Efficacy and safety of bempedoic acid in lipid disorder therapy: a review of clinical trials
DOI:
https://doi.org/10.56782/pps.208Keywords:
bempedoic acid, nonstatin therapy, statin intolerance, atherosclerotic cardiovascular disease, hypercholesterolemiaAbstract
LDL level is a key risk factor for atherosclerotic cardiovascular disease. Bempedoic acid is an innovative hypolipemic drug, particularly useful for patients with statin intolerance. The article focuses on analyzing the results of clinical trials on the mechanisms of action, efficacy and safety of bempedoic acid used both as monotherapy and in combination with other hypolipemic drugs. Scientific evidence based on the CLEAR: Tranquility, Harmony, Serenity, Wisdom, Outcomes study, among others, is presented. Its significant effects on lowering LDL-C, non-HDL-C, and hsCRP levels are highlighted, with important implications for the prevention and treatment of cardiovascular disease. It also outlines how bempedoic acid is included in current Polish guidelines for the treatment of lipid disorders. The paper also points to new areas of research, including potential applications of bempedoic acid in specific patient groups, such as pregnant women. In addition, the article addresses issues related to the long-term use and safety of bempedoic acid, particularly in the context of reducing cardiovascular risk and lowering blood lipid levels, which is crucial for patients with statin intolerance.
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References
World Health Organization (WHO), Cardiovascular diseases (CVDs). Available online: https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (accessed on 10.03.2024).
Stone, N. J.; Grundy, S. M. The 2018 AHA/ACC/Multi-Society Cholesterol guidelines: Looking at past, present and future. Prog. Cardiovasc. Dis. 2019, 62 (5), 375–383. DOI: 10.1016/j.pcad.2019.11.005 DOI: https://doi.org/10.1016/j.pcad.2019.11.005
Nayor, M.; Brown, K. J.; Vasan, R. S. The Molecular Basis of Predicting Atherosclerotic Cardiovascular Disease Risk. Circ. Res. 2021, 128 (2), 287–303. DOI: 10.1161/circresaha.120.315890 DOI: https://doi.org/10.1161/CIRCRESAHA.120.315890
Doi, T.; Langsted, A.; Nordestgaard, B. G. Lipoproteins, Cholesterol, and Atherosclerotic Cardiovascular Disease in East Asians and Europeans. J. Atheroscler. Thromb. 2023, 30 (11), 1525–1546. DOI: 10.5551/jat.rv22013 DOI: https://doi.org/10.5551/jat.RV22013
Wilkins, J. T.; Lloyd-Jones, D. M. Novel Lipid-Lowering Therapies to Reduce Cardiovascular Risk. JAMA 2021, 326 (3), 266-267. DOI: 10.1001/jama.2021.2244 DOI: https://doi.org/10.1001/jama.2021.2244
Graham, I.; Shear, C.; De Graeff, P.; Boulton, C.; Catapano, A. L.; Stough, W. G.; Carlsson, S. C.; De Backer, G.; Emmerich, J.; Greenfeder, S.; i in. New strategies for the development of lipid-lowering therapies to reduce cardiovascular risk. Eur. Heart J. - Cardiovasc. Pharmacother. 2017, 4 (2), 119–127. DOI: 10.1093/ehjcvp/pvx031 DOI: https://doi.org/10.1093/ehjcvp/pvx031
Parker, B. A.; Capizzi, J. A.; Grimaldi, A. S.; Clarkson, P. M.; Cole, S. M.; Keadle, J.; Chipkin, S.; Pescatello, L. S.; Simpson, K.; White, C. M.; i in. Effect of Statins on Skeletal Muscle Function. Circulation 2013, 127 (1), 96–103. DOI: 10.1161/circulationaha.112.136101 DOI: https://doi.org/10.1161/CIRCULATIONAHA.112.136101
Galicia-Garcia, U.; Jebari, S.; Larrea-Sebal, A.; Uribe, K. B.; Siddiqi, H.; Ostolaza, H.; Benito-Vicente, A.; Martín, C. Statin Treatment-Induced Development of Type 2 Diabetes: From Clinical Evidence to Mechanistic Insights. Int. J. Mol. Sci. 2020, 21 (13), Art. No: 4725. DOI: 10.3390/ijms21134725 DOI: https://doi.org/10.3390/ijms21134725
U.S. Food and Drug Administration, NEXLETOL. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211616s015lbl.pdf (accessed on 19.03.2024).
