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

Cicero, Arrigo F. G.; Fogacci, Federica; Hernandez, Adrian V.; Banach, Maciej

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. Maciej Banach and colleagues discuss the efficacy and safety of bempedoic acid, a drug that designed to lower LDL-C levels. Author summary: Why 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 (n = 3,788 patients) comprising 26 arms (active arm [n = 2,460]; control arm [n = 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.

GOOGLE Scholar (Web resource); BLOOD lipids; URIC acid; META-analysis; APOLIPOPROTEIN B; HIGH density lipoproteins; CREATINE kinase

PLoS Medicine, 2020, Vol 17, Issue 7, p1

1549-1277

Academic Journal

10.1371/journal.pmed.1003121