Bempedoic acid, an inhibitor of ATP citrate lyase for the treatment of hypercholesterolemia: early indications and potential

References

• World Health Organization . Cardiovascular diseases (CVDs) fact sheet. 2017 [cited 2020 Mar 17 ]. Available from: https://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
   Google Scholar
• Ference BA , Ginsberg HN , Graham I , et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European atherosclerosis society consensus panel. Eur Heart J. 2017;38:2459–2472.
   PubMed Web of Science ®Google Scholar
• Grundy SM , Stone NJ , Bailey AL , 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;73:3168–3209.
   PubMed Web of Science ®Google Scholar
• Mach F , Baigent C , Catapano AL , et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk: the task force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Eur Heart J. 2019;41:111–188.
   Web of Science ®Google Scholar
• Ródenas E , Escalona R , Pariggiano I , et al. Individual trends in LDL-C control in patients with previous myocardial infarction. REC: CardioClinics. 2020;55:23–29.
   Google Scholar
• Safarova MS , Liu H , Kullo IJ. Rapid identification of familial hypercholesterolemia from electronic health records: the SEARCH study. J Clin Lipidol. 2016;10:1230–1239.
   PubMed Web of Science ®Google Scholar
• Bucholz EM , Rodday AM , Kolor K , et al. Prevalence and predictors of cholesterol screening, awareness, and statin treatment among US adults with familial hypercholesterolemia or other forms of severe dyslipidemia (1999–2014). Circulation. 2018;137:2218–2230.
   PubMed Web of Science ®Google Scholar
• Esperion Therapeutics . Esperion announces commercial availability of the NEXLETOL™ (bempedoic acid) tablet and pledges a conscientious launch during unprecedented moment in healthcare. 2020 [cited 2020 May 25 ]. Available from: https://www.esperion.com/investors-media/press-releases/
   Google Scholar
• Pasta A , Cremonini AL , Pisciotta L , et al. PCSK9 inhibitors for treating hypercholesterolemia. Expert Opin Pharmacother. 2020;21:353–363.
   PubMed Web of Science ®Google Scholar
• Ahmad Z. Statin intolerance. Am J Cardiol. 2014;113:1765–1771.
   PubMed Web of Science ®Google Scholar
• Kennedy SP , Barnas GP , Schmidt MJ , et al. Efficacy and tolerability of once-weekly rosuvastatin in patients with previous statin intolerance. J Clin Lipidol. 2011;5(4):308–315.
   PubMed Web of Science ®Google Scholar
• Dujovne CA , Ettinger MP , McNeer JF , et al. Efficacy and safety of a potent new selective cholesterol absorption inhibitor, ezetimibe, in patients with primary hypercholesterolemia. Am J Cardiol. 2002;90:1092–1097.
   PubMed Web of Science ®Google Scholar
• Knopp R , Gitter H , Truitt T , et al. Ezetimibe reduces low-density lipoprotein cholesterol: results of a phase III, randomized, double-blind, placebo-controlled trial. Atheroscler Suppl. 2001;2:38.
   Google Scholar
• Annemans L , Packard CJ , Briggs A , et al. ‘Highest risk–highest benefit’strategy: a pragmatic, cost-effective approach to targeting use of PCSK9 inhibitor therapies. Eur Heart J. 2018;39:2546–2550.
   PubMed Web of Science ®Google Scholar
• Kazi DS , Penko J , Coxson PG , et al. Updated cost-effectiveness analysis of PCSK9 inhibitors based on the results of the FOURIER trial. JAMA. 2017;318:748–750.
   PubMed Web of Science ®Google Scholar
• Vallejo-Vaz AJ , De Marco M , Stevens CAT , et al. Overview of the current status of familial hypercholesterolaemia care in over 60 countries - the EAS familial hypercholesterolaemia studies collaboration (FHSC). Atherosclerosis. 2018;277:234–255.
   PubMed Web of Science ®Google Scholar
• Gouni-Berthold I , Berthold HK . Mipomersen and lomitapide: two new drugs for the treatment of homozygous familial hypercholesterolemia. Atheroscler Suppl. 2015;18:28–34.
   PubMed Web of Science ®Google Scholar
• European Medicines Agency . Refusal of the marketing authorisation for Kynamro (mipomersen) outcome of re-examination. 2013 [cited 2020 Mar 17 ]. Available from: https://www.ema.europa.eu/en/documents/smop-initial/questions-answers-refusal-marketing-authorisation-kynamro-outcome-re-examination_en.pdf
   Google Scholar
• Ray KK , Wright RS , Kallend D , et al. Two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020. [ Epub ahead of print]. DOI: 10.1056/NEJMoa1912387
   Web of Science ®Google Scholar
• Saeed A , Ballantyne CM , Acid B . (ETC-1002): a current review. Cardiol Clin. 2018;36:257–264.
