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Effect of Bempedoic Acid on Serum Uric Acid and Related Outcomes: A Systematic Review and Meta-analysis of the available Phase 2 and Phase 3 Clinical Studies

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Abstract

Introduction

Bempedoic acid (ETC-1002) is a first-in-class lipid-lowering agent recently approved by the United States (US) Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for commercialization.

Objective

The aim was to assess, through a systematic review of the literature and a meta-analysis of the available phase 2 and phase 3 clinical studies, the effect of treatment with bempedoic acid on serum uric acid (SUA) concentration. Secondary outcomes were treatment-related variations in creatinine serum level and incidence of gout.

Methods

A systematic literature search in SCOPUS, PubMed Medline, ISI Web of Science and Google Scholar databases was conducted up to November 13th, 2019, in order to identify clinical trials potentially eligible for the meta-analysis. Effect sizes were expressed as absolute mean differences (MDs) and 95% confidence intervals (CIs).

Results

Data were pooled from four clinical studies comprising ten arms, which included overall 3369 subjects, with 2213 in the active-treatment arm and 1156 in the control one. Meta-analysis of data suggested that treatment with bempedoic acid is related to a significant increase in SUA (MD 0.73, 95% CI 0.54–0.91, P < 0.001), serum creatinine (MD 0.04, 95% CI 0.03–0.05, P < 0.001) and the incidence of gout (odds ratio 3.56, 95% CI 1.24–10.19, P = 0.018). The relatively small number of subjects involved in the studies and the exclusion of patients with renal impairment from the clinical trials are important limitations of the meta-analysis. However, our data indicate potential safety issues with bempedoic acid and suggest that further studies are performed both to elucidate the pathogenetic mechanisms underlying these associations and to verify the long-term safety of this treatment.

Conclusion

Bempedoic acid seems to have unfavourable effects on SUA, creatinine level and the incidence of gout. The ongoing Cardiovascular Outcomes Trial (CVOT) will explore the longer-term safety of treatment with bempedoic acid and clarify its effect on cardiovascular events and mortality.

PROSPERO database registration

CRD42019146126.

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References

  1. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, et al.; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–88. https://doi.org/10.1093/eurheartj/ehz455.

  2. European Medicine Agency. Committee for Medicinal Products for Human Use (CHMP). Nilemdo—Bempedoic acid. EMA/CHMP/44961/2020. 30 January 2020.

  3. Food and Drug Administration. NEXLETOL (bempedoic acid) tablets, for oral use. Reference ID: 4564667. Initial U.S. Approval: 2020.

  4. Honigberg MC, Natarajan P. Bempedoic acid for lowering LDL cholesterol. JAMA. 2019;322(18):1769–71.

    Article  Google Scholar 

  5. Feng X, Zhang L, Xu S, Shen AZ. ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: an updated review. Prog Lipid Res. 2020;77:101006. https://doi.org/10.1016/j.plipres.2019.101006.

    Article  CAS  PubMed  Google Scholar 

  6. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, et al. CLEAR Harmony Trial. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):1022–32. https://doi.org/10.1056/NEJMoa1803917.

    Article  CAS  PubMed  Google Scholar 

  7. Zagelbaum NK, Yandrapalli S, Nabors C, Frishman WH. Bempedoic acid (ETC-1002): ATP citrate lyase inhibitor: review of a first-in-class medication with potential benefit in statin-refractory cases. Cardiol Rev. 2019;27(1):49–56. https://doi.org/10.1097/CRD.0000000000000218.

    Article  PubMed  Google Scholar 

  8. Wang X, Luo S, Gan X, He C, Huang R. Safety and efficacy of ETC-1002 in hypercholesterolaemic patients: a meta-analysis of randomised controlled trials. Kardiol Pol. 2019;77(2):207–16. https://doi.org/10.5603/KP.a2019.0013.

    Article  PubMed  Google Scholar 

  9. Ray KK, Corral P, Morales E, Nicholls SJ. Pharmacological lipid-modification therapies for prevention of ischaemic heart disease: current and future options. Lancet. 2019;394(10199):697–708. https://doi.org/10.1016/S0140-6736(19)31950-6.

    Article  CAS  PubMed  Google Scholar 

  10. Ballantyne CM, Laufs U, Ray KK, Leiter LA, Bays HE, Goldberg AC, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol. 2019;29:2047487319864671. https://doi.org/10.1177/2047487319864671(Epub ahead of print).

    Article  Google Scholar 

  11. Gutierrez MJ, Rosenberg NL, Macdougall DE, Hanselman JC, Margulies JR, Strange P, et al. Efficacy and safety of ETC-1002, a novel investigational low-density lipoprotein-cholesterol-lowering therapy for the treatment of patients with hypercholesterolemia and type 2 diabetes mellitus. Arterioscler Thromb Vasc Biol. 2014;34(3):676–83. https://doi.org/10.1161/ATVBAHA.113.302677.

