AIM-HIGH fell short, leaving experts looking for reasons in new review

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heartwire

April 19, 2012
Michael O’Riordan

Baltimore, MD – When the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) study was stopped early for futility, researchers and clinicians alike were disappointed and somewhat perplexed. The confusion stemmed from past studies with niacin, an agent used frequently in clinical practice to raise HDL-cholesterol levels, showing the drug provided a benefit in cardiovascular risk protection. In addition, observational studies have clearly shown that low levels of HDL cholesterol are associated with an increased risk of cardiovascular disease.

In a new review published online April 18, 2012 in the Journal of the American College of Cardiology, Dr Erin Michos (Johns Hopkins University School of Medicine, Baltimore, MD) and colleagues attempt to reconcile the disconnect between AIM-HIGH and other positive studies with niacin [1]. To heartwire, she noted that before the statin era, there had been studies, such as the Coronary Drug Project, suggesting a clinical benefit with niacin, as well as others such as HALTS and ARBITER-2 and -3 that showed niacin resulted in improvements in carotid intima-media thickness (IMT).

“Certainly, everybody is very interested in HDL-targeted therapeutics, given the strong observational and epidemiological data suggesting that low HDL levels, even when patients are on aggressive treatment, predict cardiovascular risk,” said Michos. “The hope was that targeting HDL levels would result in an improvement in clinical outcomes, so AIM-HIGH for a lot of people might have been a disappointment or discouraging.”

Increased HDL, but no effect on outcomes

Presented at the American Heart Association 2011 Scientific Sessions by Dr William Boden (University at Buffalo School of Medicine, NY) and published online simultaneously in the New England Journal of Medicine, the AIM-HIGH investigators showed that treatment with niacin therapy in 3414 patients increased HDL-cholesterol levels from a median of 35 mg/dL to 42 mg/dL, lowered triglyceride levels from 164 mg/dL to 122 mg/dL, and lowered LDL-cholesterol levels from 74 mg/dL to 62 mg/dL.

The primary end point, defined as the composite of coronary heart disease death, nonfatal MI, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebral revascularization, was similar in the niacin- and placebo-treated patients.

That said, Michos believes that AIM-HIGH did not answer the question that investigators set out to answer and that the HDL cholesterol hypothesis is not debunked based on the results of this one trial. For example, she pointed out that the HDL-cholesterol levels increased, somewhat surprisingly, in the placebo arm, and this resulted in a modest on-treatment HDL differential of just 4 mg/dL, which might not have been enough to observe a difference in treatment effect.

The reasons for the increase in HDL cholesterol in the placebo arm are unclear, but Michos noted that more patients in the placebo arm were taking higher doses of statins, and this might have contributed to the increase. In addition, to ensure blinding, placebo patients received a very low dose of niacin to induce flushing, and even though the 200-mg extended-release niacin dose was well below the therapeutic dose of 1500 mg/day, it is impossible to know whether this was responsible for the increase in HDL cholesterol in the placebo arm.

“What we ended up with was two groups that had very similar LDL-cholesterol values and really pretty similar HDL-cholesterol values, with just a very small increase in HDL in the niacin arm,” said Michos. “In this short period of time, with a smallish number of patients enrolled in AIM-HIGH, to expect a 25% difference between the two treatment groups might have been overly optimistic.”

Aggressively treated to low LDL cholesterol levels

Another possible reason for the disappointing results, according to Michos and colleagues, as well as many experts heartwire spoke with during the AHA meeting, might be attributed to the very low LDL-cholesterol levels of patients in AIM-HIGH. The vast majority of patients were treated with simvastatin in order to reduce LDL-cholesterol levels to less than 80 mg/dL, and these low LDL-cholesterol levels might have altered the composition of the atherosclerotic plaque.

To heartwire, Michos said the bottom line is that is not possible to rule out a possible role for extended-release niacin in clinical practice based on the AIM-HIGH results. Dr Stephen Nicholls (Cleveland Clinic, OH), who wrote an editorial accompanying the review [2], echoes the sentiment, noting that some physicians will use the agent less given the negative results from AIM-HIGH, while others might continue to use the drug until other studies with niacin are completed, such as the Heart Protection Study-2 Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE).

In his editorial, Nicholls notes that AIM-HIGH highlights the challenge for developing new medications for atherosclerosis in the statin era. To date, clinical trials have failed to show that new treatment can reduce cardiovascular disease risk when given to patients aggressively treated with statins.

“Does this imply that we have come to the end of the road in terms of reducing cardiovascular risk, when patients achieve effective LDL-cholesterol lowering, perhaps?” asks Nichols. “Is it possible that much of the residual risk that we highlight is not modifiable? Or perhaps do we need to identify alternative targets for modification? That remains the focus for future clinical trials, and for that reason, we continue to believe that we can further reduce the burden of cardiovascular disease.”

