- Email: [email protected]
Comparison of Frequency of Inflammatory Bowel Disease and Noninfectious Gastroenteritis Among Statin Users Versus Nonusers
Comparison of Frequency of Inflammatory Bowel Disease and Noninfectious Gastroenteritis Among Statin Users Versus Nonusers Dina Khalil, MDa, Moheb Boktor, MDb, Eric M. Mortensen, MD, MScc,d, Christopher R. Frei, PharmD, MSe,f, and Ishak Mansi, MDc,d,* Conflicting data exist regarding the effects of statin therapy on the prevalence of inflammatory bowel diseases. We aimed to examine the association of statin therapy with diagnoses of inflammatory bowel diseases and noninfectious gastroenteritis. This is a retrospective study using data of a military health care system from October 1, 2003, to March 1, 2012. Based on medication fills during fiscal year 2005, patients were divided into: (1) statin users (received at least 90-day supply of statin) and (2) nonusers (never received a statin). A propensity scoree matched cohort of statin users and nonusers was created using 80 variables. Primary analysis examined the risks of being diagnosed with inflammatory bowel diseases and noninfectious gastroenteritis between statin users and nonusers in the propensity scoreematched cohort. Secondary analyses examined the risk of outcomes in the whole cohort and in patients with no comorbidities according to Charlson Comorbidity Index. Of 43,438 patients meeting study criteria (13,626 statin users and 29,812 nonusers), we propensity score matched 6,342 statin users with 6,342 nonusers. For our primary analysis, 93 statin users and 92 nonusers were diagnosed with inflammatory bowel diseases (odds ratio [ 1.01, 95% confidence interval [ 0.76 to 1.35), and 632 statin users and 619 nonusers were diagnosed of noninfectious gastroenteritis (odds ratio [ 1.02, 95% confidence interval [ 0.91 to 1.15). In conclusion, the risks of inflammatory bowel diseases and noninfectious gastroenteritis among statin users and nonusers are similar after adjusting for other potential confounding factors. Published by Elsevier Inc. (Am J Cardiol 2015;115:1396e1401) Statins (3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors) exhibit anti-inflammatory and antifibrotic effects, which might be beneficial in inflammatory bowel diseases (IBD).1 In a model of experimentally induced colitis, simvastatin ameliorated inflammation and resulted in a dosedependent decrease in the level of a fibrosis-related growth factor.1 In another experimental model, simvastatin inhibited proinflammatory gene expression in intestinal epithelial cells and attenuated dextran sulfate sodium-induced colitis.2 In an observational study, patients with IBD on statins had lesser use of oral steroids and a reduced incidence of surgery for IBD.3 Additionally, in an open-label study of 10 patients with Crohn’s disease, the addition of atorvastatin 80 mg for 23 weeks resulted in significant decrease in inflammatory markers.4 In contrast, case reports have associated fatal a Urology Department, University of Texas Southwestern, Dallas, Texas; bDepartment of Medicine, Section of Gastroenterology, Louisiana State University Health Sciences Center in Shreveport, Louisiana; cDepartment of Medicine, VA North Texas Health Care System, Dallas, Texas; d Department of Internal Medicine and Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas; eDivision of Pharmacotherapy, College of Pharmacy, The University of Texas at Austin, Austin, Texas; and fPharmacotherapy Education and Research Center, School of Medicine, University of Texas Health Science Center, San Antonio, Texas. Manuscript received November 26, 2014; revised manuscript received and accepted February 6, 2015. See page 1400 for disclosure information. *Corresponding author: Tel/fax: (214) 857-1577. E-mail address: [email protected] (I. Mansi).
0002-9149/15/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjcard.2015.02.035
colitis with stain use.5,6 Additionally, some investigators argued that statins might cause mitochondrial dysfunction and proinflammatory effects, which may induce autoimmune diseases.7 The objective of this study was to examine the association of statin use on the prevalence of IBD and noninfectious gastroenteritis (NI-GE) in a cohort of patients who were followed longitudinally in a military health care system, where patients had similar access and availability of health care.
Methods This study was approved by the Institutional Review Boards of Brooke Army Medical Center and VA North Texas Healthcare System. This is a retrospective cohort study including all patients aged 30 to 85 years enrolled in the San Antonio Military Multi-Market Area as Tricare Prime or Plus. We retrieved the medical encounters and their associated medication fill histories, diagnoses, and procedure codes data, from October 1, 2003, to March 1, 2012, using the Military Health System Management Analysis and Reporting Tool (M2). The reliability and reproducibility of M2 Data are well documented.8e10 Each patient in M2 is uniquely identified by an identification code that is consistent throughout the data. These data encompass the full spectrum of all clinical and administrative data integrated with eligibility and enrollment data including outpatient electronic medical records, inpatient electronic medical records, medical benefits claims data, laboratory data performed within www.ajconline.org
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Table 1 Selected baseline characteristics of propensity score matched statin users and nonusers Variable
Age (year), mean SD Men Charlson Comorbidity Index components during baseline period* Chronic obstructive lung disease Diabetes mellitus Diabetes mellitus with complications Malignancy Cerebrovascular disease Rheumatologic diseases Peripheral vascular disease Congestive heart failure Kidney disease Peptic ulcer disease Acute myocardial infarction Metastatic neoplasm Mild liver disease Dementia Hemiplegia/paraplegia HIV Liver disease (moderate/severe) Charlson Comorbidity Index total score: mean (SD) Obesity† Smoker Alcohol abuse/dependencez Illicit drug usez Hypertensionz Hypertension with complicationsz Valvular heart diseasez Asthmaz Coronary artery diseasez Gastritis/duodenitis Rheumatoid arthritis/systemic lupusz Peripheral vascular diseasez Cardiovascular conduction disorderz Respiratory failurez Pathologic fracturez Suicidez Number of outpatient visits during baseline period: mean SD Number of inpatient admissions during baseline period: mean SD Number of encounters for immunization during baseline period: mean SD Rehabilitation carez Medications: Non-statin lipid lowering drugs NSAID ACE/ARB Proton pump inhibitor Aspirin Diuretic Sedatives Beta-blocker SSRI Calcium channel blocker Bisphosphonate Cytochrome p450 Systemic corticosteroid Oral hypoglycemic Antipsychotic
Statin users
P value
NO (n ¼ 6342)
YES (n ¼ 6342)
56.0 12.0 3486 (55.0%)
55.7 12.4 3418 (53.9%)
0.12 0.23
