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Statin use and the risk of hepatocellular carcinoma in patients at high risk: A nationwide nested case-control study

  • Author Footnotes
    † These authors contributed equally to the study.
    Gyuri Kim
    Footnotes
    † These authors contributed equally to the study.
    Affiliations
    Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
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  • Author Footnotes
    † These authors contributed equally to the study.
    Suk-Yong Jang
    Footnotes
    † These authors contributed equally to the study.
    Affiliations
    Department of Preventive Medicine, Eulji University School of Medicine, Daejeon, Republic of Korea
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  • Chung Mo Nam
    Correspondence
    Corresponding authors. Address: Department of Preventive Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Tel.: +82 361 5387; fax: +82 2 392 8133 (C.M. Nam) or Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Tel.: +82 2 2228 1968; fax: +82 2 393 6884 (E.S. Kang).
    Affiliations
    Department of Preventive Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    Institute of Health Services Research, Yonsei University College of Medicine, Seoul, Republic of Korea
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  • Eun Seok Kang
    Correspondence
    Corresponding authors. Address: Department of Preventive Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Tel.: +82 361 5387; fax: +82 2 392 8133 (C.M. Nam) or Division of Endocrinology and Metabolism, Department of Internal Medicine, Yonsei University College of Medicine, 50-1, Yonsei-ro, Seodaemun-gu, Seoul 03722, Republic of Korea. Tel.: +82 2 2228 1968; fax: +82 2 393 6884 (E.S. Kang).
    Affiliations
    Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea

    Institute of Endocrine Research, Yonsei University College of Medicine, Seoul, Republic of Korea
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  • Author Footnotes
    † These authors contributed equally to the study.
Published:October 26, 2017DOI:https://doi.org/10.1016/j.jhep.2017.10.018

      Highlights

      • Statin use was significantly associated with a reduced risk of HCC compared with nonusers.
      • The beneficial effect of statins was shown in patients with diabetes mellitus and relatively good glycemic control.
      • Statin significantly reduced the risk of HCC in subjects with cirrhosis or diabetes mellitus, a high risk factor for HCC.

      Background & Aims

      Statins are widely used to treat hypercholesterolemia. Statins may prevent hepatocellular carcinoma (HCC), but have not yet been fully studied, particularly in patients at high risk. Therefore, we investigated the risk of HCC after statin use in the whole general population and evaluated the effects of preexisting diabetes mellitus (DM) and liver cirrhosis (LC) on that risk.

      Methods

      A nationwide, nested case-control study was conducted with data from the National Health Insurance Service Physical Health Examination Cohort 2002–2013 in the Republic of Korea. Individuals diagnosed with HCC were matched to controls based on the time of the follow-up, sex, and age at index date. Odds ratios (ORs) and 95% confidence intervals (CIs) for HCC associated with statin use were analyzed by multivariable conditional logistic regression analyses. In total, 1,642 HCC cases were matched to 8,210 control individuals from 514,866 participants.

      Results

      Statin use was associated with reduced risk of HCC development (adjusted OR [AOR] 0.44; 95% CI 0.33–0.58) compared with nonusers. The reduction in risk was significant in the presence (AOR 0.28; 95% CI 0.17–0.46) and absence of DM (AOR 0.53; 95% CI 0.39–0.73) and in the presence (AOR 0.39; 95% CI 0.26–0.60) and absence of LC (AOR 0.42; 95% CI 0.32–0.57). Statin use also significantly reduced the risk of HCC among patients with DM, without chronic complications (AOR 0.19; 95% CI 0.08–0.46) or with chronic complications (AOR 0.34; 95% CI 0.19–0.64), compared to nonusers.

      Conclusions

      Statin use may have a beneficial inhibitory effect on HCC development, particularly in patients with DM or LC, at high risk of HCC.

      Lay summary

      In this longitudinal nationwide population-based nested case-control study, the association between statin use and the risk of HCC was investigated in Asian populations. Herein, we noted a beneficial effect of statin use on the development of HCC in the general population and individuals at high risk of HCC (i.e. those with diabetes or liver cirrhosis).

      Graphical abstract

      Keywords

      Introduction

      Statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are used to lower blood cholesterol levels and to prevent cardiovascular disease and related mortality.
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      Diabetes mellitus (DM) was also associated with a twofold increase in the risk of HCC.
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      Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
      Regarding insulin resistance, DM is strongly associated with NAFLD and subsequently with HCC.
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      Patients with DM commonly use statins because the prevalence of dyslipidemia is reported to be higher than in patients without DM.
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      However, the relationship between statins and HCC among patients with and without DM remains unclear. Moreover, there is a lack of studies regarding the association between statin use and HCC among patients with DM in the Asian population, the highest incident HCC population.
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      • Cleries R.
      Primary liver cancer: worldwide incidence and trends.
      Statins may prevent HCC, but this association has not been fully studied. More data are also needed on the effects of statins on HCC among individuals with common risk factors for HCC. Therefore, in the present study, we aimed to investigate the association between statin use and the risk of HCC among the whole general population and individuals in the presence or absence of underlying DM or LC, using a nationwide sample from longitudinal nested case-control data in an Asian population.

