title: Effect of Bile Acid Sequestrants on the Risk of Cardiovascular Events: A Mendelian Randomization Analysis.
abstract: BACKGROUND
  Statins lower low-density lipoprotein cholesterol (LDL-C) and risk of coronary artery disease (CAD), but they may be ineffective or not tolerated. Bile acid sequestrants (BAS) reduce LDL-C, yet their clinical efficacy on CAD remains controversial.
  
  
  RESULTS
  We conducted a systematic review and meta-analysis of randomized controlled trials to assess the effect of cholestyramine and colesevelam. We then used Mendelian randomization to estimate the effect of BAS on reducing the risk of CAD. First, we quantified the effect of rs4299376 (ABCG5/ABCG8), which affects the intestinal cholesterol absorption pathway targeted by BAS and then we used these estimates to predict the effect of BAS on CAD. Nineteen randomized controlled trials with a total of 7021 study participants were included. Cholestyramine 24 g/d was associated with a reduction in LDL-C of 23.5 mg/dL (95% confidence interval [CI] -26.8,-20.2; N=3806) and a trend toward reduced risk of CAD (odds ratio 0.81, 95% CI 0.70-1.02; P=0.07; N=3806), whereas colesevelam 3.75 g/d was associated with a reduction in LDL-C of 22.7 mg/dL (95% CI -28.3, -17.2; N=759). Based on the findings that rs4299376 was associated with a 2.75 mg/dL decrease in LDL-C and a 5% decrease in risk of CAD outcomes, we estimated that cholestyramine was associated with an odds ratio for CAD of 0.63 (95% CI 0.52-0.77; P=6.3×10(-6)) and colesevelam with an odds ratio of 0.64 (95% CI 0.52-0.79, P=4.3×10(-5)), which were not statistically different from BAS clinical trials (P>0.05).
  
  
  CONCLUSIONS
  The cholesterol lowering effect of BAS may translate into a clinically relevant reduction in CAD.
authors.affiliation: From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.).
authors.forename: Stephanie
authors.initials: S
authors.lastname: Ross
authors.affiliation: From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.).
authors.forename: Matthew
authors.initials: M
authors.lastname: D'Mello
authors.affiliation: From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.).
authors.forename: Sonia S
authors.initials: SS
authors.lastname: Anand
authors.affiliation: From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.).
authors.forename: John
authors.initials: J
authors.lastname: Eikelboom
authors.affiliation: From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.).
authors.forename: Alexandre F R
authors.initials: AF
authors.lastname: Stewart
authors.affiliation: From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.).
authors.forename: Nilesh J
authors.initials: NJ
authors.lastname: Samani
authors.affiliation: From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.).
authors.forename: Robert
authors.initials: R
authors.lastname: Roberts
authors.affiliation: From the Population Health Research Institute, Hamilton Health Sciences (S.R., M.D'M., S.S.A., J.E., G.P.), Department of Clinical Epidemiology & Biostatistics, Population Genomics Program (S.R., M.D'M., S.S.A., G.P.), Population Genomics Program, Chanchlani Research Centre (S.R., M.D'M., S.S.A., G.P.), Department of Medicine (S.S.A., J.E.), Department of Pathology & Molecular Medicine (G.P.), Thrombosis & Atherosclerosis Research Institute (G.P.), Hamilton Health Sciences, McMaster University, Hamilton; John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, ON, Canada (A.F.R.S., R.R.); Department of Cardiovascular Sciences, University of Leicester, Leicester, United Kingdom (N.J.S.); National Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom (N.J.S.); and Department of Medicine, University of Ottawa, Ottawa, ON, Canada (R.R.). pareg@mcmaster.ca.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Paré
mesh_terms: D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000924:Anticholesteremic Agents / Q000378:metabolism / Q000627:therapeutic use*; D001647:Bile Acids and Salts / Q000378:metabolism*; D008078:Cholesterol, LDL / Q000037:antagonists & inhibitors / Q000378:metabolism; D002792:Cholestyramine Resin / Q000378:metabolism / Q000627:therapeutic use*; D000069472:Colesevelam Hydrochloride / Q000378:metabolism / Q000627:therapeutic use*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D057182:Mendelian Randomization Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic
chemical_list: C416945:ABCG5 protein, human; C416946:ABCG8 protein, human; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D000924:Anticholesteremic Agents; D001647:Bile Acids and Salts; D008078:Cholesterol, LDL; D008074:Lipoproteins; D002792:Cholestyramine Resin; D000069472:Colesevelam Hydrochloride
keywords: Mendelian randomization; cholesterol-lowering drugs; coronary artery disease; genetics; lipids