771 (12.2%) 544 (8.6%) 449 (7.1%) 365 (5.8%) 176 (2.8%) 142 (2.2%) 116 (1.8%) 108 (1.7%) 77 (1.2%) 53 (0.8%) 37 (0.6%) 31 (0.5%) 28 (0.4%) 20 (0.3%) 11 (0.2%) 7 (0.1%) 4 (0.1%) 0.64 1.23 993 (15.7%) 534 (8.4%) 83 (1.3%) 24 (0.4%) 3766 (59.4%) 176 (2.8%) 402 (6.3%) 375 (5.9%) 277 (4.4%) 216 (3.4%) 172 (2.7%) 153 (2.4%) 130 (2.0%) 30 (0.5%) 25 (0.4%) 4 (0.1%) 31.67 36.76 0.25 0.75 0.48 1.60 1227 (19.3%)
780 (12.3%) 581 (9.2%) 454 (7.2%) 384 (6.1%) 185 (2.9%) 136 (2.1%) 144 (2.3%) 117 (1.8%) 83 (1.3%) 57 (0.9%) 48 (0.8%) 25 (0.4%) 28 (0.4%) 21 (0.3%) 14 (0.2%) 9 (0.1%) 5 (0.1%) 0.66 1.25 960 (15.1%) 509 (8.0%) 78 (1.2%) 22 (0.3%) 3707 (58.5%) 181 (2.9%) 403 (6.4%) 366 (5.8%) 314 (5.0%) 215 (3.4%) 156 (2.5%) 169 (2.7%) 137 (2.2%) 32 (0.5%) 28 (0.4%) 3 (0.00%) 31.81 40.63 0.26 0.77 0.49 3.71 1205 (19.0%)
0.81 0.26 0.86 0.48 0.63 0.72 0.08 0.55 0.63 0.70 0.23 0.43 1.00 0.88 0.56 0.80 0.75 0.29 0.43 0.44 0.69 0.77 0.30 0.79 0.97 0.73 0.12 1.00 0.37 0.37 0.71 0.80 0.68 0.73 0.84 0.75 0.75 0.62
373 3729 2137 2009 1835 1740 1221 1099 1059 987 573 386 257 218 85
391 3702 2141 2030 1890 1718 1243 1123 1067 1001 536 414 249 254 84
0.52 0.64 0.96 0.70 0.28 0.68 0.62 0.58 0.87 0.75 0.26 0.32 0.75 0.10 1.00
(5.9%) (58.8%) (33.7%) (31.7%) (28.9%) (27.4%) (19.3%) (17.3%) (16.7%) (15.6%) (9.0%) (6.1%) (4.1%) (3.4%) (1.3%)
(6.2%) (58.4%) (33.8%) (32.0%) (29.8%) (27.1%) (19.6%) (17.7%) (16.8%) (15.8%) (8.5%) (6.5%) (3.9%) (4.0%) (1.3%)
(continued)
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Table 1 (continued) Variable
Mean Mean Mean Mean Mean Mean
LDL-C in baseline period in mg/dL: mean SD z HDL-C in baseline period in mg/dL: mean SD x Triglycerides in baseline period in mg/dL: mean SD x LDL-C in follow-up period in mg/dL: mean SDx HDL-C in follow-up period in mg/dL: mean SDx Triglycerides in follow-up period in mg/dL: mean SDx
Statin users
P value
NO (n ¼ 6342)
YES (n ¼ 6342)
107 27 59 19 129 91 108 26 57 18 120 73
118 34 55 15 150 88 110 32 53 14 142 77
< < < < < <
0.001 0.001 0.001 0.001 0.001 0.001
ACE/ARB ¼ angiotensin-receptor blockers & angiotensin converting enzyme inhibitors; Cytochrome p 450 ¼ medications that inhibit the Cytochrome p450 system as identified in a recent FDA warning18; HIV ¼ human immunodeficiency virus; NSAID ¼ non-steroidal anti-inflammatory drugs; SD ¼ standard deviation; SSRI ¼ selective serotonin reuptake inhibitors. * Diagnosis is based on ICD-9-CM codes as identified in Deyo method for applying the Charlson Comorbidity Index.17 † Diagnosis is based on selected ICD-9-CM diagnosis codes from category 56 of the Agency of Health Research and Quality-Clinical Classification Software (other nutritional; endocrine; and metabolic disorders) related to overweight, obesity and hyperalimentation (codes: 2780, 27800, 27801, 27802, 27803, 2781, 2788, and 7831).12 z As defined by the Agency for Health Research and Quality-Clinical Classifications Software.12 x Lipid measurements represent the mean value for each patient throughout the baseline or follow-up periods; these laboratory measurements were available only for those who had their laboratory tests performed at the military treatment facilities under study (3,879 statin users and 3,320 nonusers). Lipid parameters were not included in propensity score matching.
military facilities, and pharmacy data regardless of pharmacy location or affiliation. Our study duration was divided into 2 periods: baseline period and follow-up period. Baseline period included the period from October 1, 2003, to September 30, 2005, and was used for description of baseline characteristics. The follow-up period included the period from October 1, 2005, to March 1, 2012, and was used for examining outcomes of patients. All patients were enrolled in the system throughout the study period; hence, we have no missing data. Inclusion criteria were detailed in a previous publication11; our cohort included all patients aged 30 to 85 years who were (1) enrolled in Tricare Prime or Plus in the San Antonio Multi-Market Area; (2) had at least 1 medical encounter during the baseline period and 1 during the followup period; and (3) had at least 1 prescription medication during the baseline period. We excluded the following groups: (1) patients who started on statins at the end of baseline period (after September 30, 2005), thus allowing us to have 2 treatment groups of statin users and nonusers with equal periods of follow-up; (2) patients who received statins for <90 days during the study period; and (3) patients who were diagnosed with trauma or burn throughout the study period because these patients’ outcomes were likely affected by the extent of their trauma or burn rather than statin use. Diagnoses with trauma or burn were based on the International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes as defined by the Agency for Healthcare Research and Quality Clinical Classifications Software (AHRQ-CCS), category 240,12 and previous publications.13,14 Patients who met the study criteria were divided into 2 treatment groups: (1) statin users: patients who were on statin medication for a cumulative period of at least 90 days including the period from October 1, 2004, to September 30,
2005, and (2) nonusers: patients who never received statin from October 1, 2003, to March 1, 2012. We identified ICD-9 codes consistent with outcomes of interest during the follow-up period. Our outcome diagnosis groups were defined as the followings: (1) IBD outcome group: this group included all ICD-9-CM codes of regional arteritis and ulcerative colitis as defined by AHRQ-CCS, category 144 (5550, 5551, 5552, 5559, 556, 5560, 5561, 5562, 5563, 5564, 5565, 5566, 5568, and 5569); and (2) NI-GE outcome group: this group included ICD-9-CM codes of noninfectious gastroenteritis as defined by the AHRQ-CCS, category 154 (55841, 55842, and 5589). Patients’ comorbidities were characterized using the Charlson Comorbidity Index (CCI), Deyo’s method, and several diagnostic categories of AHRQ-CCS.12 A logistic regression model was created to develop the propensity score and test the balance of covariates.15 Matching with a caliper of 0.001 was then performed.16 We included 80 candidate variables in the propensity score that we believed would either be potentially associated with using statins or the outcomes of interest. These variables included patient age, gender, 17 comorbidities that constituted all components of CCI using Deyo’s method,17 and total CCI17; the presence of the following disease categories as defined by AHRQ-CCS12: hypertension, hypertension with complications, chest pain, acute myocardial infarction, dysrhythmia, valvular heart disease, coronary artery disease, heart disease not otherwise specified, cardiovascular conduction disorder, congestive heart failure, cardiomyopathy, vascular aneurysm, arterial thromboembolism, peripheral vascular disease, cardiac arrest/ ventricular fibrillation, cerebrovascular disease, acute cerebrovascular disease, asthma, chronic obstructive lung disease, smoking, cor pulmonale, respiratory failure, diabetes mellitus, diabetes mellitus with complications, gastrointestinal ulcers, gastritis/duodenitis, gastrointestinal hemorrhage, acute kidney injury, chronic kidney disease, rheumatoid