European Medicines Agency, Nilemdo. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/nilemdo (accessed on 21.03.2024).
U.S. Food and Drug Administration, NEXLIZET. Available online: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/211617s019lbl.pdf (accessed on 20.03.2024).
European Medicines Agency, Nustendi. Available online: https://www.ema.europa.eu/en/medicines/human/EPAR/nustendi (accessed on 21.03.2024).
PubChem, Bempedoic Acid. Available online: https://pubchem.ncbi.nlm.nih.gov/compound/10472693 (accessed on 16.03.2024).
Bilen, O.; Ballantyne, C. M. Bempedoic Acid (ETC-1002): An Investigational Inhibitor of ATP Citrate Lyase. Curr. Atheroscler. Rep. 2016, 18 (10), Art. No: 61. DOI: 10.1007/s11883-016-0611-4 DOI: https://doi.org/10.1007/s11883-016-0611-4
Filippov, S.; Pinkosky, S. L.; Lister, R. J.; Pawloski, C.; Hanselman, J. C.; Cramer, C. T.; Srivastava, R. A. K.; Hurley, T. R.; Bradshaw, C. D.; Spahr, M. A.; 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), 2095–2108. DOI: 10.1194/jlr.m035212 DOI: https://doi.org/10.1194/jlr.M035212
Pinkosky, S. L.; Newton, R. S.; Day, E. A.; Ford, R. J.; Lhotak, S.; Austin, R. C.; Birch, C. M.; Smith, B. K.; Filippov, S.; Groot, P. H. E.; et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat. Commun. 2016, 7 (1), Art. No: 13457. DOI: 10.1038/ncomms13457 DOI: https://doi.org/10.1038/ncomms13457
Nguyen, H.; Akamnonu, I.; Yang, T. Bempedoic Acid: a cholesterol lowering agent with a novel mechanism of action. Expert Rev. Clin. Pharmacol. 2021, 14 (5), 545–551. DOI: 10.1080/17512433.2021.1901579 DOI: https://doi.org/10.1080/17512433.2021.1901579
Burke, A. C.; Huff, M. W. ATP-citrate lyase. Curr. Opin. Lipidol. 2017, 28 (2), 193–200. DOI: 10.1097/mol.0000000000000390 DOI: https://doi.org/10.1097/MOL.0000000000000390
Cicero, A. F. G.; Fogacci, F.; Cincione, I. Evaluating pharmacokinetics of bempedoic acid in the treatment of hypercholesterolemia. Expert Opin. Drug Metab. & Toxicol. 2021, 17 (9), 1031–1038. DOI: 10.1080/17425255.2021.1951222 DOI: https://doi.org/10.1080/17425255.2021.1951222
Zagelbaum, N. K.; Yandrapalli, S.; Nabors, C.; Frishman, W. H. Bempedoic Acid (ETC-1002). Cardiol. Rev. 2019, 27 (1), 49–56. DOI: 10.1097/crd.0000000000000218 DOI: https://doi.org/10.1097/CRD.0000000000000218
Masana Marín, L.; Plana Gil, N. Ácido bempedoico. Mecanismo de acción y propiedades farmacocinéticas y farmacodinámicas. Clin. Investig. En Arterioscler. 2021, 33, 53–57. DOI: 10.1016/j.arteri.2021.02.012 DOI: https://doi.org/10.1016/j.arteri.2021.02.012
Ruscica, M.; Sirtori, C. R.; Carugo, S.; Banach, M.; Corsini, A. Bempedoic Acid: for Whom and When. Curr. Atheroscler. Rep. 2022, 24(10), 791–801. DOI: 10.1007/s11883-022-01054-2 DOI: https://doi.org/10.1007/s11883-022-01054-2
Cicero, A. F. G.; Fogacci, F.; Hernandez, A. V.; Banach, M. Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis. PLOS Med. 2020, 17 (7), Art. No: e1003121. DOI: 10.1371/journal.pmed.1003121 DOI: https://doi.org/10.1371/journal.pmed.1003121
Markham, A. Bempedoic Acid: First Approval. Drugs 2020, 80 (7), 747–753. DOI: 10.1007/s40265-020-01308-w DOI: https://doi.org/10.1007/s40265-020-01308-w
