Pharmacokinetics of current and emerging treatments for hypercholesterolemia

References

• Grundy SM, Stone NJ, Bailey AL, et al. 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. Circulation. 2018;2019(139):e1046–e1081.
   Google Scholar
• Mach F, Baigent C, Catapano AL, et al. ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019;2020(41):111–188.
   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;376:1670–1681.
   Google Scholar
• Baigent C, Keech A, Kearney PM, 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;366:1267–1278.
   Google Scholar
• Cannon CP, Blazing MA, Giugliano RP, et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med. 2015;372:2387–2397.
   Google Scholar
• Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376:1713–1722.
   Google Scholar
• Schwartz GG, Steg PG, Szarek M, et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379:2097–2107.
   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.
   Google Scholar
• Nordestgaard BG. Triglyceride-Rich Lipoproteins and Atherosclerotic Cardiovascular Disease. Circ Res. 2016;118:547–563.
   Google Scholar
• Tsimikas S, Fazio S, Ferdinand KC, et al. NHLBI working group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis. J Am Coll Cardiol. 2018;71:177–192.
   Google Scholar
• Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR Variants With Risk Of Coronary Heart Disease. JAMA. 2019;321:364–373.
   Google Scholar
• Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 2016;316:1289–1297.
   Google Scholar
• Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med. 2010;362:1563–1574.
   Google Scholar
• Keech A, Simes RJ, Barter P, et al. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet. 2005;366:1849–1861.
   Google Scholar
• Elam MB, Ginsberg HN, Lovato LC, et al. Association of fenofibrate therapy with long-term cardiovascular risk in statin-treated patients with Type 2 diabetes. JAMA Cardiol. 2017;2:370–380.
   Google Scholar
• Scott R, O’Brien R, Fulcher G, et al. Effects of fenofibrate treatment on cardiovascular disease risk in 9,795 individuals with type 2 diabetes and various components of the metabolic syndrome: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. Diabetes Care. 2009;32:493–498.
   Google Scholar
• Pieper JA. Overview of niacin formulations: differences in pharmacokinetics, efficacy, and safety. Am J Health Syst Pharm. 2003;60: S9–14. quiz S25.
   Google Scholar
• Taylor AJ, Sullenberger LE, Lee HJ, et al. Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2: a double-blind, placebo-controlled study of extended-release niacin on atherosclerosis progression in secondary prevention patients treated with statins. Circulation. 2004;110:3512–3517.
   Google Scholar
• Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release niacin or ezetimibe and carotid intima-media thickness. N Engl J Med. 2009;361:2113–2122.
   Google Scholar
• Boden WE, Probstfield JL, Anderson T, et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. 2011;365:2255–2267.
   Google Scholar
• Landray MJ, Haynes R, Hopewell JC, et al. Effects of extended-release niacin with laropiprant in high-risk patients. N Engl J Med. 2014;371:203–212.
   Google Scholar
• Yamashita S, Masuda D, Matsuzawa Y. Did we abandon probucol too soon? Curr Opin Lipidol. 2015;26:304–316.
   Google Scholar
• Kim BJ, Lee EJ, Kwon SU, et al. Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial. Lancet Neurol. 2018;17:509–518.
   Google Scholar
• Blair HA. Pemafibrate: first global approval. Drugs. 2017;77:1805–1810.
   Google Scholar
• FDA approves use of Vascepa (icosapent ethyl) to reduce risk of cardiovascular events in certain adult patient groups. 2019 Dec 13. [cited 2020 Mar 1]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-use-drug-reduce-risk-cardiovascular-events-certain-adult-patient-groups
   Google Scholar
• Landmesser U, Chapman MJ, Farnier M, et al. European Society of Cardiology/European Atherosclerosis Society Task Force consensus statement on proprotein convertase subtilisin/kexin type 9 inhibitors: practical guidance for use in patients at very high cardiovascular risk. Eur Heart J. 2017;38:2245–2255.
