|Year : 2014 | Volume
| Issue : 4 | Page : 859-865
Effect of statins on gastric cancer incidence: A meta-Analysis of case control studies
Zhiyuan Ma1, Wenjin Wang2, Guoyin Jin3, Pei Chu2, Haitao Li4
1 Geriatrics Department ward II, The First Hospital of Lanzhou University, Lanzhou, China
2 Department of Emergency, The First Hospital of Lanzhou University, Lanzhou, China
3 College of Traditional Chinese Medicine, Hebei North University, China
4 Department of General Surgery, Second Hospital of Zhangjiakou City, Zhangjiakou, China
|Date of Web Publication||9-Jan-2015|
The First Hospital of Lanzhou University. Lanzhou - 730000
Source of Support: None, Conflict of Interest: None
Introduction: Gastric cancer is among the leading causes of cancer-related death worldwide, especially in Eastern Asia, Eastern Europe and South America. Statin is one of the most widely used medications for hypercholesterolemia. Several meta-analyses have failed to determine the relationship between statins and gastric cancer.
Aims: A meta-analysis of case control studies is conducted to evaluate the association of statin exposure and risk of gastric cancer.
Materials and Methods: Eight electronic databases (The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, 2012), PubMed, EMBASE, ISI Web of Knowledge, CNKI, CBM, CSJD and Wanfang Database) were searched for relevant publications through September 2013. Two reviewers determined the eligibility of articles and abstracted the data independently. RevMan 5.2 software was used for statistical analysis.
Results: 146 items were retrieved from the databases and 6 studies were identified in this meta-analysis, which included 5,993 cases and 54,800 matched controls. Results from the meta-analysis demonstrated that statins were inversely related to the risk of gastric cancer (RR = 0.56, 95% CI: 0.35-0.90). There was no significant difference for cumulative duration of statin exposure and gastric cancer, nor participants from Asia, Europe, or USA.
Conclusion: This meta-analysis suggests that statins have favorable effects on gastric cancer, rigorously designed and executed observational studies and randomized control trials with longer duration of follow-up are warranted to determine effects in clinical practice.
材料和方法：从8个电子数据库（Cochrane对照试验注册中心（中央）（2012年12期），PubMed，EMBASE，ISI Web of Knowledge，CNKI，CBM，中文科技期刊数据库、万方数据库）中检索相关的出版物至2013年9月。两位专家确定了文章的合格性和数据独立性。采用RevMan 5.2软件进行统计分析。
结果：146个项目从数据库检索，6项研究参与Meta分析，其中包括5993病例和54800例对照。从荟萃分析表明他汀类药物对胃癌发生的危险性呈负相关（RR = 0.56，结果95%可信区间：0.35 0.90）。对他汀类药物的暴露与胃癌累积持续时间没有显著差异，与来自亚洲、欧洲和美国也没有显著差异。
Keywords: Case control study, gastric cancer, meta-analysis, statins
|How to cite this article:|
Ma Z, Wang W, Jin G, Chu P, Li H. Effect of statins on gastric cancer incidence: A meta-Analysis of case control studies. J Can Res Ther 2014;10:859-65
| > Introduction|| |
Gastric cancer is among the leading causes of cancer-related death worldwide, especially in Eastern Asia, Eastern Europe, and South America. ,, Patients would benefit more if the disease can be diagnosed at an earlier stage.  Unfortunately, approximately two-thirds of patients are detected at an advanced stage. Survival rate is improved indeed after gastrectomy and perioperate chemotherapy, but the outcome has been disappointing. ,,, Therefore, preventive strategies to reduce morbidity are required.
Currently, chemoprevention strategies to decrease incidence of gastric cancer have become more and more attractive. Fukase et al.  demonstrated that H.pylori eradication therapies might reduce the risk of gastric cancer. In addition, several studies suggested that aspirin and other NSAIDs (non-steroidal anti-inflammatory drugs) use were associated with a decreased risk of gastric cancer. ,,,, Recently, more and more researchers had begun to pay attention to the association of statin consumption and gastric cancer.
Statin (HMG CoA reductase inhibitors) is one of the most widely used medications for hypercholesterolemia.  Several studies have confirmed the benefits of statins for cardiovascular disease. ,, As more and more statins are being used, there has been an increasing interest in the preventive effect of statins in cancer. ,,
A meta-analysis of randomized control trials  by Shimoyama suggested that statins had no short-term effect on gastric cancer incidence, meanwhile, a population-based nested case control studies demonstrated that prolonged use of statins was not associated with a reducing risk of gastric cancer,  however, several case control studies indicated that statins might reduce the rate of gastric cancer recently, , the effect of statins on gastric cancer risk is still topical and controversial. Thus, we conducted a meta-analysis to evaluate the association of statin exposure and gastric cancer risk.
| > Materials and methods|| |
We searched Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, 2012), PubMed, EMBASE, ISI Web of Knowledge, Chinese National Knowledge Infrastructure (CNKI), China BioMedical Literature (CBM), Chinese Scientific Journal Full-text Database (CSJD), and Wanfang Database. The following Medical Subject Headings and free text keywords were used: "Gastric cancer, gastric tumor, gastric carcinoma, stomach cancer, stomach carcinoma, cancer of the stomach, gastric neoplasm," "statin, statins, atorvastatin, lipitor, rosuvastatin, crestor, lovastatin, simvastatin, pravastatin." The reference lists of retrieved articles and previous meta-analysis ,, were also reviewed to search for additional trials. No language restrictions were set for the search and it was up-to-date on September 2013.
The studies identified in the meta-analysis were either case control studies or nested case control studies that evaluated the association of statin exposure and gastric cancer risk. We excluded trials that evaluated statins and multi-site of cancers where the data of gastric cancer could not be isolated. Two reviewers determined the eligibility of each article independently. Disagreement was resolved by discussion.
