Effects of PCSK9 inhibition with alirocumab on lipoprotein metabolism in healthy humans

Circulation

Volumn 135, Issue 4, 2017, Pages 352-362

  Reyes Soffer, Gissette ^a   Pavlyha, Marianna ^a   Ngai, Colleen ^a   Thomas, Tiffany ^a   Holleran, Stephen ^a   Ramakrishnan, Rajasekhar ^a   Karmally, Wahida ^a   Nandakumar, Renu ^a   Fontanez, Nelson ^a   Obunike, Joseph ^b   Marcovina, Santica M ^c   Lichtenstein, Alice H ^d   Matthan, Nirupa R ^d   Matta, James ^e   Maroccia, Magali ^f   Becue, Frederic ^e   Poitiers, Franck ^e   Swanson, Brian ^e   Cowan, Lisa ^e   Sasiela, William J ^g   Surks, Howard K ^e   Ginsberg, Henry N ^a   more..

^a College of Physicians and Surgeons ^*  (United States)

^b CITY UNIVERSITY OF NEW YORK   (United States)

^c UNIVERSITY OF WASHINGTON   (United States)

^d TUFTS UNIVERSITY   (United States)

^e SANOFI   (France)

^f Umanis   (France)

^g REGENERON PHARMACEUTICALS INC   (United States)

Author keywords

apoliprotein; LDL receptor; lipoproteins; low density lipoprotein; Lp(a); PCSK9

Indexed keywords

ALIROCUMAB; APOLIPOPROTEIN B; APOLIPOPROTEIN B48; APOLIPOPROTEIN C3; GLUCOSE; HEPARIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; INTERMEDIATE DENSITY LIPOPROTEIN; LATHOSTEROL; LIPOPROTEIN; LIVER TRIACYLGLYCEROL LIPASE; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PLACEBO; PROPROTEIN CONVERTASE 9; SITOSTEROL; TRIACYLGLYCEROL; VERY LOW DENSITY LIPOPROTEIN; MONOCLONAL ANTIBODY; PCSK9 PROTEIN, HUMAN;

ADULT; ARTICLE; CHOLESTEROL BLOOD LEVEL; CLINICAL ARTICLE; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; DRUG CLEARANCE; ENZYME INHIBITION; EXPLORATORY RESEARCH; FEMALE; GLUCOSE BLOOD LEVEL; HUMAN; HYPERLIPIDEMIA; LIPOPROTEIN BLOOD LEVEL; LIPOPROTEIN METABOLISM; MALE; MIDDLE AGED; PHASE 1 CLINICAL TRIAL; PRIORITY JOURNAL; SINGLE BLIND PROCEDURE; SUBCUTANEOUS IMMUNOTHERAPY; TRIACYLGLYCEROL BLOOD LEVEL; ADOLESCENT; AGED; ANTAGONISTS AND INHIBITORS; CLINICAL TRIAL; METABOLISM; NORMAL HUMAN; YOUNG ADULT;

ADOLESCENT; ADULT; AGED; ANTIBODIES, MONOCLONAL; FEMALE; HEALTHY VOLUNTEERS; HUMANS; LIPOPROTEINS, VLDL; MALE; MIDDLE AGED; PROPROTEIN CONVERTASE 9; YOUNG ADULT;

EID: 85007439387     PISSN: 00097322     EISSN: 15244539     Source Type: Journal    
DOI: 10.1161/CIRCULATIONAHA.116.025253     Document Type: Article

References (48)