   Google Scholar
• Lloyd-Jones DM, Morris PB, Ballantyne CM, et al. ACC expert consensus decision pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: a report of the American College of Cardiology Task Force on clinical expert consensus documents. J Am Coll Cardiol. 2016;2016(68):92–125.
   Google Scholar
• Hegele RA, Tsimikas S. Lipid-lowering agents. Circ Res. 2019;124:386–404.
   Google Scholar
• Bowman L, Hopewell JC, Chen F, et al. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med. 2017;377:1217–1227.
   Google Scholar
• Borghi C, Cicero AF. Pharmacokinetic drug evaluation of anacetrapib for the treatment of dyslipidemia. Expert Opin Drug Metab Toxicol. 2017;13:205–209.
   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. 2015;386:452–460.
   Google Scholar
• Parhofer KG. New approaches to address dyslipidemia. Curr Opin Lipidol. 2017;28:452–457.
   Google Scholar
• Sirtori CR. The pharmacology of statins. Pharmacol Res. 2014;88:3–11.
   Google Scholar
• Catapano AL. Pitavastatin - pharmacological profile from early phase studies. Atheroscler Suppl. 2010;11:3–7.
   Google Scholar
• Hu M, Tomlinson B. Evaluation of the pharmacokinetics and drug interactions of the two recently developed statins, rosuvastatin and pitavastatin. Expert Opin Drug Metab Toxicol. 2014;10:51–65.
   Google Scholar
• Mukhtar RY, Reid J, Reckless JP. Pitavastatin. Int J Clin Pract. 2005;59:239–252.
   Google Scholar
• Neuvonen PJ. Drug interactions with HMG-CoA reductase inhibitors (statins): the importance of CYP enzymes, transporters and pharmacogenetics. Curr Opin Invest Drugs. 2010;11:323–332.
   Google Scholar
• Prueksaritanont T, Tang C, Qiu Y, et al. Effects of fibrates on metabolism of statins in human hepatocytes. Drug Metab Dispos. 2002;30:1280–1287.
   Google Scholar
• Link E, Parish S, Armitage J, et al. SLCO1B1 variants and statin-induced myopathy–a genomewide study. N Engl J Med. 2008;359:789–799.
   Google Scholar
• Wilke RA, Ramsey LB, Johnson SG, et al. The clinical pharmacogenomics implementation consortium: CPIC guideline for SLCO1B1 and simvastatin-induced myopathy. Clin Pharmacol Ther. 2012;92:112–117.
   Google Scholar
• Chasman DI, Giulianini F, MacFadyen J, et al. Genetic determinants of statin-induced low-density lipoprotein cholesterol reduction: the Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial. Circ Cardiovasc Genet. 2012;5:257–264.
   Google Scholar
• Lee HK, Hu M, Lui S, et al. Effects of polymorphisms in ABCG2, SLCO1B1, SLC10A1 and CYP2C9/19 on plasma concentrations of rosuvastatin and lipid response in Chinese patients. Pharmacogenomics. 2013;14:1283–1294.
   Google Scholar
• Tomlinson B, Hu M, Lee VW, et al. ABCG2 polymorphism is associated with the low-density lipoprotein cholesterol response to rosuvastatin. Clin Pharmacol Ther. 2010;87:558–562.
   Google Scholar
• Niemi M. Transporter pharmacogenetics and statin toxicity. Clin Pharmacol Ther. 2010;87:130–133.
   Google Scholar
• Niemi M, Arnold KA, Backman JT, et al. Association of genetic polymorphism in ABCC2 with hepatic multidrug resistance-associated protein 2 expression and pravastatin pharmacokinetics. Pharmacogenet Genomics. 2006;16:801–808.
   Google Scholar
• Ho RH, Choi L, Lee W, et al. Effect of drug transporter genotypes on pravastatin disposition in European- and African-American participants. Pharmacogenet Genomics. 2007;17:647–656.
   Google Scholar
• Hirano M, Maeda K, Hayashi H, et al. Bile salt export pump (BSEP/ABCB11) can transport a nonbile acid substrate, pravastatin. J Pharmacol Exp Ther. 2005;314:876–882.
