Abstract
BackgroundBempedoic acid is a new drug that reduces cholesterol synthesis via inhibiting ATP citrate lyase. It remains unclear whether the combination of bempedoic acid and other lipid-lowering drugs is better than these drugs alone. This study systematically reviewed the efficacy and safety of bempedoic acid monotherapy or combination togethers in hypercholesterolemic patients.MethodsRandomized controlled trials were searched across Medline, Embase, Cochrane library, web of science, etc. The net change scores [least squares mean (LSM) percentage change] in LDL-C level were meta-analyzed using weighted mean difference. The reductions in other lipids including total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (ApoB) and high sensitivity C reactive protein (hsCRP) were also assessed. Odds ratio (OR) of the incidence of adverse events (AEs) were calculated to evaluate the safety of bempedoic acid.ResultsA total of 13 trials (4858 participates) were included. Pooled data showed that the combination togethers resulted in greater reductions in LDL-C level than monotherapies (bempedoic acid + statin vs. statin: LSM difference (%), − 18.37, 95% CI, − 20.16 to − 16.57, I2 = 0; bempedoic acid + ezetimibe vs. ezetimibe: LSM difference (%), − 18.89, 95% CI, − 29.66 to − 8.13, I2 = 87%). But the difference in efficacy between bempedoic acid and ezetimibe was not obvious. Meta-regression analysis showed the treatment duration was a source of heterogeneity (adj R2 = 16.92, 95% CI, 0.04 to 0.72). Furthermore, the background therapy of statin before screening decreased the efficacy of bempedoic acid. In addition, bempedoic acid also resulted in a significant reduction in TC, non-HDL-C, ApoB and hsCRP level. The OR of muscle-related AEs by the combination of bempedoic acid and statin was 1.29 (95% CI, 1.00 to 1.67, I2 = 0) when compared with statin alone.ConclusionThis study showed the efficacy of combination togethers were similar but stronger than these drugs alone. Of note, a trend of high risk of muscle-related AEs by the combination of bempedoic acid and statin was observed, though it is not statistically significant, such risk is needed to be confirmed by more trials, because it is important for us to determine which is the better combinative administration for statin-intolerant patients.
Highlights
Bempedoic acid is a new drug that reduces cholesterol synthesis via inhibiting ATP citrate lyase
Pooled data showed that the combination togethers resulted in greater reductions in Low-density lipoprotein cholesterol (LDL-C) level than monotherapies (bempedoic acid + statin vs. statin: least squares mean (LSM) difference (%), − 18.37, 95% confidence interval (CI), − 20.16 to − 16.57, I2 = 0; bempedoic acid + ezetimibe vs. ezetimibe: LSM difference (%), − 18.89, 95% CI, − 29.66 to − 8.13, I2 = 87%)
The Odds ratio (OR) of muscle-related adverse events (AEs) by the combination of bempedoic acid and statin was 1.29 when compared with statin alone
Summary
Bempedoic acid is a new drug that reduces cholesterol synthesis via inhibiting ATP citrate lyase. A mendelian randomization study reported that variants in ACLY, the gene that encodes the ACL, was significantly associated with decreased LDL-C level, as well as decreased cardiovascular risk [5] These findings provide substantial evidence that ACL could be a threptic target. Bempedoic acid (ETC-1002), an oral inhibitor of ACL, converts to the active form ETC-1002-CoA by the enzyme very long-chain acyl-CoA synthetase 1 (ACSVL1) [7], which is expressed in the liver but not in the peripheral tissues, including muscles. Such liver-specific action of bempedoic acid may avoid or decrease the statin-related muscle disorders [8, 9]
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