Peptic ulcer disease (PUD) has been known can be caused by Helicobacter pylori infection and widespread use of non-steroidal anti-inflammatory drugs (NSAIDs; Malfertheiner et al., 2009). Despite the cases of H. pylori have been decreasing in eradication treatment over the last decade, the incidence of PUD is still at high levels in some countries. Without treatment, the complications to PUD may develop into bleeding, perforation, and obstruction which lead to increase hospitalizations and mortalities (Lau et al., 2011).

Statins are inhibitors for 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase and have been found to play a protective role in several bacteria-associated diseases (Jerwood and Cohen, 2008; Nseir et al., 2013; Skerry et al., 2014). Previous studies have reported that combination treatments, including triple therapies (consisting of a proton-pump inhibitor, amoxicillin, and clarithromycin) prescribed along with statins, accelerate H. pylori clearance and ameliorate ulcer development (Tariq et al., 2007; Yamato et al., 2007; Nseir et al., 2012).

Statin use reduces cardiovascular disease-related morbidity and mortality in patients with and without coronary diseases (Maron et al., 2000). In addition to cholesterol lowering effects, statins have anti-inflammatory properties including modulation of immune responses, regulation of MHC expression, mucosal proliferation, and secretory activity (Kwak et al., 2000; Weitz-Schmidt et al., 2001). The additional benefits of statins included gastroprotective effects and attenuation of peptic ulcer development (Tariq et al., 2007; Heeba et al., 2009). However, the clinical relevance of statins on gastrointestinal disorders require further investigation.

It has been reported that statin use may decrease the incidence of chronic gastritis, and reduce the risk of several types of cancers (Nseir et al., 2010; Chiu et al., 2011; Singh and Singh, 2013; Singh et al., 2013; Liu et al., 2015; Ananthakrishnan et al., 2016). In addition, our recent study by combining a cell-based study with a nationwide population analysis revealed that statin use attenuated the risk for H. pylori-associated gastric cancer (Lin et al., 2016). However, previous studies have suggested that statin use was not associated with decrease the risk of peptic ulcer or reflux esophagitis (Fujii et al., 2009). An animal study also indicated that a statin was ineffective for suppressing gastritis and chemoprevention of gastric carcinogenesis in gerbils (Toyoda et al., 2009). The reports are clearly controversial, but there has been no large-scale epidemiologic research on the inhibitory effects of statins for treating PUD. Therefore, it is worth investigating whether statin use mitigated PUD in patients by analyzing a nationwide database. In the present study, we performed a nationwide population-based case-control analysis to compare the incidence of PUD patients who were prescribed statins and that in patients who were not. Our results indicate that statins might alleviate the risk of PUD.

For NHI database analysis, the baseline characteristics of the PUD and non-PUD groups were compared using a chi-square test. Crude and adjusted odds ratio (aOR) and 95% confidence intervals (CI) for factors associated with the risk of PUD were estimated using univariable and multivariable logistic regression models. All statistical analyses were performed using SAS statistical software for Windows (Version 9.3; SAS Institute, Inc, Cary, NC, USA). Results from experimental data analyses are expressed as mean ± SEM. Student's t-tests were used to determine the statistical significance of differences in experimental results between the two groups. A P < 0.05 was considered significant.

The results of the present study showed that after adjusting for risk factors including age, sex, urbanization level, monthly income, aspirin, NSAIDs, and the major comorbidities (aOR = 0.87, CI = 0.82–0.93, P < 0.001), patients who were prescribed statins associated with a significantly lower risk of PUD than those who were not. Overall, the results of this study suggest that statin use significantly reduces the risk of PUD. In addition, these findings are consistent with studies previously conducted in other countries (Heeba et al., 2009; Nseir et al., 2010, 2012).