Preventive Cardiology/Statins and Inflammatory Bowel Disease Table 2 Selected baseline characteristics of the No-Charlson comorbidity cohort Variable
Statin users NO (n¼5761)
Age (year), mean SD Women Charlson Comorbidity Total Score: mean (SD) Hypertension Asthma Psychosis Gastritis/duodenitis Obesity* Smoker Number of outpatient visits during baseline period: mean SD Number of inpatient admissions during baseline period: mean SD Number of encounters for immunization during baseline period: mean SD Medications: Beta-blocker Diuretic Calcium channel blocker ACE/ARB Aspirin NSAID Bisphosphonate Proton pump inhibitor
YES (n¼24366)
P value
43.13 10.21 56.46 12.16 < 0.001 13553 (55.6%) 2219 (38.5%) < 0.001 0.00 0.00 0.00 0.00 N/A 3992 (16.4%) 3654 (63.4%) 729 (3.0%) 171 (3.0%) 61 (0.3%) 18 (0.3%) 431 (1.8%) 158 (2.7%) 2108 (8.7%) 846 (14.7%) 1214 (5.0%) 445 (7.7%) 18.54 19.90 25.79 23.59
< 0.001 0.96 0.40 < 0.001 < 0.001 < 0.001 < 0.001
0.12 0.43
0.17 0.49
< 0.001
0.57 1.39
0.40 1.08
< 0.001
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excluded.17 Using a logistic regression model, as described earlier, we examined the risk of outcomes while adjusting for propensity score. Baseline characteristics of statin users and nonusers were compared using appropriate 2-way tests (chi-square for categorical variables and Student’s t for continuous variables). Continuous variables were summarized by the mean and SD. For the propensity scoreematched analyses, we presented the outcomes analyzed using the chi-square tests and odds ratios using conditional logistic regression analysis. For secondary analyses, multivariable logistic regression analysis was used to examine the risks of outcomes; each outcome measure was independently examined as a dependent variable, and statin utilization as a predictor variable, while adjusting for propensity score. Comparisons were considered to be statistically significant with a 2-tailed p value of 0.05. Statistical analyses were performed using STATA 12 (Stata Statistical Software: Release 12, 2011; StataCorp., College Station, Texas) and SPSS Statistical Software, version 21 (SPSS Statistics for Windows; IBM Corp., Armonk, New York). Results
1196 1905 887 1848 1460 14774 612 3514
(4.9%) (7.8%) (3.6%) (7.6%) (6.0%) (60.6%) (2.5%) (14.4%)
1286 1636 1024 2223 2287 3296 423 1874
(22.3%) (28.4%) (17.8%) (38.6%) (39.7%) (57.2%) (7.3%) (32.5%)
< < < < < < < <
0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001
ACE/ARB ¼ angiotensin-receptor blockers & angiotensin converting enzyme inhibitors; NSAID ¼ non-steroidal anti-inflammatory drugs; SD ¼ standard deviation. * Diagnosis is based on selected ICD-9-CM diagnosis codes from category 56 of the Agency of Health Research and Quality-Clinical Classification Software (other nutritional; endocrine; and metabolic disorders) related to overweight, obesity and hyperalimentation (codes: 2780, 27800, 27801, 27802, 27803, 2781, 2788, and 7831).12
arthritis/systemic lupus, obesity, psychosis, metastatic neoplasm, osteoarthritis, pathologic fracture, alcohol abuse/ dependence, illicit drug use, rehabilitation services, suicide, number of both inpatient and outpatient medical encounters during the baseline period as a measure for health care utilization, number of encounters for immunization as a surrogate marker for health conscious behavior, and use of 20 classes of medications.18 We compared the risk of our outcome groups (IBD and NI-GE) between statin users and nonusers in the propensity scoreematched cohort. We also determined the risk of outcomes in statin users and nonusers in the following groups: (1) All-patients cohort: all patients who met inclusion and exclusion criteria. Using logistic regression models, we examined the risk of each outcome as a dependent variable, treatment group as an independent variable, and propensity score as a covariate. (2) NoCharlson comorbidity cohort: patients from the “All-patients cohort” with any positive element of their CCI were
A total of 43,438 patients met study inclusion and exclusion criteria (13,626 statin users and 29,812 nonusers). The mean (SD) cumulative duration of statin use was 4.65 (1.82) years. Statin users received prescriptions for various forms and dosages of the drugs during the study period. Overall, the statins prescribed were simvastatin (73.5%), atorvastatin calcium (17.4%), pravastatin sodium (7.0%), rosuvastatin calcium (1.7%), and fluvastatin sodium or lovastatin (0.2%). The propensity scoreematched cohort included 12,684 patients (6,342 statin users and 6,342 nonusers). There were no statistically significant differences in baseline characteristics between the 2 groups after matching (Table 1). Of statin users, 5,276 (83.2%) continued to take their statins for 2 years and 3,887 (61.3%) for 4 years. The No-Charlson comorbidity cohort constituted 30,127 patients: 5,761 statin users and 24,366 nonusers. Statin users were older, had a higher proportion of men, obesity, and smokers, had more frequent use of most medication classes, and had higher health care utilization (Table 2). In the propensity scoreematched cohort, there were 93 statin users and 92 nonusers diagnosed with IBD, and 632 statin users and 619 nonusers were diagnosed of NI-GE. Odds ratio of IBD and NI-GE were not significantly different between statin users and nonusers (Table 3). In the noeCharlson comorbidity cohort, there were 73 statin users (1.3%) and 266 nonusers (1.1%) who were diagnosed with IBD and 534 statin users (9.3%) and 2,392 nonusers (9.8%) who were diagnosed with NI-GE. After adjusting for propensity score, adjusted odds ratio of IBD and NI-GE were not statistically different between groups (Table 3). Discussion In this study, statin use was not associated with either an increased or decreased risk of IBD or NI-GE diagnoses. Although some smaller studies investigated the impact of statin use in patients with IBD, to our knowledge, no large
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Table 3 Risk of outcomes in statin users and nonusers Outcome variable
Propensity score-matched cohort Inflammatory bowel disease Non-infectious gastroenteritis All cohort* Inflammatory bowel disease Non-infectious gastroenteritis No-Charlson comorbidity cohort* Inflammatory bowel disease Non-infectious gastroenteritis
Statin users
Odds Ratio
YES
NO
(n[6342) 93 (1.5%) 632 (10.0%) (n[13626) 224 (1.6%) 1536 (11.3%) (n[5761) 73 (1.3%) 534 (9.3%)
(n[6342) 92 (1.5%) 619 (9.8%) (n[29811) 370 (1.2%) 3148 (10.6%) (n[24366) 266 (1.1%) 2392 (9.8%)
95%CI
P value
1.01 1.02
0.76 0.91
1.35 1.15
0.94 0.70
0.96 1.01
0.75 0.92
1.23 1.1
0.76 0.87
0.88 1.08
0.63 0.95
1.23 1.22
0.45 0.24
* Adjusting for propensity score.