   Google Scholar
• Turner RM, Pirmohamed M. Statin-related myotoxicity: a comprehensive review of pharmacokinetic, pharmacogenomic and muscle components. J Clin Med. 2019; 9(1):22.
   Google Scholar
• Newman CB, Preiss D, Tobert JA, et al. Statin safety and associated adverse events: a scientific statement from the American Heart Association. Arterioscler Thromb Vasc Biol. 2019;39:e38–e81.
   Google Scholar
• Staffa JA, Chang J, Green L. Cerivastatin and reports of fatal rhabdomyolysis. N Engl J Med. 2002;346:539–540.
   Google Scholar
• Rosenson RS, Baker SK, Jacobson TA, et al. An assessment by the statin muscle safety task force: 2014 update. J Clin Lipidol. 2014;8:S58–71.
   Google Scholar
• Stroes ES, Thompson PD, Corsini A, 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;36:1012–1022.
   Google Scholar
• Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet. 2016;388:2532–2561.
   Google Scholar
• Peto R, Collins R. Trust the blinded randomized evidence that statin therapy rarely causes symptomatic side effects. Circulation. 2018;138:1499–1501.
   Google Scholar
• Thompson PD. What to believe and do about statin-associated adverse effects. JAMA. 2016;316:1969–1970.
   Google Scholar
• Mancini GB, Baker S, Bergeron J, et al. Diagnosis, prevention, and management of statin adverse effects and intolerance: Canadian consensus working group update (2016). Can J Cardiol. 2016;32:S35–65.
   Google Scholar
• Toth PP, Patti AM, Giglio RV, et al. Management of statin intolerance in 2018: still more questions than answers. Am J Cardiovasc Drugs. 2018;18:157–173.
   Google Scholar
• Ghosal A, Hapangama N, Yuan Y, et al. Identification of human UDP-glucuronosyltransferase enzyme(s) responsible for the glucuronidation of ezetimibe (Zetia). Drug Metab Dispos. 2004;32:314–320.
   Google Scholar
• Kosoglou T, Statkevich P, Johnson-Levonas AO, et al. Ezetimibe: a review of its metabolism, pharmacokinetics and drug interactions. Clin Pharmacokinet. 2005;44:467–494.
   Google Scholar
• Kosoglou T, Statkevich P, Johnson-Levonas A, et al. Ezetimibe. Clin Pharmacokinet. 2005;44:467–494.
   Google Scholar
• de Waart DR, Vlaming ML, Kunne C, et al. Complex pharmacokinetic behavior of ezetimibe depends on abcc2, abcc3, and abcg2. Drug Metab Dispos. 2009;37:1698–1702.
   Google Scholar
• Giugliano RP, Cannon CP, Blazing MA, et al. Benefit of adding ezetimibe to statin therapy on cardiovascular outcomes and safety in patients with versus without diabetes mellitus: results from IMPROVE-IT (Improved Reduction of Outcomes: vytorin Efficacy International Trial). Circulation. 2018;137:1571–1582.
   Google Scholar
• Okopien B, Buldak L, Boldys A. Fibrates in the management of atherogenic dyslipidemia. Expert Rev Cardiovasc Ther. 2017;15:913–921.
   Google Scholar
• Willson TM, Brown PJ, Sternbach DD, et al. The PPARs: from orphan receptors to drug discovery. J Med Chem. 2000;43:527–550.
   Google Scholar
• Miller DB, Spence JD. Clinical pharmacokinetics of fibric acid derivatives (fibrates). Clin Pharmacokinet. 1998;34:155–162.
   Google Scholar
• Davidson MH, Armani A, McKenney JM, et al. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99:3C–18C.
   Google Scholar
• Saurav A, Kaushik M, Mohiuddin SM. Fenofibric acid for hyperlipidemia. Expert Opin Pharmacother. 2012;13:717–722.
   Google Scholar
• Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf. 2006;5:145–156.