      Materials and methods

       Design

      We used a 2002–2013 data set from the National Health Insurance Service Physical Health Examination Cohort (NHIS-PHEC) in the Republic of Korea.
      • Lee J.
      • Lee J.S.
      • Park S.H.
      • Shin S.A.
      • Kim K.
      Cohort profile: the national health insurance service-national sample cohort (NHIS-NSC), South Korea.
      The NHIS-PHEC was comprised of 514,866 examinees over the age of 40 years, who were randomly sampled from the five million examinees who received physical health examinations provided by the Korea National Health Insurance Service in 2002 or 2003. The information in the data set included all inpatient and outpatient medical claims data, including prescription drug use, diagnostic and treatment codes, and primary and secondary diagnosis codes. Measurement of body mass index (BMI) was obtained from the data of physical health examinations. All the individuals included in the NHIS-PHEC were followed until 2013 unless there was a death or disqualification for National Health Insurance, such as emigration. The protocol of this study was approved by the Institutional Review Board ([IRB] No: 4–2015–0636) at Severance Hospital, Seoul, Republic of Korea. Written informed consent was not required by the IRB because the researchers only accessed the database for analysis purposes and personal information was not used.

       Case and control selection criteria

      We used the International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) to identify case patients. Among the NHIS-PHEC cases, eligibility criteria for the HCC incidence patients were as follows: 1) first-time diagnosis of HCC (ICD C22.0) with at least a three-year cancer free period defined by the absence of any cancer diagnosis codes (wash out period); 2) admission with a primary diagnosis code of HCC; 3) no prior diagnosis of any cancer in order to ensure or exclude recurrent and metastatic liver cancer;
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      Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma.
      and 4) exclusion of individuals without supporting clinical codes indicating the presence of HCC including any liver diagnostic tests (biopsy or arteriography of hepatic artery), any treatments of the liver (hepatectomy, liver transplantation, radiofrequency ablation, arterial embolization, radiotherapy, or chemotherapy), or death due to HCC (death code for liver cancer) (Fig. 1). The date of a cancer diagnosis was the first date of outpatient or inpatient records with a primary diagnosis of cancer. The index date was defined as the date one year prior the date of HCC diagnosis. Controls were randomly selected at a 1:5 ratio from individuals who were at risk of becoming case patients at the time when case patients were selected. Individuals excluded during case patient selection were also excluded from the risk set. Case patients and control patients were matched based on the time of follow-up, sex, and age at index date. As case patients, control patients also had to have a three-year cancer free period. In addition to the main analyses, subgroup analyses were conducted within additionally matched subgroups based on the presence or absence of DM, with or without chronic complications, according to diagnosis code, liver enzyme abnormalities, or fasting blood glucose (≥154 mg/dl or <154 mg/dl).
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      Liver enzyme abnormalities were defined as any above-normal value of aspartate transaminase (AST) ≥51 IU/L, alanine transaminase (ALT) ≥46 IU/L, or ≥78 IU/L in males or ≥46 IU/L in females for gamma-glutamyltransferase (γ-GTP) which could reflect NAFLD, chronic hepatitis, or another etiology of chronic liver disease.
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      • et al.
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      Fasting blood glucose (≥154 mg/dl or <154 mg/dl) in patients with DM indicated glycemic control status of glycated hemoglobin ≥7% or <7%, respectively.
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      For the main analysis, 8,210 control subjects were matched to 1,642 case patients at a 1:5 ratio. For the DM-matched analysis, 8,180 control subjects were matched to 1,641 case patients with DM. No control subject was matched to one case patients with DM and 12 case patients with DM did not match to control subjects at a 1:5 ratio (five case patients with a 1:4, one case patient with a 1:3, and six case patients with a 1:2 ratio). For the LC-matched analysis, 1,574 control subjects were matched to 513 case patients with LC. No control subject was matched to 50 case patients with LC and 380 case patients with LC did not match to control subjects with a 1:5 ratio (70 case patients with a 1:4 ratio, 109 case patients with a 1:3 ratio, 101 case patients with a 1:2 ratio, and 100 case patients with a 1:1 ratio). For the liver enzyme abnormalities-matched analysis, 8,210 control subjects were matched to 1,642 case patients with 1:5 ratio. Table S1 shows the characteristics of case patients with LC who did not match to control subjects.

       Use of statins

      We defined the index date as one year before the date of HCC diagnosis. Statin use was defined as prescription of more than 30 days during admissions and outpatient visits from 2002 to the index date. This definition was applied for statins and other drugs including antidiabetic agents such as insulin, sulfonylurea, metformin, and thiazolidinedione as they may confound the data. To ensure that all study subjects had at least two statin-free years, subjects who were prescribed statins between 2002–2003 were excluded. We also calculated cumulative doses of exposure for statins with the sum of the doses for all the prescribed days, which was expressed as the cumulative defined daily dose (cDDD) according to the World Health Organization definition.

       Measurements

      From the health examinations, BMI was calculated as body weight divided by the square of height in meters. Obesity was defined as ≥25 kg/m2 of BMI for the Asian population enrolled in the present study. Smoking status was categorized as non-smoker, past smoker, or current smoker. The presence of comorbidities was defined by at least two outpatient visits or one admission upon the primary or the first secondary diagnosis. After overnight fasting, blood samples were obtained, and serum glucose and liver enzymes were measured. Low density lipoprotein (LDL) cholesterol results could be obtained after 2008 as part of the health examinations.