1. Horton JD, Cohen JC, Hobbs HH, PCSK9: a convertase that coordinates LDL catabolism. J Lipid Res 2009 50 Suppl S172 S177. doi: 10.1194/jlr.R800091-JLR200
2. Seidah NG, Awan Z, Chrétien M, Mbikay M, PCSK9: a key modulator of cardiovascular health. Circ Res 2014 114 1022 1036. doi: 10.1161/CIRCRESAHA.114.301621
3. Cannon CP, Cariou B, Blom D, McKenney JM, Lorenzato C, Pordy R, Chaudhari U, Colhoun HM, ODYSSEY COMBO II investigators 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. doi: 10.1093/eurheartj/ehv028
4. Kastelein JJ, Ginsberg HN, Langslet G, Hovingh GK, Ceska R, Dufour R, Blom D, Civeira F, Krempf M, Lorenzato C, Zhao J, Pordy R, Baccara-Dinet MT, Gipe DA, Geiger MJ, Farnier M, ODYSSEY FH I and FH II: 78 week results with alirocumab treatment in 735 patients with heterozygous familial hypercholesterolaemia. Eur Heart J 2015 36 2996 3003. doi: 10.1093/eurheartj/ehv370
5. Robinson JG, Farnier M, Krempf M, Bergeron J, Luc G, Averna M, Stroes ES, Langslet G, Raal FJ, El Shahawy M, Koren MJ, Lepor NE, Lorenzato C, Pordy R, Chaudhari U, Kastelein JJ, ODYSSEY LONG TERM investigators Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015 372 1489 1499. doi: 10.1056/NEJMoa1501031
6. Kita T, Brown MS, Bilheimer DW, Goldstein JL, Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits. Proc Natl Acad Sci U S A 1982 79 5693 5697
7. Krul ES, Tikkanen MJ, Cole TG, Davie JM, Schonfeld G, Roles of apolipoproteins B and E in the cellular binding of very low density lipoproteins. J Clin Invest 1985 75 361 369. doi: 10.1172/JCI111708
8. Mahley RW, Ji ZS, Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J Lipid Res 1999 40 1 16
9. Gaudet D, Kereiakes DJ, McKenney JM, Roth EM, Hanotin C, Gipe D, Du Y, Ferrand AC, Ginsberg HN, Stein EA, Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150 mg every two weeks dosing from phase 2 trials). Am J Cardiol 2014 114 711 715. doi: 10.1016/j.amjcard.2014.05.060
10. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA, 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 2344 2353. doi: 10.1016/j.jacc.2012.03.007
11. Kostner GM, Gavish D, Leopold B, Bolzano K, Weintraub MS, Breslow JL, HMG CoA reductase inhibitors lower LDL cholesterol without reducing Lp(a) levels. Circulation 1989 80 1313 1319
12. Reyes-Soffer G, Moon B, Hernandez-Ono A, Dionizovik-Dimanovski M, Dionizovick-Dimanovski M, Jimenez J, Obunike J, Thomas T, Ngai C, Fontanez N, Donovan DS, Karmally W, Holleran S, Ramakrishnan R, Mittleman RS, Ginsberg HN, Complex effects of inhibiting hepatic apolipoprotein B100 synthesis in humans. Sci Transl Med 2016 8 323ra12. doi: 10.1126/scitranslmed.aad2195
13. Marcovina SM, Albers JJ, Scanu AM, Kennedy H, Giaculli F, Berg K, Couderc R, Dati F, Rifai N, Sakurabayashi I, Tate JR, Steinmetz A, Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a). Clin Chem 2000 46 1956 1967
14. Marcovina SM, Hobbs HH, Albers JJ, Relation between number of apolipoprotein(a) kringle 4 repeats and mobility of isoforms in agarose gel: basis for a standardized isoform nomenclature. Clin Chem 1996 42 436 439
15. Caulfield MP, Li S, Lee G, Blanche PJ, Salameh WA, Benner WH, Reitz RE, Krauss RM, Direct determination of lipoprotein particle sizes and concentrations by ion mobility analysis. Clin Chem 2008 54 1307 1316. doi: 10.1373/clinchem.2007.100586
16. Matthan NR, Resteghini N, Robertson M, Ford I, Shepherd J, Packard C, Buckley BM, Jukema JW, Lichtenstein AH, Schaefer EJ, PROSPER Group Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy: insights from the PROSPER trial. J Lipid Res 2010 51 202 209. doi: 10.1194/jlr.M900032-JLR200
17. Nagashima K, Lopez C, Donovan D, Ngai C, Fontanez N, Bensadoun A, Fruchart-Najib J, Holleran S, Cohn JS, Ramakrishnan R, Ginsberg HN, Effects of the PPARgamma agonist pioglitazone on lipoprotein metabolism in patients with type 2 diabetes mellitus. J Clin Invest 2005 115 1323 1332. doi: 10.1172/JCI23219
