An update on emerging drugs for the treatment of hypercholesterolemia

References

• 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(32):2459–2472.
   PubMed Web of Science ®Google Scholar
• Ference BA, Majeed F, Penumetcha R, et al. Effect of naturally random allocation to lower low-density lipoprotein cholesterol on the risk of coronary heart disease mediated by polymorphisms in NPC1L1, HMGCR, or both: a 2 x 2 factorial Mendelian randomization study. J Am Coll Cardiol. 2015;65(15):1552–1561.
   PubMed Web of Science ®Google Scholar
• Representatives of the Global Familial Hypercholesterolemia C, Wilemon KA, Patel J, Aguilar-Salinas C, et al. Reducing the clinical and public health burden of familial hypercholesterolemia: a global call to action. JAMA Cardiol. 2020;5(2):217–229.
   PubMed Web of Science ®Google Scholar
• Boren J, Chapman MJ, Krauss RM, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020;41(24):2313–2330.
   PubMed Web of Science ®Google Scholar
• Karlson BW, Wiklund O, Palmer MK, et al. Variability of low-density lipoprotein cholesterol response with different doses of atorvastatin, rosuvastatin, and simvastatin: results from VOYAGER. Eur Heart J Cardiovasc Pharmacother. 2016;2(4):212–217.
   PubMed Web of Science ®Google Scholar
• Baigent C, Blackwell L, Emberson J, 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):1670–1681.
   PubMed Web of Science ®Google Scholar
• Schwartz GG, Olsson AG, Ezekowitz MD, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: the MIRACL study: a randomized controlled trial. JAMA. 2001;285(13):1711–1718.
   PubMed Web of Science ®Google Scholar
• Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronarysyndromes. N Engl J Med. 2004;350(15):1495–1504.
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Ballantyne CM, Barter PJ, et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med. 2011;365(22):2078–2087.
   PubMed Web of Science ®Google Scholar
• Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROIDtrial. J AMA. 2006;295(13):1556–1565.
   PubMed Web of Science ®Google Scholar
• Nissen SE, Tuzcu EM, Schoenhagen P, et al. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. JAMA. 2004;291(9):1071–1080.
   PubMed Web of Science ®Google Scholar
• Takemoto M, Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol. 2001;21(11):1712–1719.
   Web of Science ®Google Scholar
• Nissen SE, Tuzcu EM, Schoenhagen P, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352(1):29–38.
   PubMed Web of Science ®Google Scholar
• Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statintherapy. N Engl J Med. 2005;352(1):20–28.
   PubMed Web of Science ®Google Scholar
• Savarese G, De Ferrari GM, Rosano GM, et al. Safety and efficacy of ezetimibe: a meta-analysis. Int J Cardiol. 2015;201(247–252):247–252.
   PubMedGoogle Scholar
• Tsujita K, Sugiyama S, Sumida H, et al. Impact of dual lipid-lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol. 2015;66(5):495–507.
   PubMed Web of Science ®Google Scholar
• Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–2397.
   PubMed Web of Science ®Google Scholar
• Scherer DJ, Nelson AJ, Psaltis PJ, et al. Targeting low-density lipoprotein cholesterol with PCSK9 inhibitors. Intern Med J. 2017;47(8):856–865.
   PubMed Web of Science ®Google Scholar
• Ference BA, Robinson JG, Brook RD, et al. Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes. N Engl J Med. 2016;375(2144–2153):2144–2153.
   PubMedGoogle Scholar
• Robinson JG, Nedergaard BS, Rogers WJ, et al. Effect of evolocumab or ezetimibe added to moderate- or high-intensity statin therapy on LDL-C lowering in patients with hypercholesterolemia: the LAPLACE-2 randomized clinical trial. JAMA. 2014;311(18):1870–1882.
   PubMed Web of Science ®Google Scholar
• Blom DJ, Hala T, Bolognese M, et al. A 52-week placebo-controlled trial of evolocumab in hyperlipidemia. N Engl J Med. 2014;370(19):1809–1819.
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Puri R, Anderson T, et al. Effect of evolocumab on progression of coronary disease in statin-treated patients: the GLAGOV randomized clinical trial. JAMA. 2016;316(22):2373–2384.
   PubMed Web of Science ®Google Scholar
• Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–1722.
   PubMed Web of Science ®Google Scholar
• Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–2107.
   PubMed Web of Science ®Google Scholar
• Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. 2017;376(16):1527–1539.
   PubMed Web of Science ®Google Scholar
• Raal FJ, Honarpour N, Blom DJ, et al. Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):341–350.
   PubMed Web of Science ®Google Scholar
• Moriarty PM, Parhofer KG, Babirak SP, et al. Alirocumab in patients with heterozygous familial hypercholesterolaemia undergoing lipoprotein apheresis: the ODYSSEY ESCAPE trial. Eur Heart J. 2016;37(48):3588–3595.
