Effects of extended-release niacin on lipoprotein subclass distribution

doi:10.1016/S0002-9149(03)00394-1

The American Journal of Cardiology

Volume 91, Issue 12, 15 June 2003, Pages 1432-1436

https://doi.org/10.1016/S0002-9149(03)00394-1 Get rights and content

Abstract

The efficacy of extended-release niacin (niacin ER) on lipoprotein subclasses was evaluated in patients with primary hypercholesterolemia using a proton nuclear magnetic resonance method. Paired plasma samples collected at baseline and after 12 weeks’ treatment with niacin ER 1,000 (n = 21) or 2,000 (n = 20) mg/day or placebo (n = 19) were available for 60 eligible patients from a previous multicenter, randomized, controlled trial. Niacin ER increased high-density lipoprotein (HDL) cholesterol and decreased low-density lipoprotein (LDL) cholesterol and very low-density lipoprotein triglycerides in a dose-dependent manner relative to placebo. Niacin ER increased large HDL particles (H5 and H4, corresponding to the HDL_2ab fraction) without having a net effect on small HDL particles (H3, H2, and H1, corresponding to the HDL_3abc fraction). It also decreased smaller, denser LDL particles (L1 and L2) and increased the larger, more buoyant L3 subclass. The inhibitory effect of niacin ER on very low-density lipoprotein was evident on the larger particles (V6, V5, V4, and V3 subclasses) rather than the smaller ones (V2 and V1). The results show that niacin ER produces a beneficial effect on lipoprotein subclasses, specifically decreasing the more atherogenic small, dense LDL particles and enhancing the cardioprotective large HDL particles.

Section snippets

Study design

This multicenter, double-blind, placebo-controlled, parallel-group clinical study has been described previously.2 The study protocol was approved by all participating institutional review boards, and all patients gave informed consent before enrollment. Patients with a confirmed diagnosis of primary dyslipidemia were eligible. Patients with a clinically significant history of diabetes mellitus, gout, peptic ulcer disease, or cardiac arrhythmias, and those currently using niacin were excluded.

Study patients

Of the 96 patients who completed the study, 60 patients (63%) had paired plasma samples obtained at baseline and at the end of treatment that were available for analysis. They included 19 patients from the placebo group and 21 and 20 patients from the niacin ER 1,000- and 2,000-mg groups, respectively. These 3 groups were well matched with respect to patient demographics and clinical characteristics (Table 1). Most patients were Caucasian men, and mean age was 50 ± 12 years. The 3 treatment

Discussion

Although high LDL cholesterol and low HDL cholesterol levels increase cardiovascular risk, the specific subclasses of these lipoproteins differ in their atherogenic and cardioprotective potential. In numerous retrospective and prospective studies, small, dense LDL cholesterol particles appear to be associated with an increased risk of coronary heart disease,3, 4, 5, 6, 7, 8 although some studies have not found this association.9 Conversely, larger HDL particles are believed to be associated

Acknowledgements

The investigators gratefully acknowledge Phillip D. Simmons, MS, for his expertise in data management and statistical analysis. In addition, we thank Anne Lincoff, MD, for her contributions to the content of this manuscript.

