The Association between Statins and Liver Cancer Risk in Patients with Heart Failure: A Nationwide Population-Based Cohort Study

Simple Summary Heart failure is a major public health challenge with similar risk factors to those of cancer. HMG-CoA reductase inhibitors, also known as statins, are widely prescribed lipid-lowering agents. Chemoprevention has been reported as a pleiotropic effect of statins. We aimed to evaluate the chemoprotective effect of statins on liver cancer in patients with heart failure and to further identify the differences in effectiveness among statin doses and types. The results demonstrated that statins potentially decreased the risk of liver cancer in patients with heart failure in the entire cohort as well as in sex-, age-, and dose-stratified subgroup analyses as compared with the control group. Moreover, both hydrophilic and lipophilic statins showed significant risk reductions. The findings of the present study demonstrate a potential benefit in terms of liver cancer risk for patients with heart failure using statins. Abstract Heart failure (HF) and cancer have similar risk factors. HMG-CoA reductase inhibitors, also known as statins, are chemoprotective agents against carcinogenesis. We aimed to evaluate the chemoprotective effects of statins against liver cancer in patients with HF. This cohort study enrolled patients with HF aged ≥20 years between 1 January 2001 and 31 December 2012 from the National Health Insurance Research Database in Taiwan. Each patient was followed to assess liver cancer risk. A total of 25,853 patients with HF were followed for a 12-year period; 7364 patients used statins and 18,489 did not. The liver cancer risk decreased in statin users versus non-users (adjusted hazard ratio (aHR) = 0.26, 95% confidence interval (CI): 0.20–0.33) in the entire cohort in the multivariate regression analysis. In addition, both lipophilic and hydrophilic statins reduced the liver cancer risk in patients with HF (aHR 0.34, 95% CI: 0.26–0.44 and aHR 0.42, 95% CI: 0.28–0.54, respectively). In the sensitivity analysis, statin users in all dose-stratified subgroups had a reduced liver cancer risk regardless of age, sex, comorbidity, or other concomitant drug use. In conclusion, statins may decrease liver cancer risk in patients with HF.


Introduction
Heart failure (HF) is a major public health challenge and global epidemic [1,2] caused by aging demographics and the increasing prevalence of comorbidities, such as hypertension, diabetes, coronary artery disease, obesity, and atrial fibrillation [3]. Improvements in HF treatment have further extended life expectancy and increased the prevalence of noncardiac morbidity in patients with HF. Some epidemiological studies have demonstrated that cancer is the major cause of non-cardiac death in patients with HF [4][5][6]. Predisposing conditions such as neurohormonal activation, systemic inflammation, and oxidative stress have been suggested to contribute to both HF and malignancy [7,8].
HMG-CoA reductase inhibitors (statins) are the most widely prescribed lipid-lowering agents and inhibit the mevalonate pathway. Moreover, studies have demonstrated that statins exert pleiotropic effects, such as anti-inflammatory, antioxidant, and immunomodulatory effects [9][10][11][12]. Various experimental and clinical studies have reported that statins are chemoprotective against carcinogenesis because of their potential pleiotropic mechanisms [13][14][15]. However, although statin use reportedly decreases the risk of many cancers [16], the chemoprotective effects of hydrophilic and lipophilic statins on liver cancer have been inconsistent [17,18] Primary liver cancer is the fourth leading cause of cancer-related deaths [19], and a nationwide study of statin use in patients with HF reported a lower risk of cancer incidence and cancer-related mortality [20]. In the present study, we aimed to investigate the liver cancer risk in patients with HF with or without statin treatment as well as the differences among statin doses and types.

