Effect of Bile Acid Sequestrants on the Risk of Cardiovascular Events: A Mendelian Randomization Analysis.
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. 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). The cholesterol lowering effect of BAS may translate into a clinically relevant reduction in CAD.