Fight Cholesterol with Niacin

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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Gotto AM Jr.Cornell University Medical College, New York, New York, USA.The data for an independent association between triglyceride concentrations and risk for coronary artery disease (CAD) are equivocal, unlike the data for low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, which show strong, consistent, and opposing correlations with CAD risk.

There is some evidence for triglyceride as an independent risk factor in certain subgroups, for example, women 50-69 years of age (Framingham Heart Study) and in patients with noninsulin-dependent diabetes. However, the evidence is stronger for triglyceride as a synergistic CAD risk factor. For example, patients with the “lipid triad” of high LDL cholesterol, low HDL cholesterol, and high triglyceride accounted for most of the event reduction with lipid-lowering therapy in the Helsinki Heart Study.

An important confounder of the correlation between triglyceride and CAD risk is the heterogeneity of triglyceride-rich lipoproteins: the larger triglyceride-rich particles are thought not to be associated with CAD risk, whereas the smaller (and denser) particles are believed to be atherogenic. At present, measurement of fasting triglyceride levels and triglyceride assessment in conjunction with LDL cholesterol and HDL cholesterol concentrations are the most practical methods of evaluating hypertriglyceridemia in CAD risk, although postprandial lipemia may prove a better indicator of atherogenicity.

Management of hypertriglyceridemia should initially focus on nonpharmacologic therapy (i.e., diet, exercise, weight control, and alcohol reduction). In diabetic patients, meticulous glycemic control is also important. However, if this approach proves inadequate, there are several pharmacologic options. Fibrates may be effective in decreasing triglyceride and increasing HDL cholesterol.

Nicotinic acid (niacin) has been shown to decrease triglyceride, increase HDL cholesterol, lower LDL cholesterol, and decrease lipoprotein(a); it also decreases fibrinogen. The statins appear to be effective in decreasing triglyceride and LDL cholesterol in hypertriglyceridemia; however, they do not normalize metabolism of apolipoprotein B, and HDL cholesterol may remain low. Therefore, combination with a fibrate or niacin may be appropriate. Attention to hypertriglyceridemia with respect to increased CAD risk represents an important step in assessing global risk for CAD development.PMID: 9819100 [PubMed - indexed for MEDLINE

The American Journal of Cardiology , Volume 98 , Issue 6 , Pages 743 - 745
J . Kuvin , D . Dave , K . Sliney , P . Mooney , A . Patel , C . Kimmelstiel , R . Karas

In this study, niacin was added to existing therapy for 3 months in 54 subjects with stable coronary artery disease. Average total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels were similar between groups.
Three months of niacin treatment increased total HDL by 7.5% and decreased triglycerides by 15% compared with baseline values (p <0.005 for each), whereas total cholesterol and LDL levels remained unchanged. Addition of niacin resulted in a 32% increase in large-particle HDL (p <0.001), an 8% decrease in small-particle HDL (p = 0.0032), an 82% increase in large-particle LDL (p = 0.09), and a 12% decrease in small-particle LDL (p = 0.008).

Niacin decreased lipoprotein-associated phospholipase A2 and C-reactive protein levels (20% and 15%, respectively, p <0.05 for the 2 comparisons). No significant changes from baseline were seen in any tested parameter in subjects who received placebo.

In conclusion, addition of niacin to existing medical regimens for patients with coronary artery disease and already well-controlled LDL levels favorably improves the distribution of lipoprotein particle sizes and inflammatory markers in a manner that would be expected to confer atheroprotection…
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Heinz Drexel

Vorarlberg Institute for Vascular Investigation and Treatment (VIVIT), Academic Hospital, Carinagasse 47, A-6807, Feldkirch, Austria

Low HDL-cholesterol is common among patients with cardiovascular disease.  Well-designed epidemiological studies carried out over the previous three decades have defined the prognostic significance of low HDL-cholesterol.

