Statin Use and Risk of Gallstone Disease Followed by Cholecystectomy Michael Bodmer; Yolanda B. Brauchli; Stephan Krähenbühl; et al. Online article and related content current as of November 11, 2010. JAMA. 2009;302(18):2001-2007 (doi:10.1001/jama.2009.1601) http://jama.ama-assn.org/cgi/content/full/302/18/2001 Supplementary material eFigure and eTables http://jama.ama-assn.org/cgi/content/full/302/18/2001/DC1 Correction Contact me if this article is corrected. Citations This article has been cited 4 times. Contact me when this article is cited. Topic collections Nutritional and Metabolic Disorders; Lipids and Lipid Disorders; Surgery; Surgical Interventions; Hepatobiliary Surgery; Drug Therapy; Drug Therapy, Other Contact me when new articles are published in these topic areas. Related Letters Use of Statins and Gallstone Risk Ching-Sheng Hsu et al. JAMA. 2010;303(12):1146. Tetsuji Fujita. JAMA. 2010;303(12):1146. Subscribe Email Alerts http://jama.com/subscribe http://jamaarchives.com/alerts Permissions Reprints/E-prints [email protected] [email protected] http://pubs.ama-assn.org/misc/permissions.dtl Downloaded from www.jama.com by guest on November 11, 2010 ORIGINAL CONTRIBUTION Statin Use and Risk of Gallstone Disease Followed by Cholecystectomy Michael Bodmer, MD, MSc Context Gallstone disease is a leading cause of morbidity in western countries and Yolanda B. Brauchli, PhD, MSc carries a high economic burden. Statins decrease hepatic cholesterol biosynthesis and Stephan Krähenbühl, MD, PhD may therefore lower the risk of cholesterol gallstones by reducing the cholesterol con- centration in the bile. Data on this association in humans are scarce. Susan S. Jick, DSc Objective To study the association between the use of statins, fibrates, or other lipid- Christoph R. Meier, PhD, MSc lowering agents and the risk of incident gallstone disease followed by cholecystec- tomy. PPROXIMATELY 10% TO 20% Design, Setting, and Participants Case-control analysis using the UK-based Gen- of white adults in developed eral Practice Research Database. Incident patients between 1994 and 2008 and 4 con- countries have gallstones, and trols per each patient were identified and matched on age, sex, general practice, cal- gallstone disease is a leading endar time, and years of history in the database. The study population was 76% women Acause of gastrointestinal morbidity and and the mean (SD) age was 53.4 (15.0) years at the index date. Conditional logistic inpatient admission in western coun- regression was used to estimate the odds ratio (OR) of developing gallstones fol- tries.1,2 Colicky pain and complica- lowed by cholecystectomy in relation to exposure to lipid-lowering agents, stratified tions such as cholecystitis, choledo- by exposure timing and duration. The ORs and 95% confidence intervals (CIs) were adjusted for smoking, body mass index, ischemic heart disease, stroke, and estrogen cholithiasis, or pancreatitis occur in a use. substantial portion of gallstone carri- ers.3,4 Gallstone disease represents a se- Main Outcome Measure The adjusted OR (AOR) for developing gallstone dis- rious burden for health care systems ease followed by cholecystectomy in relation to exposure to lipid-lowering agents. worldwide; more than 700 000 chole- Results A total of 27 035 patients with cholecystectomy and 106 531 matched con- cystectomies are performed annually in trols were identified, including 2396 patients and 8868 controls who had statin use. the United States.5 Compared with nonuse, current statin use (last prescription recorded within 90 days before the first-time diagnosis of the disease) was 1.0% for patients and 0.8% for Gallstones are classified as either cho- controls (AOR, 1.10; 95% CI, 0.95-1.27) for 1 to 4 prescriptions; 2.6% vs 2.4% (AOR, lesterol (80%-90%) or pigment stones 0.85; 95% CI, 0.77-0.93) for 5 to 19 prescriptions, and 3.2% vs 3.7% (AOR, 0.64; (10%-20%). Cholesterol stones are 95% CI, 0.59-0.70) for 20 or more prescriptions. The AORs for current use of statins formed on the basis of cholesterol- defined as 20 or more prescriptions were similar (around 0.6) across age, sex, and body supersaturated bile,3,5 whereas pig- mass index categories, and across the statin class. ment stones consist mainly of polymer- Conclusion Long-term use of statins was associated with a decreased risk of gall- ized calcium bilirubinate.3 Risk factors stones followed by cholecystectomy. such as age, female sex, obesity, high- JAMA. 2009;302(18):2001-2007 www.jama.com carbohydrate and high-fat diet, estro- gen-containing contraceptive use, and postmenopausal estrogen therapy pre- stone formation.7,8 In humans, some au- Author Affiliations: Division of Clinical Pharmacol- ogy and Toxicology (Drs Bodmer and Krähenbühl) and dispose to cholesterol gallstone forma- thors reported diminished gallstone for- Hospital Pharmacy (Dr Meier), University Hospital, 1,3-5 tion. mation, decreased cholesterol content Basel, Switzerland; Basel Pharmacoepidemiology Unit, Statins decrease hepatic cholesterol in bile, or gallstone dissolution,9-12 Division of Clinical Pharmacy and