18. Ramakrishnan R, Studying apolipoprotein turnover with stable isotope tracers: correct analysis is by modeling enrichments. J Lipid Res 2006 47 2738 2753. doi: 10.1194/jlr.M600302-JLR200
19. Berglund L, Witztum JL, Galeano NF, Khouw AS, Ginsberg HN, Ramakrishnan R, Three-fold effect of lovastatin treatment on low density lipoprotein metabolism in subjects with hyperlipidemia: increase in receptor activity, decrease in apoB production, and decrease in particle affinity for the receptor: results from a novel triple-Tracer approach. J Lipid Res 1998 39 913 924
20. Zhou H, Castro-Perez J, Lassman ME, Thomas T, Li W, McLaughlin T, Dan X, Jumes P, Wagner JA, Gutstein DE, Hubbard BK, Rader DJ, Millar JS, Ginsberg HN, Reyes-Soffer G, Cleary M, Previs SF, Roddy TP, Measurement of apo(a) kinetics in human subjects using a microfluidic device with tandem mass spectrometry. Rapid Commun Mass Spectrom 2013 27 1294 1302. doi: 10.1002/rcm.6572
21. Reyes-Soffer G, Holleran S, Karmally W, Ngai CI, Chen NT, Torres M, Ramakrishnan R, Blaner WS, Berglund L, Ginsberg HN, Tuck C, Measures of postprandial lipoproteins are not associated with coronary artery disease in patients with type 2 diabetes mellitus. J Lipid Res 2009 50 1901 1909. doi: 10.1194/jlr.M900092-JLR200
22. Sabatine MS, Giugliano RP, Wiviott SD, Raal FJ, Blom DJ, Robinson J, Ballantyne CM, Somaratne R, Legg J, Wasserman SM, Scott R, Koren MJ, Stein EA, Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) investigators Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015 372 1500 1509. doi: 10.1056/NEJMoa1500858
23. Ginsberg HN, Effects of statins on triglyceride metabolism. Am J Cardiol 1998 81 4A 32B 35B
24. Ginsberg HN, Review: Efficacy and mechanisms of action of statins in the treatment of diabetic dyslipidemia. J Clin Endocrinol Metab 2006 91 383 392. doi: 10.1210/jc.2005-2084
25. Brown MS, Goldstein JL, How LDL receptors influence cholesterol and atherosclerosis. Sci Am 1984 251 58 66
26. Campos H, Arnold KS, Balestra ME, Innerarity TL, Krauss RM, Differences in receptor binding of LDL subfractions. Arterioscler Thromb Vasc Biol 1996 16 794 801
27. Havel RJ, Functional activities of hepatic lipoprotein receptors. Annu Rev Physiol 1986 48 119 134. doi: 10.1146/annurev.ph.48.030186.001003
28. Packard CJ, Munro A, Lorimer AR, Gotto AM, Shepherd J, Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects. J Clin Invest 1984 74 2178 2192. doi: 10.1172/JCI111644
29. Sun H, Samarghandi A, Zhang N, Yao Z, Xiong M, Teng BB, Proprotein convertase subtilisin/kexin type 9 interacts with apolipoprotein B and prevents its intracellular degradation, irrespective of the low-density lipoprotein receptor. Arterioscler Thromb Vasc Biol 2012 32 1585 1595. doi: 10.1161/ATVBAHA.112.250043
30. Rashid S, Tavori H, Brown PE, Linton MF, He J, Giunzioni I, Fazio S, Proprotein convertase subtilisin kexin type 9 promotes intestinal overproduction of triglyceride-rich apolipoprotein B lipoproteins through both low-density lipoprotein receptor-dependent and-independent mechanisms. Circulation 2014 130 431 441. doi: 10.1161/CIRCULATIONAHA.113.006720
31. Le May C, Kourimate S, Langhi C, Chétiveaux M, Jarry A, Comera C, Collet X, Kuipers F, Krempf M, Cariou B, Costet P, Proprotein convertase subtilisin kexin type 9 null mice are protected from postprandial triglyceridemia. Arterioscler Thromb Vasc Biol 2009 29 684 690. doi: 10.1161/ATVBAHA.108.181586
32. Ouguerram K, Chetiveaux M, Zair Y, Costet P, Abifadel M, Varret M, Boileau C, Magot T, Krempf M, Apolipoprotein B100 metabolism in autosomal-dominant hypercholesterolemia related to mutations in PCSK9. Arterioscler Thromb Vasc Biol 2004 24 1448 1453. doi: 10.1161/01.ATV.0000133684.77013.88
