Mikaël Croyal1, Khadija Ouguerram1, Maxime Passard1, Véronique Ferchaud-Roucher1, Maud Chétiveaux1, Stéphanie Billon-Crossouard1, Anne-Charlotte de Gouville1, Gilles Lambert1, Michel Krempf2, Estelle Nobécourt1. 1. From the CRNH, West Human Nutrition Research Center, Nantes, France (M.C., K.O., M.P., V.F.-R., S.B.-C., G.L., M.K., E.N.); UMR 1280 PhAN Laboratory, National Institute of Agronomic Research, INRA, CHU Hôtel Dieu, HNB1, Nantes, France (M.C., K.O., M.P., V.F.-R., S.B.-C., G.L., M.K.); University of Nantes and Medical School, Nantes, France (M.C., K.O., M.P., M.C., S.B.-C., G.L., M.K., E.N.); GlaxoSmithKline, Les Ulis, France (A.-C.d.G.); and Endocrinology and Nutrition Department, G and R Laennec Hospital, Bd Jacques Monod, Nantes, France (M.K., E.N.). 2. From the CRNH, West Human Nutrition Research Center, Nantes, France (M.C., K.O., M.P., V.F.-R., S.B.-C., G.L., M.K., E.N.); UMR 1280 PhAN Laboratory, National Institute of Agronomic Research, INRA, CHU Hôtel Dieu, HNB1, Nantes, France (M.C., K.O., M.P., V.F.-R., S.B.-C., G.L., M.K.); University of Nantes and Medical School, Nantes, France (M.C., K.O., M.P., M.C., S.B.-C., G.L., M.K., E.N.); GlaxoSmithKline, Les Ulis, France (A.-C.d.G.); and Endocrinology and Nutrition Department, G and R Laennec Hospital, Bd Jacques Monod, Nantes, France (M.K., E.N.). michel.krempf@univ-nantes.fr.
Abstract
OBJECTIVE: To determine the mechanisms by which extended-release nicotinic acid reduces circulating lipoprotein (a) concentrations in hypertriglyceridemic patients. APPROACH AND RESULTS:Eight nondiabetic, obese male subjects (aged 48±12 years; body mass index, 31.2±1.8 kg/m(2)) with hypertriglyceridemia (triglycerides, 226±78 mg/dL) were enrolled in an 8 week, double blind, placebo-controlled cross-over study. At the end of each treatment phase, fasted subjects received a 10 µmol/L per kg bolus injection of [5,5,5-(2)H3]-l-Leucine immediately followed by constant infusion of [5,5,5-(2)H3]-l-Leucine (10 µmol L(-1) kg(-1) h(-1)) for 14 hours, and blood samples were collected. A liquid chromatography-tandem mass spectrometry method was used to study apolipoprotein (a) (Apo(a)) kinetics. The fractional catabolic rate of Apo(a) was calculated with a single compartmental model using the apolipoprotein B100 (ApoB100) containing very low density lipoprotein tracer enrichment as a precursor pool. Extended-release nicotinic acid decreased plasma triglycerides (-46%; P=0.023), raised high-density lipoprotein cholesterol (+20%; P=0.008), and decreased Apo(a) plasma concentrations (-20%; P=0.008). Extended-release nicotinic acid also decreased ApoB100 (22%; P=0.008) and proprotein convertase subtilisin/kexin type 9 (PCSK9, -29%; P=0.008) plasma concentrations. Apo(a) fractional catabolic rate and production rates were decreased by 37% (0.58±0.28 versus 0.36±0.19 pool/d; P=0.008) and 50% (1.4±0.8 versus 0.7±0.4 nmol/kg per day; P=0.008), respectively. CONCLUSIONS:Extended-release nicotinic acid treatment decreased Apo(a) plasma concentrations by 20%, production rates by 50%, and catabolism by 37%. ApoB100 and PCSK9 concentrations were also decreased by treatment, but no correlation was found with Apo(a) kinetic parameters.
RCT Entities:
OBJECTIVE: To determine the mechanisms by which extended-release nicotinic acid reduces circulating lipoprotein (a) concentrations in hypertriglyceridemicpatients. APPROACH AND RESULTS: Eight nondiabetic, obese male subjects (aged 48±12 years; body mass index, 31.2±1.8 kg/m(2)) with hypertriglyceridemia (triglycerides, 226±78 mg/dL) were enrolled in an 8 week, double blind, placebo-controlled cross-over study. At the end of each treatment phase, fasted subjects received a 10 µmol/L per kg bolus injection of [5,5,5-(2)H3]-l-Leucine immediately followed by constant infusion of [5,5,5-(2)H3]-l-Leucine (10 µmol L(-1) kg(-1) h(-1)) for 14 hours, and blood samples were collected. A liquid chromatography-tandem mass spectrometry method was used to study apolipoprotein (a) (Apo(a)) kinetics. The fractional catabolic rate of Apo(a) was calculated with a single compartmental model using the apolipoprotein B100 (ApoB100) containing very low density lipoprotein tracer enrichment as a precursor pool. Extended-release nicotinic acid decreased plasma triglycerides (-46%; P=0.023), raised high-density lipoprotein cholesterol (+20%; P=0.008), and decreased Apo(a) plasma concentrations (-20%; P=0.008). Extended-release nicotinic acid also decreased ApoB100 (22%; P=0.008) and proprotein convertase subtilisin/kexin type 9 (PCSK9, -29%; P=0.008) plasma concentrations. Apo(a) fractional catabolic rate and production rates were decreased by 37% (0.58±0.28 versus 0.36±0.19 pool/d; P=0.008) and 50% (1.4±0.8 versus 0.7±0.4 nmol/kg per day; P=0.008), respectively. CONCLUSIONS: Extended-release nicotinic acid treatment decreased Apo(a) plasma concentrations by 20%, production rates by 50%, and catabolism by 37%. ApoB100 and PCSK9 concentrations were also decreased by treatment, but no correlation was found with Apo(a) kinetic parameters.
Authors: Margaret R Diffenderfer; Stefania Lamon-Fava; Santica M Marcovina; P Hugh R Barrett; Julian Lel; Gregory G Dolnikowski; Lars Berglund; Ernst J Schaefer Journal: Metabolism Date: 2015-11-06 Impact factor: 8.694
Authors: Tiffany Thomas; Haihong Zhou; Wahida Karmally; Rajasekhar Ramakrishnan; Stephen Holleran; Yang Liu; Patricia Jumes; John A Wagner; Brian Hubbard; Stephen F Previs; Thomas Roddy; Amy O Johnson-Levonas; David E Gutstein; Santica M Marcovina; Daniel J Rader; Henry N Ginsberg; John S Millar; Gissette Reyes-Soffer Journal: Arterioscler Thromb Vasc Biol Date: 2017-07-20 Impact factor: 8.311