Bempedoic Acid: Safety and Efficiacy of a New Lipid-Lowering Agent

Scientific relevance. Lowering low-density lipoprotein cholesterol (LDL-C) levels with statins is a generally accepted standard treatment for dyslipidaemia. However, adverse reactions and intolerance to statins have motivated the search for lipid-modifying agents with alternative mechanisms of action. Bempedoic acid is one of these alternative agents.

Aim. The study aimed to review published data on the mechanism of action, pharmacokinetics, pharmacodynamics, safety and efficacy of bempedoic acid used as a lipid-lowering agent.

Discussion. Similar to statins, bempedoic acid inhibits cholesterol synthesis from acetyl-CoA. Statins and bempedoic acid differ in their mechanisms of action mainly because the conversion of bempedoic acid into its active metabolite takes place only in the liver. As a result, bempedoic acid does not cause adverse drug reactions in muscles. The main safety and efficacy data on bempedoic acid were obtained in phase III CLEAR trials. Compared to placebo, bempedoic acid reduced LDL-C levels by an additional 18% in combination with maximum tolerated doses of statins and by 25% in monotherapy in patients with statin intolerance. In the CLEAR Outcomes trial, long-term treatment with bempedoic acid reduced the risk of major adverse cardiovascular events in patients with statin intolerance (n=13970) by 13%. A slight increase in gout attack frequency was observed, primarily in patients with pre-existing hyperuricaemia.

Conclusions. Therefore, bempedoic acid is a safe and effective treatment option for patients with dyslipidaemia at high risk of atherosclerotic cardiovascular disease. It can be used either in combination with statins or, in the case of statin intolerance, as monotherapy and with ezetimibe.

1. GBD 2019 Risk Factors Collaborators. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet. 2020;396(10258):1223–49. https://doi.org/10.1016/S0140-6736(20)30752-2

2. Kjekshus J, Pedersen TR. Reducing the risk of coronary events: evidence from the Scandinavian Simvastatin Survival Study (4S). Am J Cardiol. 1995;76(9):64C–8C. https://doi.org/10.1016/s0002-9149(99)80473-1

3. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005;366(9493):1267–78. https://doi.org/10.1016/S0140-6736(05)67394-1

4. Rodriguez F, Maron DJ, Knowles JW, Virani SS, Lin S, Heidenreich PA. Association between intensity of statin therapy and mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol. 2017;2(1):47–54. https://doi.org/10.1001/jamacardio.2016.4052

5. Cholesterol Treatment Trialists’ (CTT) Collaboration; Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010;376(9753):1670–81. https://doi.org/10.1016/S0140-6736(10)61350-5

6. Ezhov MV, Kukharchuk VV, Sergienko IV, Alieva AS, Antsiferov MB, Ansheles AA, et al Disorders of lipid metabolism. Clinical Guidelines 2023. Russian Journal of Cardiology. 2023;28(5):5471 (In Russ.). https://doi.org/10.15829/1560-4071-2023-5471

7. 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. https://doi.org/10.1093/eurheartj/ehz455

8. 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: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. J Am Coll Cardiol. 2019;73(24):3168–209. https://doi.org/10.1016/j.jacc.2018.11.002

9. Pearson GJ, Thanassoulis G, Anderson TJ, Barry AR, Couture P, Dayan N, et al. 2021 Canadian Cardiovascular Society Guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults. Can J Cardiol. 2021;37(8):1129–50. https://doi.org/10.1016/j.cjca.2021.03.016

10. Buettner C, Davis RB, Leveille SG, Mittleman MA, Mukamal KJ. Prevalence of musculoskeletal pain and statin use. J Gen Intern Med. 2008;23(8):1182–6. https://doi.org/10.1007/s11606-008-0636-7

11. Thompson PD, Panza G, Zaleski A, Taylor B. Statin-associated side effects. J Am Coll Cardiol. 2016;67(20):2395–410. https://doi.org/10.1016/j.jacc.2016.02.071

12. Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients — the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403– 14. https://doi.org/10.1007/s10557-005-5686-z

13. Cohen JD, Brinton EA, Ito MK, Jacobson TA. Understanding statin use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol. 2012;6(3):208–15. https://doi.org/10.1016/j.jacl.2012.03.003

14. Tournadre A. Statins, myalgia, and rhabdomyolysis. Joint Bone Spine. 2020;87(1):37–42. https://doi.org/10.1016/j.jbspin.2019.01.018

15. Rajpathak SN, Kumbhani DJ, Crandall J, Barzilai N, Alderman M, Ridker PM. Statin therapy and risk of developing type 2 diabetes: a meta-analysis. Diabetes Care. 2009;32(10):1924–9. https://doi.org/10.2337/dc09-0738

16. Ma T, Tien L, Fang CL, Liou YS, Jong GP. Statins and new-onset diabetes: a retrospective longitudinal cohort study. Clin Ther. 2012;34(9):1977–83. https://doi.org/10.1016/j.clinthera.2012.08.004

17. Howard JP, Wood FA, Finegold JA, Nowbar AN, Thompson DM, Arnold AD, et al. Side effect patterns in a crossover trial of statin, placebo, and no treatment. J Am Coll Cardiol. 2021;78(12):1210–22. https://doi.org/10.1016/j.jacc.2021.07.022

18. Herrett E, Williamson E, Brack K, Beaumont D, Perkins A, Thayne A, et al.; StatinWISE Trial Group. Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials. BMJ. 2021;372:n135. https://doi.org/10.1136/bmj.n135

19. Gupta A, Thompson D, Whitehouse A, Collier T, Dahlof B, Poulter N, et al. ASCOT Investigators. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebocontrolled trial and its non-randomised non-blind extension phase. Lancet. 2017;389(10088):2473–81. https://doi.org/10.1016/S0140-6736(17)31075-9

20. Moon J, Cohen Sedgh R, Jackevicius CA. Examining the nocebo effect of statins through statin adverse events reported in the food and drug administration adverse event reporting system. Circ Cardiovasc Qual Outcomes. 2021;14(1):e007480. https://doi.org/10.1161/CIRCOUTCOMES.120.007480

21. Penson PE, Mancini GBJ, Toth PP, Martin SS, Watts GF, Sahebkar A, et al. Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group & International Lipid Expert Panel (ILEP). Introducing the ‘Drucebo’ effect in statin therapy: a systematic review of studies comparing reported rates of statin-associated muscle symptoms, under blinded and open-label conditions. J Cachexia Sarcopenia Muscle. 2018;9(6):1023–33. https://doi.org/10.1002/jcsm.12344

22. Leonova MV. Effects of nocebo and drucebo in determining statin-induced muscle symptoms. Medical Council. 2022;(17):136–42 (In Russ.). https://doi.org/10.21518/2079-701X-2022-16-17-136-142

23. Talic S, Marquina C, Ofori-Asenso R, Petrova M, Liew D, Owen AJ, et al. Persistence and adherence to statin therapy: a retrospective cohort study using the Australian national pharmacy data. Cardiovasc Drugs Ther. 2022;36(5):867–77. https://doi.org/10.1007/s10557-021-07199-7

24. Wong ND, Young D, Zhao Y, Nguyen H, Caballes J, Khan I, Sanchez RJ. Prevalence of the American College of Cardiology/American Heart Association statin eligibility groups, statin use, and low-density lipoprotein cholesterol control in US adults using the National Health and Nutrition Examination Survey 2011–2012. J Clin Lipidol. 2016;10(5):1109–18. https://doi.org/10.1016/j.jacl.2016.06.011

25. Rezende Macedo do Nascimento RC, Mueller T, Godman B, MacBride Stewart S, Hurding S, de Assis Acurcio F, et al. Real-world evaluation of the impact of statin intensity on adherence and persistence to therapy: a Scottish population-based study. Br J Clin Pharmacol. 2020;86(12):2349–61. https://doi.org/10.1111/bcp.14333

