Statin use and risk of endometrial cancer: a nationwide registry-based case control study

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1 AOGS ORIGINAL RESEARCH ARTICLE : a nationwide registry-based case control study CECILIE D. SPERLING 1, FREIJA VERDOODT 1, SØREN FRIIS 2,3,4, CHRISTIAN DEHLENDORFF 2 & SUSANNE K. KJAER 1,5 1 Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Copenhagen, 2 Unit of Statistics, Bioinformatics and Registry, Danish Cancer Society Research Center, Copenhagen, 3 Department of Public Health, University of Copenhagen, Copenhagen, 4 Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, and 5 Department of Gynecology, Rigshospitalet University Hospital, University of Copenhagen, Copenhagen, Denmark Key words Statins, endometrial neoplasms, risk, case control, pharmacoepidemiology Correspondence Susanne K. Kjaer, Virus, Lifestyle and Genes, Danish Cancer Society Research Center, Strandboulevarden 49, 2100 Copenhagen, Denmark. susanne@cancer.dk Conflict of interest The authors have stated explicitly that there are no conflicts of interest in connection with this article. Please cite this article as: Sperling CD, Verdoodt F, Friis S, Dehlendorff C, Kjaer SK. : a nationwide registry-based case control study. Acta Obstet Gynecol Scand 2017; 96: Received: 19 October 2016 Accepted: 19 November 2016 DOI: /aogs Abstract Introduction. Laboratory and epidemiological evidence have suggested that statin use may protect against the development of certain cancers, including endometrial cancer. In a nationwide registry-based case control study, we examined the association between statin use and risk of endometrial cancer. Material and methods. Cases were female residents of Denmark with a primary diagnosis of endometrial cancer during For each case, we selected 15 female population controls matched on date of birth (one month) using risk-set sampling. Ever use of statin was defined as two or more prescriptions on separate dates. Conditional logistic regressions were used to estimate agematched (by design) and multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CI) for endometrial cancer associated with statin use. The multivariable-adjusted models included parity, hormone replacement therapy (HRT), obesity, diabetes, chronic obstructive pulmonary disease and education. We evaluated whether the association between statin use and endometrial cancer varied with duration and intensity of statin use, type of endometrial cancer or patient characteristics. Results. The study population comprised 5382 endometrial cancer cases and population controls. We observed no association between ever use of statins and endometrial cancer risk (OR 1.03, 95% CI ). In addition, endometrial cancer risk did not vary substantially with duration or intensity of statin use. Stratification by type of endometrial cancer also yielded neutral ORs. Conclusions. In our nationwide case control study, we found no association between statin use and risk of endometrial cancer. Abbreviations: CI, confidence interval; HRT, hormone replacement therapy; OR, odds ratio; RR, relative risk. Introduction Endometrial cancer is the fourth most common cancer in women worldwide and the most common malignancy of the female genital tract in developed countries (1). With a generally long latent period (1), endometrial cancer is an eligible target for preventive interventions. Potential candidates include statins used for cholesterol reduction Key Message Use of statin was not associated with a decreased risk of endometrial cancer among Danish women. The null association persisted across different levels of duration and intensity of statin use, and for type I and II endometrial cancer. 144 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

2 and cardiovascular disease prevention (2). Laboratory studies of human cell lines and in vivo animal models have demonstrated anti-cancer properties of statins, including induction of apoptosis, inhibition of angiogenesis, and suppression of tumor growth and metastasis (3 5). In contrast, epidemiological studies have reported mainly null associations between statin use and endometrial cancer risk (6 9). A recent meta-analysis reported a pooled 10% reduction in risk of endometrial cancer associated with overall statin use, but statistical significance was not reached (10). The authors noted a trend towards higher risk reduction with long-term (more than five years) statin use, but this was based on small numbers. We conducted a large nationwide registry-based case control study to examine the association between statin use and risk of endometrial cancer, and to evaluate whether the association varies by duration and intensity of statin use, type of endometrial cancer, or patient characteristics. Material and methods Our case control study was based on information from five nationwide registries covering the