Indeed, a recent valuation of patients undergoing coronary angiography showed that factors related o HDL-cholesterol, but not to LDL-cholesterol, were primarily responsible for driving the elevated risk of atherosclerosis and cardiovascular events associated with dysglycaemia within this population.

Randomized intervention studies have demonstrated significant inhibition of atherosclerosis and/or improvement in cardiovascular event rates with treatments that increase HDL-cholesterol (nicotinic acid or a fibrate).

Nicotinic acid is the most powerful HDL-cholesterol raising agent currently available, and a combination of this agent with a statin facilitates simultaneous control of both HDL-cholesterol and LDL-cholesterol.  Indeed, the HDL Atherosclerosis Treatment Study demonstrated a reduction in major cardiovascular events of 90% vs. placebo in patients randomized to nicotinic acid & simvastatin.

In addition, patients randomized to nicotinic acid in the Coronary Drug Project benefited from a significant reduction in mortality after 15 years, 9 years after the trial ended.

A new prolonged-release formulation of nicotinic acid, Niaspanw, has superior tolerability compared with immediate-release nicotinic acid and facilitates the delivery of this therapy.  The evidence base supporting intervention to correct low HDL-cholesterol in addition to reducing LDL-cholesterol is now sufficiently strong to support the introduction of this strategy into routine clinical practice.
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By Kimberly Beauchamp, ND  -  (Am J Clin Nutr 2008;88:30–7)

Niacin and aerobic exercise can each separately help to lower blood fats called triglycerides.   A study in the American Journal of Clinical Nutrition recently explored how these therapies might work together to promote heart health in people with the metabolic syndrome.

The metabolic syndrome is a group of risk factors for cardiovascular disease and type 2 diabetes, including abdominal obesity (tummy fat), insulin resistance (poor ability of the body to respond to fluctuations in blood sugar), low HDL (“good”) cholesterol, high blood pressure, and high triglycerides.  When a person has three or more of these factors, they are said to have the metabolic syndrome, which affects an estimated 50 million Americans.

A two-pronged approach to treating the metabolic syndrome

The new study investigated the combined effects of niacin and aerobic exercise in 15 men with the metabolic syndrome.The study consisted of three parts:

• During the first, the men ate a high-fat meal only (control), containing 100 grams of fat;
• in the second part, the men exercised for about 50 minutes, one hour before a high-fat meal;
• In the third part, they took extended-release niacin in increasing dosages for six weeks (up to 1,500 mg per day) and then exercised for 50 minutes, one hour before a high-fat meal.

Blood levels of triglycerides and insulin were measured to assess the response to these therapies.  Compared with the control, triglyceride levels were 32% lower after the high-fat meal that was preceded by exercise.  This effect lasted for up to six hours.

While niacin lowered fasting triglyceride levels by 37%, niacin plus exercise did not decrease triglyceride levels immediately following the high-fat meal, suggesting that niacin canceled out the positive effect of exercise on after-meal triglyceride levels.

“While these results would appear to promote the use of one intervention over the other, it is important to note that a number of recent investigations provide evidence that niacin has important direct vascular anti-inflammatory properties which have not been observed with exercise alone,” said Dr. Eric Plaisance, the study’s lead author.

“I would recommend a combination of exercise and niacin for patients with the metabolic syndrome; not only to reduce fasting and postprandial triglycerides, but also to directly reduce the vascular inflammatory cascade that is so prevalent in this population.”

A potential drawback to niacin therapy is that it can decrease insulin sensitivity; this effect was not seen when niacin was combined with exercise, suggesting that exercise can help offset the negative effects of niacin on blood sugar.

Kimberly Beauchamp, ND, earned her bachelor’s degree from the University of Rhode Island and her Doctorate ofNaturopathic Medicine from Bastyr University in Kenmore, WA. She cofounded South County Naturopaths in Wakefield, RI.  Dr. Beauchamp practices as a birth doula and lectures on topics including whole-foods nutrition, detoxification, and women’s health.

