Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis

Background Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile. Methods and findings We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n =3,788) comprising 26 arms (active arm [n =2,460]; control arm [n =1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel-Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD -14.94%; 95% CI -17.31%, -12.57%;p <0.001), non-high-density lipoprotein cholesterol (MD -18.17%; 95% CI -21.14%, -15.19%;p <0.001), low-density lipoprotein cholesterol (MD -22.94%; 95% CI -26.63%, -19.25%;p <0.001), low-density lipoprotein particle number (MD -20.67%; 95% CI -23.84%, -17.48%;p <0.001), apolipoprotein B (MD -15.18%; 95% CI -17.41%, -12.95%;p <0.001), high-density lipoprotein cholesterol (MD -5.83%; 95% CI -6.14%, -5.52%;p <0.001), high-density lipoprotein particle number (MD -3.21%; 95% CI -6.40%, -0.02%;p =0.049), and hsCRP (MD -27.03%; 95% CI -31.42%, -22.64%;p <0.001). Bempedoic acid did not significantly modify triglyceride level (MD -1.51%; 95% CI -3.75%, 0.74%;p =0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI -9.81%, 17.39%;p =0.585), and apolipoprotein A-1 (MD -1.83%; 95% CI -5.23%, 1.56%;p =0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76;p =0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27;p =0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71;p =0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51;p =0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90;p =0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length. Conclusions Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety. Author summaryWhy was this study done? Lowering low-density lipoprotein cholesterol (LDL-C) is effective for reducing cardiovascular events over time. A number of phase II and phase III randomized controlled trials (RCTs) are already available showing encouraging results of bempedoic acid treatment on LDL-C. We aimed to perform a systematic review and meta-analysis on the clinical evidence available to date to better define the efficacy and tolerability profile of treatment with bempedoic acid. What did the researchers do and find? In this analysis of bempedoic acid that included 10 randomized clinical trials ( 3,788 patients) comprising 26 arms (active arm [ 2,460]; control arm [ 1,328]), we confirmed that bempedoic acid significantly reduced total cholesterol (by 15%), non-high-density lipoprotein cholesterol (by 18.2%), LDL-C (by 22.9%), low-density lipoprotein particle number (by 20.7%), apolipoprotein B (by 15.2%), and high-sensitivity C-reactive protein (hsCRP) (by 27%), while negatively affecting serum levels of high-density lipoprotein cholesterol (-5.8%) and high-density lipoprotein particle number (-3.2%). Our results also confirmed that the therapy is overall safe and well tolerated, with no significant increase of serious adverse effects. What do these findings mean? The current meta-analysis demonstrates the multiple positive effects of bempedoic acid on lipid profile and hsCRP serum levels, as well as acceptable safety profile. This could be relevant in a setting where statin intolerance is very frequent and the LDL-C target suggested by international guidelines for dyslipidemia management is hard to achieve with standard therapies. An ongoing long-term cardiovascular outcomes trial will answer questions on the effect of bempedoic acid on cardiovascular events and mortality as well as on the drug's safety issues.