STOMACH
INTRODUCTION
Statins are inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A reductase, which is a key enzyme in the rate-limiting step in cho-lesterol synthesis ( 1 ). Statins are commonly used as chocho-lesterol- cholesterol-lowering medications and have shown eff ectiveness in the primary and secondary prevention of heart attack and stroke ( 2,3 ). Th e extensive evidence has led to a widespread use of these drugs.
Rodent studies indicate that statins are carcinogenic ( 4 ). In con-trast, several recent studies of human cancer cell lines and animal tumor models indicate that statins may have chemopreventive properties through the arresting of cell-cycle progression ( 5 ), induc-ing apoptosis ( 1,6 ), suppressinduc-ing angiogenesis ( 7,8 ), and inhibitinduc-ing tumor growth and metastasis ( 9,10 ). Results of meta-analysis and observational studies revealed either no association ( 11 – 18 ) or even a decreased cancer incidence ( 19 – 28 ). Th e reasons for the varying results are unclear but may relate to methodological issues, includ-ing heterogeneous patient populations, small sample size, variable durations of statin exposure, and short follow-up periods ( 29 ).
Statins are well recognized as relatively safe drugs, although adverse eff ects include hepatotoxicity and myopathy at low inci-dence ( 30 ). Only three epidemiological studies have investigated the association between statin use and the risk of gastric cancer. All three studies reported a statistically nonsignifi cant inverse asso-ciation between statin use and gastric cancer risk ( 15,16,23 ). As a large number of people utilize statins on a long-term basis, and as epidemiological evidence for a link between statin use and the risk of gastric cancer is limited, we undertook the present study in Taiwan to determine whether statin use is associated with a decreased risk of gastric cancer.
METHODS Data source
Th e National Health Insurance (NHI) program, which provides compulsory universal health insurance, was implemented in Taiwan on 1 March 1995. Under the NHI, 99 % of the island ’ s
Statins Are Associated With a Reduced Risk of Gastric
Cancer: A Population-Based Case – Control Study
Hui-Fen Chiu , PhD 1 , Shu-Chen Ho , MS 2 , Chih-Ching Chang , MD, PhD 3 , Trong-Neng Wu , PhD 4 and Chun-Yuh Yang , PhD, MPH 5 , 6
OBJECTIVES: Experimental studies have shown that statins have potential protective effects against cancer. The aim of this study was to investigate whether the use of statins was associated with gastric cancer risk.
METHODS: We conducted a population-based case – control study in Taiwan. Data were retrospectively collected from the Taiwan National health Insurance Research Database. Cases consisted of all patients who
were aged ≥ 50 years and had a fi rst-time diagnosis of gastric cancer for the period between 2005
and 2008. The controls were matched to cases by age, sex, and index date. Adjusted odds ratios (ORs) and 95 % confi dence intervals (CIs) were estimated by using multiple logistic regression.
RESULTS: We examined 337 gastric cancer cases and 1,348 controls. We found that ever-use of any statin was associated with a signifi cant decrease in gastric cancer risk (OR = 0.68, 95 % CI = 0.49 – 0.95). Compared with no use of statins, the adjusted ORs were 0.90 (95 % CI = 0.60 – 1.36) for the group having been prescribed statins with cumulative defi ned daily doses (DDDs) < 134.25 and 0.49
(95 % CI = 0.30 – 0.79) for the group with cumulative statin use of ≥ 134.25 DDDs. Also, there was a
signifi cant trend toward decreasing gastric cancer risk with increasing cumulative dose ( χ 2 for linear
trend = 7.42, P = 0.006).
CONCLUSIONS: The results of this study are the fi rst to suggest that statins may reduce the risk of gastric cancer.
