Abstract 625: Niacin Improves Atherogenic Postprandial Lipemia in Patients at High Cardiovascular Risk Despite Reduced Cholesterol Efflux From Human Macrophages

Abstract

Introduction: The role of niacin has been called into question by recent outcome trials showing no benefit on cardiovascular events. Still, for certain high risk patients not achieving their LDL-C target niacin remains a significant therapeutic option. Hypothesis: Although the effect of niacin on fasting lipids is well established, its impact on cholesterol efflux and lipoprotein metabolism during the atherogenic postprandial state remains indeterminate. Methods: We evaluated the effect of extended-release niacin with laropiprant (ERN/LRP) on postprandial lipoprotein metabolism in 10 subjects on stable statin therapy. All subjects received 1g/20mg ERN/LRP for 4 weeks and then 2 g/40mg ERN/LRP for 8 weeks. At each experimental period, all patients consumed a standardized test meal (1100kcal). Postprandial hypertriglyceridemia (HTG) and plasma efflux capacity through THP-1 macrophages and cellular models overexpressing ABCA1, ABCG1 and SR-BI were evaluated. Results: Compared with baseline, ERN/LRP significantly improved postprandial HTG by reducing the area under the curve AUC for chylomicrons (-50%, p=0.004), VLDL-1 (-43%, p=0.0001) and VLDL-2 (-28%, p=0.01). These latter reductions induce a concomitant decrease in CETP activity during the postprandial state (-11.7%;p=0.03, -12%;p=0.01, -18%;p=0.0003, -13%;p=0.0006, 2h, 4h, 6h and 8h respectively after fat load). Plasma cholesterol efflux capacity from human THP-1 macrophages was reduced throughout the postprandial phase (AUC:-20%, p=0.05) following ERN/LRP therapy as a result of a specific reduction in ABCA1 dependent efflux pathway (AUC:-10%; p<0.05), whereas other efflux pathways such as SRBI and ABCG1 were not changed. Conclusions: ERN/LRP treatment reduces physiological triglyceride rich lipoproteins synthesis which indirectly results in a significant reduction in CETP activity. By this mechanism, intravascular remodeling of HDL is altered, thus affecting regeneration of ApoA1/preβ-HDL, the preferential cellular cholesterol acceptors via ABCA1 pathway. We conclude that Niacin therapy is associated with an overall reduction in the early step of RCT representing therefore one potential mechanistic hypothesis for the disappointing results in recent clinical trials