       Statistical analyses

      Conditional logistic regression analysis was performed to evaluate the association between statin use and the risk of HCC. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were determined. Other matching variables for the nested case-control study design, confounders that we adjusted for were DM, alcohol-related disorders (including alcoholic liver diseases and alcohol use disorders), LC, liver enzyme abnormalities, alcoholic liver disease, smoking status, obesity, Charlson Comorbidity Index (which was scored excluding the comorbid diseases listed above), aspirin use, duration of DM, use of antidiabetic agents including insulin, sulfonylurea, metformin, thiazolidinedione, or dipeptidyl peptidase-4 inhibitors, household income, and residential area, as appropriate. Because LDL cholesterol levels were available after 2008 from NHIS-PHEC, an additional study dataset after 2008 was selected and analyzed with the adjustment for LDL cholesterol levels. All of the confounders listed above were identified on the index date. The p value <0.05 was considered significant. All statistical analyses were performed using SAS software, version 9.4 (Cary, NC, USA).
      For further details regarding the materials used, please refer to the Supplementary material and the CTAT table.

      Results

      Among 514,866 participants in the NHIS-PHEC, 4,282 were diagnosed with HCC and 2,558 were excluded because they did not meet the inclusion criteria. Additionally, 82 patients were excluded due to the prescription of statin during 2002–2003 or missing data. The final number of cases was 1,642 and the mean follow-up time was 7.5 years (Fig. 1). Table 1 shows the baseline characteristics of the 1,642 HCC case patients and 8,210 control cases. The two groups had even distributions in the matching variables, including the time of follow-up, sex, and age at index date. Subjects were predominantly male (83.6%) and most subjects (69.4%) were aged 50–69 years. Compared with the control group, HCC case patients had more elevated liver enzymes, LC, chronic viral hepatitis, and alcohol-related disorders. Compared to control subjects, HCC case patients had less frequent aspirin use (OR 0.82; 95% CI 0.71–0.95) and statin use, including simvastatin (OR 0.44; 95% CI 0.33–0.58), atorvastatin (OR 0.49; 95% CI 0.37–0.65), lovastatin (OR 0.34; 95% CI 0.16–0.73), rosuvastatin (OR 0.56; 95% CI 0.31–0.98), and pitavastatin (OR 0.31; 95% CI 0.13–0.77).
      Table 1Baseline characteristics of hepatocellular carcinoma cases and matched controls.
      CharacteristicsCases

      (n = 1,642)
      Controls

      (n = 8,210)
      Crude
      n (%)n (%)OR (95% CI)
      Age at index date
      Matched on year of birth, sex, follow-up time.
       40–49175 (10.6)875 (10.7)
       50–59632 (38.5)3,160 (38.5)
       60–69507 (30.9)2,535 (30.9)
       70–79287 (17.5)1,435 (17.5)
       ≥8041 (2.5)205 (2.5)
       Mean (SD)61.8 (9.2)61.8 (9.2)
      Sex
      Matched on year of birth, sex, follow-up time.
       Male1,372 (83.6)6,860 (83.6)
       Female270 (16.4)1,350 (16.4)
      Elevated liver enzymes1,032 (62.9)1,373 (16.7)8.6 (7.6–9.7)
      Chronic viral hepatitis755 (46.0)232 (2.8)31.0 (25.4–37.9)
      Liver cirrhosis563 (34.2)94 (1.1)48.3 (36.7–63.6)
      Diabetes mellitus
       None1,324 (80.6)7,291 (88.8)1.00
       Uncomplicated156 (9.5)494 (6.0)1.74 (1.44–2.11)
       Complicated162 (9.9)425 (5.2)2.13 (1.76–2.59)
      Fasting blood glucose
       <100 mg/dl963 (58.7)5,424 (66.1)1.00
       100–125 mg/dl426 (25.9)2,089 (25.4)1.15 (1.02–1.30)
       ≥126 mg/dl253 (15.4)697 (8.5)2.06 (1.76–2.43)
       Mean (SD), mg/dl107.9 (50.3)99.1 (33.1)1.01 (1.00–1.01)
      CCI
       0877 (53.4)4,230 (51.5)1.00
       1520 (31.7)2,592 (31.6)0.96 (0.85–1.08)
       2168 (10.2)957 (11.7)0.83 (0.69–1.00)
       ≥377 (4.7)431 (5.3)0.83 (0.89–1.00)
      BMI
       <23 kg/m2620 (37.8)3,078 (37.5)1.00
       23–25 kg/m2448 (27.3)2,329 (28.4)0.96 (0.84–1.09)
       ≥25 kg/m2574 (35.0)2,803 (34.1)1.02 (0.90–1.15)
       Mean (SD)24.0 (3.1)23.9 (2.9)1.01 (1.00–1.03)
      Alcohol-related disorders277 (16.9)418 (5.1)3.90 (3.30–4.61)
      Smoking
       Non-smoker808 (49.2)4,371 (53.2)1.00
       Past smoker205 (12.5)1,092 (13.3)1.05 (0.88–1.25)
       Current smoker629 (38.3)2,747 (33.5)1.28 (1.13–1.45)
      Aspirin290 (17.7)1,676 (20.4)0.82 (0.71–0.95)
      Household income
       Low227 (13.8)1,067 (13.0)1.00
       Mid-low230 (14.0)1,088 (13.3)0.99 (0.83–1.22)
       Middle272 (16.6)1,316 (16.0)0.97 (0.80–1.18)
       Mid-high363 (22.1)1,765 (21.5)0.97 (0.80–1.16)
       High550 (33.5)2,974 (36.2)0.87 (0.73–1.03)
      Residential area
       Metropolitan703 (42.8)3,674 (44.8)1.00
       Non–metropolitan939 (57.2)4,536 (55.3)1.08 (0.971.20)
      Type of statin
       Simvastatin57 (3.5)617 (7.5)0.44 (0.33–0.58)
       Atorvastatin56 (3.4)536 (6.5)0.49 (0.37–0.65)
       Lovastatin7 (0.4)102 (1.2)0.34 (0.16–0.73)
       Fluvastatin12 (0.7)56 (0.7)1.07 (0.58–2.01)
       Pitavastatin5 (0.3)80 (1.0)0.31 (0.13–0.77)
       Pravastatin18 (1.1)91 (1.1)0.99 (0.59–1.65)
       Rosuvastatin13 (0.8)117 (1.4)0.56 (0.31–0.98)
      The index date was defined as the date one year before the date of hepatocellular carcinoma diagnosis.
      BMI, body mass index; CCI, Charlson Comorbidity Index; CI, confidence interval; OR, odds ratio; SD, standard deviation.
      * Matched on year of birth, sex, follow-up time.
      Statin use was significantly associated with a reduced risk of HCC incidence compared to that of the nonusers (AOR 0.44; 95% CI 0.33–0.58; Table 2). A trend toward risk reduction with cumulative doses of statin use was shown as AORs of 0.45 (95% CI 0.32–0.64), 0.56 (95% CI 0.31–1.00), 0.41 (95% CI 0.22–0.76), and 0.30 (95% CI 0.14–0.63) for patients with statin use of <180, 180–365, 365–720, and ≥720 cDDDs, respectively. The results of study subjects who had LDL cholesterol results after year 2008 from NHIS-PHEC data are provided (Table S2). Among 469 cases and 2,344 control subjects, statin use was significantly associated with AOR of 0.43 (95% CI 0.29–0.65) even after additionally adjusting for LDL cholesterol levels. The greatest risk reduction was shown in statin users with doses of ≥720 cDDDs with an AOR of 0.25 (95% CI 0.09–0.65), compared with that of nonusers.
      Table 2Relationship between statin use and hepatocellular carcinoma.
      CharacteristicsCases