population studies have investigated the effect of statin use on the prevalence of IBD. In vitro and animal studies have suggested potential benefits of statins in inflammatory diseases. In a study of chemically induced colitis in a murine model, a simvastatintreated group had less inflammatory changes, lower tumor necrosis factor-a (TNF-a) levels, and lower level of fibrosisrelated growth factor.1 In an in vitro model, simvastatin significantly inhibited TNF-aeinduced interleukin-8 gene expression and blocked TNF-aeinduced nuclear factor kappa B transcriptional activity in intestinal epithelial cells of experimentally induced murine colitis.2 Previous human studies have had conflicting results. In a retrospective cohort study (1,986 statin users and 9,871 nonusers), atorvastatin use was associated with an 18% reduction in the rate of steroid initiation. Statins were also associated with a reduced rate of steroid initiation in ulcerative colitis but not in Crohn’s disease.3 In another openlabel study, 10 patients with Crohn’s disease were given 80 mg of atorvastatin for 13 weeks. Atorvastatin use was associated with a decrease in several serum inflammatory markers and diminished expression of chemokine receptor expression of circulating monocytes.4 In contrast, 2 case reports describe the development of fatal ulcerative colitis after starting simvastatin in a 65-year-old man and colitis after starting pravastatin in an 80-year old woman.5,6 Some investigators speculated that statins’ effect on the omega-3 to omega-6 ratio may result in increased gastrointestinal inflammation and that statins’ effect in decreasing cholesterol may result in lower levels of vitamin D, which has been linked to protection against gastrointestinal inflammation.7 Finally, statins have been shown to have proinflammatory effects in addition to their anti-inflammatory effects.19 Although randomized controlled trials are considered to be the “gold standard” to examine medication efficacy, observational studies can serve as a good resource for studying effectiveness and unintended side effects. However, observational studies may suffer from the presence of confounders, some of which may not be apparent. For example, statin use may be a surrogate marker for the presence of health insurance and access to health care.19 Additionally, statin use may be a surrogate marker for “health-conscious patients”; hence, the beneficial effects observed in statin users might not be related to statins themselves.20 In a recent
meta-analysis of randomized controlled trials of statin therapy, statin therapy modestly increased incident diabetes risk and asymptomatic liver transaminase elevation but reduced cardiovascular morbidity and mortality.21 There were no other statin-attributable beneficial effects or adverse events related to statins’ pleotropic effects. Our study has several strengths. We included a large number of patients, who were followed longitudinally from 2003 to 2012, with complete follow-up including inpatient and outpatient medical encounters, and all prescription refills, regardless of point of care location or affiliation. To our knowledge, this is the first study to address this question using such a large number of patients over such a long period of time. We were also able to propensity score match statin users and nonusers with no imbalances. Our study has some limitations. Its retrospective nature makes it subject to possible bias from unmeasured confounders. Randomized controlled trials are the best way to minimize such confounders. Because of the retrospective study design and reliance on pharmacy data, we were unable to fully determine disease severity or confirm that patients actually ingested the medications that were filled. Pharmacy data can ascertain dispensing statins, which is used as a surrogate for medication intake but cannot ascertain actual medication intake. However, 83% and 61% of statin users continued to take statins at 2 and 4 years of follow-up, respectively, which is higher than the percentage of patients who continued statins in other populations.22e24 Therefore, it may indicate a higher adherence among patients in our study population. Disclosures Dr. Frei was supported by the US National Institutes of Health (NIH) in the form of an NIH/KL2 career development award (RR025766) during the conduct of this study. In addition, Dr. Frei has received research grants and/or served as a scientific consultant/advisor for AstraZeneca, BristolMyers Squibb, Elan, Forest, Ortho-McNeil Janssen, and Pfizer. Dr. Mortensen was supported in part by a grant from the Agency for Healthcare Research and Quality (R24 HS022418) and the University of Texas Southwestern Center for Patient-Centered Outcomes Research. No funding was provided for the conduct of this study or the preparation of this report. The views expressed here are those of the
Preventive Cardiology/Statins and Inflammatory Bowel Disease
authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, Department of Veterans Affairs, or the US Government. The investigators are the employees of the US government. This work was prepared as part of their official duties, and as such, there is no copyright to be transferred. 1. Abe Y, Murano M, Murano N, Morita E, Inoue T, Kawakami K, Ishida K, Kuramoto T, Kakimoto K, Okada T, Narabayashi K, Umegaki E, Higuchi K. Simvastatin attenuates intestinal fibrosis independent of the anti-inflammatory effect by promoting fibroblast/myofibroblast apoptosis in the regeneration/healing process from TNBS-induced colitis. Dig Dis Sci 2012;57:335e344. 2. Lee JY, Kim JS, Kim JM, Kim N, Jung HC, Song IS. Simvastatin inhibits NF-kappaB signaling in intestinal epithelial cells and ameliorates acute murine colitis. Int Immunopharmacol 2007;7: 241e248. 3. Crockett SD, Hansen RA, Sturmer T, Schectman R, Darter J, Sandler RS, Kappelman MD. Statins are associated with reduced use of steroids in inflammatory bowel disease: a retrospective cohort study. Inflamm Bowel Dis 2012;18:1048e1056. 4. Grip O, Janciauskiene S, Bredberg A. Use of atorvastatin as an anti-inflammatory treatment in Crohn’s disease. Br J Pharmacol 2008;155:1085e1092. 5. Rea WE, Durrant DC, Boldy DA. Ulcerative colitis after statin treatment. Postgrad Med J 2002;78:286e287. 6. Mukhopadhya A, Gilmour H, Plevris J. Pravastatin-induced colitis. Eur J Gastroenterol Hepatol 2008;20:810e812. 7. Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 2008;8:373e418. 8. Kugler J. Military Health System Patient Centered Medical Home Guide. Office of the Chief Medical Officer: Tricare. Department of Defense; 2011:20. Available at: http://www.tricare.mil/tma/ocmo/ download/MHSPCMHGuide.pdf. Accessed on January 11, 2012. 9. M2 MHS Management analysis and reporting tool. Executive Information and Decision Support for the MHS. Available at: www.eids.ha. osd.mil. Accessed on January 7, 2012. 10. Luhrman S, Lehr E, Hefflin C, Saund N. Interface Control Document Describing the Case Management Exchange from BEA to MDR and M2 Baseline. DHSS program management. Falls Church: DHSS, 2008. 11. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med 2013;173:1e10.
