title: Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein.
abstract: Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP.
  
  
  
  Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%; P<0.001) and apoA-I levels (29.5%; P<0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (18.2%; P=0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% (P<0.001), we could not discern significant changes in either apoA-II fractional clearance rate or production rate. CETP levels increased 102% (P<0.001) on ANA because of a significant reduction in the fractional clearance rate of CETP (57.6%, P<0.001) with no change in CETP production rate.
  
  
  
  ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein.
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.) jsmillar@upenn.edu.
authors.forename: Gissette
authors.initials: G
authors.lastname: Reyes-Soffer
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: John S
authors.initials: JS
authors.lastname: Millar
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Colleen
authors.initials: C
authors.lastname: Ngai
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Patricia
authors.initials: P
authors.lastname: Jumes
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Ellie
authors.initials: E
authors.lastname: Coromilas
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Bela
authors.initials: B
authors.lastname: Asztalos
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Amy O
authors.initials: AO
authors.lastname: Johnson-Levonas
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Donovan
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Wahida
authors.initials: W
authors.lastname: Karmally
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Rajasekhar
authors.initials: R
authors.lastname: Ramakrishnan
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Stephen
authors.initials: S
authors.lastname: Holleran
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Tiffany
authors.initials: T
authors.lastname: Thomas
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Richard L
authors.initials: RL
authors.lastname: Dunbar
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Emil M
authors.initials: EM
authors.lastname: deGoma
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Hashmi
authors.initials: H
authors.lastname: Rafeek
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Baer
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Michael E
authors.initials: ME
authors.lastname: Lassman
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: David E
authors.initials: DE
authors.lastname: Gutstein
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Rader
authors.affiliation: From the Columbia University, New York, NY (G.R.-S., C.N., E.C., D.S.D., W.K., R.R., S.H., T.T., H.N.G.); University of Pennsylvania, Philadelphia (J.S.M., R.L.D., E.M.d., A.L.B., D.J.R.); Merck & Co., Inc., Kenilworth, NJ (P.J., A.O.J.-L., J.A.W., Y.L., M.E.L., D.E.G.); Tufts University School of Medicine, Boston, MA (B.A.); and Drexel Neurological Associates, Philadelphia, PA (H.R.).
authors.forename: Henry N
authors.initials: HN
authors.lastname: Ginsberg
mesh_terms: D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D016632:Apolipoprotein A-I / Q000097:blood*; D016633:Apolipoprotein A-II / Q000097:blood; D015415:Biomarkers / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins / Q000037:antagonists & inhibitors* / Q000097:blood; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008075:Lipoproteins, HDL / Q000097:blood*; D008297:Male; D008875:Middle Aged; D023303:Oxazolidinones / Q000009:adverse effects / Q000627:therapeutic use*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: C505693:APOA1 protein, human; C115794:APOA2 protein, human; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D015415:Biomarkers; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008075:Lipoproteins, HDL; D023303:Oxazolidinones; C530884:anacetrapib
keywords: apolipoprotein A-I; apolipoprotein A-II; cardiovascular diseases; cholesterol ester transfer proteins; cholesterol, HDL