Materials and Methods
Taiwan's National Health Insurance program has been mandatory for all citizens since 1995. The program provides universal health insurance coverage to Taiwanese residents [21]. Data obtained from the National Health Insurance Research Database are similar to those of the general population in regard to age, gender, and health-care costs. Data are anonymized before being released to researchers.
Patients who received a diagnosis of HF (with the International Classification of Diseases, Ninth Revision, Clinical Modification code 428.X; n = 45,153) who had at least two outpatient department visits or one hospital admission between 1 January 2001 and 31 December 2012 were identified from the database (n = 35,043). Patients who were younger than 40 years (n = 1509), who had a history of any cancer before the enrollment date (n = 4155) or who had received a statin prescription within 6 months before the enrollment date (n = 3526) were excluded. A total of 25,853 patients with HF were included in the study cohort and were followed up for 12 years. Of the 25,853 patients with HF, 7364 used statins and 18,489 did not ( Figure 1).  Patients diagnosed with HF without subsequent outpatient or inpatient visits, aged less than 40 years, or with pre-existing cancer or a history of statins prescription within 6 months before the date of enrollment were excluded. A total of 25,853 patients were enrolled in the study cohort. The primary outcome was the incidence of primary liver cancer (with the International Classification of Diseases, Ninth Revision, Clinical Modification code 155.X) during the follow-up period. Follow-up ended on 31 December 2012 or upon receipt of a new diagnosis of liver cancer, withdrawal from the National Health Insurance program, loss to follow-up, or death, whichever occurred first. Demographic characteristics (age and sex), comorbidities (diabetes, hypertension, and dyslipidemia), Charlson comorbidity index (CCI) scores, urbanization level, monthly income, and use of non-statin lipid-lowering drugs (metformin, aspirin, and angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs)) were collected.
We aimed to evaluate the preventive effects of statins in patients with HF who have a higher risk of liver cancer. The end point was primary liver cancer. To measure statin exposure, we used the defined daily dose (DDD) as a measurement tool as defined by the World Health Organization to assume the average maintenance dose per day of a drug consumed for its main indication in adults [22]. A prescription refill lasts for 3 months and can be filled up to three times; therefore, we categorized the DDDs (for the entire observation period for each patient) of statins into four groups in each cohort (<28, 28-90, 91-365, and >365 cumulative DDDs (cDDDs)) to examine the dose-response relationship. Patients with <28 cDDDs who received statins were defined as statin non-users [23]. Furthermore, to compare the effect of the solubility difference of each statin, we categorized statin use into individual statin groups in each cohort to evaluate the preventive effects of different statins.
A Cox proportional hazards model was used to calculate the hazard ratios (HRs) for liver cancer among the statin users and non-users. In the multivariate analysis, the HRs were adjusted for age, sex, CCI score, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income. A stratified analysis was conducted to evaluate the effect of statin use on age and sex. All analyses were conducted using SAS software (version 9.3; SAS, Cary, NC, USA); two-tailed p < 0.05 was considered significant. In epidemiological studies, through external adjustments, sensitivity analyses can be used to clarify the effects of drugs and other covariates [26].
Therefore, in the present study, sensitivity analyses with adjustments were used to determine the associations of age and sex; diabetes, dyslipidemia, hypertension, and CCI score; and the use of non-statin lipid-lowering drugs (metformin, aspirin, and ACEIs/ARBs) with the incidence of liver cancer. In addition to the covariates in the main model, the models were stratified by the use of different drugs as additional covariates.

Results
The demographic characteristics, medical conditions, medication use, level of urbanization, and monthly income level of the entire cohort and for patients with HF with and without statin use are listed in Table 1. In total, 25,853 patients with HF were enrolled in the study cohort: 7364 (28.5%) patients with HF used statins and 18,489 (71.5%) did not. The prevalence of pre-existing medical comorbidities, namely hypertension (76.58% versus 72.13%, p < 0.001), diabetes (39.42% versus 31.50%, p < 0.001), and dyslipidemia (44.91% versus 28.06%, p < 0.001) was higher among statin users versus non-users. The percentage of patients with hepatitis B or hepatitis C was lower among statin users than non-users (91.12% versus 88.59%, p < 0.001). In addition, several significant differences were observed in the distribution of age, sex, CCI score, monthly income level, urbanization level, and non-statin lipid-lowering drug use, such as metformin, a renin-angiotensin-aldosterone system inhibitor (RAASI), or aspirin, between statin users and non-users. The distribution of statin use in patients with HF is shown in Table 2. In total, 17,973 (69.52%) patients never used statins, and 516 (2.00%) patients used statins for less than 28 days; 7364 (28.48%) patients used statins for more than 28 days. Among the participants who had ever used statins, 3495 (44.35%) patients used more than one type of statin. The most prescribed statin was atorvastatin (54.11%), followed by rosuvastatin (28.22%) and simvastatin (28.05%). The liver cancer risk among statin users and non-users in the study cohort is described in Table 3 and Figure 2. The total follow-up durations were 51,080.5 and 85,867.4 personyears for statin users and non-users, respectively. After adjusting for age, sex, CCI score, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income level using PS matching, the risk of liver cancer was analyzed. Compared with patients with HF without statin use, the adjusted HRs (aHRs) for liver cancer risk were decreased in patients with HF who used statins (aHR 0. 26   The incidence rates and aHRs for liver cancer associated with different statin doses during the follow-up period are listed in Table 4 and Figure 3.     Table 5 presents the sensitivity analyses results examining the association between statin treatment and reduced liver cancer risk as measured by aHRs. To estimate the effect of statin dose on liver cancer risk reduction, the entire cohort was treated with <28, 28-90, 91-365, or >365 cDDDs. Additional covariate adjustments were made to the main model, including non-statin medication, metformin, RAASI, and aspirin use, to assess the association of statin use with the risk of liver cancer for the four potential chemoprotective drugs  Table 5 presents the sensitivity analyses results examining the association between statin treatment and reduced liver cancer risk as measured by aHRs. To estimate the effect of statin dose on liver cancer risk reduction, the entire cohort was treated with <28, 28-90, 91-365, or >365 cDDDs. Additional covariate adjustments were made to the main model, including non-statin medication, metformin, RAASI, and aspirin use, to assess the association of statin use with the risk of liver cancer for the four potential chemoprotective drugs separately. The results showed a significantly lower risk of liver cancer compared with the nonusers in the main model with the additional covariates, with a tendency towards dose-dependent risk reduction. In addition, subgroup analyses by age, sex, CCI score, diabetes, dyslipidemia, hypertension, hepatitis B or C, non-statin lipid-lowering drugs, metformin, RAASI, and aspirin were conducted. All aHRs indicated that the statins in each dose-stratified group significantly reduced the liver cancer risk in all subgroups, regardless of age, sex, comorbidities, or concomitant drug use, as compared with that in the statin group with <28 cDDDs.