Below, H. Robert Superko, MD., F.A.C.C. is interviewed by C. Richard Conti, MD., M.A.C.C.Dr. Conti is Eminent Scholar, Cardiology; Prof of MedicineUniversity of Florida College of MedicineDr.Superko is Chairman, Molecular,Genetic, and Preventive CardiologySaint Joseph Hospital, Atlanta, GA

Yes, niacin requires some extra time for you or your nurses, in order to get good compliance from your patients. But the important thing to remember is that niacin addresses a much larger medical problem than the LDL problem. Plus, we have some niacin formulations that are better tolerated and there is more of a push from the scientific medical community that this is the right thing to do in the appropriate patient population.

…If we’re talking to patients with coronary disease, they need to realize they have a deadly disease. You can make an analogy with cancer; if you have cancer and I give you a drug that’s going to extend or maybe save your life, but you’re going to flush a little bit, I suspect patients would take it. We need to look at coronary disease the same way. We have to be very aggressive and, if necessary, tolerate some minor side effects, because it’s going to extend their life and maybe even stop progression of their disease.

Dr. Conti:I’m Richard Conti with Robert Superko. Rob is executive director of the Center for Genomics and Human Health at St. Joseph’s Translational Research Institute in Atlanta, Georgia. We’re talking about, “Nicotinic Acid: The New Old Wonder Drug.” We’re going to review some of the history of nicotinic acid; talk about mechanism of action; discuss why it’s not been used very often in the past; and then look at the clinical evidence of its success. Robert, let’s start with the history.

Dr. Superko:It was 1955 when Altschul first reported that nicotinic acid lowers blood cholesterol in humans12 and since then a whole series of clinical trials and basic science research has progressed. In 2001, Lorenzen discovered a nicotinic acid receptor.13 So there’s a long, long history of both scientific and clinical use of this compound.

Dr. Conti:What about its mechanism of action?

Dr. Superko:The mechanism of action was not known for many years; it was simply known to improve cholesterol, particularly it lowered triglycerides and raised HDL. Now the mechanism has been worked out with the recent identification of a nicotinic acid receptor. It’s a G-coupled protein receptor and, interestingly, at least four SNPs and five haplotypes have been identified. This means people respond to nicotinic acid very differently, in part due to genetic reasons.One thing it does is inhibit free-fatty acid mobilization from fat tissues and this accounts for the triglyceride reduction, but it also has a powerful impact on HDL by inhibiting the degradation or removal of apo A1. That’s primarily why it raises HDL cholesterol so dramatically, particularly the really beneficial HDL2.

Dr. Conti:Robert, why has the pharmaceutical industry tried to develop a drug that raises HDL when we already have a drug that raises HDL?

Dr. Superko:If we look at the clinical trial evidence, it was primarily developed through the NIH and through studies in Europe; very little of it was done by pharmaceutical companies. Yet the evidence is overwhelming that if you combine HDL raising with LDL lowering you get profoundly better results than LDL lowering alone.This was obvious to everybody in the field, including people in the pharmaceutical industry. The problem was that the best drug in the world for raising HDL was nicotinic acid, a simple compound for which no one held a patent or had any kind of intellectual property. It was not until a company that’s now been sold to Abbott, called Kos, started developing a better form of niacin several years ago that commercial interest took off.Now we have Abbott providing a very effective delayed-release or time-released nicotinic acid and Merck is working on another version. Consequently, we may see a lot of competition soon and many physicians will be invited to a lot more nicotinic acid dinner talks. Also, there are a few products coming out that involve different combinations of a statin plus nicotinic acid.

Dr. Conti:Over the years that I’ve been using nicotinic acid, it hasn’t been commonly used by most physicians. What was the reason for that? Was it because of the flushing or because it wasn’t marketable in a big pharmaceutical business sort of way?