Duarte Lau, F.; Giugliano, R. P. Adenosine Triphosphate Citrate Lyase and Fatty Acid Synthesis Inhibition. JAMA Cardiol. 2023, 8(9), 879-887. DOI: 10.1001/jamacardio.2023.2402 DOI: https://doi.org/10.1001/jamacardio.2023.2402
Ruscica, M.; Banach, M.; Sahebkar, A.; Corsini, A.; Sirtori, C. R. ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials. Expert Opin. Pharmacother. 2019, 20 (7), 791–803. DOI: 10.1080/14656566.2019.1583209 DOI: https://doi.org/10.1080/14656566.2019.1583209
Marrs, J. C.; Anderson, S. L. Bempedoic acid for the treatment of dyslipidemia. Drugs Context 2020, 9, 1–9. DOI: 10.7573/dic.2020-6-5 DOI: https://doi.org/10.7573/dic.2020-6-5
Nguyen, D.; Du, N.; Sulaica, E. M.; Wanat, M. A. Bempedoic Acid: A New Drug for an Old Problem. Ann. Pharmacother. 2020, 55 (2), 246–251. DOI: 10.1177/1060028020941083 DOI: https://doi.org/10.1177/1060028020941083
Ballantyne, C. M.; Bays, H. E.; Louie, M. J.; Smart, J.; Zhang, Y.; Ray, K. K. Factors Associated With Enhanced Low‐Density Lipoprotein Cholesterol Lowering With Bempedoic Acid. J. Am. Heart Assoc. 2022, 11 (15), Art. No: e024531. DOI: 10.1161/jaha.121.024531 DOI: https://doi.org/10.1161/JAHA.121.024531
Ballantyne, C. M.; Banach, M.; Mancini, G. B. J.; Lepor, N. E.; Hanselman, J. C.; Zhao, X.; Leiter, L. A. 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. DOI: 10.1016/j.atherosclerosis.2018.06.002 DOI: https://doi.org/10.1016/j.atherosclerosis.2018.06.002
Ray, K. K.; Bays, H. E.; Catapano, A. L.; Lalwani, N. D.; Bloedon, L. T.; Sterling, L. R.; Robinson, P. L.; Ballantyne, C. M. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. New Engl. J. Med. 2019, 380 (11), 1022–1032. DOI: 10.1056/nejmoa1803917 DOI: https://doi.org/10.1056/NEJMoa1803917
Ballantyne, C. M.; Banach, M.; Bays, H. E.; Catapano, A. L.; Laufs, U.; Stroes, E. S. G.; Robinson, P.; Lei, L.; Ray, K. K. Long-Term Safety and Efficacy of Bempedoic Acid in Patients With Atherosclerotic Cardiovascular Disease and/or Heterozygous Familial Hypercholesterolemia (from the CLEAR Harmony Open-Label Extension Study). Am. J. Cardiol. 2022, 174, 1–11. DOI: 10.1016/j.amjcard.2022.03.020 DOI: https://doi.org/10.1016/j.amjcard.2022.03.020
Laufs, U.; Banach, M.; Mancini, G. B.J.; Gaudet, D.; Bloedon, L.T.; Sterling, L.R.; Kelly, S.; Stroes, E.S.G. Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance. J. Am. Heart Assoc. 2019, 8 (7), Art. No: e011662. DOI: 10.1161/jaha.118.011662 DOI: https://doi.org/10.1161/JAHA.118.011662
Goldberg, A. C.; Leiter, L. A.; Stroes, E. S. G.; Baum, S. J.; Hanselman, J. C.; Bloedon, L. T.; Lalwani, N. D.; Patel, P. M.; Zhao, X.; Duell, P. B. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease. JAMA 2019, 322 (18), 1780-1788. DOI: 10.1001/jama.2019.16585 DOI: https://doi.org/10.1001/jama.2019.16585
Nissen, S. E.; Lincoff, A. M.; Brennan, D.; Ray, K. K.; Mason, D.; Kastelein, J. J. P.; Thompson, P. D.; Libby, P.; Cho, L.; Plutzky, J.; i in. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. New Engl. J. Med. 2023, 388 (15), 1353–1364. DOI: 10.1056/nejmoa2215024 DOI: https://doi.org/10.1056/NEJMoa2215024
Nissen, S. E.; Menon, V.; Nicholls, S. J.; Brennan, D.; Laffin, L.; Ridker, P.; Ray, K. K.; Mason, D.; Kastelein, J. J. P.; Cho, L.; i in. Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients. JAMA 2023, 330 (2), 131–140. DOI: 10.1001/jama.2023.9696 DOI: https://doi.org/10.1001/jama.2023.9696