entire Danish population. Appendix S1 provides a description of these registries with codes for covariates (available online). Unambiguous linkage of individual-level data was secured by use of the unique civil registration number assigned to all Danish citizens by the Danish Civil Registration System, which also holds continuously updated data on addresses, migration, and date of death of all Danish residents (11). Study population Case patients with endometrial cancer (cases) were identified in the Danish Cancer Registry, which contains virtually complete and accurate data on all incident cancer cases in Denmark (12). Eligible cases were all women aged years with histologically verified type I or II endometrial cancer diagnosed between 2000 and Cases were required to be resident in Denmark at the start of the Danish Prescription Registry (1 January 1995) and at the date of diagnosis. Furthermore, we required cases to have no history of cancer (except non-melanoma skin cancer) at the index date. For each case, we selected 15 female population controls matched on date of birth (one month) from the Civil Registration System using risk-set sampling, and applying the same selection criteria as for cases. Thus, eligible controls had to be alive and at risk of a first diagnosis of endometrial cancer at the date of diagnosis (defined as the index date) of the corresponding case, i.e. women with a previous hysterectomy or cancer were not eligible for selection as controls. Women were eligible as controls before they became cases; thereby, the calculated odds ratios (ORs) provide unbiased estimates of the incidence rate ratios in the source population. Statin use From the Danish Prescription Registry (13), we retrieved all prescriptions of statins (ATC = C10AA) filled by cases and controls between 1995 and one year prior to the index date. We defined ever use of statin as two or more filled prescriptions on separate dates and non-use as fewer than two prescriptions. Ever use was further divided into recent use (two or more prescriptions during one to three years before the index date) and former use (two or more prescriptions overall but fewer than 2 prescriptions during one to three years before the index date). Duration of statin use was defined as the time between the first and last filled statin prescription plus 60 days and categorized as short-term (less than five years) or long-term (five or more years) use. We estimated intensity of statin use as the cumulative number of defined daily doses (14) divided by the duration in days. The intensity was categorized into tertiles (low, medium or high) according to the distribution among controls. Covariates The selection of potential confounders was defined a priori and based on the data available in the nationwide registries (11,13,15 17). From the Danish Patient Registry (15), we retrieved information on previous diagnoses of diabetes, obesity and chronic obstructive pulmonary disease. The medical histories of diabetes and obesity were defined as composite measures of hospital diagnoses and filled prescriptions for drugs for treatment of diabetes or obesity (see Appendix S1 for details). From Statistics Denmark, we obtained information on highest achieved education (16). Information on parity was retrieved from The Fertility Database (17). For all covariates, we disregarded registrations in the year before the index date. Statistical analyses We used conditional logistic regression to estimate agematched (by design) and multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for endometrial cancer associated with statin use. The multivariable-adjusted models included parity (0, 1, 2, 3+), use of hormone replacement therapy (HRT) (two or more prescriptions), highest achieved education (basic/vocational, higher, unknown), and medical histories of ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

3 diabetes (yes/no), obesity (yes/no), and chronic obstructive pulmonary disease (yes/no). We estimated adjusted ORs for endometrial cancer among ever users, recent users, and former users of statins. In further models, we assessed associations with duration and intensity of statin use and for different histological types of endometrial cancer. In addition, we examined potential effect measure modification among women with high susceptibility of endometrial cancer, defined by nulliparity, HRT use, diabetes and obesity. We performed two preplanned sensitivity analyses. First, we added use of oral contraceptive to a model restricted to women <50 years for whom oral contraceptive prescription data (1995 ) was nearly complete. Secondly, to evaluate the influence of left truncation of the exposure data, we applied a new-user design (18) by excluding all cases and their corresponding controls, as well as all controls who filled more than one prescription of statins during All analyses were