Statins prescribed in Taiwan include lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin (Tsan et al., 2012). These statins are commonly prescribed as cholesterol-lowering agents in patients with hyperlipidemia and are considered to exert anti-inflammatory activity, as indicated by reduced levels of the inflammatory marker C-reactive protein in patients who are prescribed statins (Ridker et al., 2008). Existing clinical evidence suggests that statins reduce the incidence of coronary disease (Nissen et al., 2005; Ridker et al., 2005), rheumatoid arthritis (Chodick et al., 2010), Alzheimer's disease (Di Paolo and Kim, 2011), chronic obstructive pulmonary disease (Cao et al., 2015), and gastric cancer (Lin et al., 2016). Most importantly, statins have been reported to protect against bacterial infectious diseases (Jerwood and Cohen, 2008; Nseir et al., 2013; Skerry et al., 2014; Lin et al., 2016). The combination treatments including triple therapies and statins facilitated H. pylori clearance and attenuated ulcer development (Tariq et al., 2007; Yamato et al., 2007; Nseir et al., 2012). In addition, our recent study revealed that statin treatment reduced H. pylori burden in macrophages to alleviate H. pylori-associated pathogenesis (Liao et al., 2017). However, the molecular mechanisms underlying the effects of statins on the risk of such diseases remain to be investigated.

Although our previous study reported the protective effects of statins against peptic ulcer (Feng et al., 2015), several limitations and confounding factors exist. In the current study, we further analyzed the potential confounding medications including aspirin and NSAIDs. In addition, various statins that are commonly used in Taiwan (i.e., simvastatin, lovastatin, pravastatin, fluvastatin, atorvastatin, and rosuvastatin) were classified and the cumulative DDD of each type of statin was analyzed. Moreover, to further clarify whether socioeconomic factors were well balanced between the cases and controls, we performed a stratified analysis based on socioeconomic status such as urbanization level and monthly income. Therefore, the findings presented in the current manuscript have greatly improved with further advancement of knowledge.

Although the strength of the analyses of population-based data that possess highly representative of the general population, certain confounders and limitations emerged from our results should be considered. First, the data we collected from NHIRD contains only the disease and treatment received of patients (Cheng et al., 2011). We did not obtain the detailed information such as: occupation, alcoholic, exercise, body mass index, smoking habit, and environmental exposure, which are all potential confounding variables. Second, the evidence derived from a population-based case-control study is generally lower in statistical quality than that from randomized trials because of potential biases related to adjustments for confounding variables (Hsu C. C. et al., 2015). Third, all data in the NHIRD are anonymous, the relevant clinical variables, such as imaging results, pathology findings, and serum laboratory data were unavailable for our study cases (Chen et al., 2015). Finally, changes in statins habits over time are inevitable and may result in exposure misclassification and attenuation of the association between statin intake and PUD. Moreover, the inconsistent results might in part be due to measurement error in the assessment of different statins, diet including inaccurate recall, changes in dose over time. However, Taiwan launched a NHI program operated by a single-payer, the government, in 1995. All insurance claims are scrutinized by medical reimbursement specialists and subject to peer review. Therefore, the data regarding the diagnoses for patients with PUD and statin prescriptions were reliable.

In the present study, a population-based case-control study showed that patients who were prescribed statins had a significantly reduced incidence of PUD. Our study using a nationwide population analysis indicate that statins may be used to protect against PUD.

Conceived and designed the experiments: CK and CHL Performed the experiments and analyzed the data: CJL, WL, YC, HL, MH, and CF. Wrote the manuscript: CLL, YL, MK, CJL, and WL Revised the manuscript: CJL, WL, YC, HL, CLL, CK, and CHL. Reviewed the final version of this manuscript: all authors.

This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence (MOHW106-TDU-B-212-113004), China Medical University and Hospital (CMU102-BC-2, DMR-103-018, and DMR-103-020), Academia Sinica Taiwan Biobank Stroke Biosignature Project (BM10501010037), NRPB Stroke Clinical Trial Consortium (MOST105-2325-B-039-003), Tseng-Lien Lin Foundation, Taichung, Taiwan, Taiwan Brain Disease Foundation, Taipei, Taiwan, Ministry of Science and Technology (104-2320-B-182-040 and 105-2313-B-182-001), Chang Gung Memorial Hospital (CMRPD1F0011-3, CMRPD1F0431-3, and BMRPE90), Tomorrow Medical Foundation, and Katsuzo and Kiyo Aoshima Memorial Funds, Japan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding received for this study.