Am J Gastroenterol 2011; 106:2098–2103; doi: 10.1038/ajg.2011.277; published online 16 August 2011
1 Institute of Pharmacology, College of Medicine, Kaohsiung Medical University , Kaohsiung , Taiwan ; 2 Institute of Occupational Safety and Health, College of Health Sciences, Kaohsiung Medical University , Kaohsiung , Taiwan ; 3 Department of Environmental and Occupational Health, National Cheng Kung University , Tainan , Taiwan ; 4 Institute of Environmental Health, China Medical University , Taichung , Taiwan ; 5 Faculty of Public Health, College of Health Sciences, Kaohsiung Medical University , Kaohsiung , Taiwan ; 6 Division of Environmental Health and Occupational Medicine, National Health Research Institute , Miaoli , Taiwan . Correspondence: Chun-Yuh Yang, PhD, MPH , Faculty of Public Health, College of Health Sciences, Kaohsiung Medical University , 100 Shih-Chuan 1st Road , Kaohsiung 80708 , Taiwan . E-mail: [email protected]
STOMACH
population (23.12 million in 2009) receives all forms of health-care services including outpatient services, inpatient health-care, Chinese medicine, dental care, childbirth, physical therapy, preventive health care, home care, and rehabilitation for chronic mental ill-ness. In cooperation with the Bureau of NHI, the National Health Research Institute (NHRI) of Taiwan randomly sampled a rep-resentative database of 1,000,000 subjects from the entire NHI enrollees using a systematic sampling method for research pur-poses. Th ere were no statistically signifi cant diff erences in age, gender, and health-care costs between the sample group and all enrollees, as reported by the NHRI. Th is data set (from January 1996 to December 2008) includes all claim data for these 1,000,000 subjects, and off ers a good opportunity to explore the relation between the use of statins and the risk of gastric cancer. Th ese databases have previously been used for epidemiological research, and information on prescription use, diagnoses, and hospitaliza-tions has been shown to be of high quality ( 31 – 33 ).
Because the identifi cation numbers of all individuals in the NHRI databases were encrypted to protect the privacy of the indi-viduals, this study was exempt from full review by the Institution Review Board.
Identifi cation of cases and controls
Cases consisted of all patients who were aged ≥ 50 years and had a fi rsttime diagnosis of gastric cancer (International Classifi -cation of Diseases, 9th revision, Clinical Modifi -cation (ICD-9-CM) Code 151) over a 4-year period, from 1 January 2005 to 31 December 2008, and who had no previous diagnosis of cancer. Controls comprised patients who were admitted to the hospital for diagnoses that were unrelated to statin use, including orthopedic conditions, trauma (excluding wrist and hip fractures), and other conditions (acute infection, hernia, kidney stones, cholecystitis) ( 13,34 ). Wrist and hip fractures were excluded because previous studies have reported a reduced risk of osteoporosis among statin users ( 35 – 38 ). We identifi ed four control patients per case patient. Control patients were matched to the cases by sex, year of birth, and index date and they were without a previous cancer diagnosis. For controls, the index date (date of hospital admission) was within the same month of the index date (date of fi rst-time diagnosis of gastric cancer) of their matched case. Under the conditions of detecting an odds ratio (OR) of 0.5 with 80 % power at the 5 % signifi cance level, 20 % of the population aged ≥ 50 years are statin users, and that a control-to-case of 4 is planned, the minimum number of cases required was estimated to be 169.
Exposure to statins
Information on all statin prescription was extracted from the NHRI prescription database. We collected the date of prescrip-tion, the daily dose, and the number of days supplied. Th e defi ned daily doses (DDDs) recommended by the WHO ( 39 ) were used to quantify the usage of statins. Cumulative DDD was estimated as the sum of dispensed DDDs of any statins (lovastatin, pravas-tatin, rosuvaspravas-tatin, fl uvaspravas-tatin, simvaspravas-tatin, or atorvastatin) from 1 January 1996 to the index date.
Potential confounders
For all individuals in the study population, we obtained potential confounders that are documented predictive factors for gastric cancer, including Helicobacter pylori eradication ( 40 ) and gastric, duodenal, and peptic ulcers ( 41 ), recorded between 1 January 1996 and the index date. In addition, we also obtained prescription data for medications for aspirin, nonsteroidal antiinfl ammatory drugs, proton pump inhibitors, and other lipid-lowering drugs (includ-ing fi brate, niacin, bile-acid bind(includ-ing resins, and miscellaneous) that could potentially confound the association between statin use and cancer risk. We defi ned users of the above-mentioned medi-cations as patients with at least one prescription over 1 year prior to index date. Furthermore, the number of hospitalizations 1 year before index date were treated as confounders.