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12. Elixhauser A, Steiner C, Palmer L. Clinical Classifications Software (CCS) for ICD-9-CM Databases and Related Tools from the Healthcare Cost and Utilization Project (HCUP). US Agency for Healthcare Research and Quality, 2012; Appendix A. 13. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care 1998;36: 8e27. 14. Selim AJ, Fincke G, Ren XS, Lee A, Rogers WH, Miller DR, Skinner KM, Linzer M, Kazis LE. Comorbidity assessments based on patient report: results from the Veterans Health Study. J Ambul Care Manage 2004;27:281e295. 15. Becker S, Ichino A. Estimation of average treatment effects based on propensity scores. The Stata J 2002;2:358e377. 16. Leuven E, Sianesi B. PSMATCH2: Stata Module to Perform Full Mahalanobis and Propensity Score Matching, Common Support Graphing, and Covariate Imbalance Testing. Version 4.0.5, 2003. Available at: http:// ideas.repec.org/c/boc/bocode/s432001.html. Accessed on December 20, 2012. 17. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45:613e619. 18. FDA Drug Safety Communication: New Restrictions, Contraindications, and Dose Limitations for Zocor (Simvastatin) to Reduce the Risk of Muscle Injury. US Food and Drug Administration; US Department of Health and Human Services; 2011. Available at: http://www.fda. gov/Drugs/DrugSafety/ucm256581.htm. Accessed on June 15, 2011. 19. Mansi I, Mortensen E. The controversy of a wider statin utilization: why? Expert Opin Drug Saf 2013;12:327e337. 20. Dormuth CR, Patrick AR, Shrank WH, Wright JM, Glynn RJ, Sutherland J, Brookhart MA. Statin adherence and risk of accidents: a cautionary tale. Circulation 2009;119:2051e2057. 21. Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. Eur J Prev Cardiol 2014;21:464e474. 22. Lilly SM, Mortensen EM, Frei CR, Pugh MJ, Mansi IA. Comparison of the risk of psychological and cognitive disorders between persistent and nonpersistent statin users. Am J Cardiol 2014;114: 1035e1039. 23. Kiss Z, Nagy L, Reiber I, Paragh G, Molnar MP, Rokszin G, Abonyi-Toth Z, Mark L. Persistence with statin therapy in Hungary. Arch Med Sci 2013;9:409e417. 24. Mann DM, Woodward M, Muntner P, Falzon L, Kronish I. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother 2010;44:1410e1421.
0002-9149/15/$ - see front matter Published by Elsevier Inc. http://dx.doi.org/10.1016/j.amjcard.2015.02.035
colitis with stain use.5,6 Additionally, some investigators argued that statins might cause mitochondrial dysfunction and proinflammatory effects, which may induce autoimmune diseases.7 The objective of this study was to examine the association of statin use on the prevalence of IBD and noninfectious gastroenteritis (NI-GE) in a cohort of patients who were followed longitudinally in a military health care system, where patients had similar access and availability of health care.
Methods This study was approved by the Institutional Review Boards of Brooke Army Medical Center and VA North Texas Healthcare System. This is a retrospective cohort study including all patients aged 30 to 85 years enrolled in the San Antonio Military Multi-Market Area as Tricare Prime or Plus. We retrieved the medical encounters and their associated medication fill histories, diagnoses, and procedure codes data, from October 1, 2003, to March 1, 2012, using the Military Health System Management Analysis and Reporting Tool (M2). The reliability and reproducibility of M2 Data are well documented.8e10 Each patient in M2 is uniquely identified by an identification code that is consistent throughout the data. These data encompass the full spectrum of all clinical and administrative data integrated with eligibility and enrollment data including outpatient electronic medical records, inpatient electronic medical records, medical benefits claims data, laboratory data performed within www.ajconline.org
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Table 1 Selected baseline characteristics of propensity score matched statin users and nonusers Variable
Age (year), mean SD Men Charlson Comorbidity Index components during baseline period* Chronic obstructive lung disease Diabetes mellitus Diabetes mellitus with complications Malignancy Cerebrovascular disease Rheumatologic diseases Peripheral vascular disease Congestive heart failure Kidney disease Peptic ulcer disease Acute myocardial infarction Metastatic neoplasm Mild liver disease Dementia Hemiplegia/paraplegia HIV Liver disease (moderate/severe) Charlson Comorbidity Index total score: mean (SD) Obesity† Smoker Alcohol abuse/dependencez Illicit drug usez Hypertensionz Hypertension with complicationsz Valvular heart diseasez Asthmaz Coronary artery diseasez Gastritis/duodenitis Rheumatoid arthritis/systemic lupusz Peripheral vascular diseasez Cardiovascular conduction disorderz Respiratory failurez Pathologic fracturez Suicidez Number of outpatient visits during baseline period: mean SD Number of inpatient admissions during baseline period: mean SD Number of encounters for immunization during baseline period: mean SD Rehabilitation carez Medications: Non-statin lipid lowering drugs NSAID ACE/ARB Proton pump inhibitor Aspirin Diuretic Sedatives Beta-blocker SSRI Calcium channel blocker Bisphosphonate Cytochrome p450 Systemic corticosteroid Oral hypoglycemic Antipsychotic
Statin users
P value
NO (n ¼ 6342)
YES (n ¼ 6342)
56.0 12.0 3486 (55.0%)
55.7 12.4 3418 (53.9%)
0.12 0.23
771 (12.2%) 544 (8.6%) 449 (7.1%) 365 (5.8%) 176 (2.8%) 142 (2.2%) 116 (1.8%) 108 (1.7%) 77 (1.2%) 53 (0.8%) 37 (0.6%) 31 (0.5%) 28 (0.4%) 20 (0.3%) 11 (0.2%) 7 (0.1%) 4 (0.1%) 0.64 1.23 993 (15.7%) 534 (8.4%) 83 (1.3%) 24 (0.4%) 3766 (59.4%) 176 (2.8%) 402 (6.3%) 375 (5.9%) 277 (4.4%) 216 (3.4%) 172 (2.7%) 153 (2.4%) 130 (2.0%) 30 (0.5%) 25 (0.4%) 4 (0.1%) 31.67 36.76 0.25 0.75 0.48 1.60 1227 (19.3%)
780 (12.3%) 581 (9.2%) 454 (7.2%) 384 (6.1%) 185 (2.9%) 136 (2.1%) 144 (2.3%) 117 (1.8%) 83 (1.3%) 57 (0.9%) 48 (0.8%) 25 (0.4%) 28 (0.4%) 21 (0.3%) 14 (0.2%) 9 (0.1%) 5 (0.1%) 0.66 1.25 960 (15.1%) 509 (8.0%) 78 (1.2%) 22 (0.3%) 3707 (58.5%) 181 (2.9%) 403 (6.4%) 366 (5.8%) 314 (5.0%) 215 (3.4%) 156 (2.5%) 169 (2.7%) 137 (2.2%) 32 (0.5%) 28 (0.4%) 3 (0.00%) 31.81 40.63 0.26 0.77 0.49 3.71 1205 (19.0%)
0.81 0.26 0.86 0.48 0.63 0.72 0.08 0.55 0.63 0.70 0.23 0.43 1.00 0.88 0.56 0.80 0.75 0.29 0.43 0.44 0.69 0.77 0.30 0.79 0.97 0.73 0.12 1.00 0.37 0.37 0.71 0.80 0.68 0.73 0.84 0.75 0.75 0.62
373 3729 2137 2009 1835 1740 1221 1099 1059 987 573 386 257 218 85
391 3702 2141 2030 1890 1718 1243 1123 1067 1001 536 414 249 254 84
0.52 0.64 0.96 0.70 0.28 0.68 0.62 0.58 0.87 0.75 0.26 0.32 0.75 0.10 1.00
(5.9%) (58.8%) (33.7%) (31.7%) (28.9%) (27.4%) (19.3%) (17.3%) (16.7%) (15.6%) (9.0%) (6.1%) (4.1%) (3.4%) (1.3%)
(6.2%) (58.4%) (33.8%) (32.0%) (29.8%) (27.1%) (19.6%) (17.7%) (16.8%) (15.8%) (8.5%) (6.5%) (3.9%) (4.0%) (1.3%)
(continued)
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Table 1 (continued) Variable
Mean Mean Mean Mean Mean Mean
LDL-C in baseline period in mg/dL: mean SD z HDL-C in baseline period in mg/dL: mean SD x Triglycerides in baseline period in mg/dL: mean SD x LDL-C in follow-up period in mg/dL: mean SDx HDL-C in follow-up period in mg/dL: mean SDx Triglycerides in follow-up period in mg/dL: mean SDx
Statin users
P value
NO (n ¼ 6342)
YES (n ¼ 6342)
107 27 59 19 129 91 108 26 57 18 120 73
118 34 55 15 150 88 110 32 53 14 142 77
< < < < < <
0.001 0.001 0.001 0.001 0.001 0.001
ACE/ARB ¼ angiotensin-receptor blockers & angiotensin converting enzyme inhibitors; Cytochrome p 450 ¼ medications that inhibit the Cytochrome p450 system as identified in a recent FDA warning18; HIV ¼ human immunodeficiency virus; NSAID ¼ non-steroidal anti-inflammatory drugs; SD ¼ standard deviation; SSRI ¼ selective serotonin reuptake inhibitors. * Diagnosis is based on ICD-9-CM codes as identified in Deyo method for applying the Charlson Comorbidity Index.17 † Diagnosis is based on selected ICD-9-CM diagnosis codes from category 56 of the Agency of Health Research and Quality-Clinical Classification Software (other nutritional; endocrine; and metabolic disorders) related to overweight, obesity and hyperalimentation (codes: 2780, 27800, 27801, 27802, 27803, 2781, 2788, and 7831).12 z As defined by the Agency for Health Research and Quality-Clinical Classifications Software.12 x Lipid measurements represent the mean value for each patient throughout the baseline or follow-up periods; these laboratory measurements were available only for those who had their laboratory tests performed at the military treatment facilities under study (3,879 statin users and 3,320 nonusers). Lipid parameters were not included in propensity score matching.
