Fight Cholesterol with Niacin

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Good cholesterol may mean little for statin users: Research

Thursday, July 22nd, 2010

Chicago: People with high levels of the so-called good cholesterol HDL tend to have fewer heart attacks. But HDL may offer little protective benefit in people who take statins to lower harmful LDL cholesterol, US researchers said on Wednesday.

An analysis of a large study of healthy people who took AstraZeneca’s statin drug Crestor to prevent heart attacks found that having high HDL was not a good predictor of heart attack risk.

“Once we get LDL into these very low ranges with very potent statins, HDL no longer predicts future risk of heart disease,” said Paul Ridker of Brigham and Women’s Hospital in Boston, whose study appears in the journal Lancet.

The findings raise questions about drugs in development to raise HDL to prevent heart attacks, Ridker added.

Several companies are working on HDL-raising drugs, which might be combined with statins, in the hope of developing even more potent weapons against heart disease.

Tiny Canadian biotech company ResVerlogix has an experimental drug in clinical trials that increases production ApoA-1 in blood, which then raises HDL, a compound that helps ferry harmful fats out of the blood.

Raising HDL through increased ApoA-1 is a different approach from other HDL boosters, such as a class known as CETP inhibitors that included torcetrapib, Pfizer’s most spectacular clinical failure. Merck & Co and Roche are still developing CETP inhibitors.

Current drugs that raise natural levels of HDL, such as niacin, cause unpleasant side effects like flushing.

In the original study, called JUPITER, patients with average to low levels of low-density lipoprotein or LDL were given Crestor or rosuvastatin, which cut their bad cholesterol concentrations to levels seen in aboriginal populations but rarely seen in Western patients.

People in the study who took Crestor had 54% fewer heart attacks and 48% fewer strokes after two years compared to people who took a placebo.

In the new analysis, Ridker and colleagues looked to see if HDL was still a predictor of heart attack risk in people who took Crestor. They found that HDL was still protective in people who got the placebo, but in those whose cholesterol was lowered by the statin, having high HDL made no difference in predicting which patients would have heart problems.

“In my heart of hearts, I believe the only way to address whether or not new agents that increase HDL will be effective is through well-done, carefully taken out clinical trials. There is no other way to get there,” Ridker said.

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Tags: cholesterol, HDL, LDL, niacin, niacin therapy, statin, statins
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Higher HDL Might Lower Cancer Risk

Tuesday, June 29th, 2010

By Crystal Phend, Senior Staff Writer, MedPage Today
Published: June 14, 2010
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Explain to interested patients that this study could not determine whether higher HDL actually led to lower cancer risk or was merely a surrogate marker for lower cancer risk.
Note that lifestyle changes may be recommended for patients with low HDL regardless of any association of HDL with cancer risk.

Break out the niacin! Higher HDL cholesterol levels appear independently linked to lower cancer risk, a meta-analysis found.The analysis of two dozen randomized, controlled lipid intervention trials found that each 10-mg/dl higher increment of HDL cholesterol was associated with a relative 36% lower risk of incident cancer (95% confidence interval 24% to 47%, P<0.001), according to Richard H. Karas, MD, PhD, of Tufts Medical Center in Boston, and colleagues.

This relationship persisted even after adjusting for baseline LDL cholesterol, age, body mass index (BMI), diabetes, sex, and smoking status, Karas and colleagues reported in the June 22 issue of the Journal of the American College of Cardiology.

Epidemiologic studies have suggested higher risk of incident cancer with lower total cholesterol levels, and a meta-analysis of statin trials by Kara’s group showed the same is true for LDL cholesterol levels.

The researchers were quick to note that these association studies cannot prove cause and effect, although HDL may have anti-inflammatory and antioxidant properties that could potentially fight cancer.

There is some evidence for a causal link with HDL cholesterol, noted Jennifer G. Robinson, MD, MPH, of the University of Iowa in Iowa City, in an accompanying editorial.

“However, the most important criteria for causality have not yet been met (lack of alternative explanations and proof by experiment),” she wrote.

Rather, she added, low HDL is likely simply a marker for elevated risk of chronic diseases that “increase inflammation and insulin resistance, which may directly influence atherosclerosis and carcinogenesis.”

Regardless of whether high HDL actually lowers cancer risk, recommendations for healthy lifestyle changes — quit smoking, improve diet, engage in regular physical activity, and control weight — could particularly benefit patients with low HDL, since making such changes can help prevent many of the chronic diseases associated with aging, she said.