Statistics
For comparisons of proportions, χ 2 statistics were used. A
condi-tional logistic regression model was used to estimate the relative magnitude in relation to the use of statins. Exposure was defi ned as patients who received at least one prescription for a statin at any time between 1 January 1996 and the index date. In the analysis, the subjects were categorized into one of the three statin expo-sure categories: nonusers (subjects with no prescription for any statins at any time between 1 January 1996 and the index date), and users of doses equal to or below the median and above the median based on the distribution of use among controls. Th e ORs and their 95 % confi dence intervals (CIs) were calculated using patients with no exposure as the reference. Th e Wald χ 2 test for linear trend
was performed by entering statin exposures as a three-level ordi-nal variable (with the values 0 – 2) in the logistic regression model. Analyses were performed using the SAS statistical package (version 8.02, SAS Institute, Cary, NC). All statistical tests were two sided. Values of P < 0.05 were considered statistically signifi cant.
RESULTS
Records from 337 gastric cancer cases and 1,348 selected matched controls are included in the analyses of gastric cancer risk. Table 1 presents the distribution of demographic characteristics and selected medical conditions of the gastric cancer cases and con-trols. Cases had a signifi cantly higher rate of gastric and peptic ulcers. However, the case group had a signifi cantly lower rate of use of nonsteroidal antiinfl ammatory drugs. Th ere was no signifi -cant diff erence between cases and controls in H. pylori eradica-tion, aspirin use, and use of other lipid-lowering drugs.
Th e relationship between the use of statins and gastric cancer is shown in Table 2 . A total of 16.6 % of the cases and 22.1 % of the controls had used any quantity of at least one prescription for a statin. Ever-use of any statin was associated with a decreased crude ORs for gastric cancer risk (OR = 0.70, 95 % CI = 0.51 – 0.96). Adjust-ments for possible confounders (matching variables, number of hospitalization, H. pylori eradication, gastric ulcer, peptic ulcer, duodenal ulcer, and use of aspirin, nonsteroidal antiinfl amma-tory drug, and other lipid-lowering drugs) only slightly altered the ORs; patients who received any prescriptions of statins had a
STOMACH
32 % decrease in the risk of gastric cancer compared with nonusers (adjusted OR = 0.68, 95 % CI = 0.49 – 0.95).
When statin use was categorized by cumulative dose, the adjusted ORs were 0.90 (95 % CI = 0.60 – 1.36) for the group with cumulative statin use < 134.25 DDDs and 0.49 (95 % CI = 0.30 – 0.79) for the group with cumulative statin use of ≥ 134.25 DDDs compared with nonusers. Also, there was a signifi cant trend toward decreasing gastric cancer risk with increasing cumulative dose ( χ 2 for linear
trend = 7.42, P = 0.006).
DISCUSSION
In this population-based case – control study, ever-use of any statin was associated with a 32 % decrease in gastric cancer risk. We also
found that there was a signifi cant trend toward decreasing gastric cancer risk with increasing cumulative dose aft er controlling for potential confounders.
To our knowledge, only three previous studies have examined the association between statin use and the risk of gastric cancer. In a case – control study that was conducted using the General Practice Research Database in United Kingdom, Kaye and Jick ( 16 ) reported an OR of 0.4 (95 % CI = 0.1 – 1.3) for stomach cancer in relation to current statin use. Th e British study was based on a small number (only four cases), and therefore had limited sta-tistical power. Graaf et al. ( 23 ) used a pharmacy database in the Netherlands to defi ne exposure and observed an OR of 0.88 (95 % CI = 0.36 – 2.15) for stomach cancer in relation to statin prescrip-tions. Th e number of gastric cancer case in our study ( n = 337) is threefold that in the Dutch nested case – control study ( n = 104). Th e power of the Dutch study was therefore also relatively lim-ited. Th e inhibitory potency of diff erent statins is not equal. Of the statin-exposed patients, 79.6 % patients were prescribed simvas-tatin. However, the most commonly used statin was atorvastatin in Taiwan. Th e results of the Dutch study cannot be generalized to the use of other statins because of its relatively high frequency of simvastatin prescription. Recently, Haukka et al. ( 15 ) used data from Finland to evaluate statin use and also report no association between statin use and stomach cancer risk (relative risk = 0.98, 95 % CI = 0.94 – 1.02). Th e Finnish study consisted of 472,481 pairs of individuals and examined 1,667 stomach cancer cases (770 for statin group, 897 in the control group) during 4.2 million person-years of follow-up period. Th e Finnish study, however, did not adjust for potential confounders such as H. pylori eradication, and gastric, duodenal, and peptic ulcers, which were adjusted for in our study. To our knowledge, our present study is the fi rst epidemio-logical study to report that statin use may have a protective eff ect against gastric cancer.