Nicholls, S. J.; Nelson, A. J.; Lincoff, A. M.; Brennan, D.; Ray, K. K.; Cho, L.; Menon, V.; Li, N.; Bloedon, L.; Nissen, S. E. Impact of Bempedoic Acid on Total Cardiovascular Events. JAMA Cardiol. 2024, 9 (3), 245–253. DOI: 10.1001/jamacardio.2023.5155 DOI: https://doi.org/10.1001/jamacardio.2023.5155
Ray, K. K.; Nicholls, S. J.; Li, N.; Louie, M. J.; Brennan, D.; Lincoff, A. M.; Nissen, S. E. Efficacy and safety of bempedoic acid among patients with and without diabetes: prespecified analysis of the CLEAR Outcomes randomised trial. Lancet Diabetes & Endocrinol. 2023, 12 (1), 19–28. DOI: 10.1016/s2213-8587(23)00316-9 DOI: https://doi.org/10.1016/S2213-8587(23)00316-9
ClinicalTrials.gov, Evaluation of the Efficacy and Safety of Bempedoic Acid (ETC-1002) as Add-on to Ezetimibe Therapy in Patients With Elevated LDL-C (CLEAR Tranquility). Available online: https://clinicaltrials.gov/study/NCT03001076?tab=results#outcome-measures (accessed on 11.04.2024).
Ridker, P. M.; Lei, L.; Louie, M. J.; Haddad, T.; Nicholls, S. J.; Lincoff, A. M.; Libby, P.; Nissen, S. E. Inflammation and Cholesterol as Predictors of Cardiovascular Events Among 13970 Contemporary High-Risk Patients With Statin Intolerance. Circulation 2023, 149 (1), 28–35. DOI: 10.1161/circulationaha.123.066213 DOI: https://doi.org/10.1161/CIRCULATIONAHA.123.066213
Ballantyne, C. M.; Laufs, U.; Ray, K. K.; Leiter, L. A.; Bays, H. E.; Goldberg, A. C.; Stroes, E. S.; MacDougall, D.; Zhao, X.; Catapano, A. L. 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, 27 (6), 593–603. DOI: 10.1177/2047487319864671 DOI: https://doi.org/10.1177/2047487319864671
Banach, M., Burchardt, P., Chlebus, K., Dobrowolski, P., Dudek, D., Dyrbuś, K., Gąsior, M., Jankowski, P., Jóźwiak, J., Kłosiewicz-Latoszek, L., Kowalska, I., Małecki, M., Prejbisz, A., Rakowski, M., Rysz, J., Solnica, B., Sitkiewicz, D., Sygitowicz, G., Sypniewska, G.et al. (2021). PoLA/CFPiP/PCS/PSLD/PSD/PSH guidelines on diagnosis and therapy of lipid disorders in Poland 2021. Arch. Med. Sci., 2021,17(6), 1447–1547. DOI:10.5114/aoms/141941 DOI: https://doi.org/10.5114/aoms/141941
ClinicalTrials.gov, Aggressive Risk-Prevention Therapies for Coronary Atherosclerotic Plaque (ART-CAP) (ARTCAP). Available online: https://clinicaltrials.gov/study/NCT06280976?intr=BempBempe%20Acid%20/%20Ezetimibe&page=2&rank=12 (accessed on 17.03.2024)
ClinicalTrials.gov, Effect of Bempedoic Acid on Liver Fat in Individuals With Nonalcoholic Fatty Liver Disease and Type 2 Diabetes (B-LIFT). Available online: https://clinicaltrials.gov/study/NCT06035874?intr=BempBempe%20acid%20&rank=3 (accessed on 17.03.2024)
ClinicalTrials.gov, Bempedoic Acid Pregnancy Surveillance Program. Available online: https://clinicaltrials.gov/study/NCT05103254?intr=BempBempe%20Acid%20/%20Ezetimibe&page=1&rank=1 (accessed on 18.03.2024)
ClinicalTrials.gov, Milk-Only Lactation Study to Evaluate the Concentration of Bempedoic Acid and Bempedoic Acid/Ezetimibe Fixed Combination Drug Product (FCDP) in the Breast Milk of Healthy Lactating Women. Available online: https://clinicaltrials.gov/study/NCT06021951?intr=BempBempe%20Acid%20/%20Ezetimibe&page=1&rank=4 (accessed on 18.03.2024)
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