      (n = 1,642)
      Controls

      (n = 8,210)
      CrudeAdjusted
      Adjusted for diabetes mellitus, liver cirrhosis, Charlson comorbidity index, body mass index, alcohol related disorders, smoking, aspirin use, use of antidiabetic medications, household income level, and residential area.
      n (%)n (%)OR (95% CI)OR (95% CI)
      Statin use
       Never use1,531 (93.2)7,163 (87.3)1.001.00
       Ever use111 (6.8)1,047 (12.8)0.47 (0.38–0.58)0.44 (0.33–0.58)
      Cumulative dose of use
       Never use1,531 (93.2)7,163 (87.3)1.001.00
      Ever use
       <180 cDDDs61 (3.7)520 (6.3)0.53 (0.40–0.70)0.45 (0.32–0.64)
       180–365 cDDDs19 (1.2)180 (2.2)0.46 (0.29–0.75)0.56 (0.31–1.00)
       365–720 cDDDs19 (1.2)187 (2.3)0.45 (0.28–0.72)0.41 (0.22–0.76)
       ≥720 cDDDs12 (0.7)160 (2.0)0.32 (0.18–0.59)0.30 (0.14–0.63)
      Cumulative dose of use
       Never use1,531 (93.2)7,163 (87.3)1.001.00
       Ever use
       Q1 (<60 cDDDs)27 (1.6)247 (3.0)0.50 (0.33–0.74)0.42 (0.25–0.69)
       Q2 (60–179 cDDDs)34 (2.1)271 (3.3)0.56 (0.39–0.81)0.49 (0.31–0.79)
       Q3 (180–528 cDDDs)27 (1.6)263 (3.2)0.45 (0.30–0.68)0.51 (0.30–0.85)
       Q4 (≥528 cDDDs)23 (1.4)266 (3.2)0.38 (0.24–0.58)0.35 (0.20–0.61)
      cDDDs, cumulative defined daily doses; CI, confidence interval; OR, odds ratio, Q, quartile.
      * Adjusted for diabetes mellitus, liver cirrhosis, Charlson comorbidity index, body mass index, alcohol related disorders, smoking, aspirin use, use of antidiabetic medications, household income level, and residential area.
      The relationship between statin use and HCC in patients with and without DM is shown (Table 3). In patients with DM, statin use was significantly associated with reduced risk (AOR 0.28; 95% CI 0.17–0.46), compared to that of nonusers. For statin users, patients without DM also showed a significant risk reduction of HCC incidence (AOR 0.53, 95% CI 0.39–0.73), compared to the nonusers, and this effect was dose-dependent (AOR 0.59 [95% CI 0.40–0.88], 0.50 [95% CI 0.23–1.08], 0.55 [95% CI 0.24–1.27], and 0.33 [95% CI 0.14–0.80]) for subjects who had a cDDD of statin of <180, 180–365, 365–720, and ≥720, respectively. The risk reduction for HCC in patients using statins was less in patients without DM, relative to patients with DM. Furthermore, we investigated the association between statin use and incident HCC among patients with DM according to the presence or absence of chronic DM complications (Table 4). Patients having DM without chronic complications (AOR 0.19; 95% CI 0.08–0.46), or patients with chronic complications (AOR 0.34; 95% CI 0.19–0.64) had a lower risk of incident HCC, when compared to that of statin nonusers. Furthermore, among patients with DM, patients with fasting blood glucose <154 mg/dl, who demonstrated relatively good glycemic control, showed a significantly reduced AOR of 0.43 (95% CI 0.21–0.89) for incident HCC among statin users, compared to statin nonusers, while those with fasting blood glucose ≥154 mg/dl showed an AOR of 0.56 (95% CI 0.23–1.33), which was not significant (Table S3).
