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CME/CE Spotlights

Focus on PCSK9 Inhibitors: From Genetics to Clinical Practice

Highlights from a CME symposium held at the Cardiometabolic Health Congress (CMHC) Sheraton Boston Hotel, Boston, MA, USA, 23 October 2015

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References

  • 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.
  • Cholesterol Treatment Trialists’ (CTT) Collaboration. 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.
  • Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American heart association task force on practice guidelines. Circulation. 2014;129(Suppl 2):S1–S45.
  • Abifadel M, Varret M, Rabes JP, et al. Mutations in PCSK9 cause autosomal dominant hypercholesterolemia. Nat Genet. 2003;34:154–156.
  • 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 USA. 2003;100:928–933.
  • Horton JD, Shah NA, Warrington JA, et al. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes. Proc Natl Acad Sci USA. 2003;100:12027–12032.
  • Lagace TA, Curtis DE, Garuti R, et al. Secreted PCSK9 decreases the number of LDL receptors in hepatocytes and in livers of parabiotic mice. J Clin Invest. 2006;116:2995–3005.
  • Lose JM, Dorsch MP, Bleske BE. Evaluation of proprotein convertase subtilisin/kexin type 9: focus on potential clinical and therapeutic implications for low-density lipoprotein cholesterol lowering. Pharmacotherapy. 2013;33:447–460.
  • Maxwell K, Fisher EA, Breslow JL. Overexpression of PCSK9 accelerates the degradation of the LDLR in a post-endoplasmic reticulum compartment. Proc Natl Acad Sci USA. 2005;102:2069–2074.
  • Cohen JC, Boerwinkle E, Mosley TH Jr, et al. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006;354:1264–1272.
  • Strøm TB, Tveten K, Leren TP. PCSK9 acts as a chaperone for the LDL receptor in the endoplasmic reticulum. Biochem J. 2014;457:99–105.
  • Zhang DW, Garuti R, Tang WJ, et al. Structural requirements for PCSK9-mediated degradation of the low-density lipoprotein receptor. Proc Natl Acad Sci USA. 2008;105:13045–13050.
  • Schroeder HW Jr, Cavacini L. Structure and function of immunoglobulins. J Allergy Clin Immunol. 2010;125(2 Suppl 2):S41–S52.
  • Stein EA, Mellis S, Yancopoulos GD, et al. Effect of a monoclonal antibody to PCSK9 on LDL cholesterol. N Engl J Med. 2012;366:1108–1118.
  • Verbeek R, Stoekenbroek RM, Hovingh GK. PCSK9 inhibitors: novel therapeutic agents for the treatment of hypercholesterolemia. Eur J Pharmacol. 2015;763(Pt A):38–47.
  • Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1489–1499.
  • Sabatine MC, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372:1500–1509.
  • 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;380:2007–2017.
  • 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;36:1186–1194.
  • 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;115:1212–1221.
  • Benn M, Watts GF, Tybjaerg-Hansen A, et al. Familial hypercholesterolemia in the Danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012;97:3956–3964.
  • 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;385:331–340.
  • Kastelein JJP, Ginsberg HN, Langslet G, et al. ODYSSEY FH I and II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J. 2015. doi:10.1093/eurheartj/ehv370.
  • FDA. FDA approves evolocumab to treat certain patients with high cholesterol. [cited 2016 Feb 18]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm460082.htm.
  • FDA. FDA approves alirocumab to treat certain patients with high cholesterol. [cited 2016 Feb 18]. Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm455883.htm.
  • Raal FJ, Honarpour N, Blom DJ, et al. Trial evaluating evolocumab, a pcsk9 antibody, in patients with homozygous fh (tesla): results of the randomized, double-blind, placebo-controlled trial. Artheorsclerosis. 2014;235(2):e12.
  • 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.
  • Zhang H, Plutzky J, Skentzos S, et al. Discontinuation of statins in routine care settings: a cohort study. Ann Int Med. 2013;158:526–534.
  • Cohen JD, Brinton EA, Ito MK, et al. Understanding Statin use in America and Gaps in Patient Education (USAGE): an internet-based survey of 10,138 current and former statin users. J Clin Lipidol. 2012;6:208–215.
  • 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;63:2541–2548.
  • Moriarty PM, Jacobson TA, Bruckert E, et al. Efficacy and safety of alirocumab, a monoclonal antibody to PCSK9, in statin-intolerant patients: design and rationale of ODYSSEY ALTERNATIVE, a randomized phase 3 trial. J Clin Lipidol. 2014;8:554–561.
  • Clinical Trials.Gov. ODYSSEY Outcomes: evaluation of cardiovascular outcomes after an acute coronary syndrome during treatment with alirocumab. [cited 2016 Jan 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT01663402.
  • Clinical Trials.Gov. Further cardiovascular outcomes research with PCSK9 inhibition in subjects with elevated risk (FOURIER) [cited 2016 Jan 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT01764633.
  • Clinical Trials.Gov. The evaluation of bococizumab (PF-04950615;RN316) in reducing the occurrence of major cardiovascular events in high risk subjects (SPIRE-1). [cited 2016 Jan 12]. Available from: https://clinicaltrials.gov/ct2/show/NCT01975376.
  • Clinical Trials.Gov. The evaluation of bococizumab (PF-04950615; RN316) in reducing the occurrence of major cardiovascular events in high risk subjects (SPIRE-2). [cited 2016 Jan 12] https://clinicaltrials.gov/ct2/show/NCT01975389.
  • Goldstein JL, Brown MS. Familial hypercholesterolemia: identification of a defect in the regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity associated with overproduction of cholesterol. Proc Natl Acad Sci USA. 1973;70:2804–2808.
  • Goldberg AC, Hopkins PN, Toth P, et al. Familial hypercholesterolemia: screening, diagnosis and management of pediatric and adult patients. J Clin Lipidol. 2011;5:S1–S8.
  • Civeira F. International panel on management of familial hypercholesterolemia. Guidelines for the diagnosis and management of heterozygous familial hypercholesterolemia. Atherosclerosis. 2004;173:55–68.
  • Descamps O, Leysen X, Van Leuven F, et al. The use of Achilles tendon ultrasonography for the diagnosis of familial hypercholesterolemia. Atherosclerosis. 2001;157:514–518.

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