This study demonstrates that statin use substantially reduced the risk of HCC recurrence in patients who underwent LT for HCC. This protective effect of statins on LT recipients was consistently significant across subgroups and sensitivity analyses. The benefit of statins was dose-dependent, with the lowest risk of HCC recurrence when the medications were used for more than two years (> 730 cDDDs). This study also demonstrated that statin use significantly reduced all-cause and HCC-related mortality in LT recipients. Although clinicians often hesitate to use statins because of their potential hepatotoxicity, our study provides compelling evidence that HCC patients who undergo LT would benefit from statin use to improve their overall clinical outcomes.
HCC mostly occurs in chronically inflamed liver, and LT is a way to eliminate HCC while treating chronic liver disease. However, HCC often recurs, even in LT recipients. HCC recurrence is caused by occult metastasis remaining at the time of LT or, rarely, by circulating cancer cells that are released intraoperatively.[16] Thus, a significant proportion of HCC recurrence occurs at extrahepatic sites, such as the lungs and bones.[17, 18] Previous studies investigated the use of statins as anti-cancer agents. Statin inhibits HMG-CoA reductase, the rate-limiting enzyme, at the early step in the mevalonate cascade. Therefore, it exerts pleiotropic, anti-cancer effects by subsequently inhibiting the synthesis of several molecules in this pathway. Inhibition of the prenylation of G-proteins, especially geranylgeranyl pyrophosphate prenylation (geranylgeranylation) of Rho proteins, is considered the key to the anti-cancer effects of statin.[9] Theoretically, statins are expected to actively affect cancer cells because the expression of HMG-CoA reductase and the demand for isoprenoids intermediates in the mevalonate pathway are increased in cancer cells.[19]
To evaluate the association between statin use and HCC recurrence, this study incorporated tumor-related factors of pre-LT AFP level, tumor stage according to the Milan criteria, and pre-LT treatment history as covariates in analyses of HCC recurrence because these have the greatest influence on HCC recurrence after LT.[20] We identified the anti-cancer effect of statin even after adjusting for these tumor-related factors. The effect of statins was most pronounced in patients who used them for more than 2 years (730 cDDDs). This finding is consistent with previous results describing a cumulative effect of statins. Prior works found that CHB patients benefited most from statin use for > 3 years, and LC patients experienced an 8% reduced risk of mortality with each year of statin exposure.[6, 7] Considering this time-dependent effect, we expect that early use of statins, if clinically indicated, may be beneficial against HCC recurrence.
In this study, metformin, aspirin, and diabetes, which are known to affect HCC development in patients with liver disease, were included as covariates in the analyses of clinical outcomes in LT recipients. Although metformin use was one of the independent factors related to reduced risk of HCC recurrence, its significance was not maintained through sensitivity analyses. Previous cohort studies, as well as experiments in vitro or in vivo, have demonstrated that metformin affects carcinogenesis, either directly or by suppressing hyperinsulinemia.[21, 22] However, there is little evidence regarding the effect of metformin on the clinical outcomes of LT recipients. Importantly, the anti-cancer effect of metformin must be interpreted with caution because it is generally prescribed only for patients with diabetes. In this study, diabetes diagnosed before or after LT did not affect HCC recurrence or HCC-related mortality despite being a well-known predictor of HCC development.[23] Rather, the presence of diabetes only remained an independent predictor of all-cause mortality.
As mentioned earlier, the prevalence of metabolic diseases increased over time in LT recipients. In this study, approximately one-quarter of the enrolled patients were eventually treated with statins, and most met the treatment criteria for statins to prevent CVD. We investigated the prevalence of diabetes before and after LT but did not analyze dyslipidemia, hypertension, or obesity. These factors are components of metabolic syndrome and risk factors for HCC development in the general population.[24] Although metabolic diseases not measured in this study may have confounded the analysis of HCC recurrence or survival, there is lack of evidence regarding the impact of metabolic diseases on HCC recurrence in LT recipients. Of note, previous studies that included LT patients for any indication demonstrated inconsistent results regarding the impact of diabetes on survival and found that hypertension and dyslipidemia were not significant predictors of long-term survival.[12, 25] Furthermore, diabetes has not been shown to be associated with development of de novo cancer.[12, 25] Further studies are needed to elucidate the impact of metabolic diseases on clinical outcomes in patients who undergo LT for HCC.
This study had several limitations, mainly related to its retrospective nature. Each patient was started on a statin at a different time point in disease. This inconsistency could have caused immortal time bias in analyses of primary outcome. To overcome this limitation, we performed a dose-dependent analysis to evaluate the association between statin use and HCC recurrence. Furthermore, sensitivity analyses including that with the landmark method frequently used to avoid this type of bias showed consistent results across the cohort. In this study, we attempted to identify a specific patient group in which statins were the most effective through multivariable-stratified analyses. However, this analysis was limited by an insufficient sample size despite the large total sample size of HCC patients who underwent LT.
In conclusion, the use of statins in HCC patients who undergo LT significantly reduces HCC recurrence and improves survival. The results from this study provide insights into the early and active use of statins to improve overall liver-related events as well as prevent CVD in LT recipients.