Discussion
To the best of our knowledge, this is the first study to assess the effect of statins on the reduction of liver cancer risk in patients with HF. The effects of different statin types and doses were also investigated. Our results demonstrated that statin users had a significantly lower risk of liver cancer than nonusers among patients with HF in the entire cohort and in the sex-and age-stratified subgroup analyses. A significant risk reduction was also noted in the dose-stratified subgroups of 28-90, 91-365, and > 365 cDDDs. A potential dose-dependent effect of statins on liver disease risk reduction was observed. In addition, both hydrophilic and lipophilic statin use significantly decreased the liver cancer risk compared with that in non-users among patients with HF.
HF and cancer share common pathophysiological mechanisms [27][28][29], and several studies have indicated that patients with HF are prone to carcinogenesis [7,[30][31][32] derived from a number of predisposing conditions of malignancy, including neurohormonal activation to tumorigenesis, systemic inflammation, and oxidative stress [7,8]. Meanwhile, HMG-CoA reductase inhibitors (statins) and lipid-lowering agents [33] also exert anti-inflammatory [34], antioxidative [35], and anti-cancer effects [14,36]. Statin use may confer chemoprotective effects through various mechanisms, including the inhibition of downstream products in the mevalonate pathway [9][10][11]37,38], triggering tumor-specific apoptosis [39], arresting the growth 1 phase of the cell cycle by inhibiting the proteasome pathway [40], reversing the likelihood of malignancy, and reducing the invasiveness of carcinoma in situ [38]. The dominant anti-inflammatory effects of statins in patients with HF were reported in a previous study [34], which implied the potential of diminishing cancer progression in this patient group. A retrospective cohort study revealed that statins were associated with a lower liver cancer risk in patients with HF in a subgroup analysis [20]. Our study is the first to demonstrate that statin use is associated with a decreased risk of liver cancer in patients with HF compared with patients without statin use based on the analysis of a nationwide database, independent of sex and age.
Our study assessed the effect of statin dose on liver cancer risk reduction and revealed that statin use had a tendency towards dose-dependent risk reduction among dose-stratified groups in the entire cohort and by statin cohorts. Nevertheless, in the subgroup analysis of metformin, among the subgroup of metformin use of less than 28 cDDDs, all statin use > 28 cDDDs decreased the liver cancer risk, whereas statin use of more than 365 cDDDs was associated with a significantly lower risk of liver cancer than that of statin use of 28-90 cD-DDs, revealing a dose-dependent effect (aHR 0. 50 cDDDs respectively). Metformin is one of the standard treatments for patients with diabetes. It has been reported before that diabetes is associated with an increased risk of cancer occurrence [41]. Therefore, patients with long-duration metformin use may need longer statin use to exhibit potential chemoprotective effects. Similarly, a case-control study from a nationwide population-based database evaluated the effect of 15 exposure combinations comprising four common drugs (statins, aspirin, metformin, and ACEIs/ARBs) on chemoprotective effects in comparison with a non-exposure group. The results demonstrated that individual or concomitant use of statins, aspirin, and ACEIs/ARBs could reduce the risk of liver cancer compared with the non-exposure group, although metformin use or concomitant use with metformin may increase the risk of liver cancer [42].
Consensus on the chemoprotective effects of hydrophilic and lipophilic statins in reducing the risk of liver cancer remains controversial [17,18]. Lipophilic statins enter cells predominantly via passive diffusion and are widely distributed in tissues, whereas the uptake of hydrophilic statins involves a liver-specific carrier-mediated mechanism [43]. For hepatitis virus carriers, interruption of the mevalonate pathway prevents viral replication by potentiating antiviral therapy and stimulating anti-tumor immunity [44][45][46][47][48]. Most nationwide studies and meta-analyses have shown that lipophilic statins reduce the risk of liver cancer; however, the