performed using R version (19). Ethics approval The study was approved by the Danish Data Protection Agency (J.nr ). Approvals from Ethical Committees were not required for this type of research in Denmark. Results The study population comprised 5382 endometrial cancer cases and population controls (Table 1). The majority of cases (88.5%) had type I endometrial cancer. More cases than controls were nulliparous, and cases were more likely to use HRT and have a history of obesity or diabetes. The remaining characteristics were similar in prevalence among cases and controls. Ever use of statins was observed among 11.3% of the cases and 9.7% of the Table 1. Characteristics of the study population. Cases (n = 5382) Controls (n = ) n % n % OR (95% CI) Drug use Ever statin use ( ) Recent statin use ( ) Former statin use ( ) HRT ( ) Age at diagnosis c c c c c Education Basic/vocational Reference Higher ( ) Unknown ( ) Parity Reference ( ) ( ) ( ) Medical history Diabetes mellitus b ( ) Obesity b ( ) Chronic obstructive pulmonary disease ( ) Type of endometrial cancer Type I NA NA Type II HRT, hormone replacement therapy; OR, odds ratio. a ORs for included covariates. Adjustment: Age (by matching), parity, HRT, obesity, diabetes, chronic obstructive pulmonary disease, education. b Composite measure from National Patient Registry and Prescription Registry. c Not relevant as controls were matched on date of birth (one month). 146 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

4 Table 2. Risk of overall, type I and type II endometrial cancer according to use, duration and intensity of statins. Overall endometrial cancer Type I endometrial cancer Type II endometrial cancer Cases/controls Age-adjusted OR (95% CI) (95% CI) Cases/controls (95% CI) Cases/controls (95% CI) Use of statins Non use 4772/ Reference Reference 4237/ Reference 535/7278 Reference Ever use 610/ ( ) 1.03 ( ) 525/ ( ) 85/ ( ) Timing of use Recent use 572/ ( ) 1.02 ( ) 493/ ( ) 79/ ( ) Former use 38/ ( ) 1.27 ( ) 32/ ( ) 6/ ( ) Duration of use Short term 466/ ( ) 1.05 ( ) 398/ ( ) 68/ ( ) Long term 144/ ( ) 0.98 ( ) 127/ ( ) 17/ ( ) Intensity of use Low 196/ ( ) 1.01 ( ) 168/ ( ) 28/ ( ) Medium 200/ ( ) 1.03 ( ) 176/ ( ) 24/ ( ) High 214/ ( ) 1.06 ( ) 181/ ( ) 33/ ( ) Intensity of short-term use Low 143/ ( ) 1.07 ( ) 122/ ( ) 21/ ( ) Medium 147/ ( ) 1.00 ( ) 127/ ( ) 20/ ( ) High 176/ ( ) 1.07 ( ) 149/ ( ) 27/ ( ) Intensity of long-term use Low 53/ ( ) 0.87 ( ) 46/ ( ) 7/ ( ) Medium 53/ ( ) 1.11 ( ) 49/ ( ) 4/ ( ) High 38/ ( ) 0.97 ( ) 32/ ( ) 6/ ( ) HRT, hormone replacement therapy; OR, odds ratio. a Adjustment: Age (by matching), parity, HRT, obesity, diabetes, chronic obstructive pulmonary disease, education. controls. Most ever users of statins were recent users (cases, 94%; controls, 95%). We observed no association between ever use of statin and endometrial cancer risk (OR 1.03, 95% CI ) (Table 2), and no substantial variation in ORs between recent (OR 1.02, 95% CI ) and former (OR 1.27, 95% CI ) use of statins. In addition, endometrial cancer risk did not vary substantially with duration and intensity of statin use in separate or combined analyses. Stratification by type of endometrial cancer also showed no difference in ORs (type I, OR % CI ; type II, OR % CI ). In analyses of potential effect measure modification by known risk factors for endometrial cancer, we observed slight differences in ORs for obese (0.93, 95% CI ) and non-obese (OR 1.05, 95% CI ) women, and for HRT users (0.95, 95% CI ) compared with non-users (OR 1.11, 95% CI ) (Table 3). No material variation was found in ORs for parity or diabetes. In the sensitivity analyses, women <50 years exhibited similar associations to those of the main analysis after additional adjustment for oral contraceptive use (data not shown). The results also remained unaltered applying the new-user design (data not shown). Table 3. Risk of endometrial cancer associated with ever use of statins stratified by parity, diabetes, obesity and hormone replacement therapy (HRT). Cases (n = 5382) Discussion Controls (n = ) (95% CI) p-value Parity ( ) ( ) Obesity Yes ( ) 0.39 No ( ) Diabetes Yes ( ) 0.70 No ( ) HRT Yes ( ) 0.09 No ( ) a Adjustment: Age (by matching), parity, HRT, obesity, diabetes, chronic obstructive pulmonary disease, education. In this nationwide registry-based case control study, we found no evidence of an association between statin use ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

