Extended-release Niacin Acutely Suppresses Postprandial Triglyceridemia

Usman, Muhammad; Qamar, Arman; Gadi, Ramprasad; Lilly, Scott; Goel, Harsh; Hampson, Jaison; Mucksavage, Megan; Nathanson, Grace; Rader, Daniel J.; Dunbar, Richard L.

doi:10.1016/j.amjmed.2012.03.017

Cited by 19 publications

(14 citation statements)

References 48 publications

(55 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, we observed hepatic and plasma TG lowering when treatment was timed to feeding and not when it was timed to fasting. Indeed, mealtime dosing has previously been suggested as an approach to augment niacin's clinical efficacy (20,53). Extended-release niacin given immediately before a fat meal suppressed postprandial FFA and plasma TG excursions (53), whereas bedtime dosing failed (54).…”

Section: A Therapeutically Relevant Niac Exposurementioning

confidence: 99%

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

Kroon

Baccega

Olsen

et al. 2017

Journal of Lipid Research

View full text Add to dashboard Cite

Section: A Therapeutically Relevant Niac Exposurementioning

confidence: 99%

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

Kroon

Baccega

Olsen

et al. 2017

Journal of Lipid Research

View full text Add to dashboard Cite

“…This observation is in good accordance with a previous study showing that ERN lowered postprandial triglyceridemia in normolipidemic healthy volunteers. 19 By limiting postprandial hypertriglyceridemia, ERN/LPRT therapy reduces the atherogenicity of postprandial triglyceride-rich particles and their remnants. Indeed, during exaggerated postprandial response, the vessel wall is more exposed to proatherogenic remnants which can penetrate into the subintimal space by transcytosis, in a receptor-independent mechanism.…”

Section: Discussionmentioning

confidence: 99%

“…18 In addition, it has been reported that extended-release niacin (ERN) given in a single dose 1 hour before oral fat tolerance test significantly reduces postprandial TG levels in healthy volunteers. 19 The objective of the present study was to evaluate the impact of ERN/laropiprant (LRPT) on the overall efficacy of RCT pathway after ingestion of a typical western meal in dyslipidemic patients at high cardiovascular risk on a background of statin treatment. RCT pathway was evaluated through an integrated functional approach by measuring its major steps, including the initial macrophage cholesterol efflux, CETPmediated CE transfer from HDL to apoB-containing lipoprotein, and in vitro hepatic HDL-CE uptake, as well as in vivo HDL-mediated RCT to feces.…”

mentioning

confidence: 99%

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

Khoury

Waldmann

Huby

et al. 2016

ATVB

View full text Add to dashboard Cite

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...

show abstract

“…We are not the fi rst to suggest the potential impact of timing on niacin therapy. Usman et al ( 44 ) proposed that giving extended-release (ER) niacin at meal time, instead of bed time, could improve TG lowering. Based on the current results, it seems reasonable that this strategy might also improve glucose handling following mixed meal ingestion.…”

Section: Discussionmentioning

confidence: 99%

Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

Kroon

Kjellstedt

Thalén

et al. 2015

Journal of Lipid Research

View full text Add to dashboard Cite

explored and provide evidence supporting this concept. This includes inactivation of hormone sensitive lipase (HSL) ( 5, 6 ) and A 1 -adenosine receptor agonists ( 7 ). In addition, several other G protein-coupled receptors (GPRs) are involved in controlling adipocyte FFA release, including GPR43, GPR81, and GPR109A ( 8-10 ).The GPR109A agonist nicotinic acid (NiAc) has been used clinically ever since its antidyslipidemic effects (HDL elevation and reductions of total cholesterol, LDL-cholesterol, and TG) were discovered more than 50 years ago ( 11-15 ). Although NiAc potently lowers FFA acutely, large-scale clinical studies, with repeated oral NiAc administration, often report increased levels of fasting glycemia ( 16-19 ). NiAc has not been optimized to achieve durable and therapeutically meaningful FFA lowering. By this, we specifi cally mean reducing around-the-clock FFA area under the curve (AUC). In theory, this might be achieved by sustained NiAc exposure; however, the FFA-lowering effect seen initially appears to be lost over time despite maintained NiAc exposure (tolerance development) ( 20 ). Time-dependent loss of both FFA lowering and glucose control improvement also occur in patients with type 2 diabetes, treated with the NiAc analog acipimox ( 21,22 ). To avoid tolerance development, drug holidays are needed. However, at the end of each NiAc exposure period, there is the risk of FFA rebound (here referring to the situation where FFA overshoots pretreatment levels in connection with NiAc decline) due to the short NiAc plasma half-life ( 23 ). FFA rebound is associated with impaired glucose control ( 24, 25 ). The question of whether there might be an optimal balance between periods of continuous exposure (which would minimize rebound) and drug holidays (which would minimize tolerance) in order to achieve maximal FFA lowering has not been addressed. Lipid overload in nonadipose tissues has been linked to the pathogenesis of insulin resistance and atherogenesis ( 1-4 ). A potential means for reversing peripheral lipid overload is to restrict the release of FFAs from adipose tissues. A number of independent mechanisms have been N.D. Oakes, P. Thalén, and A. Kjellstedt Abbreviations: ATGL, adipocyte triglyceride lipase; AUC, area under the curve; ER, extended release; GIR, glucose infusion rate; GPR, G protein-coupled receptor; HOMA-IR, homeostasis model assessment for insulin resistance; HSL, hormone sensitive lipase; NiAc, nicotinic acid; PDE-3B, phosphodiesterase-3B .

show abstract

Extended-release Niacin Acutely Suppresses Postprandial Triglyceridemia

Cited by 19 publications

References 48 publications

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

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

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

Dosing profile profoundly influences nicotinic acid's ability to improve metabolic control in rats

Contact Info

Product

Resources

About