      Table 3Relationship between statin use and hepatocellular carcinoma according to diabetes mellitus.
      With diabetes mellitusWithout diabetes mellitus
      CharacteristicsCases (n = 317)Controls (n = 1,560)CrudeAdjustedCases (n = 1,324)Controls (n = 6,620)CrudeAdjusted
      n (%)n (%)OR (95% CI)OR (95% CI)
      Adjusted for liver cirrhosis, liver enzyme abnormality, Charlson comorbidity score, obesity, alcoholic liver disease, smoking, aspirin use, household income level, residential area, duration of diabetes mellitus, and use of antidiabetic agents including insulin, sulfonylurea, metformin, thiazolidinedione, and dipeptidyl peptidase-4 inhibitors.
      n (%)n (%)OR (95% CI)OR (95% CI)
      Adjusted for liver cirrhosis, liver enzyme abnormality, Charlson comorbidity score, obesity, alcoholic liver disease, smoking, aspirin use, household income level, and residential area.
      Statin use
       Never use278 (87.7)1,054 (67.6)1.001.001,252 (94.6)5,937 (89.7)1.001.00
       Ever use39 (12.3)506 (32.4)0.27 (0.19–0.39)0.28 (0.17–0.46)72 (5.4)683 (10.3)0.48 (0.38–0.63)0.53 (0.39–0.73)
      Cumulative dose of use
       Never use278 (87.7)1,054 (67.6)1.001.001,252 (94.6)5,937 (89.7)1.001.00
       Ever use
        <180 cDDDs17 (5.4)198 (12.7)0.32 (0.19–0.54)0.23 (0.11–0.46)44 (3.3)372 (5.6)0.55 (0.40–0.76)0.59 (0.40–0.88)
        180–365 cDDDs8 (2.5)93 (6.0)0.31 (0.15–0.66)0.43 (0.18–1.05)11 (0.8)124 (1.9)0.41 (0.22–0.76)0.50 (0.23–1.08)
        365–720 cDDDs9 (2.8)107 (6.9)0.28 (0.14–0.57)0.51 (0.20–1.30)10 (0.8)89 (1.3)0.50 (0.26–0.97)0.55 (0.24–1.27)
        ≥720 cDDDs5 (1.6)108 (6.9)0.15 (0.06–0.37)0.12 (0.03–0.44)7 (0.5)98 (1.5)0.32 (0.15–0.69)0.33 (0.14–0.80)
      Cumulative dose of use
       Never use278 (87.7)1,054 (67.6)1.001.001,252 (94.6)5,937 (89.7)1.001.00
       Ever use
        Q1 (<60 cDDDs)8 (2.5)81 (5.2)0.38 (0.18–0.80)0.18 (0.06–0.50)19 (1.4)181 (2.7)0.49 (0.30–0.79)0.60 (0.34–1.03)
        Q2 (60–179 cDDDs)9 (2.8)117 (7.5)0.29 (0.14–0.570.28 (0.11–0.71)25 (1.9)190 (2.9)0.60 (0.40–0.920.59 (0.34–1.02)
        Q3 (180–527 cDDDs)9 (2.8)132 (8.5)0.24 (0.12–0.49)0.40 (0.18–0.90)18 (1.4)170 (2.6)0.48 (0.30–0.79)0.53 (0.28–1.00)
        Q4 (≥528 cDDDs)13 (4.1)176 (11.3)0.24 (0.13–0.44)0.27 (0.12–0.65)10 (0.8)142 (2.2)0.31 (0.16–0.60)0.37 (0.18–0.77)
      cDDDs, cumulative defined daily doses; CI, confidence interval; OR, odds ratio; Q, quartile.
      * Adjusted for liver cirrhosis, liver enzyme abnormality, Charlson comorbidity score, obesity, alcoholic liver disease, smoking, aspirin use, household income level, residential area, duration of diabetes mellitus, and use of antidiabetic agents including insulin, sulfonylurea, metformin, thiazolidinedione, and dipeptidyl peptidase-4 inhibitors.
      ** Adjusted for liver cirrhosis, liver enzyme abnormality, Charlson comorbidity score, obesity, alcoholic liver disease, smoking, aspirin use, household income level, and residential area.
      Table 4Relationship between statin use and hepatocellular carcinoma according to the chronic complications of diabetes mellitus.
      CharacteristicsCases