5 and risk of endometrial cancer, and the null association remained consistent across different levels of duration and intensity of statin use, as well as in separate analyses of type I and II endometrial cancer. Our results are compatible with most epidemiological studies, although some studies have reported an inverse association between statin use and endometrial cancer risk. In a cohort study of women in USA, Yu et al. (7) observed a hazard ratio of 0.67 (95% CI ) for endometrial cancer (568 cases) with overall statin use. Similarly, in another US cohort study, Jacobs et al. (20) found a decreased risk of endometrial cancer associated with five or more years of statin use [relative risk (RR) 0.65, 95% CI ], whereas short-term use was not associated with endometrial cancer risk (RR 1.11, 95% CI ). Other studies have reported neutral associations (6,7,9), including a large registry-based study from Finland (6) with 1721 endometrial cancer cases (RR 1.05, 95% CI ). Seven additional studies were included in the recent meta-analysis by Liu et al. (10) of statin use and endometrial cancer risk, reporting pooled RRs of 0.90 (95% CI ) for overall statin use and 0.69 (95% CI ) for long-term (more than five years) use (10). The results of the meta-analysis were primarily driven by the study of Jacobs et al. (20) and another US cohort study by Friedman et al. (8) based on the Kaiser Permanente Health Program. Again, no risk variation with duration or intensity of statin use, as reported by Jacobs et al. (20), was found in the pooled analyses, which is also compatible with our findings. To our knowledge, this is the first study to report results for specific histological types of endometrial cancer, and our results do not support any differential protective effects of statin use against type I or II endometrial cancer. We also evaluated whether the association between statin use and endometrial cancer risk would be more pronounced among women with high susceptibility for developing endometrial cancer by examining effect measure modification according to major risk factors for endometrial cancer (21 23). We observed marginally lower risk estimates among obese women and users of HRT; however, these minor differences may be random findings. Further research of the interplay between drug use and endometrial cancer risk factors is warranted. Our study is the largest to date of statin use and endometrial cancer risk, and the major strengths are the large sample size and the long study period with a prescription history up to 15 years. Other strengths included the use of continuously updated nationwide registries with high coverage and quality, minimizing selection and information biases. The Prescription Registry provided precise data on drug use including type, quantity, duration, timing and intensity of statin and other drug use. Furthermore, all statins used during the study period were eligible for the analyses, as statins can only be obtained by a prescription in Denmark (24). Finally, cancer diagnoses were restricted to histologically verified cases of endometrial cancer, further enhancing case validity. Our study also had a number of limitations. First, a history of obesity was based on hospital and outpatient diagnoses and prescription use, and residual confounding is thus likely. Secondly, we had no information on the patients compliance with statin therapy, which might introduce exposure misclassification. However, in contrast to many other countries, compliance with statin therapy has been reported to be relatively high (>80%) in Denmark (25,26). Furthermore, we required a minimum of two prescriptions to define statin use to minimize the possibility that patients filled a statin prescription but did not actually take the drugs. Thirdly, studies of statin effects have often been criticized for being biased by healthy user effects, i.e. statin users might differ from non-users in term of lifestyle and health-seeking behavior. To reduce the influence of this potential bias, we adjusted the analyses for educational level and comorbidities, but we had no access to direct measures of the health status and lifestyle pattern among the study subjects. Lastly, left truncation of the prescription data might have introduced misclassification of statin use; however, the sensitivity analysis applying a new-user design yielded results similar to those of the main analyses. In conclusion, in our nationwide case control study, use of statins was not associated with endometrial cancer risk. The null association persisted across various levels of duration and intensity of statin use, and for type I and II endometrial cancer. Funding The study was not funded by any specific external funding body but was funded by Unit Virus, Lifestyle and Genes, Danish Cancer Society Research Center. References 1. Sorosky JI. Endometrial cancer. Obstet Gynecol. 2012;120 (2 Pt 1): Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol. 2008;52: Schointuch MN, Gilliam TP, Stine JE, Han X, Zhou C, Gehrig PA, et al. Simvastatin, an HMG-CoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic 148 ª 2016 Nordic Federation of Societies of Obstetrics and Gynecology, Acta Obstetricia et Gynecologica Scandinavica 96 (2017)

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