title: Effects of PCSK9 Inhibition With Alirocumab on Lipoprotein Metabolism in Healthy Humans.
abstract: BACKGROUND
  Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9), lowers plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B100 (apoB). Although studies in mice and cells have identified increased hepatic LDL receptors as the basis for LDL lowering by PCSK9 inhibitors, there have been no human studies characterizing the effects of PCSK9 inhibitors on lipoprotein metabolism. In particular, it is not known whether inhibition of PCSK9 has any effects on very low-density lipoprotein or intermediate-density lipoprotein (IDL) metabolism. Inhibition of PCSK9 also results in reductions of plasma lipoprotein (a) levels. The regulation of plasma Lp(a) levels, including the role of LDL receptors in the clearance of Lp(a), is poorly defined, and no mechanistic studies of the Lp(a) lowering by alirocumab in humans have been published to date.
  
  
  METHODS
  Eighteen (10 F, 8 mol/L) participants completed a placebo-controlled, 2-period study. They received 2 doses of placebo, 2 weeks apart, followed by 5 doses of 150 mg of alirocumab, 2 weeks apart. At the end of each period, fractional clearance rates (FCRs) and production rates (PRs) of apoB and apo(a) were determined. In 10 participants, postprandial triglycerides and apoB48 levels were measured.
  
  
  RESULTS
  Alirocumab reduced ultracentrifugally isolated LDL-C by 55.1%, LDL-apoB by 56.3%, and plasma Lp(a) by 18.7%. The fall in LDL-apoB was caused by an 80.4% increase in LDL-apoB FCR and a 23.9% reduction in LDL-apoB PR. The latter was due to a 46.1% increase in IDL-apoB FCR coupled with a 27.2% decrease in conversion of IDL to LDL. The FCR of apo(a) tended to increase (24.6%) without any change in apo(a) PR. Alirocumab had no effects on FCRs or PRs of very low-density lipoproteins-apoB and very low-density lipoproteins triglycerides or on postprandial plasma triglycerides or apoB48 concentrations.
  
  
  CONCLUSIONS
  Alirocumab decreased LDL-C and LDL-apoB by increasing IDL- and LDL-apoB FCRs and decreasing LDL-apoB PR. These results are consistent with increases in LDL receptors available to clear IDL and LDL from blood during PCSK9 inhibition. The increase in apo(a) FCR during alirocumab treatment suggests that increased LDL receptors may also play a role in the reduction of plasma Lp(a).
  
  
  BACKGROUND
  URL: http://www.clinicaltrials.gov. Unique identifier: NCT01959971.
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.). gr2104@cumc.columbia.edu hng1@cumc.columbia.edu.
authors.forename: Gissette
authors.initials: G
authors.lastname: Reyes-Soffer
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Marianna
authors.initials: M
authors.lastname: Pavlyha
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Colleen
authors.initials: C
authors.lastname: Ngai
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Tiffany
authors.initials: T
authors.lastname: Thomas
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Stephen
authors.initials: S
authors.lastname: Holleran
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Ramakrishnan
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Wahida
authors.initials: W
authors.lastname: Karmally
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Renu
authors.initials: R
authors.lastname: Nandakumar
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Nelson
authors.initials: N
authors.lastname: Fontanez
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Joseph
authors.initials: J
authors.lastname: Obunike
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Santica M
authors.initials: SM
authors.lastname: Marcovina
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Alice H
authors.initials: AH
authors.lastname: Lichtenstein
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Nirupa R
authors.initials: NR
authors.lastname: Matthan
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: James
authors.initials: J
authors.lastname: Matta
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Magali
authors.initials: M
authors.lastname: Maroccia
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Frederic
authors.initials: F
authors.lastname: Becue
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Franck
authors.initials: F
authors.lastname: Poitiers
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Brian
authors.initials: B
authors.lastname: Swanson
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Lisa
authors.initials: L
authors.lastname: Cowan
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: William J
authors.initials: WJ
authors.lastname: Sasiela
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.).
authors.forename: Howard K
authors.initials: HK
authors.lastname: Surks
authors.affiliation: From Columbia University College of Physicians and Surgeons, New York (G.R.-S., M.P., C.N., T.T., S.H., R.R., W.K., R.N., N.F., H.N.G.); The City University of New York (J.O.); Northwest Lipid Metabolism and Diabetes Research Laboratories, University of Washington, Seattle (S.M.M.); Cardiovascular Nutrition Laboratory, JM USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA (A.H.L., N.R.M.); Sanofi, Bridgewater, NJ (J.M., B.S., L.C., H.K.S.); Umanis, Levallois-Perret, France (M.M.); Sanofi, Montpellier, France (F.B.); Sanofi, Paris, France (F.P.); and Regeneron Pharmaceuticals, Inc., Tarrytown, NY (W.J.S.). gr2104@cumc.columbia.edu hng1@cumc.columbia.edu.
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D000091362:PCSK9 Inhibitors; D055815:Young Adult; D000071449:Proprotein Convertase 9
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008079:Lipoproteins, VLDL; D000091362:PCSK9 Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C571059:alirocumab
keywords: LDL receptor; Lp(a); PCSK9; apoliprotein; lipoproteins; low-density lipoprotein