CONTACT: Dwight Angell
Feb. 24, 2010
Dwight.Angell@hfhs.org
313-876-8709

Vitamin B3 Shows Early Promise in Treatment of Stroke

DETROIT - An early study suggests that vitamin B3 or niacin, a common water-soluble vitamin, may help improve neurological function after stroke, according to Henry Ford Hospital researchers.

When rats with ischemic stroke were given niacin, their brains showed growth of new blood vessels, and sprouting of nerve cells which greatly improved neurological outcome.

Now research is underway at Henry Ford to investigate the effects of an extended-release form of niacin on stroke patients. Henry Ford is the only site nationally conducting such a study.

“If this proves to also work well in our human trials, we’ll then have the benefit of a low-cost, easily-tolerable treatment for one of the most neurologically devastating conditions,” Michael Chopp, Ph.D., scientific director of the Henry Ford Neuroscience Institute.

Dr. Chopp will present results from the animal model study at the International Stroke Conference in San Antonio.

According to the National Stroke Association, stroke is the third-leading cause of death in America and a leading cause of disability.

Ischemic strokes occur as a result of an obstruction within a blood vessel supplying blood to the brain. Ischemic stroke accounts for about 87 percent of all cases. One underlying condition for this type of obstruction is the development of fatty cholesterol deposits lining the vessel walls.

Niacin is known to be the most effective medicine in current clinical use for increasing high-density lipoprotein cholesterol (HDL-C), which helps those fatty deposits.

Dr. Chopp and his colleagues found that in animals niacin helps restore neurological function in the brain following stroke.

In 2009, stroke physicians at Henry Ford Hospital published research which showed that HDL-C is abnormally low at the time stroke patients arrive at the hospital.

Dr. Chopp’s research found that in animals, niacin increased “good” cholesterol (HDL-C), which increased blood vessels in the brain and axonal and dendritic growth leading to a substantial improvement in neurological function.

“Niacin essentially re-wires the brain which has very exciting potential for use in humans,” says Dr. Chopp. “The results of this study may also open doors in other areas of neurological medicine, including brain injury.”

Andrew Russman, D.O., is the principal investigator of the team at Henry Ford Hospital who will evaluate in clinical trials whether niacin improves recovery for human stroke patients.

“If we are able to prove that treating patients with niacin helps to restore neurological function after stroke, we’re opening a whole new avenue of treatment for the leading cause of serious long-term disability in adults,” says Dr. Russman.

Funding for animal study: National Institutes of Health.

Funding for clinical trial now underway: Harris Stroke Fund.

American Pharmacists Association
HIGHLIGHTS Newsletter - Volume 8 Number 2

Excerpts…

• Niacin is an effective treatment for dyslipidemia, but different formulations result in great variations in clinical outcomes.
• Treatment with niacin has also been shown to slow the progression of atherosclerosis in patients with CHD.Patients were randomized to treatment with the addition of extended release niacin 1,000 mg/day or placebo for 1 year. The primary end point was the change in common carotid intima-media thickness (CIMT). (CIMT is strongly correlated with CHD event rates). After 1 year of therapy, the mean CIMT was significantly increased in patients receiving placebo plus statin but was not significantly changed in patients receiving niacin plus statin.
• HDL-C was significantly increased (21%) and TG was significantly decreased (13%) in patients receiving niacin. CVD events occurred in 9.6% of patients receiving placebo and 3.8% of patients receiving niacin representing a 50% decrease in cardiovascular events…
• Data from the Framingham Heart Study clearly demonstrate that low levels of HDL-C are synergistic with high LDL-C in raising the risk for CHD events.5 Medications that raise HDL-C include statins, bile acid sequestrants, fibric acid derivatives, and niacin. Among these classes of medications, niacin is the most effective for raising HDL-C, raising it by as much as 35% in some studies. Niacin also lowers LDL-C (although generally not as much as the statins), and has a potent effect on lowering TG levels. Therefore, niacin is particularly useful for patients who require modification of HDL-C and TG in addition to LDL-C.
• Niacin has been shown to reduce mortality and nonfatal myocardial infarction (MI) in large clinical trials. For example, in the Coronary Drug Project, patients with a history of MI were randomized to receive niacin (n = 1,119) or placebo (n = 2,789) for 5 years.6 The risk of MI was significantly reduced in patients receiving niacin at 5 years, but niacin had no significant effect on mortality at this time point. However, in a 10-year follow-up of patients in this study (15 years after the study was initiated), mortality was significantly lower in patients who had been treated with niacin than in those who had received placebo.
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Canner PL, Furberg CD, McGovern ME.Maryland Medical Research Institute, Baltimore, Maryland, USA. plcanner@juno.com

