Association of statin treatment with hepatocellular carcinoma risk in end-stage kidney disease patients with chronic viral hepatitis

Statin use was associated with a reduced risk of HCC incidence in a nationwide evaluation of 6165 dialysis patients with chronic viral hepatitis, a high-risk group for HCC. During a median follow-up duration of 2.8 years after dialysis commencement, the risk of HCC was 41% lower in statin users than in statin non-users. This relationship was independent of viral hepatitis type, comorbidities, or the prescription of concomitant medications known to influence HCC risk, such as aspirin and antiviral agents.

The reduction in incident HCC risk found in this study has been previously recognized in several patient populations. Statin use was associated with a decreased risk of HCC and HCC-related death in high-risk groups such as chronic HBV and HCV carriers18,19,20,21,22,23,24, patients with non-alcoholic liver disease25, or diabetes mellitus26,27. In a recent nested case–control study, statin use was demonstrated to lower the risk of HCC development in the general population28. CKD patients aged over 50 who have not yet initiated dialysis are recommended to use statin for cardiovascular disease prevention in current guideline. Considering the high frequency of risk factors for HCC in CKD patients, statin use might have a protective effect on HCC in patients with CKD regardless of viral hepatitis infection. Meanwhile, dialysis patients have been considered “statin resistant” based on clinical studies that have failed to recapture the efficacy of statins against cardiovascular disease noticed among the non-dialysis population. In large-scale prospective trials, such as the Die Deutsche Diabetes Dialyse (4D) study, the rate of mortality from all cardiac causes did not differ between the statin and placebo groups, despite the significant decline in low-density lipoprotein levels in the statin group3. Complex lipid abnormalities such as highly oxidized or carbamylated lipoproteins found in uremic patients have been suspected as a cause of this discrepancy in the statin effect between patients undergoing and not undergoing dialysis29. In addition, the increase in intracellular cholesterol synthesis, which is not fully inhibited by statin use, under chronic inflammatory conditions such as chronic dialysis has also been postulated to play a role in statin resistance30. The fact that the risk of HCC development was significantly lower among statin users in this study suggests that patients undergoing dialysis are not resistant to the antineoplastic effect of statins found in those without kidney disease. Considering that the risk of HCC development is increased among dialysis patients compared to that in the general population and that the initiation of statin therapy is discouraged by current guidelines, the results of the current study may open the possibility of statin use being suggested in dialysis patients with high HCC risk.

Statin use was not associated with HCC risk reduction in the subgroups with underlying liver cirrhosis. In contrast to this finding, several previous evaluations in the non-dialysis population have shown that the preventive effect of statins against HCC was maintained in patients with liver cirrhosis. A recent nested case–control study of 1642 HCC patients revealed that statin use was significantly associated with a reduction in HCC incidence in patients with liver cirrhosis as well as in those without liver cirrhosis28. The relatively small number of statin users with liver cirrhosis in this study could have played a role in producing a statistically insignificant relationship between statin use and HCC incidence. However, the probability that statin treatment alone may not be sufficient to prevent HCC development in high-risk patients, such as those with liver cirrhosis under uremic conditions, should also be considered.

In this study, only 39.8% of statin users had dyslipidemia. Since patients with kidney disease are a high-risk group for cardiovascular diseases, statins would have been also prescribed for cardio-protective purposes, in addition to the goal of managing dyslipidemia. The fact that 37.1% of the participants were reported to have a medical history of cardiovascular disease (coronary heart disease, congestive heart failure, peripheral vascular disease, or cerebral vascular disease) in this study supports this possibility.

The preventive effects of statins on HCC development could be attributed to several mechanisms. Simvastatin, fluvastatin, and lovastatin have been shown to induce a selective apoptotic effect in human HCC cell lines31,32. Statins, including atorvastatin, have been found to block MYC phosphorylation, resulting in tumor-suppressive effects33,34. Among patients with HBV, the transcriptional activation of HBV protein X alters the expression of growth control genes such as Ras, Raf, MAPK, and ERK35. By inhibiting the mevalonate pathway, statins have been demonstrated to effectively prevent the detrimental consequences of the signaling proteins encoded by these genes11. HCV is known to stimulate nuclear factor κB, resulting in chronic inflammation, a neoplastic-prone state36. HCV infection also promotes cell growth by downregulating members of the growth arrest and DNA damage (Gadd45) gene family37. Statins have been recognized to effectively counter these effects, which could lead to anti-tumor properties.

This study has several strengths. First, this study evaluated an unbiased selection from a nationwide dialysis population. Due to the obligatory copayment assistance policy of the Korean NHIS, dialysis patients and those diagnosed with cancerous disease are coded separately in the HIRA database. This allowed the detection of an entire population of patients undergoing chronic dialysis as well as those diagnosed with HCC during the study period. Second, double robust estimation, adjusting for covariates after IPTW application, was used. Since statin treatment is dependent on underlying metabolic abnormalities and comorbidities that may affect HCC development, such an evaluation strategy would further strengthen the possible independent association between statin use and incident HCC.

However, the findings of this study should be interpreted in light of the following limitations. First, limitations due to the observational nature of the study should be considered. Although a significant association between statin use and HCC development was found, the cause-effect relationship should be further assessed in future prospective evaluations. Second, due to the nature of health insurance claim data, the possibility of missing diagnostic codes for comorbidities including HBV or HCV infection, diabetes, dyslipidemia, and liver disease cannot be excluded. While claims database analysis has advantage of utilizing a large sized data, this analysis is potentially susceptible to errors from inaccuracies. However, screening for viral hepatitis (both B and C) is routinely performed before starting dialysis in real-world practice, and HIRA periodically performs a nationwide obligatory quality assessment which includes viral serologic tests, lowering the possibility of HBV or HCV carriers not being detected. In addition, specific malignant disease insurance code that were issued by the Korea NHIS (V193) was utilized for accurate HCC diagnosis although tumor staging data were not available. Third, as the evaluation used claims data from a national insurance service database, potential confounding variables including lifestyle factors; anthropometric factors; and laboratory information including hepatitis viral copy number, liver function, tumor markers, and lipid abnormalities could not be examined. Further analyses considering laboratory information associated with liver function would be needed to reduce the possibility of selection bias. Fourth, this study was conducted in a single nation, with a predominately Asian population, in which HBV and HCV infection rates are relatively higher than those in Western countries. Therefore, to generalize these findings, assessments including other populations wherein viral hepatitis is not the predominant cause of HCC should be performed.

In conclusion, this nationwide observational study showed that statin use was associated with a reduced risk of incident HCC in chronic dialysis patients with HBV or HCV infection. The decrease in risk was independent of comorbidities and was evident regardless of the viral hepatitis type. Further prospective trials are needed to verify the protective effects of statins against HCC in this patient group.

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