    Article  CAS  PubMed  Google Scholar 

  12. Goldberg AC, Leiter LA, Stroes ESG, Baum SJ, Hanselman JC, Bloedon LT, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom randomized clinical trial. JAMA. 2019;322(18):1780–8. https://doi.org/10.1001/jama.2019.16585.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bove M, Cicero AFG, Borghi C. Emerging drugs for the treatment of hypercholesterolemia. Expert Opin Emerg Drugs. 2019;24(1):63–9. https://doi.org/10.1080/14728214.2019.1591372.

    Article  CAS  PubMed  Google Scholar 

  14. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535. https://doi.org/10.1136/bmj.b2535.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Higgins J. Green S. Cochrane handbook for systematic reviews of interventions. Version 5.0. 2. 2009. Chichester: Wiley. Ref Type: Report; 2010.

  16. Fogacci F, Ferri N, Toth PP, Ruscica M, Corsini A, Cicero AFG. Efficacy and safety of mipomersen: a systematic review and meta-analysis of randomized clinical trials. Drugs. 2019;79(7):751–66. https://doi.org/10.1007/s40265-019-01114-z.

    Article  CAS  PubMed  Google Scholar 

  17. Borenstein M, Hedges L, Higgins J, Rothstein H. Comprehensive meta-analysis version 3. Englewood: Biostat; 2005. p. 104.

    Google Scholar 

  18. Follmann D, Elliott P, Suh I, Cutler J. Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol. 1992;45(7):769–73.

    Article  CAS  Google Scholar 

  19. Melsen WG, Bootsma MC, Rovers MM, Bonten MJ. The effects of clinical and statistical heterogeneity on the predictive values of results from meta-analyses. Clin Microbiol Infect. 2014;20:123–9. https://doi.org/10.1111/1469-0691.12494.

    Article  CAS  PubMed  Google Scholar 

  20. Fogacci F, Banach M, Cicero AFG. Resveratrol effect on patients with non-alcoholic fatty liver disease: a matter of dose and treatment length. Diabetes Obes Metab. 2018;20(7):1798–9. https://doi.org/10.1111/dom.13324.

    Article  PubMed  Google Scholar 

  21. Sahebkar A, Pirro M, Reiner Ž, Cicero A, Ferretti G, Simental-Mendía M, et al. A systematic review and meta-analysis of controlled trials on the effects of statin and fibrate therapies on plasma homocysteine levels. Curr Med Chem. 2016;23(39):4490–503.

    Article  CAS  Google Scholar 

  22. Fogacci F, Grassi D, Rizzo M, Cicero AFG. Metabolic effect of berberine-silymarin association: a meta-analysis of randomized, double-blind, placebo-controlled clinical trials. Phytother Res. 2019;33(4):862–70. https://doi.org/10.1002/ptr.6282.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Rosenthal R. The file drawer problem and tolerance for null results. Psychol Bull. 1979;86:638–64. https://doi.org/10.1037/0033-2909.86.3.638.

    Article  Google Scholar 

  24. Odden MC, Amadu AR, Smit E, Lo L, Peralta CA. Uric acid levels, kidney function, and cardiovascular mortality in US adults: National Health and Nutrition Examination Survey (NHANES) 1988–1994 and 1999–2002. Am J Kidney Dis. 2014;64(4):550–7. https://doi.org/10.1053/j.ajkd.2014.04.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Bataille AM, Maffeo CL, Renfro JL. Avian renal proximal tubule urate secretion is inhibited by cellular stress-induced AMP-activated protein kinase. Am J Physiol Ren Physiol. 2011;300(6):F1327–F13381338. https://doi.org/10.1152/ajprenal.00680.2010.

    Article  CAS  Google Scholar 

  26. Niemi M. Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther. 2010;87(1):130–3. https://doi.org/10.1038/clpt.2009.197.

    Article  CAS  PubMed  Google Scholar 

  27. Ward NC, Watts GF, Eckel RH. Statin toxicity. Circ Res. 2019;124(2):328–50. https://doi.org/10.1161/CIRCRESAHA.118.312782.

    Article  CAS  PubMed  Google Scholar 

  28. Benn CL, Dua P, Gurrell R, Loudon P, Pike A, Storer RI, et al. Physiology of hyperuricemia and urate-lowering treatments. Front Med. 2018;5:160. https://doi.org/10.3389/fmed.2018.00160.

    Article  Google Scholar 

  29. Verzola D, Ratto E, Villaggio B, Parodi EL, Pontremoli R, Garibotto G, et al. Uric acid promotes apoptosis in human proximal tubule cells by oxidative stress and the activation of NADPH oxidase NOX 4. PLoS One. 2014;9(12):e115210. https://doi.org/10.1371/journal.pone.0115210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Milanesi S, Verzola D, Cappadona F, Bonino B, Murugavel A, Pontremoli R, et al. Uric acid and angiotensin II additively promote inflammation and oxidative stress in human proximal tubule cells by activation of toll-like receptor 4. J Cell Physiol. 2019;234(7):10868–76. https://doi.org/10.1002/jcp.27929.

