87
Views
3
CrossRef citations to date
0
Altmetric
Review

Cardiovascular Outcomes and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors: Current Data and Future Prospects

, ORCID Icon &
Pages 403-418 | Published online: 07 Oct 2020

References

  • Benjamin EJ, Muntner P, Alonso A, et al. Heart disease and stroke statistics—2019 update: a report from the American Heart Association. Circulation. 2019;139(10):e56–e528. doi:10.1161/CIR.0000000000000659
  • Joseph P, Leong D, McKee M, et al. Reducing the global burden of cardiovascular disease, Part 1: the epidemiology and risk factors. Circ Res. 2017;121(6):677–694. doi:10.1161/CIRCRESAHA.117.308903
  • 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. doi:10.1093/eurheartj/ehx144
  • 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(24):3168–3209. doi:10.1016/j.jacc.2018.11.002
  • Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017;23(Suppl 2):1–87. doi:10.4158/ep171764.appgl
  • 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. 2019. https://www.ncbi.nlm.nih.gov/pubmed/31504418.
  • Cholesterol Treatment Trialists Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393(10170):407–415. doi:10.1016/S0140-6736(18)31942-1.
  • 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(2):e38–e81. doi:10.1161/atv.0000000000000073
  • Jones PH, Nair R, Thakker KM. Prevalence of dyslipidemia and lipid goal attainment in statin-treated subjects from 3 data sources: a retrospective analysis. J Am Heart Assoc. 2012;1(6):e001800. doi:10.1161/JAHA.112.001800
  • Ridker PM, Mora S, Rose L, Jupiter Trial Study Group. Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J. 2016;37(17):1373–1379. doi:10.1093/eurheartj/ehw046
  • Adhyaru BB, Jacobson TA. Safety and efficacy of statin therapy. Nat Rev Cardiol. 2018;15(12):757–769. doi:10.1038/s41569-018-0098-5
  • 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(3):157–173. doi:10.1007/s40256-017-0259-7
  • Pedro-Botet J, Climent E, Benaiges D. Muscle and statins: from toxicity to the nocebo effect. Expert Opin Drug Saf. 2019;18(7):573–579. doi:10.1080/14740338.2019.1615053
  • Zhang H, Plutzky J, Turchin A. Discontinuation of statins in routine care settings. Ann Intern Med. 2013;159(1):75–76. doi:10.7326/0003-4819-159-1-201307020-00022
  • Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359(21):2195–2207. doi:10.1056/NEJMoa0807646
  • Sattar N, Preiss D, Murray HM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. 2010;375(9716):735–742. doi:10.1016/S0140-6736(09)61965-6
  • Thakker D, Nair S, Pagada A, Jamdade V, Malik A. Statin use and the risk of developing diabetes: a network meta-analysis. Pharmacoepidemiol Drug Saf. 2016;25(10):1131–1149. doi:10.1002/pds.4020
  • 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. doi:10.1056/NEJMoa1410489
  • Jakob T, Nordmann AJ, Schandelmaier S, Ferreira-Gonzalez I, Briel M. Fibrates for primary prevention of cardiovascular disease events. Cochrane Database Syst Rev. 2016;11:CD009753. doi:10.1002/14651858.CD009753.pub2
  • Schandelmaier S, Briel M, Saccilotto R, et al. Niacin for primary and secondary prevention of cardiovascular events. Cochrane Database Syst Rev. 2017;6:CD009744. doi:10.1002/14651858.CD009744
  • Seidah NG, Benjannet S, Wickham L, et al. The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation. Proc Natl Acad Sci U S A. 2003;100(3):928–933. doi:10.1073/pnas.0335507100
  • Cohen JC, Boerwinkle E, Mosley TH Jr., Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354(12):1264–1272. doi:10.1056/NEJMoa054013