33. Kempen HJ, Glatz JF, Gevers Leuven JA, van der Voort HA, Katan MB, Serum lathosterol concentration is an indicator of whole-body cholesterol synthesis in humans. J Lipid Res 1988 29 1149 1155
34. Stellaard F, von Bergmann K, Sudhop T, Lütjohann D, The value of surrogate markers to monitor cholesterol absorption, synthesis and bioconversion to bile acids under lipid lowering therapies. J Steroid Biochem Mol Biol 2016 S0960-0760(16)30076-0. pii. doi: 10.1016/j.jsbmb.2016.03.030. [Epub ahead of print]
35. Berg K, A new serum type system in man-The Lp system. Acta Pathol Microbiol Scand 1963 59 369 382
36. Schmidt K, Noureen A, Kronenberg F, Utermann G, Structure, function, and genetics of lipoprotein (a). J Lipid Res 2016 57 1339 1359. doi: 10.1194/jlr.R067314
37. Rader DJ, Cain W, Ikewaki K, Talley G, Zech LA, Usher D, Brewer HB Jr., The inverse association of plasma lipoprotein(a) concentrations with apolipoprotein(a) isoform size is not due to differences in Lp(a) catabolism but to differences in production rate. J Clin Invest 1994 93 2758 2763. doi: 10.1172/JCI117292
38. Rader DJ, Mann WA, Cain W, Kraft HG, Usher D, Zech LA, Hoeg JM, Davignon J, Lupien P, Grossman M, The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans. J Clin Invest 1995 95 1403 1408. doi: 10.1172/JCI117794
39. Cain WJ, Millar JS, Himebauch AS, Tietge UJ, Maugeais C, Usher D, Rader DJ, Lipoprotein [a] is cleared from the plasma primarily by the liver in a process mediated by apolipoprotein [a]. J Lipid Res 2005 46 2681 2691. doi: 10.1194/jlr.M500249-JLR200
40. Romagnuolo R, Scipione CA, Boffa MB, Marcovina SM, Seidah NG, Koschinsky ML, Lipoprotein(a) catabolism is regulated by proprotein convertase subtilisin/kexin type 9 through the low density lipoprotein receptor. J Biol Chem 2015 290 11649 11662. doi: 10.1074/jbc.M114.611988
41. Tada H, Kawashiri MA, Yoshida T, Teramoto R, Nohara A, Konno T, Inazu A, Mabuchi H, Yamagishi M, Hayashi K, Lipoprotein(a) in familial hypercholesterolemia with proprotein convertase subtilisin/kexin type 9 (PCSK9) gain-of-function mutations. Circ J 2016 80 512 518. doi: 10.1253/circj.CJ-15-0999
42. Welder G, Zineh I, Pacanowski MA, Troutt JS, Cao G, Konrad RJ, High-dose atorvastatin causes a rapid sustained increase in human serum PCSK9 and disrupts its correlation with LDL cholesterol. J Lipid Res 2010 51 2714 2721. doi: 10.1194/jlr.M008144
43. Raal FJ, Honarpour N, Blom DJ, Hovingh GK, Xu F, Scott R, Wasserman SM, Stein EA, TESLA investigators Inhibition of PCSK9 with evolocumab in homozygous familial hypercholesterolaemia (TESLA Part B): a randomised, double-blind, placebo-controlled trial. Lancet 2015 385 341 350. doi: 10.1016/S0140-6736(14)61374-X
44. Diffenderfer MR, Lamon-Fava S, Marcovina SM, Barrett PH, Lel J, Dolnikowski GG, Berglund L, Schaefer EJ, Distinct metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein(a). Metabolism 2016 65 381 390. doi: 10.1016/j.metabol.2015.10.031
45. Jenner JL, Seman LJ, Millar JS, Lamon-Fava S, Welty FK, Dolnikowski GG, Marcovina SM, Lichtenstein AH, Barrett PH, deLuca C, Schaefer EJ, The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a) in human beings. Metabolism 2005 54 361 369. doi: 10.1016/j.metabol.2004.10.001
46. Frischmann ME, Ikewaki K, Trenkwalder E, Lamina C, Dieplinger B, Soufi M, Schweer H, Schaefer JR, König P, Kronenberg F, Dieplinger H, In vivo stable-isotope kinetic study suggests intracellular assembly of lipoprotein(a). Atherosclerosis 2012 225 322 327. doi: 10.1016/j.atherosclerosis.2012.09.031
47. Parhofer KG, Demant T, Ritter MM, Geiss HC, Donner M, Schwandt P, Lipoprotein (a) metabolism estimated by nonsteady-state kinetics. Lipids 1999 34 325 335
48. Brown MS, Goldstein JL, The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 1997 89 331 340