    Article  CAS  PubMed  Google Scholar 

  31. De Cosmo S, Viazzi F, Pacilli A, Giorda C, Ceriello A, Gentile S, AMD-Annals Study Group, et al. Serum uric acid and risk of CKD in type 2 diabetes. Clin J Am Soc Nephrol. 2015;10(11):1921–9. https://doi.org/10.2215/CJN.03140315.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Newman CB, Preiss D, Tobert JA, Jacobson TA, Page RL 2nd, Goldstein LB, American Heart Association Clinical Lipidology, Lipoprotein, Metabolism, and Thrombosis Committee, a Joint Committee of the Council on Atherosclerosis, Thrombosis, and Vascular Biology, and Council on Lifestyle, and Cardiometabolic Health; Council on Cardiovascular Disease in the Young; Council on Clinical Cardiology;, and Stroke Council, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019;39(2):e38–e81. https://doi.org/10.1161/ATV.0000000000000073.

    Article  CAS  PubMed  Google Scholar 

  33. Mychaleckyj JC, Craven T, Nayak U, Buse J, Crouse JR, Elam M, et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care. 2012;35(5):1008–144. https://doi.org/10.2337/dc11-1811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Derosa G, Maffioli P, Reiner Ž, Simental-Mendía LE, Sahebkar A. Impact of statin therapy on plasma uric acid concentrations: a systematic review and meta-analysis. Drugs. 2016;76(9):947–56. https://doi.org/10.1007/s40265-016-0591-2.

    Article  CAS  PubMed  Google Scholar 

  35. Derosa G, Maffioli P, Sahebkar A. Plasma uric acid concentrations are reduced by fenofibrate: a systematic review and meta-analysis of randomized placebo-controlled trials. Pharmacol Res. 2015;102:63–70. https://doi.org/10.1016/j.phrs.2015.09.012.

    Article  CAS  PubMed  Google Scholar 

  36. Yusuf S, Bosch J, Dagenais G, Zhu J, Xavier D, Liu L, HOPE-3 Investigators, et al. Cholesterol lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374(21):2021–31. https://doi.org/10.1056/NEJMoa1600176.

    Article  CAS  PubMed  Google Scholar 

  37. Ting RD, Keech AC, Drury PL, Donoghoe MW, Hedley J, Jenkins AJ, FIELD Study Investigators, et al. Benefits and safety of long-term fenofibrate therapy in people with type 2 diabetes and renal impairment: the FIELD Study. Diabetes Care. 2012;35(2):218–25. https://doi.org/10.2337/dc11-1109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Casiglia E, Tikhonoff V, Virdis A, Masi S, Barbagallo CM, Bombelli M, Working Group on Uric Acid, and Cardiovascular Risk of the Italian Society of Hypertension (SIIA), et al. Serum uric acid and fatal myocardial infarction: detection of prognostic cut-off values: The URRAH (Uric Acid Right for Heart Health) study. J Hypertens. 2019. https://doi.org/10.1097/HJH.0000000000002287(Epub ahead of print).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Li L, Yang C, Zhao Y, Zeng X, Liu F, Fu P. Is hyperuricemia an independent risk factor for new-onset chronic kidney disease? A systematic review and meta-analysis based on observational cohort studies. BMC Nephrol. 2014;15:122. https://doi.org/10.1186/1471-2369-15-122.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Authors wish to thank Claudia Cavicchi, librarian at the Clinical Library of the University of Bologna, for her support in finding the articles to prepare the manuscript.

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Authors and Affiliations

  1. Department of Medical and Surgical Sciences, Sant’Orsola-Malpighi University Hospital, University of Bologna, Via Albertoni, 15, 40138, Bologna, Italy

    Arrigo F. G. Cicero, Federica Fogacci & Claudio Borghi

  2. Department of Internal Medicine, Università degl Studi and IRCCS Ospedale Policlinico San Martino, Genoa, Italy

    Roberto Pontremoli & Francesca Viazzi

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  1. Arrigo F. G. Cicero
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Correspondence to Arrigo F. G. Cicero.

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No sources of funding were used to assist in the preparation of this study.

Conflict of interest

Claudio Borghi, Arrigo F.G. Cicero, Federica Fogacci, Roberto Pontremoli and Francesca Viazzi have no conflicts of interest that are directly relevant to the content of this study.

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Data are available from the corresponding author upon reasonable request.

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Cicero, A.F.G., Pontremoli, R., Fogacci, F. et al. Effect of Bempedoic Acid on Serum Uric Acid and Related Outcomes: A Systematic Review and Meta-analysis of the available Phase 2 and Phase 3 Clinical Studies. Drug Saf 43, 727–736 (2020). https://doi.org/10.1007/s40264-020-00931-6

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