UF team unlocks secrets of niacin

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By Anne Geggis
Staff writer, Ocala.com
Published: Saturday, February 25, 2012 at 6:49 p.m.
Last Modified: Saturday, February 25, 2012 at 6:49 p.m.

GAINESVILLE — A University of Florida team has unlocked the secrets behind a common vitamin’s ability to boost “good” cholesterol and, as a result, opened the door to possibly finding a formula that avoids its side effects, researchers say.

High-density lipoprotein, or HDL, can protect against heart attacks and stroke because it flushes out the “bad” cholesterol — low-density lipoprotein or LDL — that clogs arteries.

Niacin has long been prescribed for its ability to maintain the good cholesterol. For some, though, the vitamin produces side effects, such as stomach upset, jaundice and trouble breathing.

But UF research published in a recent edition of the journal “Metabolism, Clinical and Experimental” found that a property of niacin does even more than maintain the body’s good cholesterol — actually boosting production of it.

“There was no consensus on how it worked, only a lot of suggestions,” said Michael Haas, a research associate professor of medicine. “This (research) shows it could be of even more benefit than we thought.”

With a $20,000 grant from the Endocrine Fellows Association for a former UF fellow, the researchers observed how niacin increased the activity of a gene that produces the good cholesterol and were able to identify the area of the gene responsible for making it, according to Haas, who is based at the University of Florida College of Medicine-Jacksonville.

The hope is that the quality of niacin that achieves this reaction can be formulated into a medication that can avoid the undesirable side effects, Haas said.

The researchers found that the niacin increased the protein called apolipoprotein — a major component of HDL, the good cholesterol, according to the article published.

AIM-HIGH Study Stirs Niacin Controversy

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By: BRUCE JANCIN, Internal Medicine News Digital Network
“I do not believe that we should draw any conclusions or change
clinical practice on the basis of this underpowered study.

ORLANDO – Adding extended-release niacin to raise HDL cholesterol levels in patients with stable coronary heart disease who are maintaining their LDL cholesterol below 70 mg/dL with intensive statin therapy doesn’t further reduce their cardiovascular event risk, according to the large National Institutes of Heath–sponsored AIM-HIGH trial.

But enthusiasm at the annual scientific sessions of the American Heart Association was low for AIM-HIGH, despite its lofty name. Numerous critics pointed to study design flaws they said render the findings tough to interpret.

“This trial disturbs me greatly,” said discussant Dr. Philip Barter of the Heart Research Institute in Sydney.

“Whatever conclusions are drawn from this trial, it cannot be emphasized too much that [the trial] has not tested the HDL hypothesis, nor was it powered sufficiently to test the potential benefits of adding niacin to statins,” he added.

The AIM-HIGH trial (Niacin Plus Statins to Prevent Vascular Events) involved 3,414 patients with stable coronary artery disease and low HDL cholesterol levels who were placed on 40-80 mg/day of simvastatin supplemented as necessary by 10 mg/day of ezetimibe in order to maintain an LDL cholesterol level of 40-80 mg/dL.

Participants were randomized to 1,500-2,000 mg/day of extended-release niacin (Niaspan) or placebo to see if niacin plus simvastatin reduced cardiovascular events to a greater extent than did the statin alone. The primary end point was a composite of MI, ischemic stroke, death due to coronary heart disease, hospitalization for an acute coronary syndrome, or symptom-driven revascularization.

Niacin produced the anticipated favorable lipid changes: a 25% boost in HDL cholesterol at 2 years from a baseline median of 35 mg/dL, a 29% drop in triglycerides, and a 12% decrease in LDL cholesterol from a baseline of 74 mg/dL.

Yet AIM-HIGH was stopped early on the grounds of futility: After a mean 3 years of follow-up, the rate of the primary end point was 16.4% in the niacin group and nearly identical at 16.2% in controls.

“I think the take-away message from the study would be that if you – as a patient with stable, nonacute cardiac disease – are able to achieve and maintain the levels of LDL we got in this study (that is, in the 60s), then there is not evidence from this trial to support continued use of niacin for the purpose of reducing clinical events,” said Dr. William E. Boden, lead researcher and professor of medicine and public health at the State University of New York at Buffalo.

Dr. Barter wasn’t buying it.

“I totally disagree with that interpretation,” he said. “I do not believe that we should draw any conclusions or change clinical practice on the basis of this underpowered study. We really must not overreact to a trial that had no ability to answer the question.”

“Fortunately, the value of adding niacin to effective statin therapy is currently being investigated in the very much larger [HPS2-THRIVE (Heart Protection Study 2 – Treatment of HDL to Reduce the Incidence of Vascular Events) trial] that has randomized more than 25,000 participants. Within the next 12-18 months we’ll have that result. If that study doesn’t show a positive effect, niacin is finished. But to prejudge that before we’ve got the results of that trial and to stop patients from being treated on niacin is, I think, in the public health disinterest,” Dr. Barter said.