military facilities, and pharmacy data regardless of pharmacy location or affiliation. Our study duration was divided into 2 periods: baseline period and follow-up period. Baseline period included the period from October 1, 2003, to September 30, 2005, and was used for description of baseline characteristics. The follow-up period included the period from October 1, 2005, to March 1, 2012, and was used for examining outcomes of patients. All patients were enrolled in the system throughout the study period; hence, we have no missing data. Inclusion criteria were detailed in a previous publication11; our cohort included all patients aged 30 to 85 years who were (1) enrolled in Tricare Prime or Plus in the San Antonio Multi-Market Area; (2) had at least 1 medical encounter during the baseline period and 1 during the followup period; and (3) had at least 1 prescription medication during the baseline period. We excluded the following groups: (1) patients who started on statins at the end of baseline period (after September 30, 2005), thus allowing us to have 2 treatment groups of statin users and nonusers with equal periods of follow-up; (2) patients who received statins for <90 days during the study period; and (3) patients who were diagnosed with trauma or burn throughout the study period because these patients’ outcomes were likely affected by the extent of their trauma or burn rather than statin use. Diagnoses with trauma or burn were based on the International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes as defined by the Agency for Healthcare Research and Quality Clinical Classifications Software (AHRQ-CCS), category 240,12 and previous publications.13,14 Patients who met the study criteria were divided into 2 treatment groups: (1) statin users: patients who were on statin medication for a cumulative period of at least 90 days including the period from October 1, 2004, to September 30,
2005, and (2) nonusers: patients who never received statin from October 1, 2003, to March 1, 2012. We identified ICD-9 codes consistent with outcomes of interest during the follow-up period. Our outcome diagnosis groups were defined as the followings: (1) IBD outcome group: this group included all ICD-9-CM codes of regional arteritis and ulcerative colitis as defined by AHRQ-CCS, category 144 (5550, 5551, 5552, 5559, 556, 5560, 5561, 5562, 5563, 5564, 5565, 5566, 5568, and 5569); and (2) NI-GE outcome group: this group included ICD-9-CM codes of noninfectious gastroenteritis as defined by the AHRQ-CCS, category 154 (55841, 55842, and 5589). Patients’ comorbidities were characterized using the Charlson Comorbidity Index (CCI), Deyo’s method, and several diagnostic categories of AHRQ-CCS.12 A logistic regression model was created to develop the propensity score and test the balance of covariates.15 Matching with a caliper of 0.001 was then performed.16 We included 80 candidate variables in the propensity score that we believed would either be potentially associated with using statins or the outcomes of interest. These variables included patient age, gender, 17 comorbidities that constituted all components of CCI using Deyo’s method,17 and total CCI17; the presence of the following disease categories as defined by AHRQ-CCS12: hypertension, hypertension with complications, chest pain, acute myocardial infarction, dysrhythmia, valvular heart disease, coronary artery disease, heart disease not otherwise specified, cardiovascular conduction disorder, congestive heart failure, cardiomyopathy, vascular aneurysm, arterial thromboembolism, peripheral vascular disease, cardiac arrest/ ventricular fibrillation, cerebrovascular disease, acute cerebrovascular disease, asthma, chronic obstructive lung disease, smoking, cor pulmonale, respiratory failure, diabetes mellitus, diabetes mellitus with complications, gastrointestinal ulcers, gastritis/duodenitis, gastrointestinal hemorrhage, acute kidney injury, chronic kidney disease, rheumatoid
Preventive Cardiology/Statins and Inflammatory Bowel Disease Table 2 Selected baseline characteristics of the No-Charlson comorbidity cohort Variable
Statin users NO (n¼5761)
Age (year), mean SD Women Charlson Comorbidity Total Score: mean (SD) Hypertension Asthma Psychosis Gastritis/duodenitis Obesity* Smoker Number of outpatient visits during baseline period: mean SD Number of inpatient admissions during baseline period: mean SD Number of encounters for immunization during baseline period: mean SD Medications: Beta-blocker Diuretic Calcium channel blocker ACE/ARB Aspirin NSAID Bisphosphonate Proton pump inhibitor
YES (n¼24366)
P value
43.13 10.21 56.46 12.16 < 0.001 13553 (55.6%) 2219 (38.5%) < 0.001 0.00 0.00 0.00 0.00 N/A 3992 (16.4%) 3654 (63.4%) 729 (3.0%) 171 (3.0%) 61 (0.3%) 18 (0.3%) 431 (1.8%) 158 (2.7%) 2108 (8.7%) 846 (14.7%) 1214 (5.0%) 445 (7.7%) 18.54 19.90 25.79 23.59
< 0.001 0.96 0.40 < 0.001 < 0.001 < 0.001 < 0.001
0.12 0.43
0.17 0.49
< 0.001
0.57 1.39
0.40 1.08
< 0.001