   Google Scholar
• Yamazaki M, Li B, Louie SW, et al. Effects of fibrates on human organic anion-transporting polypeptide 1B1-, multidrug resistance protein 2- and P-glycoprotein-mediated transport. Xenobiotica. 2005;35:737–753.
   Google Scholar
• Fruchart JC. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc Diabetol. 2017;16:124.
   Google Scholar
• Fruchart JC, Santos RD, Aguilar-Salinas C, et al. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMalpha) paradigm: conceptual framework and therapeutic potential: A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation. Cardiovasc Diabetol. 2019;18:71.
   Google Scholar
• Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the pemafibrate to reduce cardiovascular outcomes by reducing triglycerides in patients with diabetes (PROMINENT) study. Am Heart J. 2018;206:80–93.
   Google Scholar
• Ogawa SI, Tsunenari Y, Kawai H, et al. Pharmacokinetics and metabolism of pemafibrate, a novel selective peroxisome proliferator-activated receptor-alpha modulator, in rats and monkeys. Biopharm Drug Dispos. 2019;40:12–17.
   Google Scholar
• Ogawa SI, Uehara S, Tsunenari Y, et al. Prediction of circulating human metabolites of pemafibrate, a novel antidyslipidemic drug, using chimeric mice with humanized liver. Xenobiotica. 2019;1–7. DOI:10.1080/00498254.2019.1694198
   Google Scholar
• Japanese Pharmaceuticals and Medical Devices Agency. Japanese pharmaceuticals and medical devices agency. Parmodia (pemafibrate tablet 0.1 mg): Japanese prescribing information. 2018. [cited 2019 Dec 31]. Available from: http://www.pmda.go.jp/files/000226672.pdf
   Google Scholar
• Araki E, Yamashita S, Arai H, et al. Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52-week data from the PROVIDE study. Diabetes Obes Metab. 2019;21:1737–1744.
   Google Scholar
• Ooi EM, Watts GF, Ng TW, et al. Effect of dietary Fatty acids on human lipoprotein metabolism: a comprehensive update. Nutrients. 2015;7:4416–4425.
   Google Scholar
• Sahebkar A, Simental-Mendia LE, Mikhailidis DP, et al. Effect of omega-3 supplements on plasma apolipoprotein C-III concentrations: a systematic review and meta-analysis of randomized controlled trials. Ann Med. 2018;50:565–575.
   Google Scholar
• Ballantyne CM, Braeckman RA, Soni PN. Icosapent ethyl for the treatment of hypertriglyceridemia. Expert Opin Pharmacother. 2013;14:1409–1416.
   Google Scholar
• Bhatt DL, Steg PG, Miller M, et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med. 2019;380:11–22.
   Google Scholar
• Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of eicosapentaenoic acid on major coronary events in hypercholesterolaemic patients (JELIS): a randomised open-label, blinded endpoint analysis. Lancet. 2007;369:1090–1098.
   Google Scholar
• Braeckman RA, Stirtan WG, Soni PN. Pharmacokinetics of eicosapentaenoic acid in plasma and red blood cells after multiple oral dosing with icosapent ethyl in healthy subjects. Clin Pharmacol Drug Dev. 2014;3:101–108.
   Google Scholar
• Bays HE, Ballantyne CM, Doyle RT Jr., et al. Icosapent ethyl: eicosapentaenoic acid concentration and triglyceride-lowering effects across clinical studies. Prostaglandins Other Lipid Mediat. 2016;125:57–64.
   Google Scholar
• Braeckman RA, Stirtan WG, Soni PN. Phase 1 study of the effect of icosapent ethyl on warfarin pharmacokinetic and anticoagulation parameters. Clin Drug Investig. 2014;34:449–456.
   Google Scholar
• Braeckman RA, Stirtan WG, Soni PN. Effect of icosapent ethyl (eicosapentaenoic acid ethyl ester) on omeprazole plasma pharmacokinetics in healthy adults. Drugs R D. 2014;14:159–164.
   Google Scholar
• Braeckman RA, Stirtan WG, Soni PN. Effect of concomitant icosapent ethyl (eicosapentaenoic acid ethyl ester) on the pharmacokinetics of atorvastatin. Clin Drug Investig. 2015;35:45–51.