Th e results of our study are consistent with the assumed biologi-cal mechanism of statins, although the mechanism whereby statin use may decrease gastric cancer risk is not well understood. Sev-eral potential mechanisms have been investigated, including the following. (i) Inhibiting downstream products of the mevalonate pathway, primary geranylgeranyl pyrophosphate (GGPP) and far-nesylpyrophophosphate (FPP) ( 42 – 44 ). Derivatives of the meval-onate pathway GGPP and FPP are important in the activation of a number of cellular proteins, including small guanosine-5 ′ -triphos-phate-binding proteins, such as K-ras, N-ras, and the Rho family ( 42 – 45 ). Statins interfere with the production of GGPP and FPP and disrupt the growth of malignant cells, eventually leading to apoptosis ( 1 ). (ii) Statins inhibit the activation of the proteosome pathway, limiting the breakdown of both p21 and p27, allowing these molecules to exert their growth-inhibitory eff ects and in turn to retard cancer cell mitosis ( 10,45,46 ).
To be eligible as a control disease, the control disease must not be associated with gastric cancer and statin exposure. If we included those diseases that were related to statin use as one of the control diseases, the cases and control groups will be forced to be more alike in terms of the proportion of statin use, and thus an under-estimate of the association between statin use and the risk of gastric
Table 2 . Associations between statin use and gastric cancer risk in a population-based case – control study, Taiwan, 2005 – 2008
No. of cases / no. of controls Crude OR (95 % CI) Adjusted OR a (95 % CI) Overall No statin use 281 / 1,050 1.00 1.00 Any statin use 56 / 298 0.70 (0.51 – 0.96) 0.68 (0.49 – 0.95) Cumulative use
0 281 / 1,050 1.00 1.00
≤ 134.25 DDD 36 / 149 0.89 (0.60 – 1.32) 0.90 (0.60 – 1.36) > 134.25 DDD 20 / 149 0.51 (0.31 – 0.82) 0.49 (0.30 – 0.79) P for trend χ 2 =7.16, P =0.007 χ 2 =7.42, P =0.006
CI, confi dence interval; DDD, defi ned daily dose; OR, odds ratio.
a Adjusted for matching variable, number of hospitalization, Helicobacter pylori
eradication, gastric ulcer, peptic ulcer, duodenal ulcer, and use of aspirin, nonsteroidal antiinfl ammatory drug (NSAID), and other lipid-lowering drugs.
Table 1 . Demographic characteristics of gastric cancer cases and controls Variable Cases ( n =337) Controls ( n =1,348) OR (95 % CI) Age (mean ± s.d.) 69.64 ± 10.18 69.51 ± 10.07 P = 0.82 No. of hospitalizations 0.35 ± 0.86 0.50 ± 1.14 P = 0.01 HP eradication ( % ) 46 (13.65) 216 (16.02) 0.83 (0.59 – 1.17) Gastric ulcer ( % ) 138 (40.95) 326 (24.18) 2.17 (1.69 – 2.79) Peptic ulcer ( % ) 203 (60.24) 594 (44.07) 1.92 (1.51 – 2.45) Duodenal ulcer ( % ) 53 (15.73) 227 (16.84) 0.92 (0.67 – 1.28) Aspirin ( % ) 31 (9.20) 130 (9.64) 0.95 (0.63 – 1.43) NSAIDs ( % ) 171 (50.74) 794 (58.90) 0.72 (0.57 – 0.91) Use of other
lipid-lowering drugs ( % )
9 (2.67) 48 (3.56) 0.74 (0.36 – 1.53)
CI, confi dence interval; HP, Helicobacter pylori ; NSAID, nonsteroidal antiinfl am-matory drug; OR, odds ratio.