Aside from lifestyle factors, niacin is the most effective agent for boosting HDL — elevating so-called “good cholesterol” by 20% to 30%. Fibrates can also increase HDL between 10% to 20%. However, statins have little, if any, benefit for raising HDL.

Karas’ group analyzed 24 randomized controlled lipid intervention trials with at least 1,000 patient-years of follow-up each for a total of 76,265 intervention-group patients and 69,478 controls followed for a median of five years.

The 8,185 incident cancers appeared significantly linked to HDL cholesterol in the unadjusted analysis, with a 28% lower risk for each 10-mg/dl higher level (P=0.018).

However, the magnitude of the link did not differ between intervention and control groups (P=0.95) or by type of intervention (P=0.726).

After controlling for the other significant factors in cancer risk, the link became even stronger.

The researchers cautioned that the meta-analysis was limited by the available randomized, control trial-level data, a lack of individual patient data, lack of uniform identification of cancers across trials, and follow-up periods that were potentially too short (a median of five years) to see if the associations changed over time.

“These findings underscore the importance of reporting cancer rates in future lipid intervention trials and further support the importance of basic scientific research to determine potential underlying mechanisms that might mediate these associations,” they concluded in JACC.

Karas reported having received speaker and consulting fees from Abbott Laboratories and Merck.

A co-author reported being a recipient of a faculty development award from Pfizer/Tufts Medical Center.

Robinson reported that her institution has received grants from Abbott, Aegerion, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Hoffman-La Roche, Merck, and Merck Schering-Plough.

Primary source: Journal of the American College of Cardiology
Source reference:
Jafri H, et al “Baseline and on-treatment high-density lipoprotein cholesterol and the risk of cancer in randomized controlled trials of lipid-altering therapy” J Am Coll Cardiol 2010; 55: 2846–54.

Additional source: Journal of the American College of Cardiology
Source reference:
Robinson JG “Low high-density lipoprotein cholesterol and chronic disease risk marker or causal?” J Am Coll Cardiol 2010; 55: 2855–57.

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Tags: cancer, cholesterol, HDL, mortality, niacin
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Niacin can help raise HDL cholesterol levels

Tuesday, June 1st, 2010

By Tom Valeo, Special to the Times
In Print: Wednesday, May 26, 2010

If we were to compare niacin against all the cholesterol medications, it far and away would have the best profile,” said Dr. John J. Mentel of the Mayo Clinic in Jacksonville. “You get an HDL increase of 15 to 35 percent, depending on which study you look at. Your LDL falls by 10 to 25 percent. And you get a decrease of 20 to 50 percent in your triglycerides. It really is an ideal drug. I think it would be the No. 1 choice if it weren’t for the side effects.

If you’re like most middle-aged Americans, you’ve been concerned about lowering your LDL or “bad” cholesterol.

But raising your HDL or “good” cholesterol might help even more.

The problem is that statins, like Crestor and Lipitor, which can lower LDL dramatically, have very little effect on HDL.

How can you boost your HDL?

By taking niacin, an inexpensive and widely available B vitamin also known as nicotinic acid.

In one recent study reported in the Journal of the American College of Cardiology, patients already taking statins to improve their cholesterol levels boosted their HDL by 23 percent when they took 2,000 milligrams of niacin per day. They also reduced the plaque buildup in their carotid arteries by about 1 millimeter over 12 months.

A study in the New England Journal of Medicine a few months earlier reported similar results. Patients who took 2,000 milligrams of niacin a day raised their HDL by 18.4 percent, and also reduced the plaque buildup in their carotid arteries.

Such results make niacin sound like a drug with enormous potential for reducing heart disease, and that’s precisely how many physicians regard it.

“If we were to compare niacin against all the cholesterol medications, it far and away would have the best profile,” said Dr. John J. Mentel of the Mayo Clinic in Jacksonville. “You get an HDL increase of 15 to 35 percent, depending on which study you look at. Your LDL falls by 10 to 25 percent. And you get a decrease of 20 to 50 percent in your triglycerides. It really is an ideal drug. I think it would be the No. 1 choice if it weren’t for the side effects.”

Side effects?

Niacin at high doses, such as those used in the study, can cause mild liver toxicity in some patients.

