Effects of Extended-Release Nicotinic Acid on Apolipoprotein ( a) Kinetics in Hypertriglyceridemic Patients

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 4812 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 mu mol/L per kg bolus injection of [5,5,5-H-2(3)]-l-Leucine immediately followed by constant infusion of [5,5,5-H-2(3)]-l-Leucine (10 mu mol 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.