Results support the use of niacin in post-infarction patients with and without the metabolic syndrome (MS).Of the 5 drug regimens, only niacin significantly decreased definite recurrent nonfatal MI at 6 years and total mortality at a 15-year follow-up.Niacin decreased the occurrence of 6-year MI and 15-year total mortality similarly among patients with or without the MS.

This post hoc analysis from the Coronary Drug Project (CDP) evaluated the effects of niacin mono-therapy on clinical outcomes in patients with and without the metabolic syndrome (MS).

The Coronary Drug Project (CDP) was a randomized, placebo-controlled clinical trial of lipid-modifying agents in men with previous myocardial infarction (MI).  Of the 5 drug regimens, only niacin significantly decreased definite recurrent nonfatal MI at 6 years and total mortality at a 15-year follow-up.  Patients treated with niacin (n = 1,119) and placebo (n = 2,787) were grouped according to the presence or absence of the MS at baseline.The MS was defined on the basis of meeting > or =3 of 5 criteria from the current National Cholesterol Education Program guidelines in a small subgroup of patients with high-density lipoprotein cholesterol determinations at baseline and on the basis of > or =3 of 4 criteria in the total population, excluding the high-density lipoprotein cholesterol criterion.Niacin decreased the occurrence of 6-year MI and 15-year total mortality similarly among patients with or without the MS. For example, in the total population, 15-year total mortality rates were 60% and 64% (hazard ratio 0.86) in patients with the MS treated with niacin and placebo, respectively, and 50% and 57% (hazard ratio 0.86) in those without the MS (Z for interaction = 0.06, indicating homogeneity of the treatment effect across groups).In conclusion, these results support the use of niacin in postinfarction patients with and without the MS.FULL TEXT

Source: Zhang LH, Kamanna VS, Zhang MC, Kashyap ML: Niacin inhibits surface expression of ATP synthase β-chain in HepG2 cells: implications for raisingHDL.
J. Lipid Res. 49(6), 1195-1201 (2008).

Niacin, also known as vitamin B3, can lower blood lipid levels. It may be used in the treatment of hyperlipidemia, where it reduces the LDL precursor VLDL. Niacin locks the breakdown of fats, resulting in a decrease in blood free fatty acid levels and consequently decreased VLDL and cholesterol secretion by the liver. In addition, by
lowering VLDL levels niacin also increases HDL levels.

Until recently, the mechanism of action of niacin was unknown, although it was thought that it did not increase HDL production. However, Moti Kashyap and colleagues (Veterans Administration Healthcare System, CA, USA) have now identified the ATP synthase β-chain as the likely target of niacin. This finding provides a clearer picture of how niacin maintains adequate blood HDL-C levels, thereby lowering the risk of heart disease.

Recently, it was shown that a component of ATP synthase is present on the surface of liver cells. This component was identified as the β-chain, which was found to be a HDL/ApoA-I receptor for HDL endocytosis in liver cells. Kashyap and colleagues demonstrated that niacin exerts its effects through this β-chain. Niacin was added to human HepG2 cells, leading to a 27% decrease in β-chain cell surface expression.

As a result, HDL uptake was reduced to 35%. By comparison, nicotinamide, a niacin metabolite that does not have a clinical effect on lipid levels, had weaker effects. HDL uptake was also reduced by the addition of anti-β-chain antibody; moreover, addition of the antibody abolished the inhibitory effect of niacin. β-chain mRNA expression was not altered by niacin administration.

The results from this study suggest that niacin reduces the liver’s capacity to remove HDL from the blood by a mechanism that inhibits the cell surface expression of ATP synthase β-chain. As a result, this maintains high HDL plasma levels. It should be noted that niacin does not affect the reverse cholesterol transport pathway. This is important as it means that HDL levels can be maintained, but other cholesterol types can still be removed from the blood.