26. Hagen AN, Ariansen I, Hanssen TA, Lappegård KT, Eggen AE, Løchen ML, et al. Achievements of primary prevention targets in individuals with high risk of cardiovascular disease: an 8-year follow-up of the Tromsø study. Eur Heart J Open. 2022;2(5):oeac061. https://doi.org/10.1093/ehjopen/oeac061

27. Reiner Z. Resistance and intolerance to statins. Nutr Metab Cardiovasc Dis. 2014;24(10):1057–66. https://doi.org/10.1016/j.numecd.2014.05.009

28. Pinkosky SL, Groot PHE, Lalwani ND, Steinberg GR. Targeting ATP-citrate lyase in hyperlipidemia and metabolic disorders. Trends Mol Med. 2017;23(11):1047–63. https://doi.org/10.1016/j.molmed.2017.09.001

29. Pearce NJ, Yates JW, Berkhout TA, Jackson B, Tew D, Boyd H, et al. The role of ATP citrate-lyase in the metabolic regulation of plasma lipids. Hypolipidaemic effects of SB-204990, a lactone prodrug of the potent ATP citrate-lyase inhibitor SB-201076. Biochem J. 1998;334(Pt 1):113–9. https://doi.org/10.1042/bj3340113

30. Burke AC, Telford DE, Huff MW. Bempedoic acid: effects on lipoprotein metabolism and atherosclerosis. Curr Opin Lipidol. 2019;30(1):1–9. https://doi.org/10.1097/MOL.0000000000000565

31. 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. https://doi.org/10.1194/jlr.M030528

32. Nissen SE, Lincoff AM, Brennan D, Ray KK, Mason D, Kastelein JJP, et al. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(15):1353–64. https://doi.org/10.1056/NEJMoa2215024

33. 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. https://doi.org/10.1056/NEJMoa1803917

34. 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

35. 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. https://doi.org/10.1161/JAHA.118.011662

36. 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. https://doi.org/10.1016/j.atherosclerosis.2018.06.002

37. Banach M, Duell PB, Gotto AM, Laufs U, Leiter LA, Mancini GBJ, et al. Association of bempedoic acid administration with atherogenic lipid levels in phase 3 randomized clinical trials of patients with hypercholesterolemia. JAMA Cardiol. 2020;5(10):1124–35. https://doi.org/10.1001/jamacardio.2020.2314

38. Agarwala A, Quispe R, Goldberg AC, Michos ED. Bempedoic acid for heterozygous familial hypercholesterolemia: from bench to bedside. Drug Des Devel Ther. 2021;15:1955–63. https://doi.org/10.2147/DDDT.S251865

39. Ballantyne CM, Bays H, Catapano AL, Goldberg A, Ray KK, Saseen JJ. Role of bempedoic acid in clinical practice. Cardiovasc Drugs Ther. 2021;35(4):853–64. https://doi.org/10.1007/s10557-021-07147-5

40. Bays HE, Banach M, Catapano AL, Duell PB, Gotto AM, 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. https://doi.org/10.1016/j.jacl.2020.08.009

41. Stroes ES, Thompson PD, Corsini A, Vladutiu GD, Raal FJ, Ray KK, et al. Statin-associated muscle symptoms: impact on statin therapy — European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J. 2015;36(17):1012–22. https://doi.org/10.1093/eurheartj/ehv043

42. Ray K, Bakris G, Banach M, Catapano A, Duell P, Mancini G, et al. Effect of bempedoic acid on uric acid and gout in 3621 patients with hypercholesterolemia: pooled analyses from phase 3 trials. Eur Heart J. 2020;41(Suppl 2):ehaa946.3001. https://doi.org/10.1093/ehjci/ehaa946.3001

43. Chou R, Dana T, Blazina I, Daeges M, Jeanne TL. Statins for prevention of cardiovascular disease in adults: evidence report and systematic review for the US preventive services task force. JAMA. 2016;316(19):2008–24. https://doi.org/10.1001/jama.2015.15629

