Abstract 19: Single-Dose Extended-Release Niacin Acutely Attenuates HDL Reduction in the Setting of Experimental Oral Fat Challenge: A Possible Role of ANGPTL-3 and CETP Modulation

Abstract

Background: High density lipoprotein (HDL-c) levels are inversely correlated with the development of atherosclerosis and are reduced postprandially. Niacin is the most potent elevator of fasting HDL-c but the mechanisms are not fully elucidated, and its effects on postprandial HDL-c are largely unknown. Aim: Our aim was to determine whether a single dose ER niacin before a fat challenge acutely attenuates the postprandial drop in HDL-c compared to placebo, and to determine whether angiopoeitin like protein 3 (ANGPTL3) and cholesterol ester transfer protein (CETP) contribute to increased postprandial HDL-c by niacin. Method: We conducted 2 postprandial studies in healthy volunteers: 1. a double-blinded, placebo-controlled, random-order crossover experiment comparing 2 grams of ER niacin to matching placebo, and 2. open-label administration of 1 gram of ER niacin compared to a fat load without niacin. Study drug was administered 1 hour prior to an oral fat load of heavy cream followed by serial plasma sampling for triglyceride (TG), apolipoprotein A-1 (Apo A-1), ANGPTL3, and CETP mass and activity, and HDL-c over 12 hours. Data are expressed as means (95% CI) for incremental (iAUC) or total (tAUC) area under the curve. Results: Study 1 involved 304 fat challenges in 152 subjects. As expected HDL-c dropped after the fat load alone, with an iAUC of -71.9 mg/dL*h (-65.1 to -78.6),whereas 1 gram ER niacin reduced the drop to -32.5 mg/dL*h (-25.6 to -39.3) a 55% difference (p<0.00001). In Study 2, 2 grams ER-Niacin mitigated the drop in HDLc more effectively: the iAUC was -19.0 (-35.7 to -2.3) on placebo vs. -2.1 (-18.8 to +14.6) mg/dL*h on niacin, an 89% difference ( p=0.047). ANGPTL3 iAUC was +2206 ng/mL*h (+1811 to +2602) on placebo vs. +2560 ng/mL*h (+2165 to +2955) on ER-niacin, a 16% rise (p=0.001). CETP activity decreased from an iAUC of +118.2 nmol/L*h (95%CI +90.5 to +146) to -15.7 nmol/L*h (95%CI -36.4 to +5.1) on niacin, so that the usual postprandial increase in CETP activity was abolished by niacin (p<0.00001). Postprandial TG tAUC was strongly inversely correlated with HDL tAUC (Spearman’s rho -0.62, p<0.00005). Conclusions: HDL-c decreases significantly in the setting of an experimental oral fat load. We found that one-time dosing with either 1 or 2 grams of ER-Niacin mitigated this decline in drug-naive subjects. Acute pharmacodynamic effects of ER-niacin including TG lowering, ANGPTL3 elevation and CETP suppression may play a mechanistic role in this process.