      (n = 317)
      Controls

      (n = 1,560)
      CrudeAdjusted
      n (%)n (%)OR (95% CI)OR (95% CI)
      Adjusted for liver cirrhosis, liver enzyme abnormality, Charlson comorbidity score, obesity, alcoholic liver disease, smoking, aspirin use, household income level, residential area, duration of diabetes mellitus, and use of antidiabetic agents including insulin, sulfonylurea, metformin, thiazolidinedione, and dipeptidyl peptidase-4 inhibitors.
      Without complication
      Never use143 (91.7)558 (72.7)1.001.00
      Ever use13 (8.3)210 (27.3)0.22 (0.12–0.40)0.19 (0.08–0.46)
      With complication
      Never use135 (83.9)484 (61.1)1.001.00
      Ever use26 (16.2)308 (38.9)0.29 (0.18–0.45)0.34 (0.19–0.64)
      CI, confidence interval; OR, odds ratio.
      * Adjusted for liver cirrhosis, liver enzyme abnormality, Charlson comorbidity score, obesity, alcoholic liver disease, smoking, aspirin use, household income level, residential area, duration of diabetes mellitus, and use of antidiabetic agents including insulin, sulfonylurea, metformin, thiazolidinedione, and dipeptidyl peptidase-4 inhibitors.
      The relationship between statins and HCC among individuals with and without LC is shown (Table 5). Among patients with LC, statin use was significantly associated with a reduction of HCC incidence (AOR 0.39; 95% CI 0.26–0.70) and the association was also observed in patients without LC (AOR 0.42; 95% CI 0.32–0.57), compared to nonusers. In addition, we evaluated the relationship between statin use and HCC development according to the presence or absence of elevated liver enzymes (Table S4). Statin use was significantly associated with reduced AORs of 0.34 (95% CI 0.25–0.44) and 0.51 (95% CI 0.36–0.72) for incident HCC in subjects with and without liver enzyme abnormalities, compared to statin nonusers, respectively.
      Table 5Relationship of statin use to hepatocellular carcinoma according to liver cirrhosis.
      With liver cirrhosisWithout liver cirrhosis
      CharacteristicsCases (n = 513)Controls (n = 1,574)CrudeAdjustedCases (n = 513)Controls (n = 1,574)CrudeAdjusted
      n (%)n (%)OR (95% CI)OR (95% CI)
      Adjusted for liver enzyme abnormality, diabetes, Charlson comorbidity score, obesity, alcoholic liver disease, smoking, aspirin use, household income level, and residential area.
      n (%)n (%)OR (95% CI)OR (95% CI)
      Adjusted for liver enzyme abnormality, diabetes, Charlson comorbidity score, obesity, alcoholic liver disease, smoking, aspirin use, household income level, and residential area.
      Statin use
       Never use480 (93.6)1,318 (83.7)1.001.001,004 (93.1)4,704 (87.2)1.001.00
       Ever use33 (6.4)256 (16.3)0.34 (0.22–0.50)0.39 (0.26–0.60)75 (7.0)691 (12.8)0.49 (0.38–0.63)0.42 (0.32–0.57)
      Cumulative dose of use
       Never use480 (93.6)1,318 (83.7)1.001.001,004 (93.1)4,704 (87.2)1.001.00
       Ever use
       <180 cDDDs20 (3.9)154 (9.8)0.37 (0.23–0.61)0.42 (0.25–0.71)39 (3.6)348 (6.5)0.51 (0.37–0.72)0.50 (0.35–0.73)
       180–365 cDDDs3 (0.6)44 (2.8)0.12 (0.03–0.49)0.14 (0.03–0.59)16 (1.5)123 (2.3)0.58 (0.34–0.99)0.43 (0.24–0.79)
       365–720 cDDDs7 (1.4)30 (1.9)0.48 (0.20–1.15)0.68 (0.27–1.76)12 (1.1)124 (2.3)0.42 (0.23–0.77)0.32 (0.16–0.62)
       ≥720 cDDDs3 (0.6)28 (1.8)0.33 (0.10–1.12)0.37 (0.11–1.28)8 (0.7)96 (1.8)0.36 (0.18–0.75)0.29 (0.13–0.63)
      Cumulative dose of use
       Never use480 (93.6)1,318 (83.7)1.001.001,004 (93.1)4,704 (87.2)1.001.00
       Ever use
        Q1 (<60 cDDDs)8 (1.6)68 (4.3)0.31 (0.14–0.68)0.33 (0.15–0.76)18 (1.7)173 (3.2)0.47 (0.29–0.77)0.46 (0.27–0.78)
        Q2 (60–179 cDDDs)12 (2.3)86 (5.5)0.42 (0.23–0.78)0.49 (0.26–0.94)21 (2.0)174 (3.2)0.56 (0.35–0.88)0.55 (0.33–0.92)
        Q3 (180–527cDDDs)6 (1.2)53 (3.4)0.25 (0.10–0.63)0.29 (0.11–0.77)21 (2.0)179 (3.3)0.52 (0.33–0.83)0.37 (0.22–0.61)
        Q4 (≥528 cDDDs)7 (1.4)49 (3.1)0.33 (0.14–0.77)0.41 (0.17–1.01)15 (1.4)165 (3.1)0.40 (0.23–0.68)0.33 (0.18–0.60)
      cDDDs, cumulative defined daily doses; CI, confidence interval; OR, odds ratio; Q, quartile.
      * Adjusted for liver enzyme abnormality, diabetes, Charlson comorbidity score, obesity, alcoholic liver disease, smoking, aspirin use, household income level, and residential area.