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Citation Excerpt :
Several clinical trials have shown that niacin improves blood lipid profiles, including LDL-c, triglycerides, and HDL-c [6–8]. However, most of these were small-scale clinical trials conducted in patients with chronic diseases, including dyslipidemia, type 2 diabetes, and cardiovascular disease [6,10], and investigated the effect of relatively large doses of pharmaceutical niacin over a short period of time [6–8]. The biological availability and health effects of niacin may differ depending on its chemical form or sources [11–15].
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Higher dietary niacin intake was associated with a reduced risk of dyslipidemia (pooled, multivariable-adjusted HR: 0.71, 95% CI: 0.62–0.82). Compared with the group whose dietary niacin intake was above the recommended dietary allowance in Korea, the risk of dyslipidemia increased by 32% (pooled, multivariable-adjusted HR: 1.32, 95% CI: 1.19–1.46) in the group below the estimated average requirement in Korea. Spline regression showed a dose–response linear relationship between dietary niacin intake and the risk of dyslipidemia (all p-values for nonlinearity >0.05).
Consumption of foods with high niacin levels may help prevent or delay the onset of dyslipidemia.
Niacin increases diet-induced hepatic steatosis in B6129 mice
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Nonalcoholic fatty liver disease (NAFLD) is a very common disorder affecting between 20 and 30% of adults in the United States. However, there is no effective pharmacotherapy for treating NAFLD. Niacin, a water-soluble vitamin (B3), at pharmacological doses, decreases hepatic triglyceride (TG) content in NAFLD through inhibition of diacylglycerol acyltransferase 2, a key enzyme that catalyzes the final step in TG synthesis. Alternatively, some studies indicate that niacin induces fatty liver in high-fat diet (HFD)-fed rats. Therefore, in this study we investigated whether niacin is beneficial in treating NAFLD in two strains of mice, C57BL/6J (B6) and B6129SF2/J (B6129) mice, with 20 weeks of HFD feeding. Niacin treatment was started from week 5 until the end of the study. Niacin treatment increased normalized liver weight, hepatic TG content and NAFLD score in HFD-fed B6129 mice but had no impact on B6 mice. Metabolomics analysis revealed that in B6129 mice, 4-hydroxyphenylpyruvic acid (4-HPP), which is associated with fatty acid oxidation, did not change with HFD feeding but significantly decreased with niacin treatment. Lipidomics analysis discovered that the abundance of phosphocholine (PC), which is critical for very low-density lipoprotein (VLDL)–TG production and secretion, was decreased in HFD-fed B6129 with niacin treatment. In conclusion, niacin had no impact on diet-induced NAFLD development in B6 mice but potentiated hepatic steatosis in HFD-fed B6129 mice due to impaired fatty acid oxidation and decreased VLDL-TG production and secretion.
Long-chain omega-3 fatty acids, fibrates and niacin as therapeutic options in the treatment of hypertriglyceridemia: A review of the literature
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Hypertriglyceridemia affects approximately 33% of the US population. Elevated triglyceride levels are independently associated with cardiovascular disease (CVD) risk, and severe hypertriglyceridemia is a risk factor for acute pancreatitis. Guidelines for the management of severe hypertriglyceridemia (≥5.6 mmol/L [≥500 mg/dL]) recommend immediate use of triglyceride-lowering agents; however, statins remain the first line of therapy for the management of mild to moderate hypertriglyceridemia (1.7–5.6 mmol/L [150–499 mg/dL]). Statins primarily target elevated low-density lipoprotein cholesterol levels, but have also been shown to reduce mean triglyceride levels by up to 18% (or 43% in patients with triglyceride levels ≥ 3.1 mmol/L [≥273 mg/dL]). However, individuals with hypertriglyceridemia may need additional reduction in triglyceride-rich lipoproteins and remnant particles to further reduce residual CVD risk. A number of guidelines recommend the addition of fibrates, niacin, or long-chain omega-3 fatty acids if elevated triglyceride or non-high-density lipoprotein cholesterol levels persist despite the use of high-intensity statin therapy. This review evaluates the impact of fibrates, niacin, and long-chain omega-3 fatty acids on lipid profiles and cardiovascular outcomes in patients with hypertriglyceridemia. It also assesses the adverse effects and drug–drug interactions associated with these triglyceride-lowering agents, because although they have all been shown to effectively reduce triglyceride levels in patients with hypertriglyceridemia, they differ with regard to their associated benefit–risk profiles. Long-chain omega-3 fatty acids may be a well-tolerated and effective alternative to fibrates and niacin, yet further large-scale clinical studies are required to evaluate their effects on cardiovascular outcomes and CVD risk reduction in patients with hypertriglyceridemia.
Prolonged niacin treatment leads to increased adipose tissue PUFA synthesis and anti-inflammatory lipid and oxylipin plasma profile
