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Bempedoic Acid: A New Non-statin Drug for the Treatment of Dyslipidemia

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Abstract

Statins are currently the first-line drugs for managing dyslipidemia due to their substantial clinical efficacy in reducing low-density lipoprotein cholesterol (LDL-C) and the risk of atherosclerotic cardiovascular disease (ASCVD). However, many patients do not reach their LDL-C target despite taking high-dose statins and some patients are intolerant of these drugs. Therefore, an additional or alternative pharmacological intervention may be required. Bempedoic acid is a novel lipid-lowering drug recently approved for the treatment of dyslipidemia. This review describes the pharmacology of bempedoic acid and its clinical role in patients with dyslipidemia. Bempedoic acid, via its active coenzyme A (CoA) form, inhibits adenosine triphosphate (ATP)-citrate lyase, and reduces hepatic cholesterol synthesis through the mevalonate pathway. The reduction in plasma LDL-C by bempedoic acid is approximately 20%. In addition, this drug is able to lower the level of high-sensitivity C-reactive protein (hs-CRP) by 20%, which suggests anti-inflammatory activity. Bempedoic acid is well tolerated by the majority of patients. Possible common adverse drug reactions include upper respiratory tract infection, urinary tract infection and arthralgia. Serum creatinine and uric acid should be monitored since increased creatinine and hyperuricemia-associated new onset of gout and gout flares have been reported in patients taking bempedoic acid. Decreased hemoglobin levels and rare tendon ruptures have also been observed. Due to its efficacy and good safety profile, bempedoic acid might serve as a potential therapeutic alternative for the management of dyslipidemia.

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References

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

    Article  Google Scholar 

  2. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–143.

    PubMed  Google Scholar 

  3. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352(1):20–8.

    Article  CAS  Google Scholar 

  4. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347(20):1557–65.

    Article  CAS  Google Scholar 

  5. Romanelli RJ, Ito MK, Karalis DG, Huang HC, Iorga SR, Kam IW, et al. Statin utilization and low-density lipoprotein cholesterol in statin-treated patients with atherosclerotic cardiovascular disease: trends from a community-based health care delivery system, 2002–2016. J Clin Lipidol. 2020;14(3):305–14.

    Article  Google Scholar 

  6. Kunlamas Y, Areepium N, Ariyachaipanich A, Bunditanukul K. Real-world effectiveness of high-versus moderate-intensity statin therapy in Thai patients with acute coronary syndrome and who had undergone primary percutaneous coronary intervention. J Pharm Pract. 2020;33(5):640–6.

    Article  Google Scholar 

  7. Phan BA, Dayspring TD, Toth PP. Ezetimibe therapy: mechanism of action and clinical update. Vasc Health Risk Manag. 2012;8:415–27.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Hess CN, Low Wang CC, Hiatt WR. PCSK9 inhibitors: mechanisms of action, metabolic effects, and clinical outcomes. Annu Rev Med. 2018;29(69):133–45.

    Article  Google Scholar 

  9. Markham A. Bempedoic acid: first approval. Drugs. 2020;80(7):747–53.

    Article  Google Scholar 

  10. Wang Q, Jiang L, Wang J, Li S, Yu Y, You J, et al. Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice. Hepatology. 2009;49(4):1166–75.

    Article  CAS  Google Scholar 

  11. Ference BA, Ray KK, Catapano AL, Ference TB, Burgess S, Neff DR, et al. Mendelian randomization study of ACLY and cardiovascular disease. N Engl J Med. 2019;380(11):1033–42.

    Article  CAS  Google Scholar 

  12. Ference BA, Ray KK, Nicholls SJ. Mendelian randomization study of ACLY and cardiovascular disease. Reply. N Engl J Med. 2020;383(7):e50.

    Article  Google Scholar 

  13. Damask A, Paulding C, Baras A, Carey D, Abecasis GR. Mendelian randomization study of ACLY and cardiovascular disease. N Engl J Med. 2020;383(7):e50.