   PubMed Web of Science ®Google Scholar
• Underberg JA, Cannon CP, Larrey D, et al. Long-term safety and efficacy of lomitapide in patients with homozygous familial hypercholesterolemia: five-year data from the Lomitapide Observational Worldwide Evaluation Registry (LOWER). J Clin Lipidol. 2020;14(6):807–817.
   PubMed Web of Science ®Google Scholar
• Raal FJ, Santos RD, Blom DJ, et al. Mipomersen, an apolipoprotein B synthesis inhibitor, for lowering of LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia: a randomised, double-blind, placebo-controlled trial. Lancet. 2010;375(9719):998–1006.
   PubMed Web of Science ®Google Scholar
• Fogacci F, Ferri N, Toth PP, et al. Efficacy and safety of mipomersen: a systematic review and meta-analysis of randomized clinical trials. Drugs. 2019;79(7):751–766.
   PubMed Web of Science ®Google Scholar
• Bove M, Cicero AFG, Borghi C. Emerging drugs for the treatment of hypercholesterolemia. Expert Opin Emerg Drugs. 2019;24(1):63–69.
   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. Eur Heart J. 2020;41(1):111–188.
   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: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082–e1143.
   PubMed Web of Science ®Google Scholar
• Ray KK, Molemans B, Schoonen WM, et al. EU-wide cross-sectional observational study of lipid-modifying therapy use in secondary and primary care: the DA VINCI study. Eur J Prev Cardiol. 2021;28(11):1279–1289.
   PubMed Web of Science ®Google Scholar
• Taylor BA, Thompson PD. Statin-associated muscle disease: advances in diagnosis and management. Neurotherapeutics. 2018;15(4):1006–1017.
   PubMed Web of Science ®Google Scholar
• Bruckert E, Hayem G, Dejager S, et al. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients–the PRIMO study. Cardiovasc Drugs Ther. 2005;19(6):403–414.
   PubMed Web of Science ®Google Scholar
• Khunti K, Danese MD, Kutikova L, et al. Association of a combined measure of adherence and treatment intensity with cardiovascular outcomes in patients with atherosclerosis or other cardiovascular risk factors treated with statins and/or ezetimibe. JAMA Network Open. 2018;1(8):e185554.
   PubMed Web of Science ®Google Scholar
• Pecin I, Reiner Z. Novel experimental agents for the treatment of hypercholesterolemia. J Exp Pharmacol. 2021;13(91–100):91–100.
   PubMedGoogle Scholar
• Beshir SA, Hussain N, Elnor AA, et al. Umbrella Review on Non-Statin Lipid-Lowering Therapy. J Cardiovasc Pharmacol Ther. 2021;26(5):437–452.
   PubMed Web of Science ®Google Scholar
• Rossi M, Fabris E, Barbisan D, et al. Lipid-lowering drug therapy: critical approach for implementation in clinical practice. Am J Cardiovasc Drugs. 2021. https://doi.org/10.1007/s40256-021-00497-3
   Google Scholar
• Ray KK, Corral P, Morales E, et al. Pharmacological lipid-modification therapies for prevention of ischaemic heart disease: current and future options. Lancet. 2019;394(10199):697–708.
   PubMed Web of Science ®Google Scholar
• Raal FJ, Kallend D, Ray KK, et al. Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520–1530.
   PubMed Web of Science ®Google Scholar
• Ray KK, Landmesser U, Leiter LA, et al., Inclisiran in patients at high cardiovascular risk with elevated LDLcholesterol. N Engl J Med. 376(15): 1430–1440. 2017.
   PubMed Web of Science ®Google Scholar
• Ray KK, Wright RS, Kallend D, et al. Two phase 3 trials of inclisiran in patients with elevated LDLcholesterol. N Engl J Med. 2020;382(16):1507–1519.
   PubMed Web of Science ®Google Scholar
• Pinkosky SL, Filippov S, Srivastava RA, 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):134–151.
   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(7):1289–1301.
   PubMed Web of Science ®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: results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. J Am Coll Cardiol. 2013;62(13):1154–1162.
   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(3):676–683.
   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(3):295–304.
   PubMed Web of Science ®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(12):1928–1933.
   PubMed Web of Science ®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
• Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med. 2019;380(11):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(18):1780–1788.
   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(7):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(6):593–603.
   Web of Science ®Google Scholar
• Rubino J, MacDougall DE, Sterling LR, et al. Combination of bempedoic acid, ezetimibe, and atorvastatin in patients with hypercholesterolemia: a randomized clinical trial. Atherosclerosis. 2021;320:122–128.