   Google Scholar
• Braeckman RA, Stirtan WG, Soni PN. Effects of icosapent ethyl (eicosapentaenoic acid ethyl ester) on pharmacokinetic parameters of rosiglitazone in healthy subjects. Clin Pharmacol Drug Dev. 2015;4:143–148.
   Google Scholar
• Nicholls SJ, Lincoff AM, Bash D, et al. Assessment of omega-3 carboxylic acids in statin-treated patients with high levels of triglycerides and low levels of high-density lipoprotein cholesterol: rationale and design of the STRENGTH trial. Clin Cardiol. 2018;41:1281–1288.
   Google Scholar
• Update on Phase III STRENGTH trial for Epanova in mixed dyslipidaemia. 2020 Jan 13. [cited 2020 Mar 1]. Available from: https://www.astrazeneca.com/media-centre/press-releases/2020/update-on-phase-iii-strength-trial-for-epanova-in-mixed-dyslipidaemia-13012020.html
   Google Scholar
• Davidson MH, Johnson J, Rooney MW, et al. A novel omega-3 free fatty acid formulation has dramatically improved bioavailability during a low-fat diet compared with omega-3-acid ethyl esters: the ECLIPSE (Epanova((R)) compared to Lovaza((R)) in a pharmacokinetic single-dose evaluation) study. J Clin Lipidol. 2012;6:573–584.
   Google Scholar
• Davidson MH, Phillips AK, Kling D, et al. Addition of omega-3 carboxylic acids to statin therapy in patients with persistent hypertriglyceridemia. Expert Rev Cardiovasc Ther. 2014;12:1045–1054.
   Google Scholar
• Offman E, Davidson M, Abu-Rashid M, et al. Systemic bioavailability and dose proportionality of Omega-3 administered in free fatty acid form compared with ethyl ester form: results of a phase 1 study in healthy volunteers. Eur J Drug Metab Pharmacokinet. 2017;42:815–825.
   Google Scholar
• Berberich AJ, Hegele RA. Lomitapide for the treatment of hypercholesterolemia. Expert Opin Pharmacother. 2017;18:1261–1268.
   Google Scholar
• Davis KA, Miyares MA. Lomitapide: A novel agent for the treatment of homozygous familial hypercholesterolemia. Am J Health Syst Pharm. 2014;71:1001–1008.
   Google Scholar
• Rader DJ, Kastelein JJ. Lomitapide and mipomersen: two first-in-class drugs for reducing low-density lipoprotein cholesterol in patients with homozygous familial hypercholesterolemia. Circulation. 2014;129:1022–1032.
   Google Scholar
• Goulooze SC, Cohen AF, Rissmann R. Lomitapide. Br J Clin Pharmacol. 2015;80:179–181.
   Google Scholar
• Geary RS, Baker BF, Crooke ST. Clinical and preclinical pharmacokinetics and pharmacodynamics of mipomersen (kynamro((R))): a second-generation antisense oligonucleotide inhibitor of apolipoprotein B. Clin Pharmacokinet. 2015;54:133–146.
   Google Scholar
• Yu RZ, Kim TW, Hong A, et al. Cross-species pharmacokinetic comparison from mouse to man of a second-generation antisense oligonucleotide, ISIS 301012, targeting human apolipoprotein B-100. Drug Metab Dispos. 2007;35:460–468.
   Google Scholar
• Crooke ST, Geary RS. Clinical pharmacological properties of mipomersen (Kynamro), a second generation antisense inhibitor of apolipoprotein B. Br J Clin Pharmacol. 2013;76:269–276.
   Google Scholar
• Santos RD, Duell PB, East C, et al. Long-term efficacy and safety of mipomersen in patients with familial hypercholesterolaemia: 2-year interim results of an open-label extension. Eur Heart J. 2015;36:566–575.
   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;376:1527–1539.