“It’s not too different from Tylenol,” Mentel said. “All cholesterol drugs have some liver toxicity associated with them. We monitor that with periodic blood tests. You have to check their cholesterol anyway to see if you’re winning the battle, so you check their liver function at the same time.”

But toxicity is not the only problem. Niacin causes about 10 minutes of intense skin flushing after each dose, which causes many people to stop taking it. Over-the-counter niacin, described as timed-release and “no-flush” forms, reduces this problem dramatically, but doesn’t improve cholesterol levels significantly.

Abbott Laboratories markets an “extended-release” form of prescription-only niacin called Niaspan, which slows the delivery of niacin somewhat, but not so much that it compromises niacin’s beneficial effects. The only problem is the cost. Whereas drugstore.com charges about 8 cents for a 500-milligram tablet of plain niacin, it charges about $2.36 for an equal dose of prescription Niaspan. Prescription drug plans with 90-day refills can offset a great deal of that cost, however.

Pharmacologically the two substances are identical.

“Nicotinic acid is nicotinic acid,” Mentel said.

However, he regularly prescribes Niaspan for his patients because it allows them to take one pill a day with less flushing than they would experience with plain niacin. Also, since Niaspan is considered a drug monitored by the FDA, he can be confident his patients get precisely the dose he prescribes.

“I needed something reliable, and I needed something timed-release to avoid the side effect of flushing if I could,” Mentel said. “Niaspan allows the patient to take one dose, usually at bedtime, which leads to better compliance. That’s the No. 1 problem with using niacin to treat cholesterol: You get poor compliance.”

If you want to take ordinary, inexpensive niacin, you can minimize the flushing by taking it with meals, and by avoiding alcohol, hot beverages or other substances that might cause flushing, according to Dr. Terry A. Jacobson of Emory University School of Medicine, author of How to Beat a Flush, in the most recent Mayo Clinic Proceedings. An ordinary aspirin taken 30 minutes before the niacin also helps reduce flushing, he says, and you can take the niacin just before going to bed so you sleep through the flushing.

Also, increasing the dose gradually over several weeks seems to help some people reduce the flushing, according to Mentel.

“We always start with a small dose and increase gradually,” he said, “but if they build up tolerance and miss a dose or three and start back up again where they left off, they’re going to have trouble again with flushing.”

Before taking niacin, or switching types, talk with your doctor about what kind and how much niacin supplementation might be right for you.

Tom Valeo writes frequently about health matters. He welcomes reader mail but cannot respond to individual queries. You may write him at tom.valeo@gmail.com.

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Tags: cholesterol, HDL, heart disease, LDL, niacin
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How Can I Prevent Niacin Side Effects?

Wednesday, March 17th, 2010

By Jennifer Moll, About.com Guide

Question: How Can I Prevent Niacin Side Effects?

Answer: While nicotinic acid can greatly help to lower cholesterol levels, it also has those typical niacin side effects. This leads many people to wonder how they can prevent the side effects of niacin.
If you’ve ever taken nicotinic acid, a form of niacin, you might be familiar with its side effects, such as flushing, itching, and hot flashes. Although these side effects are pretty common, they can be intolerable to the point that some people stop taking nicotinic acid. The side effects usually subside over a couple of weeks, but in the meantime, they might be very bothersome.

These are some simple tips that might help reduce the side effects experienced by taking nicotinic acid:

* If you are taking an immediate-release form of nicotinic acid, you may want to gradually increase your dose. For instance, if you are supposed to take 500 mg of nicotinic acid a day, take 250 mg the first few days until you are able to tolerate the side effects and gradually increase your dose until you reach the recommended dose each day. This only works for immediate-release products (never cut sustained or extended-release pills in half). Also, you might try to divide your dose throughout the day. In this case, you would take 250 mg twice a day, instead of 500 mg once a day.

* If you are having trouble with side effects, such as flushing or itching, you may take a 325 mg aspirin dose at least 15 to 30 minutes before your nicotinic acid dose. Studies have shown that taking aspirin before your nicotinic acid dose can decrease the flushing and itching associated with nicotinic acid.

* Don’t drink hot beverages (such as coffee and hot tea) or alcohol around the time you take your niacin dose, since these drinks may increase the likelihood of flushing.

* If you are still having trouble tolerating the immediate-release form of niacin, you might want to ask your health care provider about a sustained-release or extended-release form of niacin. These forms of niacin release nicotinic acid into the body gradually and somewhat reduce side effects. There are sustained-release forms available over-the-counter, however, in some cases, they have caused hepatitis. Niaspan is the only extended-release form of nicotinic acid and it is only available by prescription.