44. Sun H, Wu Y, Bian H, Yang H, Wang H, Meng X, et al. Function of uric acid transporters and their inhibitors in hyperuricaemia. Front Pharmacol. 2021;12:667753. https://doi.org/10.3389/fphar.2021.667753

45. Ruscica M, Sirtori CR, Carugo S, Banach M, Corsini A. Bempedoic acid: for whom and when. Curr Atheroscler Rep. 2022;24(10):791–801. https://doi.org/10.1007/s11883-022-01054-2

46. Elsby R, Hilgendorf C, Fenner K. Understanding the critical disposition pathways of statins to assess drug-drug interaction risk during drug development: it’s not just about OATP1B1. Clin Pharmacol Ther. 2012;92(5):584–98. https://doi.org/10.1038/clpt.2012.163

47. Shitara Y. Clinical importance of OATP1B1 and OATP1B3 in drug-drug interactions. Drug Metab Pharmacokinet. 2011;26(3):220–7. https://doi.org/10.2133/dmpk.DMPK-10-RV-094

48. Jadhav SB, Crass RL, Chapel S, Kerschnitzki M, Sasiela WJ, Emery MG, et al. Pharmacodynamic effect of bempedoic acid and statin combinations: predictions from a dose-response model. Eur Heart J Cardiovasc Pharmacother. 2022;8(6):578–86. https://doi.org/10.1093/ehjcvp/pvab064

49. Laakso M, Kuusisto J. Diabetes secondary to treatment with statins. Curr Diab Rep. 2017;17(2):10. https://doi.org/10.1007/s11892-017-0837-8

50. Shpagina OV, Bondarenko IZ, Kolesnikova GS. Statin administration is associated with higher IGF-1 levels in patients without diabetes mellitus. Problems of Endocrinology. 2018;64(4):200–7 (In Russ.). https://doi.org/10.14341/probl8759

51. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577–85. https://doi.org/10.1007/s00125-017-4342-z

52. Zhao X, Ma X, Luo X, Shi Z, Deng Z, Jin Y, et al. Efficacy and safety of bempedoic acid alone or combining with other lipid-lowering therapies in hypercholesterolemic patients: a meta-analysis of randomized controlled trials. BMC Pharmacol Toxicol. 2020;21(1):86. https://doi.org/10.1186/s40360-020-00463-w

53. Lin Y, Parco C, Karathanos A, Krieger T, Schulze V, Chernyak N, et al. Clinical efficacy and safety outcomes of bempedoic acid for LDL-C lowering therapy in patients at high cardiovascular risk: a systematic review and meta-analysis. BMJ Open. 2022;12(2):e048893. https://doi.org/10.1136/bmjopen-2021-048893

54. Sayed A, Shazly O, Slipczuk L, Krittanawong C, Baloch F, Virani SS. The clinical efficacy and safety of bempedoic acid in patients at elevated risk of cardiovascular disease: a meta-analysis of randomized clinical trials. Cardiovasc Drugs Ther. 2023 Jun 1. https://doi.org/10.1007/s10557-023-07474-9

55. Khan MU, Khan MZ, Munir MB, Balla S, Khan SU. Meta-analysis of the safety and efficacy of bempedoic acid. Am J Cardiol. 2020;131:130–2. https://doi.org/10.1016/j.amjcard.2020.06.028

56. Di Minno A, Lupoli R, Calcaterra I, Poggio P, Forte F, Spadarella G, et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia: systematic review and meta-analysis of randomized controlled trials. J Am Heart Assoc. 2020;9(15):e016262. https://doi.org/10.1161/jaha.119.016262

57. Thompson PD, MacDougall DE, Newton RS, Margulies JR, Hanselman JC, Orloff DG, et al. Treatment with ETC-1002 alone and in combination with ezetimibe lowers LDL cholesterol in hypercholesterolemic patients with or without statin intolerance. J Clin Lipidol. 2016;10(3):556–67. https://doi.org/10.1016/j.jacl.2015.12.025

58. 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