   Google Scholar
• Ridker PM, Tardif JC, Amarenco P, et al. Lipid-reduction variability and antidrug-antibody formation with bococizumab. N Engl J Med. 2017;376:1517–1526.
   Google Scholar
• Praluent (alirocumab) injection. FDA document – BLA 125559. fda center for drug evaluation and research. The endocrinologic and metabolic drugs advisory committee meeting; 2015 Jun 9; [cited 2019 Dec 1]. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/UCM449865.pdf.
   Google Scholar
• Tomlinson B, Hu M, Zhang Y, et al. Alirocumab for the treatment of hypercholesterolemia. Expert Opin Biol Ther. 2017;17:633–643.
   Google Scholar
• Robinson JG, Farnier M, Kastelein JJP, et al. Relationship between alirocumab, PCSK9, and LDL-C levels in four phase 3 ODYSSEY trials using 75 and 150 mg doses. J Clin Lipidol. 2019;13:979–988 e910.
   Google Scholar
• Sanofi Aventis and Regeneron Pharmaceuticals Inc. Praluent (alirocumab injection) manufacturer’s prescribing information. 2015 July.[cited 2019 Dec 1]. Available from: http://products.sanofi.us/praluent/praluent.pdf
   Google Scholar
• Neef D, Berthold HK, Gouni-Berthold I. Lomitapide for use in patients with homozygous familial hypercholesterolemia: a narrative review. Expert Rev Clin Pharmacol. 2016;9:655–663.
   Google Scholar
• Repatha (evolocumab) injection prescribing information 2015. Amgen2015 Aug 27. [cited 2019 Dec 1]. Available from: http://pi.amgen.com/united_states/repatha/repatha_pi_hcp_english.pdf
   Google Scholar
• Stein EA, Wasserman SM, Dias CS, et al. AMG-145. Drugs Future. 2013;38:451–459.
   Google Scholar
• Giugliano RP, Mach F, Zavitz K, et al. Cognitive function in a randomized trial of evolocumab. N Engl J Med. 2017;377:633–643.
   Google Scholar
• Fitzgerald K, Frank-Kamenetsky M, Shulga-Morskaya S, et al. Effect of an RNA interference drug on the synthesis of proprotein convertase subtilisin/kexin type 9 (PCSK9) and the concentration of serum LDL cholesterol in healthy volunteers: a randomised, single-blind, placebo-controlled, phase 1 trial. Lancet. 2014;383:60–68.
   Google Scholar
• Frank-Kamenetsky M, Grefhorst A, Anderson NN, et al. Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates. Proc Natl Acad Sci U S A. 2008;105:11915–11920.
   Google Scholar
• Nair JK, Willoughby JL, Chan A, et al. Multivalent N-acetylgalactosamine-conjugated siRNA localizes in hepatocytes and elicits robust RNAi-mediated gene silencing. J Am Chem Soc. 2014;136:16958–16961.
   Google Scholar
• Fitzgerald K, White S, Borodovsky A, et al. A Highly Durable RNAi Therapeutic Inhibitor of PCSK9. N Engl J Med. 2016;376:41–51.
   Google Scholar
• Nishikido T, Ray KK. Inclisiran for the treatment of dyslipidemia. Expert Opin Investig Drugs. 2018;27:287–294.
   Google Scholar
• Ruscica M, Banach M, Sahebkar A, et al. ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials. Expert Opin Pharmacother. 2019;20:791–803.
   Google Scholar
• Saeed A, Ballantyne CM. Bempedoic acid (ETC-1002): a current review. Cardiol Clin. 2018;36:257–264.
   Google Scholar
• Penson P, McGowan M, Banach M. Evaluating bempedoic acid for the treatment of hyperlipidaemia. Expert Opin Investig Drugs. 2017;26:251–259.
   Google Scholar
• Nikolic D, Mikhailidis DP, Davidson MH, et al. ETC-1002: a future option for lipid disorders? Atherosclerosis. 2014;237:705–710.
   Google Scholar
• Lalwani ND, Hanselman JC, MacDougall DE, et al. 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;13:568–579.
   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.