STOMACH
cancer will result. Th erefore, we chose control patients with diag-noses that we judged to be unrelated to statin use. Th is criterion is required from the methodological point of view and will also min-imize the possibility of selection bias. We assessed the exposure to statins measured as the sum of dispensed DDDs of any statin from 1 January 1996 to the index date (cumulative DDDs). Cumu-lative DDD is a time-dependent variable in which the number of days of supplies of each statin prescription dispensed was summed over time from 1 January 1996 to the index date. Th e present study attempted to control for this possible bias by choosing controls who had exposure duration similar to the cases. In other words, cases and controls were matched on index date. Th is is the reason that we select controls from hospitalized patients, rather than a random sample of the 1,000,000 representative NHI enrollees who were free of cancer. One of the strengths of our study is the use of a computerized database, which is population based and is highly representative. Statins were available only on prescription. Because statin use data were obtained from a historical database that col-lects all prescription information before the date of gastric cancer, the recall bias for statin use was avoided.
Several limitations of the present study should be noted. First, although we adjusted for several potential confounders in the statis-tical analysis, a number of possible confounding variables, includ-ing smokinclud-ing, alcohol use, diet, and occupation that are associated with gastric cancer, were not included in our database. Second, we were not able to contact the patients directly regarding their use of statins because of anonymization of their identifi cation number. Using pharmacy records representing dispensing data rather than usage data might have introduced an overestimation of statin use. However, there is no reason to assume that this would be diff er-ent for cases and controls. Even if the patier-ents did not take all of the statins prescribed, our fi ndings would underestimate the eff ect of statin use. Th ird, lovastain and pravastatin (available in 1990), Simvastatin (available in 1992), and Fluvastatin (available in April, 1996) became available prior to patient enrollment in the database. Prescriptions for these drugs prior to 1996 would not be captured in our analysis. Th is could have underestimated the cumulative DDDs and may weaken the observed association. In addition, some exposure misclassifi cation was likely caused by the fact that information on prescription was available only since 1996. Such misclassifi cation, however, was likely to be nondiff erential, which would tend to underestimate rather than overestimate the associa-tion. Fourth, we are unable to separately analyze the risks for users of distinct statins because of the relatively small number of cases and the relatively small number of statin users. Fift h, diagnoses of gastric cancer or any other comorbid medical conditions and pre-scription information that rely on administrative claims data may be less accurate than those obtained according to standardized cri-teria, and misclassifi cation is possible. However, this misclassifi ca-tion is likely to be nondiff erential (i.e., there is no reason to assume that this would be diff erent for cases and controls) and therefore would tend to underestimate rather than overestimate the true association. Sixth, H. pylori infection is associated with gastric cancer development ( 47 ). Th ere is no information available on this variable for an individual study subject and, hence, it could not be
adjusted for directly in the analysis. However, there is no reason to believe that there would be any correlation between this variable and the use of statin. Furthermore, we found that gastric and pep-tic ulcers were more prevalent in the case group, whereas controls had a higher rate of H. pylori eradication (although not statistically signifi cant). Th ese features are consistent with previous fi ndings ( 40,41 ) and increase the internal validity of our study. Seventh, we did not have information on the socioeconomic status of our study subjects. However, confounding by socioeconomic status is mini-mal because the NHI system in Taiwan has comprehensive cover-age and allows patients to visit any clinic or hospital freely without referral by a general practitioner, and patients only need to pay a small co-payment (the co-payment for prescription is ~ 10 % of the cost of the drugs dispensed). People in Taiwan have nearly no barriers to medical service in terms of accessibility and costs ( 48 ). Finally, as with any observational study, residual confounding by unmeasured factors that are diff erent between cases and controls is also possible. However, the confounding eff ect of medical atten-tion could be corrected for by introducing the number of hospitali-zations into the conditional logistic regression model.