  • Seidah NG, Awan Z, Chretien M, Mbikay M. PCSK9: a key modulator of cardiovascular health. Circ Res. 2014;114(6):1022–1036. doi:10.1161/circresaha.114.301621
  • Lambert G, Sjouke B, Choque B, Kastelein JJ, Hovingh GK. The PCSK9 decade. J Lipid Res. 2012;53(12):2515–2524. doi:10.1194/jlr.R026658
  • Ballantyne CM, Neutel J, Cropp A, et al. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebo-controlled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am J Cardiol. 2015;115(9):1212–1221. doi:10.1016/j.amjcard.2015.02.006
  • 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. doi:10.1056/NEJMoa1701488
  • Giugliano RP, Desai NR, Kohli P, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet. 2012;380(9858):2007–2017. doi:10.1016/S0140-6736(12)61770-X
  • McKenney JM, Koren MJ, Kereiakes DJ, et al. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol. 2012;59(25):2344–2353. doi:10.1016/j.jacc.2012.03.007
  • Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367(20):1891–1900. doi:10.1056/NEJMoa1201832
  • Stein EA, Gipe D, Bergeron J, et al. Effect of a monoclonal antibody to PCSK9, REGN727/SAR236553, to reduce low-density lipoprotein cholesterol in patients with heterozygous familial hypercholesterolaemia on stable statin dose with or without ezetimibe therapy: a phase 2 randomised controlled trial. Lancet. 2012;380(9836):29–36. doi:10.1016/S0140-6736(12)60771-5
  • Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366(12):1108–1118. doi:10.1056/NEJMoa1105803
  • Koren MJ, Scott R, Kim JB, et al. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 as monotherapy in patients with hypercholesterolaemia (MENDEL): a randomised, double-blind, placebo-controlled, phase 2 study. Lancet. 2012;380(9858):1995–2006. doi:10.1016/s0140-6736(12)61771-1
  • Roth EM, Taskinen MR, Ginsberg HN, et al. Monotherapy with the PCSK9 inhibitor alirocumab versus ezetimibe in patients with hypercholesterolemia: results of a 24 week, double-blind, randomized Phase 3 trial. Int J Cardiol. 2014;176(1):55–61. doi:10.1016/j.ijcard.2014.06.049
  • Cannon CP, Cariou B, Blom D, et al. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: the ODYSSEY COMBO II randomized controlled trial. Eur Heart J. 2015;36(19):1186–1194. doi:10.1093/eurheartj/ehv028
  • Kastelein JJ, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015;36(43):2996–3003. doi:10.1093/eurheartj/ehv370
  • Navarese EP, Kolodziejczak M, Schulze V, et al. Effects of proprotein convertase subtilisin/kexin type 9 antibodies in adults with hypercholesterolemia: a systematic review and meta-analysis. Ann Intern Med. 2015;163(1):40–51. doi:10.7326/M14-2957
  • 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. doi:10.1016/S0140-6736(14)61374-X
  • Raal FJ, Stein EA, Dufour R, et al. PCSK9 inhibition with evolocumab (AMG 145) in heterozygous familial hypercholesterolaemia (RUTHERFORD-2): a randomised, double-blind, placebo-controlled trial. Lancet. 2015;385(9965):331–340. doi:10.1016/s0140-6736(14)61399-4
  • 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. doi:10.1001/jama.2014.4030
  • Stroes E, Colquhoun D, Sullivan D, et al. Anti-PCSK9 antibody effectively lowers cholesterol in patients with statin intolerance: the GAUSS-2 randomized, placebo-controlled phase 3 clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2541–2548. doi:10.1016/j.jacc.2014.03.019