   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.
   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.
   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.
   Google Scholar
• Bempedoic Acid FDA approval. Drugs@FDA: FDA-Approved Drugs. 2020 Feb 21. [cited 2020 Mar 1]. Available from: https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211616
   Google Scholar
• Bays HE, McKenney JM, Dujovne CA, et al. Effectiveness and tolerability of a new lipid-altering agent, gemcabene, in patients with low levels of high-density lipoprotein cholesterol. Am J Cardiol. 2003;92:538–543.
   Google Scholar
• Bisgaier CL, Essenburg AD, Barnett BC, et al. A novel compound that elevates high density lipoprotein and activates the peroxisome proliferator activated receptor. J Lipid Res. 1998;39:17–30.
   Google Scholar
• Bisgaier CL, Oniciu DC, Srivastava RAK. Comparative evaluation of gemcabene and peroxisome proliferator-activated receptor ligands in transcriptional assays of peroxisome proliferator-activated receptors: implication for the treatment of hyperlipidemia and cardiovascular disease. J Cardiovasc Pharmacol. 2018;72:3–10.
   Google Scholar
• Stein E, Bays H, Koren M, et al. Efficacy and safety of gemcabene as add-on to stable statin therapy in hypercholesterolemic patients. J Clin Lipidol. 2016;10:1212–1222.
   Google Scholar
• Bauman JN, Goosen TC, Tugnait M, et al. Udp-glucuronosyltransferase 2b7 is the major enzyme responsible for gemcabene glucuronidation in human liver microsomes. Drug Metab Dispos. 2005;33:1349–1354.
   Google Scholar
• Yuan H, Feng B, Yu Y, et al. Renal organic anion transporter-mediated drug-drug interaction between gemcabene and quinapril. J Pharmacol Exp Ther. 2009;330:191–197.
   Google Scholar
• Milonas D, Tziomalos K. Experimental therapies targeting apolipoprotein C-III for the treatment of hyperlipidemia - spotlight on volanesorsen. Expert Opin Investig Drugs. 2019;28:389–394.
   Google Scholar
• Paik J, Duggan S. Volanesorsen: first global approval. Drugs. 2019;79:1349–1354.
   Google Scholar
• FDA Rejects Volanesorsen (Waylivra) for Rare Triglyceride Disorder. [cited 2019 Dec 31]. Available from: https://www.medscape.com/viewarticle/901515
   Google Scholar
• Post N, Yu R, Greenlee S, et al. Metabolism and disposition of volanesorsen, a 2ʹ-O-(2 methoxyethyl) antisense oligonucleotide, across species. Drug Metab Dispos. 2019;47:1164–1173.
   Google Scholar
• Witztum JL, Gaudet D, Freedman SD, et al. Volanesorsen and triglyceride levels in familial chylomicronemia syndrome. N Engl J Med. 2019;381:531–542.
   Google Scholar
• Alexander VJ, Xia S, Hurh E, et al. N-acetyl galactosamine-conjugated antisense drug to APOC3 mRNA, triglycerides and atherogenic lipoprotein levels. Eur Heart J. 2019;40:2785–2796.
   Google Scholar
• Park Y, Harris WS. Omega-3 fatty acid supplementation accelerates chylomicron triglyceride clearance. J Lipid Res. 2003;44:455–463.
   Google Scholar
• Meyers CD, Amer A, Majumdar T, et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of pradigastat, a novel diacylglycerol acyltransferase 1 inhibitor in overweight or obese, but otherwise healthy human subjects. J Clin Pharmacol. 2015;55:1031–1041.
   Google Scholar
• Hirano M, Meyers D, Golla G, et al. Effect of hepatic Impairment on the pharmacokinetics of pradigastat, a diacylglycerol acyltransferase 1 (DGAT1) Inhibitor. Clin Pharmacokinet. 2015;54:761–770.
   Google Scholar
• Mita S, Meyers D, Pal P, et al. Effect of renal impairment on the pharmacokinetics of pradigastat, a novel Diacylglycerol Acyltransferase1 (DGAT1) Inhibitor. Clin Pharmacokinet. 2015;54:751–760.