Numerous observational studies of various designs have demonstrated a positive association between the presence of anti- H. pylori antibodies and the risk of stomach cancer. The H. pylori infection appears to be the strongest and the most important risk factor for gastric cancer, especially for noncardia cancer ( 49 ). Although the ultimate proof of cau-sality is still missing, a recent meta-analysis ( 50 ) showed that the pooled relative risk of developing gastric cancer after H. pylori eradication was 0.56 (95 % CI = 0.4 – 0.8). These data were considered to be very suggestive that H. pylori eradica-tion would protect against the development of gastric cancer ( 49 ). Efforts to improve the treatment of gastric cancer have had limited success. Population screening and treatment of H. pylori infection is likely to become the first target in future prevention strategies, particularly in high gastric cancer risk countries ( 49 ) such as Taiwan.
In summary, our study demonstrates that ever-use of any statin was associated with a 32 % risk reduction for gastric cancer. Th ere was also a trend toward stronger risk reduction with more statin prescriptions. Given the widespread use of statins, this magnitude of risk reduction would have a substantial public health impact. Th is study is the fi rst to suggest that statins have a potential role in chemoprevention of gastric cancer. Further and larger studies, particularly prospective randomized trial studies, are necessary to confi rm our fi ndings and the value of statins in gastric cancer prevention and treatment.
ACKNOWLEDGMENTS
Th is study is based in part on data from the National Health Insurance Research Database provided by the Bureau of National Health Insurance, Department of Health and managed by National Health Research Institutes. Th e interpretation and conclusions contained herein do not represent those of the Bureau of National Health Insurance, Department of Health or National Health Research Institutes.
STOMACH
13 . Coogan PF , Rosenberg L , Strom BL . Statin use and the risk of 10 cancers . Epidemiology 2007 ; 18 : 213 – 9 .
14 . Dale KM , Coleman CI , Henyan NN et al. Statins and cancer risk: a meta-analysis . JAMA 2006 ; 295 : 74 – 80 .
15 . Haukka J , Sankila R , Klaukka T et al. Incidence of cancer and statin usage-record linkage study . Int J Cancer 2010 ; 126 : 279 – 84 .
16 . Kaye JA , Jick H . Statin use and cancer risk in the General Practice Research Database . Br J Cancer 2004 ; 90 : 635 – 7 .
17 . Kuoppala J , Lamminpaa A , Pukkala E . Statins and cancer: a systematic review and meta-analysis . Eur J Cancer 2008 ; 44 : 2122 – 32 .
18 . Setoguchi S , Glynn RJ , Avorn J et al. Statins and the risk of lung, breast, and colorectal cancer in the elderly . Circulation 2007 ; 115 : 27 – 33 .
19 . Blais L , Desgagne A , LeLorier J . 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and the risk of cancer: a nested case-control study . Arch Intern Med 2000 ; 160 : 2363 – 8 .
20 . Boudreau DM , Gardner JS , Malone KE et al. Th e association between 3-hydroxy-3-methylglutaryl-coenzyme A inhibitor use and breast carci-noma risk among postmenopausal women . Cancer 2004 ; 100 : 2308 – 16 . 21 . Cauley JA , Zmuda JM , Lui LY et al. Lipid-lowering drug use and breast
can-cer in older women: a prospective study . J Womens Health 2003 ; 12 : 749 – 56 . 22 . El-Serag HB , Johnson ML , Hachem C et al. Statins are associated with a
reduced risk of hepatocellular carcinoma in a large cohort of patients with diabetes . Gastroenterology 2009 ; 136 : 1601 – 8 .
23 . Graaf MR , Beiderbeck AB , Egberts AC et al. Th e risk of cancer in users of statins . J Clin Oncol 2004 ; 22 : 2388 – 94 .
24 . Hachem C , Morgan R , Johnson M et al. Statins and the risk of colorectal carcinoma: a nested case-control study in veterans with diabetes . Am J Gastroenterol 2009 ; 104 : 1241 – 8 .
25 . Khurana V , Bejjanki HR , Caldito G et al. Statins reduce the risk of lung cancer: a large case-control study of US veterans . Chest 2007 ; 131 : 1282 – 8 . 26 . Khurana V , Sheth A , Caldito G et al. Statins reduce the risk of pancreatic
cancer in humans: a case-control study of half a million veterans . Pancreas 2007 ; 34 : 260 – 5 .
27 . Poynter JN , Gruber SB , Higgins PD et al. Statins and the risk of colorectal cancer . N Engl J Med 2005 ; 352 : 2184 – 92 .