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Prolonged niacin treatment elicits beneficial effects on the plasma lipid and lipoprotein profile that is associated with a protective CVD risk profile. Acute niacin treatment inhibits nonesterified fatty acid release from adipocytes and stimulates prostaglandin release from skin Langerhans cells, but the acute effects diminish upon prolonged treatment, while the beneficial effects remain. To gain insight in the prolonged effects of niacin on lipid metabolism in adipocytes, we used a mouse model with a human-like lipoprotein metabolism and drug response [female APOE*3-Leiden.CETP (apoE3 Leiden cholesteryl ester transfer protein) mice] treated with and without niacin for 15 weeks. The gene expression profile of gonadal white adipose tissue (gWAT) from niacin-treated mice showed an upregulation of the “biosynthesis of unsaturated fatty acids” pathway, which was corroborated by quantitative PCR and analysis of the FA ratios in gWAT. Also, adipocytes from niacin-treated mice secreted more of the PUFA DHA ex vivo. This resulted in an increased DHA/arachidonic acid (AA) ratio in the adipocyte FA secretion profile and in plasma of niacin-treated mice. Interestingly, the DHA metabolite 19,20-dihydroxy docosapentaenoic acid (19,20-diHDPA) was increased in plasma of niacin-treated mice. Both an increased DHA/AA ratio and increased 19,20-diHDPA are indicative for an anti-inflammatory profile and may indirectly contribute to the atheroprotective lipid and lipoprotein profile associated with prolonged niacin treatment.
Differential effects of fenofibrate and extended-release niacin on high-density lipoprotein particle size distribution and cholesterol efflux capacity in dyslipidemic patients
2013, Journal of Clinical Lipidology
Citation Excerpt :
Treatment with either fenofibrate or ER niacin increased the number of medium and large particles, although this was most striking for large particles in the ER niacin-treated normal HDL-C group and corresponded to an increase in mean HDL size. These results correlate with 2 studies that have shown significant increases in large HDL2 particles in patients with dyslipidemia treated with 1, 2, or 3 mg/d ER niacin,9,20 although a third study showed small decreases.22 Notably, a greater plasma concentration of large HDL particles, assessed by nuclear magnetic resonance, as in the current study, has been associated recently with reduced CHD risk in various populations,23–25 suggesting that the more pronounced increase of these particles with niacin might affect CHD risk favorably in treated patients.
The effectiveness of therapies that raise high-density lipoprotein cholesterol (HDL-C) to lower cardiovascular disease risk is currently under debate, and further research into the relationship between HDL-C and function is required.
o investigate whether 2 established HDL-C-raising therapies had differential effects on parameters of high-density lipoprotein (HDL) quality and function, such as HDL particle profile and cholesterol efflux capacity (CEC), in patients with dyslipidemia.
Sixty-six patients with dyslipidemia, 24 with low HDL-C levels (<40 mg/dL) and 42 with normal HDL-C levels (40–59 mg/dL), were treated for 6 weeks with fenofibrate (160 mg/d) or extended-release (ER) niacin (0.5 g/d for 3 weeks, then 1 g/d) with 4 weeks of washout between treatments. Lipoprotein particle size distribution was determined using nuclear magnetic resonance, and pathway-specific serum CECs were assessed in J774 macrophages, hepatoma, and Chinese hamster ovary–human adenosine triphosphate-binding cassette transporter G1 cells. Comparable increases in HDL-C and apolipoprotein A-I levels were seen with fenofibrate and ER niacin. There was a shift toward larger HDL, predominantly to medium-size HDL particles for fenofibrate (+209%) and to large HDL particles for ER niacin (+221%). Minor changes in serum CECs were observed with fenofibrate and ER niacin for all the efflux pathways measured. Small increases in plasma cholesteryl ester transfer protein and lecithin: cholesterol acyltransferase concentrations, and decreases in cholesteryl ester transfer protein activity were seen with both drugs.
Fenofibrate and ER niacin increased plasma HDL-C level similarly, but modulated HDL particle size distribution differently; however, these changes did not result in differential effects on serum CECs.
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Fusion of modified LDL in the arterial wall promotes atherogenesis. Earlier we showed that thermal denaturation mimics LDL remodeling and fusion, and revealed kinetic origin of LDL stability. Here we report the first quantitative analysis of LDL thermal stability. Turbidity data show sigmoidal kinetics of LDL heat denaturation, which is unique among lipoproteins, suggesting that fusion is preceded by other structural changes. High activation energy of denaturation, E_a= 100 ± 8 kcal/mol, indicates disruption of extensive packing interactions in LDL. Size-exclusion chromatography, nondenaturing gel electrophoresis, and negative-stain electron microscopy suggest that LDL dimerization is an early step in thermally induced fusion. Monoclonal antibody binding suggests possible involvement of apoB N-terminal domain in early stages of LDL fusion. LDL fusion accelerates at pH < 7, which may contribute to LDL retention in acidic atherosclerotic lesions. Fusion also accelerates upon increasing LDL concentration in near-physiologic range, which likely contributes to atherogenesis. Thermal stability of LDL decreases with increasing particle size, indicating that the pro-atherogenic properties of small dense LDL do not result from their enhanced fusion. Our work provides the first kinetic approach to measuring LDL stability and suggests that lipid-lowering therapies that reduce LDL concentration but increase the particle size may have opposite effects on LDL fusion.

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^☆: This study was supported by a grant from Kos Pharmaceuticals, Inc., Miami Lakes, Florida.

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Effects of extended-release niacin on lipoprotein subclass distribution☆

Abstract

Section snippets

Study design

Study patients

Discussion

Acknowledgements

Am J Cardiol

Atherosclerosis

Am J Cardiol

Atherosclerosis

Am J Cardiol

Effect of nicotinic acid on LDL subclass patterns (abstr)

Circulation

Treatment effect of Niaspan, a controlled-release niacin, in patients with hypercholesterolemiaa placebo-controlled trial

J Cardiovasc Pharmacol Ther

Development of a proton nuclear magnetic resonance spectroscopic method for determining plasma lipoprotein concentrations and subspecies distributions from a single, rapid measurement

Clin Chem