The ATP synthase β-chain may be a new drug target, as no other drug is currently known to raise HDL levels by the reported mechanism.

by ET Bodor and S Offermanns
Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld, Heidelberg, Germany - British Journal of Pharmacology (2008) 153, S68–S75; doi:10.1038/sj.bjp.0707528

Excerpts from…

• Nicotinic acid has been used for decades to treat dyslipidaemic states.  In particular its ability to raise the plasma HDL cholesterol concentration has led to an increased interest in its pharmacological potential. The clinical use of nicotinic acid is somewhat limited due to several harmless but unpleasant side effects, most notably a cutaneous flushing phenomenon.

• Nicotinic acid has profound and unique effects on lipid metabolism and is thus referred to as a ‘broad-spectrum lipid drug’ (Carlson, 2005). In addition to elevating HDL  cholesterol (Parsons and Flinn, 1959; Shepherd et al., 1979) as well as decreasing both LDL and total cholesterol (Altschul et al., 1955; Carlson et al., 1977), nicotinic acid also induces a decrease in the concentrations of both ‘very-low-density lipoproteins’ (VLDL) and plasma triglyceride (TG) (Table 1; Carlson et al., 1989).
• The plasma concentration of lipoprotein Lp(a), which has been suggested to play a role as an independent risk factor for coronary heart disease, is also decreased by nicotinic acid (Carlson et al., 1989; Berglund and Ramakrishnan, 2004).

Soon after the initial discovery of the lipid-modifying effect of high doses of nicotinic acid (Altschul et al., 1955), the water-soluble vitamin nicotinic acid was introduced into clinical therapy as the first lipid-modifying drug.

• In the Coronary drug project, conducted from 1966 to 1975, nicotinic acid administered as monotherapy at 3 g day_1 was shown to lead to an efficient secondary prevention of myocardial infarction (Table 2) (Coronary Drug Project Research Group, 1975).

A follow-up study of the Coronary Drug project revealed that nicotinic acid also reduced the mortality of patients who had been treated with nicotinic acid (Canner et al., 1986). The Stockholm ischaemic heart disease secondary  prevention study came to similar findings (Carlson and Rosenhamer, 1988).

• The most rapid effect of nicotinic acid on lipid metabolism is a decrease in plasma levels of free fatty acid, which can be observed within minutes upon administration of the drug.

• Nicotinic acid, when given at pharmacological doses, has several unwanted yet harmless effects. The most common and most prominent unwanted effect of nicotinic acid is a cutaneous vasodilation, most prominently in the upper half of the body and in the face, which lasts for 1–2 h after an oral dose of nicotinic acid (Goldsmith and Cordill, 1943). This cutaneous reaction, called flushing, is relatively unpleasant and therefore negatively influences patients’ compliance.
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by Robert S. Rosenson
Preventive Cardiology Center, Northwestern University, The Feinberg School of Medicine, 201 East Huron Street, Galter Pavilion 11-120, Chicago, IL 60612, USA

Abstract

Cardiovascular event reduction in hypercholesterolemic subjects appropriately emphasizes the prominent role of statin therapy; however, niacin (nicotinic acid) is also an effective lipid-altering agent that prevents atherosclerosis and reduces cardiovascular events.

Niacin has multifarious lipoprotein and anti-atherothrombosis effects that improve endothelial function, reduce inflammation, increase plaque stability, and diminish thrombosis. Niacin reduces the atherogenicity of low-density lipoprotein (LDL) by changing the distribution of small LDL to large LDL subclass, and the susceptibility of LDL to oxidative modification.  It is the most effective agent for increasing high-density lipoprotein cholesterol.  Moreover, it favorably alters high-density lipoprotein composition, increasing apolipoprotein AI relative to apolipoprotein AII.

Niacin reduces blood viscosity through a variety of mechanisms, thus improving blood flow and perfusion through stenotic segments of the vasculature. Finally, niacin has cardioprotective effects that may limit ischemia–reperfusion injury. By preserving glycolysis during periods of ischemia and improving subendocardial blood flow during reperfusion, niacin can improve the functional recovery of the myocardium.
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by S. Tavintharan, MD, and Moti L. Kashyap, MD

Cholesterol Research Center, Department of Veterans Affairs
Healthcare System, University of California, Irvine,
5901 East Seventh Street (11/111-I)
Long Beach, CA 90822, USA.
E-mail: moti.kashyap@med.va.gov
Current Atherosclerosis Reports 2001, 3:74–82
Current Science Inc. ISSN 1523-3804
Copyright © 2001 by Current Science Inc.