28 . Shannon J , Tewoderos S , Garzotto M et al. Statins and prostate cancer risk: a case-control study . Am J Epidemiol 2005 ; 162 : 318 – 25 .
29 . Friis S , Poulsen AH , Johnsen SP et al. Cancer risk among statin users: a population-based cohort study . Int J Cancer 2005 ; 114 : 643 – 7 .
30 . Tobert JA . Effi cacy and long-term adverse eff ect pattern of lovastatin . Am J Cardiol 1988 ; 62 : 28J – 34J .
31 . Chiang CW , Chen CY , Chiu HF et al. Trends in the use of antihypertensive drugs by outpatients with diabetes in Taiwan, 1997-2003 . Pharmacoepide-miol Drug Saf 2007 ; 16 : 412 – 21 .
32 . Kuo HW , Tsai SS , Tiao MM et al. Epidemiologic features of CKD in Taiwan . Am J Kidney Dis 2007 ; 49 : 46 – 55 .
33 . Tiao MM , Tsai SS , Kuo HW et al. Epidemiological features of biliary atresia in Taiwan, a national study 1996-2003 . J Gastroenterol Hepatol 2008 ; 23 : 62 – 6 .
34 . Coogan PF , Rosenberg L , Palmer JR et al. Statin use and the risk of breast and prostate cancer . Epidemiology 2002 ; 13 : 262 – 7 .
35 . Jadhav SB , Jain GK . Statins and osteoporosis: new role for old drugs . J Pharm Pharmacol 2006 ; 58 : 3 – 18 .
36 . Meier CR , Scheinger RG , Kraenzlin ME et al. HMG-CoA reductase inhibi-tors and the risk of fractures . JAMA 2000 ; 283 : 3205 – 10 .
37 . Rejnmark L , Plsen ML , Johnsen SP et al. Hip fracture risk in statin users-a population-based Danish case-control study . Osteoporos Int 2004 ; 15 : 452 – 8 . 38 . Wang PS , Solomon DH , Mogun H et al. HMG-CoA reductase inhibitors
and the risk of fractures . JAMA 2000 ; 283 : 3211 – 6 .
39 . WHO Collaborating Center for Drugs Statistics Methodology . ATC Index with DDDs 2003 . WHO: Oslo , 2003 .
40 . Wu CY , Kuo KN , Wu MS et al. Early Helicobacter pylori eradication decreases risk of gastric cancer in patients with peptic ulcer disease . Gastro-enterology 2009 ; 137 : 1641 – 8 .
41 . Hansson LE , Nyren O , Hsing AW et al. The risk of stomach cancer in patients with gastric or duodenal ulcer disease . N Engl J Med 1996 ; 335 : 242 – 9 .
42 . Blanco-Colio LM , Villa A , Ortego M et al. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, atorvastatin and simvastatin, induce apoptosis of vascular smooth muscle cells by downregulation of Bcl-2 expression and Rho A prenylation . Atherosclerosis 2002 ; 161 : 17 – 26 . 43 . Danesh FR , Sadeghi MM , Amro N et al.
3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors prevent high glucose-induced proliferation
CONFLICT OF INTEREST
Guarantor of the article: Chun-Yuh Yang, PhD, MPH. Specifi c author contributions: Hui-Fen Chiu: draft ing of the manuscript; Shu-Chen Ho: performed the statistical analysis; Chih-Ching Chang and Trong-Neng Wu: interpretation of the data; Chun-Yuh Yang: study concepts and design, acquisition of the data revised, and edited the manuscript. All authors approved the fi nal draft submitted.
Financial support: Th is study was supported in part by a grant from the National Science Council, Executive Yuan, Taiwan (NSC-96-2628-B-037-039-MY3). However, the work is independent of the funding.
Potential competing interests: None.
Study Highlights
WHAT IS CURRENT KNOWLEDGE
3
Experimental studies have shown that statins have potentialprotective effects against cancer.
3
Only three studies have investigated the association between statin use and the risk of gastric cancer.3
All three studies reported a statistically nonsignifi cant inverse association between statin use and gastric cancer risk.WHAT IS NEW HERE
3
Statins are associated with a reduction in the risk of gastriccancer.