      Discussion

      In a nationwide longitudinal nested case-control study, we evaluated 1,642 HCC cases and 8,210 control cases with matching variables including age, sex, and the time of the follow-up at a 1:5 ratio, from the NHIS-PHEC, including the follow-up data from 2002–2013 of 514,866 participants over the age of 40 years. We found that statin use was significantly associated with a reduced risk of HCC. The beneficial effect of statins on incident HCC was also exhibited in individuals with risk factors, including DM, LC, or elevated liver enzymes. Although patients with DM and chronic complications were associated with a high risk of HCC, statin use also significantly reduced risk of HCC among those patients. Furthermore, the beneficial effect of statin use on HCC was greater in patients with DM or LC than in patients without DM or LC.
      Previously, using a data source of 229 HCC case patients and 1,145 control cases, from patients with type 2 DM, statin initiation was reported to reduce the risk of incident HCC with an AOR of 0.36 (95% CI 0.22–0.60).
      • Kim G.
      • Jang S.Y.
      • Han E.
      • Lee Y.H.
      • Park S.Y.
      • Nam C.M.
      • et al.
      Effect of statin on hepatocellular carcinoma in patients with type 2 diabetes: A nationwide nested case-control study.
      In the present study, we included the general population and examined the effect of statin use for HCC from the whole general population. In the DM-matched analysis, consistent with the previous results, the beneficial effect of statin use on HCC was greater in patients with DM, compared to subjects without DM, although DM alone was an increasing risk factor of HCC. DM was reported to be related to a twofold increased risk of HCC, independent of underlying liver disease,
      • El-Serag H.B.
      • Tran T.
      • Everhart J.E.
      Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma.
      and the risk was correlated with a long duration of DM.
      • Hassan M.M.
      • Curley S.A.
      • Li D.
      • Kaseb A.
      • Davila M.
      • Abdalla E.K.
      • et al.
      Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma.
      In the current study, we showed that HCC case patients had more DM without chronic complications and DM with chronic complications, compared to individuals without DM. However, statin use significantly reduced the risk of incident HCC among patients with DM, with or without chronic complications. Statin use had the greatest impact on patients with DM. Additionally, we analyzed patients with DM according to glycemic control by fasting glucose level, and found that, for statin users, the risk of incident HCC was significantly reduced in patients with DM and relatively good glycemic control, compared to statin nonusers. Moreover, previous studies showed that statin use was significantly related to a reduced risk of HCC among patients with liver disease, including individuals with HBV or HCV infection.
      • Tsan Y.T.
      • Lee C.H.
      • Ho W.C.
      • Lin M.H.
      • Wang J.D.
      • Chen P.C.
      Statins and the risk of hepatocellular carcinoma in patients with hepatitis C virus infection.
      • Tsan Y.T.
      • Lee C.H.
      • Wang J.D.
      • Chen P.C.
      Statins and the risk of hepatocellular carcinoma in patients with hepatitis B virus infection.
      McGlynn et al. reported that statin use reduced the risk of HCC in the presence (AOR 0.32, 95% CI 0.17–0.57) and absence of chronic liver disease (AOR 0.65, 95% CI 0.52–0.81).
      • McGlynn K.A.
      • Hagberg K.
      • Chen J.
      • Graubard B.I.
      • London W.T.
      • Jick S.
      • et al.
      Statin use and risk of primary liver cancer in the Clinical Practice Research Datalink.
      In a similar context, we showed that statin use significantly reduced the risk of HCC in patients with LC or elevated liver enzymes, with a larger reduction than that observed in patients without LC or elevated liver enzymes.
      The relationships regarding both hydrophilic and lipophilic statins and incident HCC were also investigated. Hydrophilic statins included pravastatin and rosuvastatin and lipophilic statins included simvastatin, atorvastatin, lovastatin, fluvastatin, and pitavastatin. The hydrophilic statins are known to be more liver-specific,
      • Nezasa K.
      • Higaki K.
      • Matsumura T.
      • Inazawa K.
      • Hasegawa H.
      • Nakano M.
      • et al.
      Liver-specific distribution of rosuvastatin in rats: comparison with pravastatin and simvastatin.
      but significantly, both types of statins showed beneficial effects.
      • McGlynn K.A.
      • Hagberg K.
      • Chen J.
      • Graubard B.I.
      • London W.T.
      • Jick S.
      • et al.
      Statin use and risk of primary liver cancer in the Clinical Practice Research Datalink.
      Statins are approved as cholesterol-lowering agents and have been safely prescribed worldwide for decades for patients with hypercholesterolemia. Recently, the mevalonate pathway inhibited by statins in the liver was suggested to be an essential metabolic pathway involving metabolites that are integral to tumor growth and progression.
      • Mullen P.J.
      • Yu R.
      • Longo J.
      • Archer M.C.
      • Penn L.Z.
      The interplay between cell signalling and the mevalonate pathway in cancer.
      Farnesyl diphosphate, geranylgeranyl diphosphate isoprenylate, and small GTPases such as Ras and Rho are involved in tumorigenesis and cancer cell survival.
      • Kang S.
      • Kim E.S.
      • Moon A.
      Simvastatin and lovastatin inhibit breast cell invasion induced by H-Ras.
      • Pandyra A.
      • Mullen P.J.
      • Kalkat M.
      • Yu R.
      • Pong J.T.
      • Li Z.
      • et al.
      Immediate utility of two approved agents to target both the metabolic mevalonate pathway and its restorative feedback loop.
      In addition, statins also ameliorated hepatic steatosis and inflammation, which were strongly associated with DM and liver disease, related to the development of HCC.
      • Ekstedt M.
      • Franzen L.E.
