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

      research-article
      1 , * , 1 , 2 , 3 , 4 , 5 , 6 , * , on behalf of the Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group and the International Lipid Expert Panel (ILEP)
      PLoS Medicine
      Public Library of Science

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          Abstract

          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.

          Abstract

          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.

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          Most cited references31

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          The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses.

          Variance between studies in a meta-analysis will exist. This heterogeneity may be of clinical, methodological or statistical origin. The last of these is quantified by the I(2) -statistic. We investigated, using simulated studies, the accuracy of I(2) in the assessment of heterogeneity and the effects of heterogeneity on the predictive value of meta-analyses. The relevance of quantifying I(2) was determined according to the likely presence of heterogeneity between studies (low, high, or unknown) and the calculated I(2) (low or high). The findings were illustrated by published meta-analyses of selective digestive decontamination and weaning protocols. As expected, I(2) increases and the likelihood of drawing correct inferences from a meta-analysis decreases with increasing heterogeneity. With low levels of heterogeneity, I(2) does not appear to be predictive of the accuracy of the meta-analysis result. With high levels of heterogeneity, even meta-analyses with low I(2) -values have low predictive values. Most commonly, the level of heterogeneity in a meta-analysis will be unknown. In these scenarios, I(2) determination may help to identify estimates with low predictive values (high I(2) ). In this situation, the results of a meta-analysis will be unreliable. With low I(2) -values and unknown levels of heterogeneity, predictive values of pooled estimates may range extensively, and findings should be interpreted with caution. In conclusion, quantifying statistical heterogeneity through I(2) -statistics is only helpful when the amount of clinical heterogeneity is unknown and I(2) is high. Objective methods to quantify the levels of clinical and methodological heterogeneity are urgently needed to allow reliable determination of the accuracy of meta-analyses.
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            Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study

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              Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance

              Background Inability to tolerate statins because of muscle symptoms contributes to uncontrolled cholesterol levels and insufficient cardiovascular risk reduction. Bempedoic acid, a prodrug that is activated by a hepatic enzyme not present in skeletal muscle, inhibits ATP‐citrate lyase, an enzyme upstream of β‐hydroxy β‐methylglutaryl‐coenzyme A reductase in the cholesterol biosynthesis pathway. Methods and Results The phase 3, double‐blind, placebo‐controlled CLEAR (Cholesterol Lowering via Bempedoic acid, an ACL‐Inhibiting Regimen) Serenity study randomized 345 patients with hypercholesterolemia and a history of intolerance to at least 2 statins (1 at the lowest available dose) 2:1 to bempedoic acid 180 mg or placebo once daily for 24 weeks. The primary end point was mean percent change from baseline to week 12 in low‐density lipoprotein cholesterol. The mean age was 65.2 years, mean baseline low‐density lipoprotein cholesterol was 157.6 mg/dL, and 93% of patients reported a history of statin‐associated muscle symptoms. Bempedoic acid treatment significantly reduced low‐density lipoprotein cholesterol from baseline to week 12 (placebo‐corrected difference, −21.4% [95% CI, −25.1% to −17.7%]; P<0.001). Significant reductions with bempedoic acid versus placebo were also observed in non–high‐density lipoprotein cholesterol (−17.9%), total cholesterol (−14.8%), apolipoprotein B (−15.0%), and high‐sensitivity C‐reactive protein (−24.3%; P<0.001 for all comparisons). Bempedoic acid was safe and well tolerated. The most common muscle‐related adverse event, myalgia, occurred in 4.7% and 7.2% of patients who received bempedoic acid or placebo, respectively. Conclusions Bempedoic acid offers a safe and effective oral therapeutic option for lipid lowering in patients who cannot tolerate statins. Clinical Trial Registration URL: https://www.clinicaltrials.gov. Unique identifier: NCT02988115.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Writing – original draftRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – review & editing
                Role: ConceptualizationRole: Project administrationRole: Writing – original draftRole: Writing – review & editing
                Role: Academic Editor
                Journal
                PLoS Med
                PLoS Med
                plos
                plosmed
                PLoS Medicine
                Public Library of Science (San Francisco, CA USA )
                1549-1277
                1549-1676
                16 July 2020
                July 2020
                : 17
                : 7
                : e1003121
                Affiliations
                [1 ] Hypertension and Cardiovascular Risk Factors Research Group, Department of Medicine and Surgery Sciences, University of Bologna, Bologna, Italy
                [2 ] Health Outcomes, Policy, and Evidence Synthesis (HOPES) Group, University of Connecticut/Hartford Hospital Evidence-based Practice Center, Hartford, Connecticut, United States of America
                [3 ] Vicerrectorado de Investigacion, Universidad San Ignacio de Loyola, Lima, Peru
                [4 ] Chair of Nephrology and Hypertension, Department of Hypertension, Medical University of Lodz, Lodz, Poland
                [5 ] Polish Mother’s Memorial Hospital Research Institute, Lodz, Poland
                [6 ] Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland
                St. Thomas' Hospital, UNITED STATES
                Author notes

                I have read the journal's policy and the authors of this manuscript have the following competing interests: MB has received research grant(s)/support from Sanofi and Valeant, and has served as a consultant for Abbott/Mylan, Akcea, Amgen, KRKA, MSD, Polfarmex, Polpharma, Sanofi-Aventis/Regeneron, Servier, Esperion, and Resverlogix. AFGC was scientific consultant for Mylan and Menarini International. FF was scientific consultant for Mylan. AH has no conflict of interest to declare.

                ¶ Membership of the International Lipid Expert Panel (ILEP) is provided in the Acknowledgments.

                Author information
                http://orcid.org/0000-0002-4367-3884
                http://orcid.org/0000-0001-7853-0042
                http://orcid.org/0000-0001-6690-6874
                Article
                PMEDICINE-D-19-03833
                10.1371/journal.pmed.1003121
                7365413
                32673317
                b28d41dc-b35b-410b-b97c-46a49082feb4
                © 2020 Cicero et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 October 2019
                : 9 June 2020
                Page count
                Figures: 13, Tables: 2, Pages: 21
                Funding
                The authors received no specific funding for this work.
                Categories
                Research Article
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Statins
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Metaanalysis
                Physical Sciences
                Mathematics
                Statistics
                Statistical Methods
                Metaanalysis
                Biology and Life Sciences
                Biochemistry
                Proteins
                Lipoproteins
                Biology and Life Sciences
                Biochemistry
                Lipids
                Cholesterol
                Biology and Life Sciences
                Biochemistry
                Lipids
                Research and Analysis Methods
                Database and Informatics Methods
                Database Searching
                Biology and Life Sciences
                Biochemistry
                Proteins
                Plasma Proteins
                Science Policy
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                Publication Ethics
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                All relevant data are within the manuscript and its Supporting Information files.

                Medicine
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