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Published on: November 27, 2016
Effect of Bile Acid Sequestrants on the Risk of Cardiovascular Events: A Mendelian Randomization Analysis
Stephanie Ross1, Matthew D'Mello1, Sonia S Anand1
1From 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.).
Insights
Bile acid sequestrants (BAS) effectively lower LDL-C and may significantly reduce coronary artery disease (CAD) risk. These findings support BAS as a viable alternative for CAD risk reduction.
Area of Science:
- Cardiovascular Medicine
- Pharmacology
- Genetics
Background:
- Statins are primary treatments for lowering LDL-C and CAD risk, but patient adherence and efficacy vary.
- Bile acid sequestrants (BAS) lower LDL-C, but their impact on clinical CAD outcomes is debated.
Purpose of the Study:
- To systematically review and meta-analyze randomized controlled trials on cholestyramine and colesevelam efficacy.
- To utilize Mendelian randomization to estimate the effect of BAS on CAD risk.
Main Methods:
- Systematic review and meta-analysis of 19 RCTs (N=7021) assessing cholestyramine and colesevelam.
- Mendelian randomization using rs4299376 (ABCG5/ABCG8) to predict BAS effect on CAD risk.
Main Results:
- Cholestyramine (24 g/d) reduced LDL-C by 23.5 mg/dL and showed a trend toward reduced CAD risk (OR 0.81, P=0.07).
- Colesevelam (3.75 g/d) reduced LDL-C by 22.7 mg/dL.
- Mendelian randomization predicted significant CAD risk reduction with cholestyramine (OR 0.63) and colesevelam (OR 0.64).
Conclusions:
- The LDL-C lowering effect of BAS is likely to translate into a clinically significant reduction in CAD risk.
- BAS demonstrate potential as an effective therapeutic option for managing CAD risk.
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.
Methods And 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.
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