Statins and the Risk of Hepatocellular Carcinoma in Patients with Hepatitis B Virus Infection

PURPOSE
Statins have potential protective effects against cancers, but no studies have focused on patients with chronic hepatitis B virus (HBV) infection. The purpose of this study was to investigate the association between the use of statins in HBV-infected patients and the risk of hepatocellular carcinoma (HCC).


PATIENTS AND METHODS
We conducted a population-based cohort study from the Taiwan National Health Insurance Research Database. A total of 33,413 HBV-infected patients were included as the study cohort. Each patient was individually tracked from 1997 to 2008 to identify incident cases of HCC since 1999. Subsequent use of statin, other lipid-lowering agents, aspirin, and angiotensin-converting enzyme inhibitors was identified. Cox proportional hazards regression was used to calculate the hazard ratios (HRs) and 95% CIs for the association between the use of statins and the occurrence of HCC in the HBV-infected cohort.


RESULTS
There were 1,021 HCCs in the HBV cohort during the follow-up period of 328,946 person-years; the overall incidence rate was 310.4 HCCs per 100,000 person-years. There was a dose-response relationship between statin use and the risk of HCC in the HBV cohort. The adjusted HRs were 0.66 (95% CI, 0.44 to 0.99), 0.41 (95% CI, 0.27 to 0.61), and 0.34 (95% CI, 0.18 to 0.67) for statin use of 28 to 90, 91 to 365, and more than 365 cumulative defined daily doses (cDDDs), respectively, relative to no statin use (< 28 cDDDs).


CONCLUSION
Statin use may reduce the risk for HCC in HBV-infected patients in a dose-dependent manner. Further mechanistic research is needed.


Data Sources
 The data files also contained information on patient prescriptions, including the names of prescribed drugs, dosage, duration of prescription, and total expenditure.
 These databases have previously been used for epidemiological research, and information on prescription use, diagnoses, and hospitalizations is of high quality. Kaplan-Meier method to estimate HCC cumulative incidences.
 The log-rank test was performed to examine differences in the risk for HCC between the cohort.
 Cox proportional hazard models were used to compute the 10-year hazard ratios (HRs) accompanying 95% confidence intervals (CIs) after adjustment for the variables mentioned.
 Sensitivity Analyses Result    Incidence Rate  The overall incidence rate of HCC was 310.4 cases per 100,000 person-years in the HBVinfected cohort, which was similar to Chen's incidence rate 324.3 among cases who were positive only for HBsAg.
 The incidence rate 450.0 in the male HBVinfected subjects was also similar to Chen's overall incidence rate for HBV-infected cases.
 A significant inverse trend between the dose and the cumulative incidences of HCC  Yang et al. suggested statins are associated with a reduction in the risk of liver cancer without a doseresponse relationship after cumulative statin use ≥215.4DDD.This may have been due to the relatively small number of subjects.

Subgroups
 Old age and male gender showed more risk for HCC in the HBV-infected cohort.
 Anti-HBV treatment also had beneficial effects on preventing HCC development, which was consistent with the effect of statin use.
 ACE inhibitors and aspirin also showed mild protective effects on HCC.
 protective trend against the risk with a higher economic status.

Potential Limitations
 Unmeasured confounders, including body mass index, smoking, alcohol intake, and other over-the-counter drug use  Because the smoking rates for men and women in Taiwan in the last two decades have ranged from 47% to 62% and from 2.3% to 5.3%, respectively, we assumed that sex was, in part, a surrogate variable for smoking.
 Presumed that all prescribed medications were actually taken by subjects as prescribed, which may overestimate the actual ingested dosage, as some degree of noncompliance is always expected.

Flowchart
WHO, A unit for measuring a prescribed amount of drug, average maintenance dose per day of a drug consumed for its main indication in adults. (total amount of drug)/(amount of drug in a DDD) = number of DDDs  Compare any statins based upon the same standard.WHO Collaborating Center for Drugs Statistics Methodology .ATC Index with DDDs 2003 .WHO: Oslo , 2003.15 Different efficacy of statin drugs, how to calculate together?Exposure to Statins  Defined non-frequent user vs frequent user? To examine the dose-effect relationship, we categorized the cumulative DDD of statins in four groups in each cohort: <28, 28-90, 91-365, and >365 DDD?  Chronic refill card  Calculated the p value for trend to confirm the dose-response relationship.16 Wu CY, Kuo KN, Wu MS, et al: Early Helicobacter pylori eradication decreases risk of gastric cancer in patients with peptic ulcer disease.Gastroenterology 137:1641-8 e1-2, 2009

Table 2 .
Incidence of Hepatocellular Carcinoma (HCC) during the 10-year Follow-up Period in the HBV-infected Cohort.*

Table 4 .
Sensitivity Analysis of Adjusted Hazard Ratios of Cumulative Defined Daily Dose (DDD) of Statin Use in Risk Reduction of Hepatocellular Carcinoma during the 10-year Followup Period in the HBV-infected Cohort.* Figure 1.Cumulative Incidence of Hepatocellular Carcinoma by Cumulative Defined Dauily Dose (cDDD) of Statin Use during the Follow-up Period in the HBV-infected Cohort.25 Discussion Strengths that deserve attention  From a computerized database, highly representative, can rule out the possibility of selection bias.Historicaldatabase, no recall bias.Conducted sensitivity analyses to clarify the misclassifications and potential confounders, and the results revealed no significant changes.Latent period of 1 year before diagnosis.Research, N. H. R. I. N. H. I., database.http://www.nhri.org.tw/nhird/date_01.html#_edn1.Accessed January 1, 2011.27 Nonstatin lipid-lowering medications  Nonstatin lipid-lowering and triglyceride lowering medications had no protective effects on HCC when comparing with statins. A dose-response relationship exists between the use of statins and the risk of HCC.Yang X, Ma RC, Yee So W, et al: Low triglyceride and nonuse of statins is associated with cancer in type 2 diabetes mellitus: the Hong Kong Diabetes Registry.Cancer, 2010 Ulmer H, Borena W, Rapp K, et al: Serum triglyceride concentrations and cancer risk in a large cohort study in Austria.Br J Cancer 101:1202-6, 2009

Table 1 .
Characteristics in Subjects of HCC and control groups in the HBV-infected cohort.* Conclusion A reduced risk of hepatocellular carcinoma is associated with dose-dependent statin use in patients with hepatitis B infection.Furthermechanistic research is needed.～ThankYou～ hepatotoxicity  Risk reduction in the HBV-infected group, but there was no statistically significant trend of protective effects in the cohort without liver disease  Exclude statin uses recorded within 1 year preceding HCC.