBV-related HCC, while we investigated all etiologies. Since no RCTs have been published in this field, our results further emphasize the need for large-scale RCTs to validate the potential chemopreventive effect of statins on HCC recurrence.
We found that age, liver cirrhosis, diabetes, number of tumors, tumor size and vascular invasion represented the major risk factors for HCC recurrence, and antiviral therapy may reduce the risk of HCC recurrence. These results are consistent with previous reports.[7, 9, 11–14, 45]
Increasing evidence indicates that gut microbiota alterations promote the development of HCC by inducing a leaky gut and gut dysbiosis; both of which are prominent features of all stages of chronic liver disease, and promote the stepwise progression from fibrosis to cirrhosis and HCC. In addition to dysbiosis, gut microbiota-derived metabolites may also promote hepatocarcinogenesis via a variety of metabolic pathways. Although there is no evidence to prove statin use affects HCC development and recurrence by altering the human gut microbiome, several studies have indicated statin therapy lowers the prevalence of gut microbiota dysbiosis and also affects the virulence and growth of bacterial pathogens in microbial infections[49, 50]. Therefore, we hypothesize that statin use may affect the human gut microbiome, and in turn directly or indirectly reduce hepatocarcinogenesis via the gut-liver axis. Further animal experiments are required to delineate the effects of statins on the development and recurrence of HCC through the gut-microbiota-liver axis.
There are some limitations to this study. First, this was a retrospective study of patients from a single institution and the data were collected from medical records. Despite the use of multivariable analysis and propensity score-matching analysis, not all confounding factors can be completely adjusted for. Secondly, the number of patients was relatively low. There were 46 (5.6%) patients in the statin group; however, this is comparable to the study in Japan (31/734, 4.2%) and may reflect the real-world situation. Finally, we could not obtain information on tobacco use and alcohol consumption, which may also be risk factors in survival analysis. Ultimately, a large randomized trial of a suitable regimen in well-selected patients treated using standard approaches is required to obtain this important information.