  • Kastelein JJ, Hovingh GK, Langslet G, et al. Efficacy and safety of the proprotein convertase subtilisin/kexin type 9 monoclonal antibody alirocumab vs placebo in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017;11(1):195–203e4. doi:10.1016/j.jacl.2016.12.004
  • Hovingh GK, Raal FJ, Dent R, et al. Long-term safety, tolerability, and efficacy of evolocumab in patients with heterozygous familial hypercholesterolemia. J Clin Lipidol. 2017;11(6):1448–1457. doi:10.1016/j.jacl.2017.09.003
  • Ginsberg HN, Tuomilehto J, Hovingh GK, et al. Impact of age on the efficacy and safety of alirocumab in patients with heterozygous familial hypercholesterolemia. Cardiovasc Drugs Ther. 2019;33(1):69–76. doi:10.1007/s10557-019-06852-6
  • Harvey PD, Sabbagh MN, Harrison JE, et al. No evidence of neurocognitive adverse events associated with alirocumab treatment in 3340 patients from 14 randomized Phase 2 and 3 controlled trials: a meta-analysis of individual patient data. Eur Heart J. 2018;39(5):374–381. doi:10.1093/eurheartj/ehx661
  • Koren MJ, Lundqvist P, Bolognese M, et al. Anti-PCSK9 monotherapy for hypercholesterolemia: the MENDEL-2 randomized, controlled Phase III clinical trial of evolocumab. J Am Coll Cardiol. 2014;63(23):2531–2540. doi:10.1016/j.jacc.2014.03.018
  • Moriarty PM, Thompson PD, Cannon CP, et al. Efficacy and safety of alirocumab vs ezetimibe in statin-intolerant patients, with a statin rechallenge arm: the ODYSSEY ALTERNATIVE randomized trial. J Clin Lipidol. 2015;9(6):758–769. doi:10.1016/j.jacl.2015.08.006
  • Leiter LA, Tinahones FJ, Karalis DG, et al. Alirocumab safety in people with and without diabetes mellitus: pooled data from 14 ODYSSEY trials. Diabet Med. 2018;35(12):1742–1751. doi:10.1111/dme.13817
  • Ginsberg HN, Farnier M, Robinson JG, et al. Efficacy and safety of alirocumab in individuals with diabetes mellitus: pooled analyses from five placebo-controlled Phase 3 studies. Diabetes Ther. 2018;9(3):1317–1334. doi:10.1007/s13300-018-0439-8
  • Sattar N, Preiss D, Robinson JG, et al. Lipid-lowering efficacy of the PCSK9 inhibitor evolocumab (AMG 145) in patients with type 2 diabetes: a meta-analysis of individual patient data. Lancet Diabetes Endocrinol. 2016;4(5):403–410. doi:10.1016/S2213-8587(16)00003-6
  • Leiter LA, Cariou B, Muller-Wieland D, et al. Efficacy and safety of alirocumab in insulin-treated individuals with type 1 or type 2 diabetes and high cardiovascular risk: the ODYSSEY DM-INSULIN randomized trial. Diabetes Obes Metab. 2017;19(12):1781–1792. doi:10.1111/dom.13114
  • Ray KK, Leiter LA, Muller-Wieland D, et al. Alirocumab vs usual lipid-lowering care as add-on to statin therapy in individuals with type 2 diabetes and mixed dyslipidaemia: the ODYSSEY DM-DYSLIPIDEMIA randomized trial. Diabetes Obes Metab. 2018;20(6):1479–1489. doi:10.1111/dom.13257
  • Rosenson RS, Jacobson TA, Preiss D, et al. Efficacy and safety of the PCSK9 inhibitor evolocumab in patients with mixed hyperlipidemia. Cardiovasc Drugs Ther. 2016;30(3):305–313. doi:10.1007/s10557-016-6666-1
  • Taskinen MR, Del Prato S, Bujas-Bobanovic M, et al. Efficacy and safety of alirocumab in individuals with type 2 diabetes mellitus with or without mixed dyslipidaemia: analysis of the ODYSSEY LONG TERM trial. Atherosclerosis. 2018;276:124–130. doi:10.1016/j.atherosclerosis.2018.07.017
  • Charytan DM, Sabatine MS Efficacy and Safety of Evolocumab in CKD: data from the FOURIER Trial. American Society of Nephrology Annual Conference, San Diego, CA; 2018.