Niacin favorably alters all major lipid subfractions at pharmacologic doses. Alone or in combination, it promotes regression of coronary artery disease, decreases coronary events, stroke, and total mortality.

Major recent progress in niacin is in four areas.  Firstly, recent data indicate that it increases high-density lipoprotein (HDL) and lowers triglycerides and low-density lipoprotein (LDL) by mechanisms different from statins, fibrates, and bile-sequestrants, giving rationale for combination therapy to achieve synergistic effects for complete lipid goal achievement.

Secondly, new data on an extended-release preparation of niacin given once nightly indicates that it is as effective and has greater tolerability than immediate-release niacin.

Thirdly, preliminary data with a single tablet formulation extended-release niacin and an HMG CoA reductase inhibitor (lovastatin) shows it to be safe and very effective, especially for raising HDL.

Finally, emerging evidence indicates that niacin can be used effectively and safely in patients with type 2 diabetes mellitus, who often have low HDL levels.

Introduction
Niacin, an essential B vitamin, has favorable effects on all major lipid subfractions at pharmacologic doses [1•]. Reports of its use in lipid-lowering therapy have been available since 1955 [2]. Although it is a potent lipid modifying agent, its usefulness in the past has been limited by adverse events. Nevertheless, there is renewed interest on the back of convincing data from clinical trials [3–9] and the development and availability of newer formulations of this agent. Tables 1 and 2 highlight the key facts of these clinical trials, which indicate that this agent significantly reduces atherosclerotic cardiovascular disease complications and total mortality.

The Veteran Affairs HDL Intervention Trial (VA-HIT) [10•] showed for the first time that increasing high-density lipoprotein (HDL) cholesterol and decreasing triglycerides (TG) (even without altering low-density lipoprotein [LDL] cholesterol) with gemfibrozil significantly reduced the risk of recurrent major cardiovascular events. The Bezafibrate Infarction Prevention (BIP) study [11] showed similar benefits, significantly in the subgroup with TG greater than 200 mg/dL.

With evidence showing extended-release niacin gives a twofold greater HDL cholesterol increase when compared with gemfibrozil [12•], there is strong rationale for the use of niacin for targeting increases in HDL cholesterol to prevent or reduce progression of atherosclerotic disease.

Efficacy and Toxicity of Niacin
The benefits of niacin in atherosclerosis are not surprising, looking at the broad-spectrum effects on the lipid profile.

Lowering of total cholesterol (TC), LDL cholesterol, very low-density lipoprotein (VLDL) cholesterol, TG, small dense LDL, apolipoprotein (apo) B, and lipoprotein (a) [Lp(a)] are achieved with niacin. In addition, it is also the most potent agent to raise HDL cholesterol, thus favorably reducing the ratios of total cholesterol to HDL cholesterol, and LDL cholesterol to HDL cholesterol, and apo B to apo A1.

The magnitude of cholesterol modification depends on patients’ baseline lipid levels and on the dose and preparation of niacin. On average it lowers LDL cholesterol by 15% to 30%, TG by 20% to 40%, Lp(a) by 30% to 40%, and raises HDL cholesterol by 15% to 30%.

Evidence suggests that antiatherogenic properties for LPAI particles (HDL cholesterol subfraction containing apo AI without apo AII) are greater than LP-AI +AII particles (HDL cholesterol subfraction containing apo AI with apo AII particles) [1•].

Niacin, apart from being the most potent agent in raising HDL cholesterol, has also been shown to improve HDL cholesterol quality by selectively increasing LPAI compared with LP-AI + AII particle concentration in patients with low HDL cholesterol levels [13].

Besides quantitative changes in LDL cholesterol levels, niacin mediates the generation of the more buoyant, less dense LDL particles. Data from observational studies by Austin et al. [14] show that small dense LDL particles are associated with a threefold risk of myocardial infarction (MI), and this is not related to LDL cholesterol levels [15].