      • Mathiesen U.L.
      • Holmqvist M.
      • Bodemar G.
      • Kechagias S.
      Statins in non-alcoholic fatty liver disease and chronically elevated liver enzymes: a histopathological follow-up study.
      • Huang Y.W.
      • Lee C.L.
      • Yang S.S.
      • Fu S.C.
      • Chen Y.Y.
      • Wang T.C.
      • et al.
      Statins reduce the risk of cirrhosis and its decompensation in chronic hepatitis B patients: a nationwide cohort study.
      • Park H.S.
      • Jang J.E.
      • Ko M.S.
      • Woo S.H.
      • Kim B.J.
      • Kim H.S.
      • et al.
      Statins increase mitochondrial and peroxisomal fatty acid oxidation in the liver and prevent non-alcoholic steatohepatitis in mice.
      However, how statins have protective effects in patients with DM or liver disease is poorly understood. Further investigations regarding the specific mechanisms of statins’ anticancer properties, coupled with DM and liver disease relationships should be elucidated.
      The present study has several strengths. First, we used well established and validated national longitudinal data, sourced from the NHIS-PHEC, and included follow-up data from 2002–2013 on 514,866 participants. Using a nested case-control study design, control patients were matched to case patients at a ratio of 1:5 based on sex, age at index date, and the time of the follow-up with strict inclusion criteria for the study population. We firstly used matched laboratory data in the analyses to ascertain the effects of statin on incident HCC in relation to liver enzymes, fasting blood glucose, and LDL cholesterol. In addition, adjustments for various potential confounding parameters including laboratory data were adopted in the analyses to provide accurate results. There has been a lack of research into the relationship between statin use and incident HCC in the Asian population, in which the prevalence of HBV infection is high and the number of people with obesity or NAFLD is growing due to changes in lifestyle and diet. The results from a large Asian population study could have the potential to provide strong evidence to link these factors. Moreover, we investigated the association between statin use and incident HCC in subgroups including DM, LC, or liver enzyme abnormalities as high-risk groups of HCC, as well as all the general population. We also investigated the association between statin use and the risk of HCC in patients having DM, according to the presence of chronic complications or glycemic control status. Furthermore, multiple types of statins were also evaluated including both hydrophilic and lipophilic statins.
      There were also limitations in this study which should be addressed in further studies. A case-control study has several limitations, particularly selection bias considering its nature as an observational study. However, in the present study, the case and control subjects were selected from a population-based cohort, the NHIS-PHEC. In general, when cases and controls are selected from the same source, the likelihood of selection bias tends to be diminished in comparison with a traditional case-based case-control study.
      • Szklo M.
      • Nieto J.
      Basic study designs in analytic epidemiology epidemiology beyond the basics.
      In addition, we could not assess other interventions that could be related with hypercholesterolemia, such as the use of other lipid-lowering medications including fibrate, bile acid sequestrants, nicotinic acid, and/or ezetimibe. The subgroup analysis according to the use of those medications was not available due to a low prescription rate of 3.4% for those medications, which may have a relatively low power in the present study.
      • Petrie A.
      • Sabin C.
      Errors in hypothesis testing. Medical Statistics at a Glance.
      This should be evaluated in future studies. Moreover, the effect of statins on HCC development according to other etiologies of chronic liver disease was not evaluated, because of difficulty in diagnosing other etiologies by diagnostic code. Therefore, we used laboratory results of liver enzymes and analyzed the effect of statin use on HCC incidence in relation with liver enzyme abnormalities. Furthermore, although we conducted multivariable-adjusted analysis after adjustment of LDL cholesterol level, the significant association between statin use and the reduced risk of HCC development remained. However, in this subset of data with LDL cholesterol levels after 2008, the majority of the LDL levels available were obtained after statin use, large portions of LDL cholesterol level data prior to statin use were unavailable. We could only analyze a single point LDL cholesterol level per study subject after 2008, regardless of the time of statin use. Therefore, it might be difficult to interpret the results in the subgroup analysis according to LDL cholesterol level and bias could exist. We were unable to confirm the association between LDL cholesterol level and the risk of HCC development. The mechanism of statin use and HCC development should be addressed in connection with LDL cholesterol levels in animal studies and human clinical trials.
      In conclusion, statin use may have a beneficial inhibitory effect on HCC development. The effect may be stronger in patients with DM or LC, who are at a higher risk of HCC than those without DM or LC.

      Financial support

      The study was funded by the Bio & Medical Technology Development Program of the NRF , Korea, MSIP ( 2016R1A2B4013029 to E.S. Kang).

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      E.S.K. and C.M.N. had the idea for and designed the study, supervised the study intervention, revised drafts of article, and obtained funding; G.K. designed the study, analyzed, interpreted the data, wrote the first draft, and revised the article; S-Y.J. designed the study, analyzed, performed the statistical analysis, interpreted the data, and revised the article. All authors approved the submitted manuscript.

      Supplementary data

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