Effects of Niacin on LDL Particle Number

Abstract and Niacin Overview

Abstract

Niacin has long been used as an effective lipid-altering therapy, particularly for raising HDL-C and lowering triglyceride levels. In addition, niacin modestly lowers LDL-C levels. LDL-C circulates in the blood as a heterogeneous population of various sized particles, with smaller LDL particles widely considered to be more closely associated with atherosclerosis and coronary heart disease. Recent evidence suggests that it is the total number of circulating LDL-C particles of various sizes that most closely predicts atherosclerosis risk. This review focuses on the growing body of literature suggesting that niacin favorably alters the number of circulating LDL particles of various sizes.

Niacin Overview

It was initially reported in 1955 that nicotinic acid (niacin) lowered cholesterol levels in normal subjects as well as in patients with hypercholesterolemia.^[1] There have been many subsequent studies that have supported niacin as a broad-spectrum lipid-regulating medication.^[2] Niacin reduces total cholesterol, triglycerides, VLDL-C, LDL-C and lipoprotein (a) (Lp[a]) levels, in addition to increasing HDL-C levels.^[3]

In its present clinical use, niacin is available in a number of formulations. Extended-release niacin (ERN) is the most widely used prescription niacin and has a better side-effect profile than the other available preparations, including dietary supplement versions of niacin. Dietary supplement niacin comes in many forms, including immediate-release or crystalline, sustained- or time-released and no-flush or flush-free formulations. Immediate-release niacin is effective and safe, even at relatively high doses (up to 12 g/day), but it has the highest incidence of flushing. Sustained-release niacin causes flushing less frequently, but it is associated with increased hepatotoxicity. Flush-free niacin is safe and well tolerated, but it has low efficacy because of limited bioavailability.^[4] In an analysis of the US FDA adverse event reporting (AER) database, Alsheikh-Ali et al. described that the rate of serious AERs associated with dietary supplement formulations of niacin was 6.2-fold higher and the rate of liver toxicity was 6.7-fold higher when compared with ERN.^[5] Of note, in this database, there was no distinction amongst the three types of dietary supplement niacin.

It should also be mentioned that previously, diabetes mellitus was a relative contraindication to niacin use; however, recent data suggest that niacin has modest and transient effects on hemoglobin A1C levels in patients with diabetes, which are amenable to adjustments in antidiabetic regimens. However, these same studies recommend that on an individual patient basis, glucose control should be monitored on initiating or increasing the dose of niacin in patients with diabetes or the metabolic syndrome.^[6]

One of the main uses of niacin is its ability to increase circulating levels of HDL-C and its major apoplipoprotein, ApoA-I.^[7] Niacin inhibits the uptake and removal of HDL-C and ApoA-I, but does not inhibit the scavenger receptor class B type 1, thereby augmenting plasma levels without interfering with function.^[7–9] However, it should be noted that in a recent study from the Schaefer laboratory, niacin, in its extended-release formulation, is noted to have a slightly varied mechanism of action. This study supports that niacin increases ApoA-I but does so by increased production, and not by decreased removal, while having no effect on ApoA-II.

In addition to raising HDL-C, niacin also lowers circulating levels of ApoB-containing particles (VLDL-C, LDL-C and Lp[a]). This may be due to several different mechanisms. The first is by modulation of triglyceride synthesis and secretion of ApoB-containing compounds from the liver.^[7] Work from the Kayshap laboratory has shown that niacin inhibits the activity of diacylglycerol acyltransferase-2, an enzyme that is necessary for the synthesis of triglycerides. Moreover, this retards VLDL-C assembly, eventually resulting in ApoB degradation, thereby lowering circulating VLDL-C and LDL-C levels. The second mechanism by which niacin regulates circulating triglyceride levels is by inhibiting lipolysis in adipocytes, resulting in lower plasma levels.^[10] Recently, it has also been shown that niacin significantly lowers ApoB-100 and ApoB-48, mainly owing to increased clearance.^[11]

In addition to the beneficial effects on lipid levels, niacin has been shown to have potentially beneficial cardiovascular effects via other mechanisms.^[12] Niacin therapy improves peripheral vascular endothelial function and increases endothelial nitric oxide synthase protein expression.^[13] In addition, niacin decreases inflammatory markers, namely levels of lipoprotein-associated phospholipase A2 and C-reactive protein (CRP).^[14] Furthermore, in an in vitro system, niacin has been shown to have antioxidant and anti-inflammatory properties. This is mediated by increases in NADP, reductions in glutathione levels and inhibition of the following: angiotensin II-induced reactive oxygen species production; LDL-C oxidation; TNF-α-induced redox-sensitive vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1 messenger ribonucleic acid expression; and, TNF-α-induced and oxidized LDL-induced monocyte adhesion to endothelial cells.^[7] Finally, niacin favorably alters the distribution of LDL-C particles (LDL-Ps).^[15–18]

