Extended-Release Niacin/Laropiprant Improves Overall Efficacy of Postprandial Reverse Cholesterol Transport

Abstract

Objectives-Postprandial atherogenic lipoproteins, characterizing high-risk patients, correlate positively with cardiovascular events. Although the effect of niacin on fasting lipids is well established, its impact on atheroprotective reverse cholesterol transport (RCT) pathway and on functional features of circulating lipoproteins during the postprandial state remains indeterminate. Approach and Results-We evaluated RCT pathway during postprandial phase in dyslipidemic patients displaying a low high-density lipoprotein (HDL) cholesterol phenotype. Ten subjects on stable statin therapy received 1 g/20 mg extendedrelease niacin/laropiprant (ERN/LRPT) for 4 weeks followed by 2 g/40 mg ERN/LRPT for additional 8 weeks. At each experimental period, postprandial hypertriglyceridemia and major steps of RCT, including cholesterol efflux from human macrophages, cholesteryl ester transfer protein-mediated cholesteryl ester transfer, and hepatic HDL-cholesteryl ester selective uptake were evaluated. Equally, the capacity of postprandial HDL particles isolated from patients before and after ERN/LRPT treatment to mediate RCT to feces was evaluated in vivo in human apolipoprotein B/cholesteryl ester transfer protein double transgenic mouse model. Compared with baseline, ERN/LRPT significantly reduced postprandial hypertriglyceridemia (incremental area under the curve-triglyceride: −53%; P=0.02). Postprandial increase in endogenous plasma cholesteryl ester transfer protein activity was completely abolished after ERN/LRPT treatment. Despite a slight reduction in plasma cholesterol efflux capacity from human THP-1 macrophages, evaluation of global RCT efficacy by combining both ex vivo and in vivo approaches indicate that postprandial HDL particles formed under ERN/LRPT therapy displayed a greater capacity for HDL-mediated RCT to feces. 9 It has been demonstrated that the capacity of HDL to mediate cholesterol efflux represents a strong predictor of the presence and the extend of atherosclerosis. Conclusions-ERN/LRPT10 Equally, an inverse association between the prevalence of coronary disease and HDL efflux capacity has been observed; however, HDL-mediated efflux was paradoxically associated with increase in prospective risk of myocardial infarction, stroke, and death.11 These observations suggest that it is important to consider the overall efficacy of RCT pathway, including not only macrophage cholesterol efflux, but also the return of cholesterol to the liver and the ultimate excretion of cholesterol from the body.The efficacy of RCT pathway can be influenced by several factors. Postprandial lipemia, characterized by a transient production and accumulation of TRL, is associated with an acceleration of RCT.12,13 Indeed, it is important to consider that intravascular metabolism of both TRL and HDL is intimately intricate: (1) CETP-mediated neutral lipid heteroexchange between TRL and HDL induces the formation of cholesteryl ester (CE)-rich TRL remnants and TG-rich HDL particles and (2) the transfer of phospholipids and cholester...

Nicotinic acid timed to feeding reverses tissue lipid accumulation and improves glucose control in obese Zucker rats[S]

“…Extended-release niacin given immediately before a fat meal suppressed postprandial FFA and plasma TG excursions (53), whereas bedtime dosing failed (54). In addition, patient studies continue to report impairments in insulin sensitivity and/or glycemic control (12)(13)(14)(15)(16)(17) and even increased risk of new-onset diabetes (18). Based on the current results, it seems reasonable to speculate that mealtime dosing might reverse these negative effects on glucose control.…”

Translational and Therapeutic Approaches to the Understanding and Treatment of Dyslipidemia

“…42 Statin alone did not increase HDL particle concentration or macrophage cholesterol efflux capacity, even though it raised HDL-C. 42 In dyslipidemic patients on stable statin therapy, 12 weeks of extended-release niacin/laropiprant therapy reduced CETP activity, moderately improved plasma efflux capacity from macrophages, and increased the ability of HDL particles to deliver CE back to the liver during the postprandial phase. 43 These results suggest that specific subgroups of patients at high cardiovascular risk might benefit from combination therapy of statin and niacin for cardioprotection. However, as the authors pointed out, whether the subtle benefits may translate into improved clinical outcome and whether the benefits were sufficient to overcome the side effects is unclear.…”

“…However, as the authors pointed out, whether the subtle benefits may translate into improved clinical outcome and whether the benefits were sufficient to overcome the side effects is unclear. 43 The controversy regarding the benefits of niacin combinations with statins on RCT and reducing cardiovascular events in human continues, and further investigation is needed.…”

Time to ditch HDL-C as a measure of HDL function?

“…Thus, studies showed that niacin improved [37, 38] or did not change [39] HDL’s overall efflux capacity without improving ABCA1-specific efflux [37, 38]. Importantly, the improvement in total efflux correlated with the increase in HDL-C [38].…”

“…Niacin reduced ABCA1-dependent efflux after dyslipidemic patients ingested a typical western meal. However, HDL particles isolated from patients receiving niacin displayed an enhanced capacity to deliver cholesteryl esters to hepatic cells, improving overall reverse cholesterol transport [37]. Of note, a secondary analysis of a subset of dyslipidemic patients in the AIM-HIGH trial uncovered a significant reduction in cardiovascular risk [56].…”