   PubMed Web of Science ®Google Scholar
• Cicero AFG, Fogacci F, Hernandez AV, et al., Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: a systematic review and meta-analysis. PLoS Med. 17(7): e1003121. 2020.
   PubMed Web of Science ®Google Scholar
• Nicholls S, Lincoff AM, Bays HE, 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. 2021;235(104–112):104–112.
   PubMedGoogle Scholar
• Lim GB. ANGPTL3 inhibition for hypercholesterolaemia. Nat Rev Cardiol. 2021;18(2):72.
   Google Scholar
• Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med. 2017;377(3):211–221.
   PubMed Web of Science ®Google Scholar
• Raal FJ, Rosenson RS, Reeskamp LF, et al., Evinacumab for homozygous familial hypercholesterolemia. N Engl J Med. 383(8): 711–720. 2020.
   PubMed Web of Science ®Google Scholar
• Barter PJ, Rye K-A. Cholesteryl ester transfer protein, high density lipoprotein and arterialdisease. Current Opinion in Lipidology. 2001;12:377–382.
   PubMed Web of Science ®Google Scholar
• Rittershaus CW, Miller DP, Thomas LJ, et al. Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis. Arterioscler Thromb Vasc Biol. 2000;20(9):2106–2112.
   PubMed Web of Science ®Google Scholar
• Sugano M, Makino N, Sawada S, et al. Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits. J Biol Chem. 1998;273(9):5033–5036.
   PubMed Web of Science ®Google Scholar
• Okamoto H, Yonemori F, Wakitani K, et al. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000;406(6792):203–207.
   PubMed Web of Science ®Google Scholar
• Morehouse LA, Sugarman ED, Bourassa PA, et al. Inhibition of CETP activity by torcetrapib reduces susceptibility to diet-induced atherosclerosis in New Zealand White rabbits. J Lipid Res. 2007;48(6):1263–1272.
   PubMed Web of Science ®Google Scholar
• Barter PJ, Caulfield M, Eriksson M, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. 2007;357(21):2109–2122.
   PubMed Web of Science ®Google Scholar
• Barter P. Lessons learned from the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial. Am J Cardiol. 2009;104(10Suppl):10E–15E.
   PubMedGoogle Scholar
• Vergeer M, Stroes ES. The pharmacology and off-target effects of some cholesterol ester transfer protein inhibitors. Am J Cardiol. 2009;104(10Suppl):32E–38E.
   PubMedGoogle Scholar
• Schwartz GG, Olsson AG, Abt M, et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012;367(22):2089–2099.
   PubMed Web of Science ®Google Scholar
• Nicholls SJ, Lincoff AM, Barter PJ, et al. Assessment of the clinical effects of cholesteryl ester transfer protein inhibition with evacetrapib in patients at high-risk for vascular outcomes: rationale and design of the ACCELERATE trial. Am Heart J. 2015;170(6):1061–1069.
   PubMed Web of Science ®Google Scholar
• Gotto AM Jr., Cannon CP, Li XS, et al. Evaluation of lipids, drug concentration, and safety parameters following cessation of treatment with the cholesteryl ester transfer protein inhibitor anacetrapib in patients with or at high risk for coronary heart disease. Am J Cardiol. 2014;113(1):76–83.
   PubMed Web of Science ®Google Scholar
• Hovingh GK, Kastelein JJ, van Deventer SJ, et al., Cholesterol ester transfer protein inhibition by TA-8995 in patients with mild dyslipidaemia (TULIP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 386(9992): 452–460. 2015.
   PubMed Web of Science ®Google Scholar
• Voight BF, Peloso GM, Orho-Melander M, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012;380(9841):572–580.
   PubMed Web of Science ®Google Scholar
• Ference BA, Kastelein JJP, Ginsberg HN, et al., Association of genetic variants related to CETP Inhibitors and statins with lipoprotein levels and cardiovascular risk. JAMA. 318(10): 947–956. 2017.
   PubMed Web of Science ®Google Scholar
• Musunuru K, Chadwick AC, Mizoguchi T, et al., In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature. 593(7859): 429–434. 2021.
   PubMed Web of Science ®Google Scholar
• Arrieta A, Hong JC, Khera R, et al. Updated Cost-effectiveness assessments of PCSK9 inhibitors from the perspectives of the health system and private payers: insights derived from the fourier trial. JAMA Cardiol. 2017;2(12):1369–1374.
   PubMed Web of Science ®Google Scholar
• Perera K, Kam N, Ademi Z, et al. Bempedoic acid for high-risk patients with CVD as adjunct lipid-lowering therapy: a cost-effectiveness analysis. J Clin Lipidol. 2020;14(6):772–783.
   PubMed Web of Science ®Google Scholar