* There are also other forms of niacin, such as nicotinamide and inositol hexaniacinate, that are designated as ”flush-free” forms of niacin. Although they may not produce the side effects that nicotinic acid can cause, some studies have shown that these forms of niacin may not be effective in lowering cholesterol.

Before trying any of these tips, make sure your health care provider is aware that you are taking a nicotinic acid product, since some individuals may need to be monitored more closely due to health conditions they may have or medications they are taking.

There is also a new a chemical, laropiprant, designed to lower the side effects associated with nicotinic acid. Laropiprant is not available on the market yet, however tests so far have shown that it promises to lower the incidence of side effects associated with nicotinic acid. It is still undergoing testing.
Sources:

Cefali EA, Simmons PD, Stanek EJ, et al. Aspirin reduces cutaneous flushing after administration of an optimized extended-release niacin formulation. Int J Clin Pharmacol Ther. 2007; 45(2):78-88.

Dipiro JT, Talbert RL. Pharmacotherapy: A Pathophysiological Approach, 6th ed 2005.

Lai E, De Lepeleire I, Crumley TM, et al. Suppression of niacin-induced vasodilation with an antagonist to prostaglandin D2 receptor subtype 1. Clin Pharmacol Ther. 2007; 81(6):849-57.

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Evidence That Niacin Inhibits Acute Vascular Inflammation and Improves Endothelial Dysfunction Independent of Changes in Plasma Lipids

Tuesday, March 16th, 2010

Ben J. Wu ; Ling Yan ; Francesca Charlton ; Paul Witting ; Philip J. Barter ; and Kerry-Anne Rye E-mail: ryek@hri.org.au; karye@ozemail.com.au

The study showed that niacin inhibits vascular inflammation and protects against endothelial dysfunction independent of changes in plasma lipid levels.

From the Lipid Research Group (B.J.W., L.Y., F.C., P.J.B., and K.-A.R.), Heart Research Institute, Sydney, Australia; the Faculty of Medicine (P.W., P.J.B., and K.-A.R.), University of Sydney, Sydney, Australia; and the Department of Medicine (K.-A.R.), University of Melbourne, Melbourne, Australia.

Objective—To determine if niacin can confer cardiovascular benefit by inhibiting vascular inflammation and improving endothelial function independent of changes in plasma lipid and lipoprotein levels.

Methods and Results—New Zealand white rabbits received normal chow or chow supplemented with 0.6% or 1.2% (wt/wt) niacin. This regimen had no effect on plasma cholesterol, triglyceride, or high-density lipoprotein level. Acute vascular inflammation and endothelial dysfunction were induced in the animals with a periarterial carotid collar. At the 24-hour postcollar implantation, the endothelial expression of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, and monocyte chemotactic protein 1 was markedly decreased in the niacin-supplemented animals compared with controls. Niacin also inhibited intima-media neutrophil recruitment and myeloperoxidase accumulation, enhanced endothelial-dependent vasorelaxation and cyclic guanosine monophosphate production, increased vascular reduced glutathione content, and protected against hypochlorous acid–induced endothelial dysfunction and tumor necrosis factor {alpha}–induced vascular inflammation.

Conclusion—Previous human intervention studies have demonstrated that niacin inhibits coronary artery disease. This benefit is thought to be because of its ability to reduce low-density lipoprotein and plasma triglyceride levels and increase high-density lipoprotein levels. The present study showed that niacin inhibits vascular inflammation and protects against endothelial dysfunction independent of changes in plasma lipid levels.

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Solving Drug Therapy Issues in Patients Using Niacin

Wednesday, March 25th, 2009

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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Benefits of niacin in patients with, versus without, the metabolic syndrome and healed myocardial infarction (from the Coronary Drug Project).

Tuesday, February 17th, 2009

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

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Niacin’s mechanism of action has been determined, revealing a new drug target

Wednesday, January 28th, 2009

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.

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Tags: cholesterol, endur-acin, Enduracin, HDL-C levels, lipid levels, niacin, synthase β-chain, vldl
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Nicotinic acid: an old drug with a promising future

Wednesday, December 31st, 2008

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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The Benefits of Niacin in Atherosclerosis

Wednesday, December 3rd, 2008

(excerpts selected from the full text)

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].

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