   Google Scholar
• Chen J, Bhansali S, Neelakantham S, et al. Effect of pradigastat, a diacylglycerol acyltransferase 1 inhibitor, on the pharmacokinetics of a combination oral contraceptive in healthy female subjects. Int J Clin Pharmacol Ther. 2015;53:317–324.
   Google Scholar
• Denison H, Nilsson C, Löfgren L, et al. Diacylglycerol acyltransferase 1 inhibition with AZD7687 alters lipid handling and hormone secretion in the gut with intolerable side effects: a randomized clinical trial. Diabetes Obesity Metab. 2014;16:334–343.
   Google Scholar
• Gaudet D, Stroes ES, Methot J, et al. Long-term retrospective analysis of gene therapy with alipogene tiparvovec and its effect on lipoprotein lipase deficiency-induced pancreatitis. Hum Gene Ther. 2016;27:916–925.
   Google Scholar
• Salmon F, Grosios K, Petry H. Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera(R)). Expert Rev Clin Pharmacol. 2014;7:53–65.
   Google Scholar
• Scott LJ. Alipogene tiparvovec: a review of its use in adults with familial lipoprotein lipase deficiency. Drugs. 2015;75:175–182.
   Google Scholar
• Athyros VG, Katsiki N, Dimakopoulou A, et al. Drugs that mimic the effect of gene mutations for the prevention or the treatment of atherosclerotic disease: from PCSK9 Inhibition to ANGPTL3 inactivation. Curr Pharm Des. 2018;24:3638–3646.
   Google Scholar
• Dewey FE, Gusarova V, Dunbar RL, et al. Genetic and pharmacologic inactivation of ANGPTL3 and cardiovascular disease. N Engl J Med. 2017;377:211–221.
   Google Scholar
• Gusarova V, Alexa CA, Wang Y, et al. ANGPTL3 blockade with a human monoclonal antibody reduces plasma lipids in dyslipidemic mice and monkeys. J Lipid Res. 2015;56:1308–1317.
   Google Scholar
• Banerjee P, Chan KC, Tarabocchia M, et al. Functional analysis of LDLR (low-density lipoprotein receptor) variants in patient lymphocytes to assess the effect of evinacumab in homozygous familial hypercholesterolemia patients with a spectrum of LDLR activity. Arterioscler Thromb Vasc Biol. 2019;39:2248–2260.
   Google Scholar
• Regeneron Announces Positive Topline Results from Phase. 3 Trial of Evinacumab in Patients with Severe, Inherited Form of High Cholesterol 2019 Aug 14 . [cited 2020 Mar 1]. Available from: https://investor.regeneron.com/news-releases/news-release-details/regeneron-announces-positive-topline-results-phase-3-trial.
   Google Scholar
• Graham MJ, Lee RG, Brandt TA, et al. Cardiovascular and metabolic effects of ANGPTL3 antisense oligonucleotides. N Engl J Med. 2017;377:222–232.
   Google Scholar
• Borrelli MJ, Youssef A, Boffa MB, et al. New frontiers in Lp(a)-targeted therapies. Trends Pharmacol Sci. 2019;40:212–225.
   Google Scholar
• Thanassoulis G, Campbell CY, Owens DS, et al. Genetic associations with valvular calcification and aortic stenosis. N Engl J Med. 2013;368:503–512.
   Google Scholar
• Tsimikas S. RNA-targeted therapeutics for lipid disorders. Curr Opin Lipidol. 2018;29:459–466.
   Google Scholar
• Viney NJ, van Capelleveen JC, Geary RS, et al. Antisense oligonucleotides targeting apolipoprotein(a) in people with raised lipoprotein(a): two randomised, double-blind, placebo-controlled, dose-ranging trials. Lancet. 2016;388:2239–2253.
   Google Scholar
• Mach F, Ray KK, Wiklund O, et al. Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract.. Eur Heart J. 2018;39:2526–2539.
   Google Scholar