Table 1. Niacin therapy: data from clinical trials.
Study	Year	Niacin type	Primary end point	Patient population	Main outcome	Ref.
CDP	1975	IRN	ACM	Men with a history of MI	Niacin decreased nonfatal MI (8.9% vs 12.2% in placebo-treated patients). 11% reduction in ACM when compared with placebo (p = 0.0004).	^[19]
FATS	1990	IRN	Change in stenosis in 1 out of 9 proximal coronary artery segments	Men less than 62 years of age, with elevated ApoB levels, coronary atherosclerosis and a family history of CHD	Progression of atherosclerosis less frequent in niacin–colestipol group when compared with conventional therapy (25% vs 46%). Plaque regression more common in niacin–colestipol group when compared with placebo (p < 0.005). Clinical events (death, MI, revascularization) occurred in 2 out of 48 subjects as compared with 10 out of 52 subjects in conventional therapy group (RR: 0.27; 95% CI: 0.1–0.77).	^[20]
HATS	2001	IRN and SRN	Mean percent change per patient of stenosis in each of the nine proximal coronary artery segments Primary clinical end point was the time to first of the following events: death from coronary causes, nonfatal MI, stroke or revascularization for worsening ischemia	Men and women with clinical coronary disease and at least three stenoses of at least 30% of the luminal diameter or one stenosis of at least 50%	Mean percent coronary artery stenosis progressed by 0.7% for simvastatin–niacin plus antioxidant group, whereas by 3.9% and 1.8% for the placebo and antioxidant groups alone, respectively (p = 0.004). Plaque regressed by 0.4% for the simvastatin–niacin group (p < 0.001). Frequency of clinical end points highest for placebo group (24%) and lowest for simvastatin–niacin group (3%). Benefits of statin–niacin attenuated in patients receiving antioxidants.	^[21]
ARBITER 2	2004	ERN	Mean change from baseline in CIMT after 1 year as detected by high-resolution ultrasound	Men and women over 30 years of age with known coronary vascular disease and who were on background statin therapy	Patients randomized to placebo had a significant increase in mean CIMT (0.044 ± 0.100 mm; p < 0.001). Patients on ERN had no change in CIMT (0.014±0.104 mm; p < 0.23). Subanalysis of patients with insulin resistance showed that ERN reduced rate of CIMT progression when compared with placebo (p = 0.026). Also, when compared with placebo, therapy with ERN resulted in a 60% nonsignificant reduction in clinical events (p = 0.20).	^[22]
ARBITER 3	2006	ERN	Time-dependent change in mean CIMT in patients treated with ERN for 12 versus 24 months.	Subjects who successfully completed the 12-month CIMT assessment of ARBITER 2	HDL-C increased in the ERN group by 23% (p < 0.001) Patients treated with ERN for 12 months had a net regression of CIMT of −0.027 ± 0.011mm (p < 0.001) versus placebo. Patients treated with ERN for 24 months had an additional significant regression of CIMT of −0.041 ± 0.021mm (p = 0.001) versus placebo. There was no significant difference between the 12 and 24 month ERN-treated patients for change in CIMT. After controlling for LDL-C and triglycerides, only changes in HDL-C were associated with regression in CIMT (p = 0.001).	^[23]

Table 1. Niacin therapy: data from clinical trials.

Study

Year

Niacin type

Primary end point

Patient population

Main outcome

Ref.

CDP

1975

IRN

ACM

Men with a history of MI

Niacin decreased nonfatal MI (8.9% vs 12.2% in placebo-treated patients).
11% reduction in ACM when compared with placebo (p = 0.0004).

^[19]

FATS

1990

IRN

Change in stenosis in 1 out of 9 proximal coronary artery segments

Men less than 62 years of age, with elevated ApoB levels, coronary atherosclerosis and a family history of CHD

Progression of atherosclerosis less frequent in niacin–colestipol group when compared with conventional therapy (25% vs 46%).
Plaque regression more common in niacin–colestipol group when compared with placebo (p < 0.005).
Clinical events (death, MI, revascularization) occurred in 2 out of 48 subjects as compared with 10 out of 52 subjects in conventional therapy group (RR: 0.27; 95% CI: 0.1–0.77).

^[20]

HATS

2001

IRN and SRN

Mean percent change per patient of stenosis in each of the nine proximal coronary artery segments
Primary clinical end point was the time to first of the following events: death from coronary causes, nonfatal MI, stroke or revascularization for worsening ischemia

Men and women with clinical coronary disease and at least three stenoses of at least 30% of the luminal diameter or one stenosis of at least 50%

Mean percent coronary artery stenosis progressed by 0.7% for simvastatin–niacin plus antioxidant group, whereas by 3.9% and 1.8% for the placebo and antioxidant groups alone, respectively (p = 0.004).
Plaque regressed by 0.4% for the simvastatin–niacin group (p < 0.001).
Frequency of clinical end points highest for placebo group (24%) and lowest for simvastatin–niacin group (3%).
Benefits of statin–niacin attenuated in patients receiving antioxidants.

^[21]

ARBITER 2

2004

ERN

Mean change from baseline in CIMT after 1 year as detected by high-resolution ultrasound

Men and women over 30 years of age with known coronary vascular disease and who were on background statin therapy

Patients randomized to placebo had a significant increase in mean CIMT (0.044 ± 0.100 mm; p < 0.001).
Patients on ERN had no change in CIMT (0.014±0.104 mm; p < 0.23).
Subanalysis of patients with insulin resistance showed that ERN reduced rate of CIMT progression when compared with placebo (p = 0.026).
Also, when compared with placebo, therapy with ERN resulted in a 60% nonsignificant reduction in clinical events (p = 0.20).

^[22]

ARBITER 3

2006

ERN

Time-dependent change in mean CIMT in patients treated with ERN for 12 versus 24 months.

Subjects who successfully completed the 12-month CIMT assessment of ARBITER 2

HDL-C increased in the ERN group by 23% (p < 0.001)
Patients treated with ERN for 12 months had a net regression of CIMT of −0.027 ± 0.011mm (p < 0.001) versus placebo.
Patients treated with ERN for 24 months had an additional significant regression of CIMT of −0.041 ± 0.021mm (p = 0.001) versus placebo.
There was no significant difference between the 12 and 24 month ERN-treated patients for change in CIMT.
After controlling for LDL-C and triglycerides, only changes in HDL-C were associated with regression in CIMT (p = 0.001).

^[23]

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Effects of Niacin on LDL Particle Number

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