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CETP (Cholesteryl Ester Transfer Protein) Inhibition With Anacetrapib Decreases Production of Lipoprotein(a) in Mildly Hypercholesterolemic Subjects.
Thomas, Tiffany; Zhou, Haihong; Karmally, Wahida; Ramakrishnan, Rajasekhar; Holleran, Stephen; Liu, Yang; Jumes, Patricia; Wagner, John A; Hubbard, Brian; Previs, Stephen F; Roddy, Thomas; Johnson-Levonas, Amy O; Gutstein, David E; Marcovina, Santica M; Rader, Daniel J; Ginsberg, Henry N; Millar, John S; Reyes-Soffer, Gissette.
Afiliação
  • Thomas T; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Zhou H; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Karmally W; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Ramakrishnan R; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Holleran S; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Liu Y; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Jumes P; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Wagner JA; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Hubbard B; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Previs SF; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Roddy T; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Johnson-Levonas AO; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Gutstein DE; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Marcovina SM; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Rader DJ; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Ginsberg HN; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Millar JS; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.).
  • Reyes-Soffer G; From the Columbia University, New York (T.T., W.K., R.R., S.H., H.N.G., G.R.-S.); Merck & Co, Inc, Kenilworth, NJ (H.Z., Y.L., P.J., J.A.W., B.H., S.F.P., T.R., A.O.J.-L., D.E.G.); University of Washington, Seattle (S.M.M.); and University of Pennsylvania, Philadelphia (D.J.R., J.S.M.). gr2104@c
Arterioscler Thromb Vasc Biol ; 37(9): 1770-1775, 2017 09.
Article em En | MEDLINE | ID: mdl-28729361
ABSTRACT

OBJECTIVE:

Lp(a) [lipoprotein (a)] is composed of apoB (apolipoprotein B) and apo(a) [apolipoprotein (a)] and is an independent risk factor for cardiovascular disease and aortic stenosis. In clinical trials, anacetrapib, a CETP (cholesteryl ester transfer protein) inhibitor, causes significant reductions in plasma Lp(a) levels. We conducted an exploratory study to examine the mechanism for Lp(a) lowering by anacetrapib. APPROACH AND

RESULTS:

We enrolled 39 participants in a fixed-sequence, double-blind study of the effects of anacetrapib on the metabolism of apoB and high-density lipoproteins. Twenty-nine patients were randomized to atorvastatin 20 mg/d, plus placebo for 4 weeks, and then atorvastatin plus anacetrapib (100 mg/d) for 8 weeks. The other 10 subjects were randomized to double placebo for 4 weeks followed by placebo plus anacetrapib for 8 weeks. We examined the mechanisms of Lp(a) lowering in a subset of 12 subjects having both Lp(a) levels >20 nmol/L and more than a 15% reduction in Lp(a) by the end of anacetrapib treatment. We performed stable isotope kinetic studies using 2H3-leucine at the end of each treatment to measure apo(a) fractional catabolic rate and production rate. Median baseline Lp(a) levels were 21.5 nmol/L (interquartile range, 9.9-108.1 nmol/L) in the complete cohort (39 subjects) and 52.9 nmol/L (interquartile range, 38.4-121.3 nmol/L) in the subset selected for kinetic studies. Anacetrapib treatment lowered Lp(a) by 34.1% (P≤0.001) and 39.6% in the complete and subset cohort, respectively. The decreases in Lp(a) levels were because of a 41% reduction in the apo(a) production rate, with no effects on apo(a) fractional catabolic rate.

CONCLUSIONS:

Anacetrapib reduces Lp(a) levels by decreasing its production. CLINICAL TRIAL REGISTRATION URL http//www.clinicaltrials.gov. Unique identifier NCT00990808.
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Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Lipoproteína(a) / Oxazolidinonas / Proteínas de Transferência de Ésteres de Colesterol / Hipercolesterolemia / Anticolesterolemiantes Tipo de estudo: Clinical_trials / Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged País/Região como assunto: America do norte Idioma: En Revista: Arterioscler Thromb Vasc Biol Assunto da revista: ANGIOLOGIA Ano de publicação: 2017 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Temas: Geral Base de dados: MEDLINE Assunto principal: Lipoproteína(a) / Oxazolidinonas / Proteínas de Transferência de Ésteres de Colesterol / Hipercolesterolemia / Anticolesterolemiantes Tipo de estudo: Clinical_trials / Diagnostic_studies / Prognostic_studies / Risk_factors_studies Limite: Adult / Aged / Female / Humans / Male / Middle aged País/Região como assunto: America do norte Idioma: En Revista: Arterioscler Thromb Vasc Biol Assunto da revista: ANGIOLOGIA Ano de publicação: 2017 Tipo de documento: Article