   PubMed Web of Science ®Google Scholar
• Cramer CT , Goetz B , Hopson KL , et al. Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome. J Lipid Res. 2004;45:1289–1301.
   PubMed Web of Science ®Google Scholar
• Pinkosky SL , Newton RS , Day EA , et al. Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis. Nat Commun. 2016;7:13457.
   PubMed Web of Science ®Google Scholar
• Briggs MR , Yokoyama C , Wang X , et al. Nuclear protein that binds sterol regulatory element of low density lipoprotein receptor promoter. I. Identification of the protein and delineation of its target nucleotide sequence. J Biol Chem. 1993;268:14490–14496.
   PubMed Web of Science ®Google Scholar
• Pinkosky SL , Filippov S , Srivastava RAK , 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;54:134–151.
   PubMed Web of Science ®Google Scholar
• Herzig S , Shaw RJ . AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol. 2018;19:121–135.
   PubMed Web of Science ®Google Scholar
• Esperion Therapeutics . Nexletol® (bempedoic acid). Prescribing information. 2020 [cited 2020 Mar 23 ]. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf
   Google Scholar
• Ballantyne CM , Davidson MH , MacDougall DE , et al. Efficacy and safety of a novel dual modulator of adenosine triphosphate-citrate lyase and adenosine monophosphate-activated protein kinase in patients with hypercholesterolemia. J Am Coll Cardiol. 2013;62:1154–1162.
   PubMed Web of Science ®Google Scholar
• Thompson PD , Rubino J , Janik MJ , et al. Use of ETC-1002 to treat hypercholesterolemia in patients with statin intolerance. J Clin Lipidol. 2015;9:295–304.
   PubMed Web of Science ®Google Scholar
• Gutierrez MJ , Rosenberg NL , MacDougall DE , 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;34:676–683.
   PubMed Web of Science ®Google Scholar
• Thompson PD , MacDougall DE , Newton RS , 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;10:556–567.
   PubMed Web of Science ®Google Scholar
• Newton RS , Thompson PD , MacDougall DE , et al. ETC-1002 lowers LDL-cholesterol and is well tolerated in hypercholesterolemic patients with statin intolerance. J Clin Lipidol. 2014;8:340–341.
   Google Scholar
• Ballantyne CM , McKenney JM , MacDougall DE , et al. Effect of ETC-1002 on serum low-density lipoprotein cholesterol in hypercholesterolemic patients receiving Statin therapy. Am J Cardiol. 2016;117:1928–1933.
   PubMed Web of Science ®Google Scholar
• McKenney J , MacDougall D , Sterling LR , et al. Lipid lowering with bempedoic acid added to proprotein convertase subtilisin/kexin type 9 inhibitor therapy: a randomized controlled trial. J Clin Lipidol. 2019;13:e55–e56.
   Google Scholar
• Ballantyne CM , Banach M , Mancini GBJ , 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.
   PubMed Web of Science ®Google Scholar
• Laufs U , Banach M , Mancini GBJ , et al. Efficacy and safety of bempedoic acid in patients with hypercholesterolemia and statin intolerance. J Am Heart Assoc. 2019;8:e011662.
   PubMed Web of Science ®Google Scholar
• Ballantyne CM , Laufs U , Ray KK , 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. 2020;27:593–603.
   PubMed Web of Science ®Google Scholar
• Ray KK , Bays HE , Catapano AL , et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380:1022–1032.
   PubMed Web of Science ®Google Scholar
• Goldberg AC , Leiter LA , Stroes ESG , 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;322:1780–1788.
   PubMed Web of Science ®Google Scholar
• Banach M , Duell PB , Gotto A , et al. Abstract 12268: efficacy of bempedoic acid: a pooled analysis of 4 pivotal phase 3 clinical trials. Circulation. 2019;140:A12268–A12268.
   Web of Science ®Google Scholar
• Esperion Therapeutics . CLEAR outcomes. 2020 [cited 2020 Mar 30 ]. Available from: https://www.esperion.com/science/clinical-trials/
   Google Scholar
• Ference BA , Neff D , Cabot M , et al. Genetic target validation for ATP-citrate lyase inhibition. J Am Coll Cardiol. 2017;69:1655.
   Web of Science ®Google Scholar