Dr. Superko:In the past, we were using 4 or 5 grams of immediate-release niacin a day. It was very effective and was absolutely the right thing to do in the appropriate patient, but it took a fair amount of effort. You had to talk to the patient a lot; they’d come back – you’d hear the flushing complaint, which is the one most people appreciate. It certainly was not an easy drug to use compared to the statins.Around this time the LRC-CPPT (Lipid Research Clinics Coronary Primary Prevention Trial) was completed and the whole field of lowering LDL cholesterol took off. Subsequently, we’ve had tremendous success designing drugs that primarily lower LDL cholesterol – the statins – that are well tolerated with very few side effects. As physicians, we have gotten used to the concept of, “Let me give you this pill. You’re not likely to have any side effects.” The numbers look better on the lab report and we think we’ve done our job. Yet, we’ve known for 20 years that LDL cholesterol is not the most common cause of coronary disease; it’s the triglyceride-rich particles and the low HDLs, that are more common and more important — and statins don’t address them adequately.Yes, niacin requires some extra time for you or your nurses in order to get good compliance from your patients, but the important thing to remember is that niacin addresses a much larger medical problem than the LDL problem. Plus, we have some niacin formulations that are better tolerated and there is more of a push from the scientific medical community that this is the right thing to do in the appropriate patient population.

Dr. Conti:Why don’t you tell our audience the David Blankenhorn story?Dr. Superko:Dave Blankenhorn unfortunately passed away recently; a great man who did the CLAS (Cholesterol Lowering Atherosclerosis Study I and II) trial. The average dose of nicotinic acid in the CLAS trial was about 5 grams per day. That’s a high dose and Dave told me that patients would come in and complain about the flushing. Dave would open up their shirt and point to the bypass scar on their chest and say, “Hey, do you want another one of these?” In other words, “Do you want surgery or do you want to put up with a little flushing?” The patients put up with the flushing.

Dr. Conti:A good story. Let’s review some of the clinical evidence for success with this drug.

Dr. Superko:The clinical evidence goes back a long way to the Stockholm Heart Study, a non-randomized study that showed about a 26% mortality reduction associated with nicotinic acid.14 The evidence proceeds through the Coronary Drug Project and finally into the NIH trials – Greg Brown’s FATS and HATS trial and our ownSCRIP study.If you line these studies up and compare them against the statin studies, you would ask, “What’s the reduction in clinical events?” In the statin studies you get about a 25% relative risk reduction – not absolute, but relative: and that’s considered a success. If you look at the combination studies that used, for example, a resin and niacin or a statin and niacin, you get an 80-90% risk reduction; far, far better. If you look at the arteriographic studies using QCA, statins reduce the rate of disease progression but there’s essentially no regression. It’s only in the combination studies that used niacin and an LDL-lowering agent that you actually got arteriographic regression.By any parameter of success, the combination of adding nicotinic acid to an LDL-lowering program is overwhelmingly successful and I’ve just been amazed that this has not been embraced by the cardiology community over the past 10-15 years.

Dr. Conti:Yes, it is amazing. I guess it all boils down to side effects; people don’t like them and doctors don’t like patients complaining about side effects. I’ve used the old trick of telling my patients, “Well, you’re flushing. You’re flushing the bad cholesterol right out of your system,” and that seems to work in some cases.

Dr. Superko:That’s a good analogy. If we’re talking to patients with coronary disease, they need to realize they have a deadly disease. You can make an analogy with cancer; if you have cancer and I give you a drug that’s going to extend or maybe save your life but you’re going to flush a little bit, I suspect patients would take it. We need to look at coronary disease the same way. We have to be very aggressive and, if necessary, tolerate some minor side effects, because it’s going to extend their life and maybe even stop progression of their disease.

Dr. Conti:We’ll end this discussion on that wise advice, Robert. Thank you very much for coming and discussing this with our ACCEL audience.

Dr. Superko:Thank you, Dick. It’s always a pleasure.