  • Toth PP, Dwyer JP, Cannon CP, et al. Efficacy and safety of lipid lowering by alirocumab in chronic kidney disease. Kidney Int. 2018;93(6):1397–1408. doi:10.1016/j.kint.2017.12.011
  • Ganda OP, Plutzky J, Sanganalmath SK, et al. Efficacy and safety of alirocumab among individuals with diabetes mellitus and atherosclerotic cardiovascular disease in the ODYSSEY phase 3 trials. Diabetes Obes Metab. 2018;20(10):2389–2398. doi:10.1111/dom.13384
  • McCullough PA, Ballantyne CM, Sanganalmath SK, et al. Efficacy and safety of alirocumab in high-risk patients with clinical atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia (From 5 placebo-controlled ODYSSEY trials). Am J Cardiol. 2018;121(8):940–948. doi:10.1016/j.amjcard.2017.12.040
  • Kereiakes DJ, Lepor NE, Gerber R, et al. Efficacy and safety of alirocumab in patients with or without prior coronary revascularization: pooled analysis of eight ODYSSEY phase 3 trials. Atherosclerosis. 2018;277:211–218. doi:10.1016/j.atherosclerosis.2018.07.010
  • Ray KK, Del Prato S, Muller-Wieland D, et al. Alirocumab therapy in individuals with type 2 diabetes mellitus and atherosclerotic cardiovascular disease: analysis of the ODYSSEY DM-DYSLIPIDEMIA and DM-INSULIN studies. Cardiovasc Diabetol. 2019;18(1):149. doi:10.1186/s12933-019-0951-9
  • Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489–1499. doi:10.1056/NEJMoa1501031
  • Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500–1509. doi:10.1056/NEJMoa1500858
  • 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. doi:10.1056/NEJMoa1801174
  • 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. doi:10.1056/NEJMoa1615664
  • Gaudet D, Watts GF, Robinson JG, et al. Effect of alirocumab on lipoprotein(a) over ≥1.5 years (from the Phase 3 ODYSSEY Program). Am J Cardiol. 2017;119(1):40–46. doi:10.1016/j.amjcard.2016.09.010
  • Raal FJ, Giugliano RP, Sabatine MS, et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1300 patients in 4 Phase II trials. J Am Coll Cardiol. 2014;63(13):1278–1288. doi:10.1016/j.jacc.2014.01.006
  • Ray KK, Vallejo-Vaz AJ, Ginsberg HN, et al. Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: pooled analysis of alirocumab phase 3 trials. Atherosclerosis. 2019;288:194–202. doi:10.1016/j.atherosclerosis.2019.06.896
  • O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation. 2019;139(12):1483–1492. doi:10.1161/CIRCULATIONAHA.118.037184
  • Murphy SA, Pedersen TR, Gaciong ZA, et al. Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: a prespecified analysis from the FOURIER trial. JAMA Cardiol. 2019;4(7):613–619. doi:10.1001/jamacardio.2019.0886
  • Bonaca MP, Nault P, Giugliano RP, et al. Low-density lipoprotein cholesterol lowering with evolocumab and outcomes in patients with peripheral artery disease: insights from the FOURIER trial (Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk). Circulation. 2018;137(4):338–350. doi:10.1161/CIRCULATIONAHA.117.032235
  • Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(12):941–950. doi:10.1016/S2213-8587(17)30313-3
  • Sabatine MS, De Ferrari GM, Giugliano RP, et al. Clinical benefit of evolocumab by severity and extent of coronary artery disease. Circulation. 2018;138(8):756–766. doi:10.1161/CIRCULATIONAHA.118.034309
  • Bays HE. Alirocumab, decreased mortality, nominal significance, P values, Bayesian statistics, and the duplicity of multiplicity. Circulation. 2019;140(2):113–116. doi:10.1161/CIRCULATIONAHA.119.041496
  • Steg PG, Szarek M, Bhatt DL, et al. Effect of alirocumab on mortality after acute coronary syndromes. Circulation. 2019;140(2):103–112. doi:10.1161/CIRCULATIONAHA.118.038840
  • Szarek M, White HD, Schwartz GG, et al. Alirocumab reduces total nonfatal cardiovascular and fatal events: the ODYSSEY OUTCOMES trial. J Am Coll Cardiol. 2019;73(4):387–396. doi:10.1016/j.jacc.2018.10.039