The importance of reduction of this LDL subfraction thus assumes greater significance. Hydroxy methyl glutaryl (HMG) CoA reductase inhibitors (statins), which powerfully lower LDL cholesterol, do not decrease small dense LDL concentration [16], whereas fibrates like niacin do [17].

Niacin favorably alters all major lipid subfractions at pharmacologic doses. Alone or in combination, it promotes regression of coronary artery disease, decreases coronary events, stroke, and total mortality.
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by Karam Kostner‌ & Soneil Gupta

University of Queensland, Department of Cardiology, Mater Hospital, Raymond Terrace, South Brisbane 4101, Australia +61 4 38638617; k.kostner@uq.edu.au

Niacin is one of the oldest yet also most diverse lipid lowering agents. As it not only lowers low-density-lipoprotein (LDL) cholesterol, triglycerides (TG) and lipoprotein(a) [Lp(a)] but also increases high-density-lipoprotein (HDL) cholesterol, it is useful for treating a wide variety of lipid disorders including mixed hyperlipidaemia, hypertriglyceridaemia and isolated low HDL cholesterol, as well as elevated Lp(a).

Niacin, which exists in several different formulations, such as immediate release (IR), extended release (ER) and slow release (SR) niacin, has several modes of action: it modulates liver TG synthesis, which leads to increased intracellular apolipoprotein (apo) B degradation and increases TG lipolysis in adipose tissue. Recently, a specific niacin receptor has also been discovered. Several clinical outcome trials have demonstrated that niacin reduces coronary artery disease risk in combination with statins and two large mortality trials are currently underway looking at hard end-point reduction with niacin and statin compared to statin alone. 

Niacin’s major adverse event (AE) is flushing, and this prevents many patients from either taking it or reaching target doses of this drug. Flushing incidence and intensity is reduced with ER-niacin and by co-administration of aspirin and a selective or non-selective prostaglandin inhibitor.

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By Bi-lian Yu, Shui-ping Zhao
Department of Cardiology, The Second Xiangya Hospital of Central South University, Middle Ren-Min Road, No. 139, Changsha, Hunan 410011, PR China

Summary
Niacin has been used for decades to lower the plasma concentrations of cholesterol, free fatty acids, and triglycerides in humans, and in addition it raises more than any other drug the levels of the protective high density lipoprotein. These effects have been used to treat dyslipidemic states.

Trials have shown that treatment with niacin reduces progression of atherosclerosis, and clinical events and mortality from coronary heart disease. The beneficial clinical efficacy of niacin appropriately emphasizes the prominent role of its lipid-altering effects; however, high expression of niacin receptor in a variety of immune cell types, lowering of inflammatory markers, and beneficial impact on adipokines expression could provide rational to the hypothesis that anti-inflammatory effect is also an important property of niacin on atherosclerosis beyond its lipid-altering effects.
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by Shaista Malik and Moti L. Kashyap
Atherosclerosis Research Center, Department of Veterans Affairs Healthcare System, Division of Cardiology, University of California at Irvine, 5901 East Seventh Street (11-111-I), 90822 Long Beach, CA, USA

Niacin is the most effective medication in current clinical use for increasing high-density lipoprotein (HDL) cholesterol. It has the broadest effect on the lipid profile, reducing all atherogenic apolipoprotein (apo) B and increasing all antiatherogenic apo AI-containing lipoproteins, resulting in significant reduction in atherosclerotic complications and total mortality in trials.

Recent research indicates novel major target sites of action in the liver to 1) directly inhibit diacylglycerol acyltransferase 2 (DGAT2), explaining its effect on triglycerides and apo B lipoproteins, and 2) inhibit the HDL apo AI catabolism pathway, resulting in higher HDL levels. Such information may lead to new drug discovery and supply the rationale for combination with other lipid regulators that are known to have different mechanisms of action.  Trial evidence shows that niacin is not only safe to use in persons with diabetes, but that its combination with 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) is also safe and effective.

Recently, a new formulation of niacin has made it easier to tolerate and administer. Clinical trials are needed to determine whether niacin in combination with other lipidmodulating agents decreases the risk of cardiovascular events beyond the approximately 30% that has been noted with monotherapy.
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