    Article  Google Scholar 

  14. Holm H, Sulem P, Helgadottir A, Tragante V, Thornorleifsson G, Guethbjartsson D, et al. Mendelian randomization study of ACLY and cardiovascular disease. N Engl J Med. 2020;383(7):e50.

    Article  Google Scholar 

  15. Klarin D, O’Donnell CJ, Kathiresan S. Mendelian randomization study of ACLY and cardiovascular disease. N Engl J Med. 2020;383(7):e50.

    Article  Google Scholar 

  16. Cramer CT, Goetz B, Hopson KL, Fici GJ, Ackermann RM, Brown SC, et al. Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome. J Lipid Res. 2004;45(7):1289–301.

    Article  CAS  Google Scholar 

  17. Pinkosky SL, Filippov S, Srivastava RA, Hanselman JC, Bradshaw CD, Hurley TR, et al. AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism. J Lipid Res. 2013;54(1):134–51.

    Article  CAS  Google Scholar 

  18. Pinkosky SL, Newton RS, Day EA, Ford RJ, Lhotak S, Austin RC, et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;28(7):13457.

    Article  Google Scholar 

  19. Mendoza-Oliva A, Zepeda A, Arias C. The complex actions of statins in brain and their relevance for Alzheimer’s disease treatment: an analytical review. Curr Alzheimer Res. 2014;11(9):817–33.

    CAS  PubMed  Google Scholar 

  20. 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.

    Article  CAS  Google Scholar 

  21. Samsoondar JP, Burke AC, Sutherland BG, Telford DE, Sawyez CG, Edwards JY, et al. Prevention of diet-induced metabolic dysregulation, inflammation, and atherosclerosis in Ldlr(-/-) mice by treatment with the ATP-Citrate lyase inhibitor bempedoic acid. Arterioscler Thromb Vasc Biol. 2017;37(4):647–56.

    Article  CAS  Google Scholar 

  22. Ballantyne CM, Bays H, Catapano AL, Goldberg A, Ray KK, Saseen JJ. Role of bempedoic acid in clinical practice. Cardiovasc Drugs Ther. 2021;5:853–64.

    Article  Google Scholar 

  23. Zhao S, Torres A, Henry RA, Trefely S, Wallace M, Lee JV, et al. ATP-citrate lyase controls a glucose-to-acetate metabolic switch. Cell Rep. 2016;17(4):1037–52.

    Article  CAS  Google Scholar 

  24. Burke AC, Telford DE, Sutherland BG, Edwards JY, Sawyez CG, Barrett PHR, et al. Bempedoic acid lowers low-density lipoprotein cholesterol and attenuates atherosclerosis in low-density lipoprotein receptor-deficient (LDLR(+/-) and LDLR(-/-)) Yucatan miniature pigs. Arterioscler Thromb Vasc Biol. 2018;38(5):1178–90.

    Article  CAS  Google Scholar 

  25. Dominguez M, Brune B, Namgaladze D. Exploring the role of ATP-citrate lyase in the immune system. Front Immunol. 2021;12:632526.

    Article  CAS  Google Scholar 

  26. Infantino V, Iacobazzi V, Palmieri F, Menga A. ATP-citrate lyase is essential for macrophage inflammatory response. Biochem Biophys Res Commun. 2013;440(1):105–11.

    Article  CAS  Google Scholar 

  27. Baardman J, Verberk SGS, van der Velden S, Gijbels MJJ, van Roomen C, Sluimer JC, et al. Macrophage ATP citrate lyase deficiency stabilizes atherosclerotic plaques. Nat Commun. 2020;11(1):6296.

    Article  CAS  Google Scholar 

  28. Filippov S, Pinkosky SL, Lister RJ, Pawloski C, Hanselman JC, Cramer CT, et al. ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK. J Lipid Res. 2013;54(8):2095–108.