  • Bittner VA, Szarek M, Aylward PE, et al. Effect of alirocumab on lipoprotein(a) and cardiovascular risk after acute coronary syndrome. J Am Coll Cardiol. 2020;75(2):133–144. doi:10.1016/j.jacc.2019.10.057
  • Goodman SG, Aylward PE, Szarek M, et al. Effects of alirocumab on cardiovascular events after coronary bypass surgery. J Am Coll Cardiol. 2019;74(9):1177–1186. doi:10.1016/j.jacc.2019.07.015
  • Jukema JW, Szarek M, Zijlstra LE, et al. Alirocumab in patients with polyvascular disease and recent acute coronary syndrome: ODYSSEY OUTCOMES trial. J Am Coll Cardiol. 2019;74(9):1167–1176. doi:10.1016/j.jacc.2019.03.013
  • Ray KK, Colhoun HM, Szarek M, et al. Effects of alirocumab on cardiovascular and metabolic outcomes after acute coronary syndrome in patients with or without diabetes: a prespecified analysis of the ODYSSEY OUTCOMES randomised controlled trial. Lancet Diabetes Endocrinol. 2019;7(8):618–628. doi:10.1016/S2213-8587(19)30158-5
  • Sinnaeve PR, Schwartz GG, Wojdyla DM, et al. Effect of alirocumab on cardiovascular outcomes after acute coronary syndromes according to age: an ODYSSEY OUTCOMES trial analysis. Eur Heart J. 2019. doi:10.1093/eurheartj/ehz809
  • Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA. 2016;316(7):743–753. doi:10.1001/jama.2016.11004
  • Navar AM, Taylor B, Mulder H, et al. Association of prior authorization and out-of-pocket costs with patient access to PCSK9 inhibitor therapy. JAMA Cardiol. 2017;2(11):1217–1225. doi:10.1001/jamacardio.2017.3451
  • Robinson JG, Jayanna MB, Brown AS, et al. Enhancing the value of PCSK9 monoclonal antibodies by identifying patients most likely to benefit. A consensus statement from the National Lipid Association. J Clin Lipidol. 2019;13(4):525–537. doi:10.1016/j.jacl.2019.05.005
  • Szarek M, Steg PG, DiCenso D, et al. Alirocumab reduces total hospitalizations and increases days alive and out of hospital in the ODYSSEY OUTCOMES trial. Circ Cardiovasc Qual Outcomes. 2019;12(11):e005858. doi:10.1161/circoutcomes.119.005858
  • Bhatt DL, Briggs AH, Reed SD, et al. Cost-effectiveness of alirocumab in patients with acute coronary syndromes: the ODYSSEY OUTCOMES trial. J Am Coll Cardiol. 2020;75(18):2297–2308. doi:10.1016/j.jacc.2020.03.029
  • Farnier M, Hovingh GK, Langslet G, et al. Long-term safety and efficacy of alirocumab in patients with heterozygous familial hypercholesterolemia: an open-label extension of the ODYSSEY program. Atherosclerosis. 2018;278:307–314. doi:10.1016/j.atherosclerosis.2018.08.036
  • Koren MJ, Giugliano RP, Raal FJ, et al. Efficacy and safety of longer-term administration of evolocumab (AMG 145) in patients with hypercholesterolemia: 52-week results from the Open-Label Study of Long-Term Evaluation Against LDL-C (OSLER) randomized trial. Circulation. 2014;129(2):234–243. doi:10.1161/CIRCULATIONAHA.113.007012
  • Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term low-density lipoprotein cholesterol-lowering efficacy, persistence, and safety of evolocumab in treatment of hypercholesterolemia: results up to 4 years from the open-label OSLER-1 extension study. JAMA Cardiol. 2017;2(6):598–607. doi:10.1001/jamacardio.2017.0747
  • Koren MJ, Sabatine MS, Giugliano RP, et al. Long-term efficacy and safety of evolocumab in patients with hypercholesterolemia. J Am Coll Cardiol. 2019;74(17):2132–2146. doi:10.1016/j.jacc.2019.08.1024
  • Ray KK, Ginsberg HN, Davidson MH, et al. Reductions in atherogenic lipids and major cardiovascular events: a pooled analysis of 10 ODYSSEY trials comparing alirocumab with control. Circulation. 2016;134(24):1931–1943. doi:10.1161/circulationaha.116.024604
  • Robinson JG, Rosenson RS, Farnier M, et al. Safety of very low low-density lipoprotein cholesterol levels with alirocumab: pooled data from randomized trials. J Am Coll Cardiol. 2017;69(5):471–482. doi:10.1016/j.jacc.2016.11.037