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excluded.17 Using a logistic regression model, as described earlier, we examined the risk of outcomes while adjusting for propensity score. Baseline characteristics of statin users and nonusers were compared using appropriate 2-way tests (chi-square for categorical variables and Student’s t for continuous variables). Continuous variables were summarized by the mean and SD. For the propensity scoreematched analyses, we presented the outcomes analyzed using the chi-square tests and odds ratios using conditional logistic regression analysis. For secondary analyses, multivariable logistic regression analysis was used to examine the risks of outcomes; each outcome measure was independently examined as a dependent variable, and statin utilization as a predictor variable, while adjusting for propensity score. Comparisons were considered to be statistically significant with a 2-tailed p value of 0.05. Statistical analyses were performed using STATA 12 (Stata Statistical Software: Release 12, 2011; StataCorp., College Station, Texas) and SPSS Statistical Software, version 21 (SPSS Statistics for Windows; IBM Corp., Armonk, New York). Results
1196 1905 887 1848 1460 14774 612 3514
(4.9%) (7.8%) (3.6%) (7.6%) (6.0%) (60.6%) (2.5%) (14.4%)
1286 1636 1024 2223 2287 3296 423 1874
(22.3%) (28.4%) (17.8%) (38.6%) (39.7%) (57.2%) (7.3%) (32.5%)
< < < < < < < <
0.001 0.001 0.001 0.001 0.001 0.001 0.001 0.001
ACE/ARB ¼ angiotensin-receptor blockers & angiotensin converting enzyme inhibitors; NSAID ¼ non-steroidal anti-inflammatory drugs; SD ¼ standard deviation. * Diagnosis is based on selected ICD-9-CM diagnosis codes from category 56 of the Agency of Health Research and Quality-Clinical Classification Software (other nutritional; endocrine; and metabolic disorders) related to overweight, obesity and hyperalimentation (codes: 2780, 27800, 27801, 27802, 27803, 2781, 2788, and 7831).12
arthritis/systemic lupus, obesity, psychosis, metastatic neoplasm, osteoarthritis, pathologic fracture, alcohol abuse/ dependence, illicit drug use, rehabilitation services, suicide, number of both inpatient and outpatient medical encounters during the baseline period as a measure for health care utilization, number of encounters for immunization as a surrogate marker for health conscious behavior, and use of 20 classes of medications.18 We compared the risk of our outcome groups (IBD and NI-GE) between statin users and nonusers in the propensity scoreematched cohort. We also determined the risk of outcomes in statin users and nonusers in the following groups: (1) All-patients cohort: all patients who met inclusion and exclusion criteria. Using logistic regression models, we examined the risk of each outcome as a dependent variable, treatment group as an independent variable, and propensity score as a covariate. (2) NoCharlson comorbidity cohort: patients from the “All-patients cohort” with any positive element of their CCI were
A total of 43,438 patients met study inclusion and exclusion criteria (13,626 statin users and 29,812 nonusers). The mean (SD) cumulative duration of statin use was 4.65 (1.82) years. Statin users received prescriptions for various forms and dosages of the drugs during the study period. Overall, the statins prescribed were simvastatin (73.5%), atorvastatin calcium (17.4%), pravastatin sodium (7.0%), rosuvastatin calcium (1.7%), and fluvastatin sodium or lovastatin (0.2%). The propensity scoreematched cohort included 12,684 patients (6,342 statin users and 6,342 nonusers). There were no statistically significant differences in baseline characteristics between the 2 groups after matching (Table 1). Of statin users, 5,276 (83.2%) continued to take their statins for 2 years and 3,887 (61.3%) for 4 years. The No-Charlson comorbidity cohort constituted 30,127 patients: 5,761 statin users and 24,366 nonusers. Statin users were older, had a higher proportion of men, obesity, and smokers, had more frequent use of most medication classes, and had higher health care utilization (Table 2). In the propensity scoreematched cohort, there were 93 statin users and 92 nonusers diagnosed with IBD, and 632 statin users and 619 nonusers were diagnosed of NI-GE. Odds ratio of IBD and NI-GE were not significantly different between statin users and nonusers (Table 3). In the noeCharlson comorbidity cohort, there were 73 statin users (1.3%) and 266 nonusers (1.1%) who were diagnosed with IBD and 534 statin users (9.3%) and 2,392 nonusers (9.8%) who were diagnosed with NI-GE. After adjusting for propensity score, adjusted odds ratio of IBD and NI-GE were not statistically different between groups (Table 3). Discussion In this study, statin use was not associated with either an increased or decreased risk of IBD or NI-GE diagnoses. Although some smaller studies investigated the impact of statin use in patients with IBD, to our knowledge, no large
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Table 3 Risk of outcomes in statin users and nonusers Outcome variable
Propensity score-matched cohort Inflammatory bowel disease Non-infectious gastroenteritis All cohort* Inflammatory bowel disease Non-infectious gastroenteritis No-Charlson comorbidity cohort* Inflammatory bowel disease Non-infectious gastroenteritis
Statin users
Odds Ratio
YES
NO
(n[6342) 93 (1.5%) 632 (10.0%) (n[13626) 224 (1.6%) 1536 (11.3%) (n[5761) 73 (1.3%) 534 (9.3%)
(n[6342) 92 (1.5%) 619 (9.8%) (n[29811) 370 (1.2%) 3148 (10.6%) (n[24366) 266 (1.1%) 2392 (9.8%)
95%CI
P value
1.01 1.02
0.76 0.91
1.35 1.15
0.94 0.70
0.96 1.01
0.75 0.92
1.23 1.1
0.76 0.87
0.88 1.08
0.63 0.95
1.23 1.22
0.45 0.24
* Adjusting for propensity score.