    Article  CAS  Google Scholar 

  29. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):1022–32.

    Article  CAS  Google Scholar 

  30. 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.

    Article  CAS  Google Scholar 

  31. Laufs U, Banach M, Mancini GBJ, Gaudet D, Bloedon LT, Sterling LR, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019;8(7):e011662.

    Article  Google Scholar 

  32. Ballantyne CM, Banach M, Mancini GBJ, Lepor NE, Hanselman JC, Zhao X, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: a randomized, placebo-controlled study. Atherosclerosis. 2018;277:195–203.

    Article  CAS  Google Scholar 

  33. Wang X, Zhang Y, Tan H, Wang P, Zha X, Chong W, et al. Efficacy and safety of bempedoic acid for prevention of cardiovascular events and diabetes: a systematic review and meta-analysis. Cardiovasc Diabetol. 2020;19(1):128.

    Article  CAS  Google Scholar 

  34. Nicholls S, Lincoff AM, Bays HE, Cho L, Grobbee DE, Kastelein JJ, et al. Rationale and design of the CLEAR-outcomes trial: evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance. Am Heart J. 2020;24(235):104–12.

    Google Scholar 

  35. Handelsman Y, Jellinger PS, Guerin CK, Bloomgarden ZT, Brinton EA, Budoff MJ, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Management of Dyslipidemia and Prevention of Cardiovascular Disease Algorithm—2020 executive summary. Endocr Pract. 2020;26(10):1196–224.

    Article  Google Scholar 

  36. Bays HE, Banach M, Catapano AL, Duell PB, Gotto AM Jr, Laufs U, et al. Bempedoic acid safety analysis: pooled data from four phase 3 clinical trials. J Clin Lipidol. 2020;14(5):649-59 e6.

    Article  Google Scholar 

  37. Backes JM, Hilleman DE. New and emerging lipid-lowering therapy. Future Cardiol. 2021. https://doi.org/10.2217/fca-2020-0217.

  38. Kunze A, Huwyler J, Camenisch G, Poller B. Prediction of organic anion-transporting polypeptide 1B1- and 1B3-mediated hepatic uptake of statins based on transporter protein expression and activity data. Drug Metab Dispos. 2014;42(9):1514–21.

    Article  Google Scholar 

  39. Lalwani ND, Hanselman JC, MacDougall DE, Sterling LR, Cramer CT. Complementary low-density lipoprotein-cholesterol lowering and pharmacokinetics of adding bempedoic acid (ETC-1002) to high-dose atorvastatin background therapy in hypercholesterolemic patients: a randomized placebo-controlled trial. J Clin Lipidol. 2019;13(4):568–79.

    Article  Google Scholar 

  40. Delevry D, Gupta EK. Bempedoic acid: review of a novel therapy in lipid management. Am J Health Syst Pharm. 2021;78(2):95–104.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Faculty of Pharmacy, Mahidol University, 447 Sri-Ayuthaya road, Rajathevi, Bangkok, 10400, Thailand

    Surasak Wichaiyo

  2. Centre of Biopharmaceutical Science for Healthy Ageing, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand

    Surasak Wichaiyo & Wasu Supharattanasitthi

  3. Department of Physiology, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand

    Wasu Supharattanasitthi

Authors
  1. Surasak Wichaiyo
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  2. Wasu Supharattanasitthi
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Correspondence to Surasak Wichaiyo.

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Author contributions

SW designed the concept and structure of the review. SW reviewed the pharmacological properties and clinical studies. WS assisted with the interpretation of the preclinical and clinical studies. SW drafted the manuscript. SW and WS critically reviewed and approved the final version of the manuscript.

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Wichaiyo, S., Supharattanasitthi, W. Bempedoic Acid: A New Non-statin Drug for the Treatment of Dyslipidemia. Clin Drug Investig 41, 843–851 (2021). https://doi.org/10.1007/s40261-021-01075-w

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