Epidemiology, De- partment of Pharmaceutical Sciences, University of biosynthesis and may thereby de- whereas others did not find evidence Basel, Basel, Switzerland (Drs Brauchli and Meier); and crease biliary cholesterol secretion,6 for such an effect.13-15 The authors of a Boston Collaborative Drug Surveillance Program, Bos- ton University School of Medicine, Lexington, Mas- consequently leading to diminished recent observational study reported a sachusetts (Drs Jick and Meier). cholesterol concentration in bile. Stud- slightly decreased frequency of chole- Corresponding Author: Christoph R. Meier, PhD, MSc, Basel Pharmacoepidemiology Unit, Hospital Phar- ies in animals have reported beneficial cystectomy in women with self- macy, University Hospital Basel, Spitalstrasse 26, effects of statins in preventing gall- reported long-term statin therapy.16 CH-4031 Basel, Switzerland ([email protected]). ©2009 American Medical Association. All rights reserved. (Reprinted) JAMA, November 11, 2009—Vol 302, No. 18 2001 Downloaded from www.jama.com by guest on November 11, 2010 STATIN USE, GALLSTONE DISEASE RISK, AND CHOLECYSTECTOMY Two small studies reported conflict- demographics and characteristics (eg, Controls ing results; one found no association be- age, sex, height, weight, smoking sta- From the base population, 4 control pa- tween statin use and gallstone risk,17 tus), symptoms, medical diagnoses, re- tients were identified at random for each and the other reported a risk reduc- ferrals to consultants, and hospitaliza- patient with cholecystectomy, matched tion with limited statistical power.18 tions. Because physicians generate drug on calendar time (same index date), age Fibrates affect lipid metabolism prescriptions directly with the com- (same year of birth), sex, general prac- mainly by acting as synthetic ligands of puter using a coded drug dictionary, all tice, and number of years of active his- the peroxisome proliferator–activated recorded prescriptions include the tory in the GPRD prior to the index receptor ␣. Activation of peroxisome name of the preparation, route of ad- date. Controls had no recording of gall- proliferator–activated receptor ␣ af- ministration, dose of a single unit, num- stones, clinical complications sugges- fects numerous metabolic pathways in- ber of units prescribed, and intake regi- tive of gallstones, or cholecystectomy. cluding glucose and lipid metabolism, men (in most instances). The database The same exclusion criteria were ap- reducing level of plasma triglycerides has been described in detail else- plied to patients and controls. and glucose concentration, and increas- where,22-25 has been validated exten- ing high-density lipoprotein choles- sively,26-28 and has been the source for Exposure to Statins and Other terol levels. Studies in humans dem- numerous epidemiological studies pub- Lipid-Lowering Agents onstrated that short-term fibrate lished in peer-reviewed journals. From the computer record, exposure treatment is associated with decreased The study protocol was approved by was assessed to statins, fibrates, or other bile acid synthesis and biliary excre- the Independent Scientific Advisory lipid-lowering agents (anion-exchanger tion.19,20 In a randomized controlled Committee for Medicines and Health- resin, probucol, acipimox, niacin, fish trial, a higher incidence of cholecys- care Products Regulatory Agency Da- oil, or omega fatty acids) prior to the tectomy was noted in patients taking fi- tabase for Research. Informed consent index date for patients and controls. Pa- brates,21 and another study reported a by patients was not needed for this da- tients were classified as currently tak- higher prevalence of gallstones in pa- tabase study. ing medications if the last prescrip- tients taking fibrates.17 tion was recorded less than 90 days, or Therefore, currently available clini- Case Definition and Ascertainment as formerly taking medications if the last cal studies on the possible effect of stat- Patients aged 20 years or older with a prescription was recorded 90 or more ins on gallstone formation and the risk first-time diagnosis of gallstone dis- days prior to the index date. Medica- of cholecystectomy are limited by either ease or cholecystectomy between 1994 tion use was classified by duration of small sample size, lack of long-term fol- and 2008 were identified based on the use prior to the index date based on the low-up, sex restriction, or methodologi- Oxford Medical Information System number of prescriptions (statins: short- cal drawbacks. We conducted a large and Read codes. All patients were re- term, 1-4; medium-term, 5-19; or long- long-term observational study to ex- quired to have both a recorded diag- term, Ն20; fibrates and other lipid- plore the association between statin use nosis for gallstone disease or a compli- lowering drugs: short- to medium- and the risk of developing an incident cation thereof (such as bile duct term, 1-9; long-term, Ն10). Statin use diagnosis of gallstone disease fol- obstruction, cholecystitis, or cholan- was also classified according to the tab- lowed by cholecystectomy.