population studies have investigated the effect of statin use on the prevalence of IBD. In vitro and animal studies have suggested potential benefits of statins in inflammatory diseases. In a study of chemically induced colitis in a murine model, a simvastatintreated group had less inflammatory changes, lower tumor necrosis factor-a (TNF-a) levels, and lower level of fibrosisrelated growth factor.1 In an in vitro model, simvastatin significantly inhibited TNF-aeinduced interleukin-8 gene expression and blocked TNF-aeinduced nuclear factor kappa B transcriptional activity in intestinal epithelial cells of experimentally induced murine colitis.2 Previous human studies have had conflicting results. In a retrospective cohort study (1,986 statin users and 9,871 nonusers), atorvastatin use was associated with an 18% reduction in the rate of steroid initiation. Statins were also associated with a reduced rate of steroid initiation in ulcerative colitis but not in Crohn’s disease.3 In another openlabel study, 10 patients with Crohn’s disease were given 80 mg of atorvastatin for 13 weeks. Atorvastatin use was associated with a decrease in several serum inflammatory markers and diminished expression of chemokine receptor expression of circulating monocytes.4 In contrast, 2 case reports describe the development of fatal ulcerative colitis after starting simvastatin in a 65-year-old man and colitis after starting pravastatin in an 80-year old woman.5,6 Some investigators speculated that statins’ effect on the omega-3 to omega-6 ratio may result in increased gastrointestinal inflammation and that statins’ effect in decreasing cholesterol may result in lower levels of vitamin D, which has been linked to protection against gastrointestinal inflammation.7 Finally, statins have been shown to have proinflammatory effects in addition to their anti-inflammatory effects.19 Although randomized controlled trials are considered to be the “gold standard” to examine medication efficacy, observational studies can serve as a good resource for studying effectiveness and unintended side effects. However, observational studies may suffer from the presence of confounders, some of which may not be apparent. For example, statin use may be a surrogate marker for the presence of health insurance and access to health care.19 Additionally, statin use may be a surrogate marker for “health-conscious patients”; hence, the beneficial effects observed in statin users might not be related to statins themselves.20 In a recent
meta-analysis of randomized controlled trials of statin therapy, statin therapy modestly increased incident diabetes risk and asymptomatic liver transaminase elevation but reduced cardiovascular morbidity and mortality.21 There were no other statin-attributable beneficial effects or adverse events related to statins’ pleotropic effects. Our study has several strengths. We included a large number of patients, who were followed longitudinally from 2003 to 2012, with complete follow-up including inpatient and outpatient medical encounters, and all prescription refills, regardless of point of care location or affiliation. To our knowledge, this is the first study to address this question using such a large number of patients over such a long period of time. We were also able to propensity score match statin users and nonusers with no imbalances. Our study has some limitations. Its retrospective nature makes it subject to possible bias from unmeasured confounders. Randomized controlled trials are the best way to minimize such confounders. Because of the retrospective study design and reliance on pharmacy data, we were unable to fully determine disease severity or confirm that patients actually ingested the medications that were filled. Pharmacy data can ascertain dispensing statins, which is used as a surrogate for medication intake but cannot ascertain actual medication intake. However, 83% and 61% of statin users continued to take statins at 2 and 4 years of follow-up, respectively, which is higher than the percentage of patients who continued statins in other populations.22e24 Therefore, it may indicate a higher adherence among patients in our study population. Disclosures Dr. Frei was supported by the US National Institutes of Health (NIH) in the form of an NIH/KL2 career development award (RR025766) during the conduct of this study. In addition, Dr. Frei has received research grants and/or served as a scientific consultant/advisor for AstraZeneca, BristolMyers Squibb, Elan, Forest, Ortho-McNeil Janssen, and Pfizer. Dr. Mortensen was supported in part by a grant from the Agency for Healthcare Research and Quality (R24 HS022418) and the University of Texas Southwestern Center for Patient-Centered Outcomes Research. No funding was provided for the conduct of this study or the preparation of this report. The views expressed here are those of the
Preventive Cardiology/Statins and Inflammatory Bowel Disease
authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, Department of Veterans Affairs, or the US Government. The investigators are the employees of the US government. This work was prepared as part of their official duties, and as such, there is no copyright to be transferred. 1. Abe Y, Murano M, Murano N, Morita E, Inoue T, Kawakami K, Ishida K, Kuramoto T, Kakimoto K, Okada T, Narabayashi K, Umegaki E, Higuchi K. Simvastatin attenuates intestinal fibrosis independent of the anti-inflammatory effect by promoting fibroblast/myofibroblast apoptosis in the regeneration/healing process from TNBS-induced colitis. Dig Dis Sci 2012;57:335e344. 2. Lee JY, Kim JS, Kim JM, Kim N, Jung HC, Song IS. Simvastatin inhibits NF-kappaB signaling in intestinal epithelial cells and ameliorates acute murine colitis. Int Immunopharmacol 2007;7: 241e248. 3. Crockett SD, Hansen RA, Sturmer T, Schectman R, Darter J, Sandler RS, Kappelman MD. Statins are associated with reduced use of steroids in inflammatory bowel disease: a retrospective cohort study. Inflamm Bowel Dis 2012;18:1048e1056. 4. Grip O, Janciauskiene S, Bredberg A. Use of atorvastatin as an anti-inflammatory treatment in Crohn’s disease. Br J Pharmacol 2008;155:1085e1092. 5. Rea WE, Durrant DC, Boldy DA. Ulcerative colitis after statin treatment. Postgrad Med J 2002;78:286e287. 6. Mukhopadhya A, Gilmour H, Plevris J. Pravastatin-induced colitis. Eur J Gastroenterol Hepatol 2008;20:810e812. 7. Golomb BA, Evans MA. Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs 2008;8:373e418. 8. Kugler J. Military Health System Patient Centered Medical Home Guide. Office of the Chief Medical Officer: Tricare. Department of Defense; 2011:20. Available at: http://www.tricare.mil/tma/ocmo/ download/MHSPCMHGuide.pdf. Accessed on January 11, 2012. 9. M2 MHS Management analysis and reporting tool. Executive Information and Decision Support for the MHS. Available at: www.eids.ha. osd.mil. Accessed on January 7, 2012. 10. Luhrman S, Lehr E, Hefflin C, Saund N. Interface Control Document Describing the Case Management Exchange from BEA to MDR and M2 Baseline. DHSS program management. Falls Church: DHSS, 2008. 11. Mansi I, Frei CR, Pugh MJ, Makris U, Mortensen EM. Statins and musculoskeletal conditions, arthropathies, and injuries. JAMA Intern Med 2013;173:1e10.
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12. Elixhauser A, Steiner C, Palmer L. Clinical Classifications Software (CCS) for ICD-9-CM Databases and Related Tools from the Healthcare Cost and Utilization Project (HCUP). US Agency for Healthcare Research and Quality, 2012; Appendix A. 13. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care 1998;36: 8e27. 14. Selim AJ, Fincke G, Ren XS, Lee A, Rogers WH, Miller DR, Skinner KM, Linzer M, Kazis LE. Comorbidity assessments based on patient report: results from the Veterans Health Study. J Ambul Care Manage 2004;27:281e295. 15. Becker S, Ichino A. Estimation of average treatment effects based on propensity scores. The Stata J 2002;2:358e377. 16. Leuven E, Sianesi B. PSMATCH2: Stata Module to Perform Full Mahalanobis and Propensity Score Matching, Common Support Graphing, and Covariate Imbalance Testing. Version 4.0.5, 2003. Available at: http:// ideas.repec.org/c/boc/bocode/s432001.html. Accessed on December 20, 2012. 17. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases. J Clin Epidemiol 1992;45:613e619. 18. FDA Drug Safety Communication: New Restrictions, Contraindications, and Dose Limitations for Zocor (Simvastatin) to Reduce the Risk of Muscle Injury. US Food and Drug Administration; US Department of Health and Human Services; 2011. Available at: http://www.fda. gov/Drugs/DrugSafety/ucm256581.htm. Accessed on June 15, 2011. 19. Mansi I, Mortensen E. The controversy of a wider statin utilization: why? Expert Opin Drug Saf 2013;12:327e337. 20. Dormuth CR, Patrick AR, Shrank WH, Wright JM, Glynn RJ, Sutherland J, Brookhart MA. Statin adherence and risk of accidents: a cautionary tale. Circulation 2009;119:2051e2057. 21. Finegold JA, Manisty CH, Goldacre B, Barron AJ, Francis DP. What proportion of symptomatic side effects in patients taking statins are genuinely caused by the drug? Systematic review of randomized placebo-controlled trials to aid individual patient choice. Eur J Prev Cardiol 2014;21:464e474. 22. Lilly SM, Mortensen EM, Frei CR, Pugh MJ, Mansi IA. Comparison of the risk of psychological and cognitive disorders between persistent and nonpersistent statin users. Am J Cardiol 2014;114: 1035e1039. 23. Kiss Z, Nagy L, Reiber I, Paragh G, Molnar MP, Rokszin G, Abonyi-Toth Z, Mark L. Persistence with statin therapy in Hungary. Arch Med Sci 2013;9:409e417. 24. Mann DM, Woodward M, Muntner P, Falzon L, Kronish I. Predictors of nonadherence to statins: a systematic review and meta-analysis. Ann Pharmacother 2010;44:1410e1421.