Two reviewers extracted the data independently. For each study, we extracted details on study design, study location, publication year, investigational therapy, number of events, total number of participants, and duration of statin exposure.
The summary RR (Risk Ratio) for exposure to statins vs. no exposure was the measure of interest. The heterogeneity assumption was assessed by Q statistic test  and I-square test.  When significant heterogeneity [P < 0.10, I 2 >50%] was found, random effects model was used. Otherwise, fixed effects model was used. Subgroup analysis by the duration of statin exposure or different regions of trials were conducted to reduce the impact of heterogeneity and achieve more accurate results. RevMan software (Version 5.2, Cochrane Collaboration)  was used for the statistical analysis. It was considered statistical significant when P values were less than 0.05.
| > Results|| |
[Figure 1] shows the process of study selection. 146 items were retrieved through eight electronic databases. We excluded 139 papers which did not satisfy the inclusion criteria. Seven case control studies ,,,,,, were considered to be eligible for this meta-analysis. One study  was excluded because data of gastric cancer could not be isolated. Finally, six case control studies ,,,,, were included in this meta-analysis.
[Table 1] describes baseline characteristics for all six case control studies included. Three studies, ,, were carried out in Taiwan, one  in Korea, one  in UK, and one  in USA. A total of 5993 individuals participated in these trials, and 54,800 matched controls were included.
[Table 2] shows the number of cumulative duration of statin use. Cumulative duration of statin exposure was divided into: Less than 12 months, 13-24 months, 25-48 months, and more than 49 months, pooled RRs were also demonstrated in [Table 2].
[Figure 2] demonstrates results from the meta-analysis of statin exposure and gastric cancer. A total of 5993 cases and 54,800 matched controls were found in all six case control studies included. ,,,,, The pooled RR was significant at 0.56 with a 95% CI: 0.35-0.90.
[Figure 3] shows the meta-analysis of cumulative duration of statin use and gastric cancer. A total of four subgroups were conducted. There is no statistical significance for either subgroup.
|Figure 3: Subgroup meta analysis of different type of statins use and gastric cancer|
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[Figure 4] is the result from the meta-analysis of statin consumption and gastric cancer in different regions. There is no significant difference among participants from Asia, Europe and USA.
|Figure 4: Subgroup meta analysis of different areas of statins use and gastric cancer|
Click here to view
| > Discussion|| |
The present meta-analysis suggests that statins are inversely related to the risk of gastric cancer, with a 44% decrease in gastric cancer risk among statin users. There was no significant difference for cumulative duration of statin exposure and gastric cancer, nor participants from Asia, Europe and USA.
The result of this meta-analysis of case control studies indicates a favorable effect for statin use and gastric cancer. The relationship between statins and gastric cancer has been evaluated in numerous meta-analyses of randomized control trials or observational studies, ,,, but there has been conflicts among these meta analyses, inverse,  neutral. ,, Similar controversial results have also been observed in the meta-analysis of statins and risk of colorectal cancer ,,,,, and liver cancer. ,,, Although unified conclusion was still not reached from these meta-analyses of statin exposure and gastric cancer, a modest protective effect cannot be excluded.
It has been indicated that participants benefitted more when statins were used for longer than 4 years,  but our meta analysis showed no such evidence for longer duration of statin exposure. Two studies , contributed to this meta analysis, especially, for more than 25 months, however, only the data from Vinogradova Y ' s study  was available. Thus, data for present meta-analysis is not sufficient. In future, comprehensive report and a long time fellow-up of statin exposure are required.
In present meta-analysis, a comprehensive research was carried out, which ensured all the relevant publications were included. As a result, six case control studies ,,,,, were included, and five ,,,, of which were published in last 3 years. Thus, all the latest information about statins and gastric cancers was included in present meta-analysis.
There are some limitations to this meta-analysis. First, a lot of data specific for gastric cancer were not available. Only three studies ,, included were conducted to evaluate the relationship between statins and gastric cancer exclusively, while other trials ,, evaluated its association with multi-site cancer, and many data could not be isolated successfully. Thus, clinical trials about statins and gastric cancer should be reported more distinctively and prescriptively. Second, information of other confounding factor, such as H. pylori infection, use of other lipid lowering drugs, exposure of aspirin and other NSAIDs could not be adjusted. Although there is no definitive evidence demonstrating that H. pylori eradication therapy reduced gastric cancer risk, World Health Organization concluded in 1994 that H. pylori is carcinogenic to humans and plays a causal role in the development of gastric cancer.  Available evidence also demonstrated that there was an inversely association between aspirin and other NSAIDs use and gastric cancer. , Third, there is significant heterogeneity between studies: P <0.00001, I2 = 97%. Significant difference of statin exposure ratio in case and control in studies of Leung HW (4.05 vs. 20.08%) and Lee J (10.07 vs. 37.33%) contributed to heterogeneity, and I2 dropped to 49% (P = 0.12) when studies of Leung HW and Lee J were excluded from this meta-analysis.
Chemoprevention for gastric cancer will be more attractive in future. There is few high quality evidences indicating that participants benefit from H. pylori eradication therapy, aspirin and other NSAIDs. Currently there are no sufficient further trials demonstrating the protective effect of statins in gastric cancer.  Therefore, we recommend that clinicians should make a greater effort to chemoprevention for gastric cancer.
In summary, results from present meta-analysis suggest that statins have favorable effects on gastric cancer, however, subtype evidence of statins and long term effects is lacking. Rigorously designed and executed observational studies and randomized control trials with long follow-up duration are warranted to determine its effects in clinical practice.
| > Acknowledgment|| |
We thank the library of Lanzhou University for database access and acquiring full texts.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]