3
There was a dose-response relationship between statin use and the risk of gastric cancer.REFERENCES
1 . Wong WW , Dimitroulakos J , Minden MD et al. HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specifi c apoptosis . Leukemia 2002 ; 16 : 508 – 19 .
2 . Hebert PR , Gaziano JM , Chan KS et al. Cholesterol lowering with statin drugs, risk of stroke, and total mortality. An overview of randomized trials . JAMA 1997 ; 278 : 313 – 21 .
3 . Baigent C , Keech A , Kearney PM et al. Effi cacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 partici-pants in 14 randomized trials of statins . Lancet 2005 ; 366 : 1267 – 78 . 4 . Newman TB , Hulley SB . Carcinogenicity of lipid-lowering drugs . JAMA
1996 ; 275 : 55 – 60 .
5 . Keyomarsi K , Sandoval L , Band V et al. Synchronization of tumor and normal cells from G1 to multiple cell cycles by lovastatin . Cancer Res 1991 ; 51 : 3602 – 9 .
6 . Dimitroulakos J , Marhin WH , Tokunaga J et al. Microarray and biochemi-cal analysis of lovastatin-induced apoptosis of squamous cell carcinoma . Neoplasia 2002 ; 4 : 337 – 46 .
7 . Park HJ , Hong D , Iruela-Arispe L et al. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA . Circ Res 2002 ; 91 : 143 – 50 .
8 . Weis M , Heeschen C , Glassford AJ et al. Statins have biphasic eff ects on angiogenesis . Circulation 2002 ; 105 : 739 – 45 .
9 . Alonso DF , Farina HG , Skilton G et al. Reduction of mouse mammary tumor formation and metastasis by lovastatin, an inhibitor of the meval-onate pathway of cholesterol synthesis . Breast Cancer Res Treat 1998 ; 50 : 83 – 93 .
10 . Kusama T , Mukai M , Iwasaki T et al. 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis . Gastroenterology 2002 ; 122 : 308 – 17 . 11 . Bonovas S , Filioussi K , Tsavaris N et al. Statins and cancer risk: a
litera-ture-based meta-analysis and meta-regression analysis of 35 randomized controlled trials . J Clin Oncol 2006 ; 24 : 4808 – 17 .
12 . Browning DR , Martin RM . Statins and risk of cancer: a systematic review and metaanalysis . Int J Cancer 2006 ; 120 : 833 – 43 .
STOMACH
of mesangial cells via modulation of Rho GTPase/p21 signaling pathway: implications for diabetic nephropathy . Proc Natl Acad Sci USA 2002 ; 99 : 8301 – 5 .
44 . Takemoto M , Liao JK . Pleiotropic eff ects of 3-hydroxy-3-methylglu-taryl-coenzyme A reductase inhibitors . Arterioscler Th romb Vasc Biol 2001 ; 21 : 1712 – 9 .
45 . Shibata MA , Avanaugh C , Shibata E et al. Comparative eff ects of lovastatin on mammary and prostate oncogenesis in transgenic mouse models . Car-cinogenesis 2003 ; 24 : 453 – 9 .
46 . Rao S , Porter DC , Chen X et al. Lovastatin-mediated G1 arrest is through inhibition of the proteasome, independent of hydroxymethyl glutaryl-CoA reductase . Proc Natl Acad Sci USA 1999 ; 96 : 7797 – 802 .
47 . Amieve MR , El-Omar EM . Host-bacterial interactions in Helicobacter
pylori infection . Gastroenterology 2008 ; 134 : 306 – 23 .
48 . Kuo HW , Tsai SS , Tiao MM et al. Analgesic use and the risk for progression of chronic kidney disease . Pharmacoepidemiol Drug Saf 2010 ; 19 : 745 – 51 .
49 . Talley NJ , Fock KM , Moayyedi P . Gastric cancer consensus conference recommends Helicobacter pylori screening and treatment in asymptomatic persons from high-risk populations to prevent gastric cancer . Am J Gastro-enterol 208 ; 103 : 510 – 4 .
50 . Fock KM , Talley N , Moayyedi P et al. Asia-Pacific consensus guidelines on gastric cancer prevention . J Gastroenterol Hepatol 2008 ; 23 : 351 – 65 .