results for hydrophilic statins have been inconsistent [15,18,49]. In our study, two hydrophilic statins were evaluated, with rosuvastatin being the most commonly used hydrophilic statin in our cohort (28.22%), followed by pravastatin (12.91%). Our findings showed that hydrophilic statins reduced the risk of liver cancer; however, in our single-drug analysis, only rosuvastatin significantly reduced the risk of liver cancer. Similar results were reported in two other meta-analysis studies [18,50]. Rosuvastatin has a more potent affinity for the active site of HMG-CoA reductase than other statins, and the hepatic uptake of rosuvastatin is reportedly more selective and efficient compared with other drugs [51][52][53][54]. Hence, these features potentially make rosuvastatin different from other hydrophilic statins and exhibit a strong chemoprotective effect in reducing the risk of liver cancer. However, as a high-potency statin [55], rosuvastatin may be more commonly indicated for patients with higher cholesterol levels and more severe heart failure, introducing bias by indication. Future studies are warranted to validate the findings of the present study.
Despite efforts to balance confounding factors, the present study has several limitations. First, this study was conducted using data from a health insurance claims database that lacks information on certain liver cancer risk factors, such as alcohol consumption, smoking habits, aflatoxin exposure, body mass index, and atherosclerosis [56,57]. Hence, we were unable to control for these potential confounding factors. However, we used PS matching to match patients by age, sex, CCI score, diabetes, hypertension, dyslipidemia, urbanization level, and monthly income. Urbanization level and monthly income were alternative factors for lifestyle and environmental factors [25,58]. Moreover, CCI scores include myocardial infarction, peripheral vascular disease, and cerebrovascular disease, which have a strong relationship with atherosclerosis. Second, we had no access to laboratory data or details of medical treatments for patients with hyperlipidemia. However, we conducted a sensitivity analysis of the adjusted HRs by dose-exposure-stratified subgroup analysis, which revealed persistent effectiveness trends in the main mode with additional covariates. Further investigations of the relationship between the effectiveness and dosage of statins may be considered to assist clinical novelty in real-world practice. Third, this was not a prospective, randomized control study. Although our study demonstrated significant results, further research is warranted to investigate the precise cause-effect relationship between statin use and liver cancer in patients with HF. Fourth, the HF patients were enrolled through the codes of International Classification of Diseases, Ninth Revision, which could not reveal the etiology of heart failure, such as cardiogenic or non-cardiogenic HF. Finally, the main factors underlying liver cancer in Taiwan differ from those in Western countries. Thus, the transferability of our findings to other healthcare systems may not be feasible.

Conclusions
This is the first nationwide population-based cohort study to investigate the effects of statins on liver cancer risk in patients with HF. Our study revealed that statin use is associated with decreased liver cancer risk in patients with HF in the entire cohort, as well as in sex-and age-stratified subgroup analyses, compared with participants without statin use. A reduction in liver cancer risk was also observed in each dose-stratified subgroup. In addition, both hydrophilic and lipophilic statins showed significant risk reduction.

Informed Consent Statement:
The Joint Institutional Review Board of Taipei Medical University waived the need for informed consents from participants. This waiver does not affect the rights and welfare of the participants.

Data Availability Statement:
The data supporting the findings of the present research were sourced from the NHIRD in Taiwan. Due to legal restrictions imposed by the government of Taiwan related to the Personal Information Protection Act, the database cannot be made publicly available. However, upon reasonable request to the authors and with permission from the NHIRD, the relevant data are available.

Conflicts of Interest:
The authors declare no conflict of interest.