Guyton JR.
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.

Niacin has been studied in 6 major clinical trials with cardiovascular endpoints. The Coronary Drug Project (CDP) was the largest of these trials and the only one to use niacin monotherapy affecting cardiovascular outcomes: recurrent myocardial infarction and cerebrovascular events were significantly decreased. After long-term (15 years) follow-up, total mortality was also found to be decreased.

The other 5 trials used varying combinations of niacin with other pharmacologic agents, examining coronary and total mortality, coronary events, and angiographic progression/regression. Significant benefit was found in all trials except for one in patients with normal cholesterol levels at entry. Thus, the use of niacin to prevent or treat atherosclerotic cardiovascular disease is based on strong and consistent evidence from clinical trials.

David Tanne, MD; Shlomit Yaari, BSc Uri Goldbourt, PhD

the Department of Epidemiology and Preventive Medicine, Sackler School of Medicine, Tel-Aviv University (U.G.); the Department of Neurology (D.T.) and Neufeld Cardiac Research Institute (U.G.), Sheba Medical Center, Tel-Hashomer; and the Computing Center, Bar-Ilan University, Ramat Gan (S.Y.), Israel.

A 21-Year Follow-up of 8586 Men From the Israeli Ischemic Heart Disease Study

Methods The subjects of this report are 8586 men, tenured civil servants and municipal employees, aged 42 years or older at the time of HDL-C measurements in 1965. They were followed up for mortality for 21 years.

HDL levels were increased with niacin therapy in the large test-group.  In multivariate analysis, a low concentration of HDL-C appeared to be significantly predictive of ischemic stroke mortality.  Decreasing rates of ischemic stroke mortality were observed with increasing %HDL.

Conclusions: In this prospective study of middle-aged and elderly men from a healthy, working population, has demonstrated an independent negative association between HDL-C and ischemic stroke mortality during a long-term (21-year) follow-up.

“Physicians who know little about niacin, mistrust it, and their patients have much more trouble with it. “  Abram Hoffer, M.D., Ph.D.

During a career spanning more than four decades, Abram Hoffer, M.D., Ph.D., has not only made some of the most original contributions to the field of nutritional healing, but he’s also pioneered the field of orthomolecular medicine (orthomolecular medicine achieves or preserves health by manipulating substances such as vitamins that are normally present in the body).

Hoffer is the author of more than 500 papers plus 15 books including his latest about cancer and nutrition–begun as a collaboration with the late Linus Pauling, Ph.D. Hoffer is president of the Canadian Schizophrenia Foundation and editor of the Journal of Orthomolecular Medicine. He runs a private clinical practice in Victoria, British Columbia, Canada.

Dr. Hoffer has prescibed niacin therapy to more than four thousand patients over the last fifty years.  His opinions regarding the therapeutic use of niacin, therefore, are based on real, time-tested, hands-on experience.

Below are excerpts from the Journal of Orthomolecular Medicine Vol. 14, 11/2/1999.
by A. Hoffer, M.D., Ph.D. FRCP(C)

RE: Niacin Side Effcts

The vasodilatation (flushing) is not a side effect. It is an essential effect of the niacin as a general vasodilator. Cutaneous reactions include browning of the skin, especially in the flexor surfaces. It occurs most often in schizophrenic patients. This is totally safe and usually is gone within a matter of months or years, leaving normal, even healthier skin behind.

Gout is listed as a side effect. I have used niacin, since we first discovered it lowered cholesterol levels in 1955 and have given it to well over 4,000 patients.  I have not seen a single case of gout. In fact I have given it to patients with gout who are no better nor worse while on niacin and respond to the usual medication for gout.

It is a general rule that physicians comfortable with niacin and who appreciate its therapeutic properties have very little problem with it and their patients have very few side effects. When they occur, they are easily dealt with. Physicians who know little about niacin, mistrust it, and their patients have much more trouble with it.
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