  • Jones PH, Bays HE, Chaudhari U, et al. Safety of alirocumab (a PCSK9 monoclonal antibody) from 14 randomized trials. Am J Cardiol. 2016;118(12):1805–1811. doi:10.1016/j.amjcard.2016.08.072
  • Jukema JW, Zijlstra LE, Bhatt DL, et al. Effect of alirocumab on stroke in ODYSSEY OUTCOMES. Circulation. 2019;140(25):2054–2062. doi:10.1161/CIRCULATIONAHA.119.043826
  • Stoekenbroek RM, Lambert G, Cariou B, Hovingh GK. Inhibiting PCSK9 - biology beyond LDL control. Nat Rev Endocrinol. 2018;15(1):52–62. doi:10.1038/s41574-018-0110-5
  • Turgeon RD, Tsuyuki RT, Gyenes GT, Pearson GJ. Cardiovascular efficacy and safety of pcsk9 inhibitors: systematic review and meta-analysis including the ODYSSEY OUTCOMES trial. Can J Cardiol. 2018;34(12):1600–1605. doi:10.1016/j.cjca.2018.04.002
  • Karatasakis A, Danek BA, Karacsonyi J, et al. Effect of PCSK9 inhibitors on clinical outcomes in patients with hypercholesterolemia: a meta-analysis of 35 randomized controlled trials. J Am Heart Assoc. 2017;6:12. doi:10.1161/JAHA.117.006910
  • 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. doi:10.1001/jama.285.13.1711
  • de Lemos JA, Blazing MA, Wiviott SD, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: phase Z of the A to Z trial. JAMA. 2004;292(11):1307–1316. doi:10.1001/jama.292.11.1307
  • Cannon CP, Braunwald E, McCabe CH, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. 2004;350(15):1495–1504. doi:10.1056/NEJMoa040583
  • Seidah NG, Prat A, Pirillo A, Catapano AL, Norata GD. Novel strategies to target proprotein convertase subtilisin kexin 9: beyond monoclonal antibodies. Cardiovasc Res. 2019;115(3):510–518. doi:10.1093/cvr/cvz003
  • Ferri N, Tibolla G, Pirillo A, et al. Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels. Atherosclerosis. 2012;220(2):381–386. doi:10.1016/j.atherosclerosis.2011.11.026
  • Ray KK, Landmesser U, Leiter LA, et al. Inclisiran in patients at high cardiovascular risk with elevated LDL cholesterol. N Engl J Med. 2017;376(15):1430–1440. doi:10.1056/NEJMoa1615758
  • Leiter LA, Teoh H, Kallend D, et al. Inclisiran lowers LDL-C and PCSK9 irrespective of diabetes status: the ORION-1 randomized clinical trial. Diabetes Care. 2019;42(1):173–176. doi:10.2337/dc18-1491
  • Wright RS, Collins MG, Stoekenbroek RM, et al. Effects of renal impairment on the pharmacokinetics, efficacy, and safety of inclisiran: an analysis of the ORION-7 and ORION-1 studies. Mayo Clin Proc. 2020;95(1):77–89. doi:10.1016/j.mayocp.2019.08.021
  • Ray KK, Stoekenbroek RM, Kallend D, et al. Effect of 1 or 2 doses of inclisiran on low-density lipoprotein cholesterol levels: one-year follow-up of the ORION-1 randomized clinical trial. JAMA Cardiol. 2019;4(11):1067. doi:10.1001/jamacardio.2019.3502
  • 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. doi:10.1056/NEJMoa1913805
  • 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;382(16):1507–1519. doi:10.1056/NEJMoa1912387
  • Robinson JG, Gidding SS. Curing atherosclerosis should be the next major cardiovascular prevention goal. J Am Coll Cardiol. 2014;63(25Pt A):2779–2785. doi:10.1016/j.jacc.2014.04.009
  • Luirink IK, Wiegman A, Kusters DM, et al. 20-year follow-up of statins in children with familial hypercholesterolemia. N Engl J Med. 2019;381(16):1547–1556. doi:10.1056/NEJMoa1816454
  • Damask A, Steg PG, Schwartz GG, et al. Patients with high genome-wide polygenic risk scores for coronary artery disease may receive greater clinical benefit from alirocumab treatment in the ODYSSEY OUTCOMES trial. Circulation. 2019. https://www.ncbi.nlm.nih.gov/pubmed/31707832.
  • Marston NA, Kamanu FK, Nordio F, et al. Predicting benefit from evolocumab therapy in patients with atherosclerotic disease using a genetic risk score: results from the FOURIER trial. Circulation. 2019. https://www.ncbi.nlm.nih.gov/pubmed/31707849.
  • Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2019 executive summary. Endocr Pract. 2019;25(1):69–100. doi:10.4158/cs-2018-0535