A major problem with AIM-HIGH, according to Dr. Eliot Brinton, was the investigators’ decision to incorporate 150-200 mg/day of immediate-release niacin into the placebo tablets so the control group would experience niacin-induced flushing and thus wouldn’t be able to tell which study arm they were in.

That decision may explain the average 9.8% increase in HDL cholesterol seen in the control arm. As a result of this unanticipated rise in HDL, the difference in HDL levels between the two study arms was a mere 4 mg/dL, which could account for the closely similar outcomes in the two groups.

“My suggestion, with all due respect to the people who worked very hard on AIM-HIGH, is that we not try to draw clinical conclusions based on this study that was, in many ways, rather complicated,” said Dr. Brinton of the University of Utah, Salt Lake City.

Niacin has multiple beneficial metabolic effects in addition to being the most effective HDL-raising agent approved at present. It reduces levels of the highly atherogenic lipoprotein (a), triglycerides, and LDL cholesterol, and – in combination with statin therapy – it has been shown in angiographic studies to cause atherosclerotic plaque regression. While awaiting the results of HPS2-THRIVE, clinicians might want to continue to offer niacin therapy to patients who appear to be at residual risk of events because of low HDL levels, despite effective LDL-lowering therapy, he suggested.

“Talk to your patients. If they’re high risk and they want more treatment, then you consider it. We don’t force niacin. It’s not mandated. I think that’s where we are at the moment. Maybe a year or two from now, we’ll have some better answers,” he said.

Simultaneously with Dr. Boden’s detailed presentation of the AIM-HIGH results in a late-breaking-trials session at the AHA meeting, the study was published online (N. Engl. J. Med. 2011 Nov. 15 [doi:10.1056/NEJMoa1107579]).

The AIM-HIGH study was funded by the National Heart, Lung, and Blood Institute and an unrestricted grant from Abbott Laboratories. Dr. Boden disclosed having received consulting fees from the company. Dr. Barter and Dr. Brinton declared having no financial conflicts.

Niacin The Cholesterol Wars Champion

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Niacin once again emerges as a low-cost, highly effective agent to reduce cholesterol, raise HDL, and lower LDL and triglycerides.

A just-published study in Archives of Internal Medicine (Guyton, et al, 2000) confirms my long-held belief in the superiority of niacin (vitamin B3) as a lipid-lowering agent. A proprietary timed-release version of niacin (Niaspan) was compared to the pharmaceutical drug gemfibrozil (Lopid).

The study involved 399 male and female subjects ranging in age from 21 to 75, all of whom had low levels of HDL (high density lipoproteins—”good cholesterol”) less than 40 mg/l. Other criteria for inclusion in this study were triglycerides less than 400 mg/l, and LDL (low density lipoproteins—”bad cholesterol”) less than 260 mg/l. Niacin was administered once daily at bedtime.

The niacin dosage was begun at 375 mg/day, and then increased progressively over the course of the study, and maintained at a level of 2,000 mg nightly for 8 weeks. The duration of the study was 16 weeks. Subjects took an aspirin as-needed to prevent flushing. Gemfibrozil 600 mg was administered twice daily over the entire 16 weeks.

Niacin increased HDL levels over 25%, compared to an increase of 13.3% due to gemfibrozil. Gemfibrozil actually raised LDL (the “bad” cholesterol, remember?), while niacin slightly lowered this fraction. Gemfibrozil lowered triglyceride levels by 40%, compared to a 30% decrease from niacin. Thus, niacin resulted in an overall improvement in the lipid profile which exceeded that induced by gemfibrozil (Fig. 1).

niacin vitamin b3

However, niacin favorably altered several other cardiovascular risk factors as well. Apolipoprotein (a) levels were significantly (20%) reduced by niacin, but were not altered by gemfibrozil. Both substances reduced serum apolipoprotein (b) levels by the same amount. Fibrinogen, a third risk factor, was reduced by niacin, but increased 6-9% by gemfibrozil. The authors concluded, “Niaspan, 2,000 mg, had a significantly better effect on fibrinogen levels than gemfibrozil.”

These results support many previous studies on the use of niacin as a lipid-lowering nutrient. For example, in the Coronary Drug Project, which enrolled men with a previous myocardial infarction, niacin use resulted in a 26% decrease in second non-fatal heart attacks over a six-year period, and an 11% decrease in total mortality after 15 years of followup (Canner, et al, 1986) (Fig. 2).

niacin b3 Cholesterol

Niacin Stimulates Growth Hormone

While extolling the benefits of niacin, one frequently overlooked “side effect” is that niacin is a powerful releaser of growth hormone (Quabbe, et al, 1983) (Fig. 3). Quabbe and colleagues administered 500 mg niacin intravenously to humans, and noted a dramatic rise in growth hormone. In a second phase of their study, they simultaneously administered an infusion of fatty acids. Note that the fat completely blunted any rise in growth hormone. The practical take-home lesson of this study is that anyone using niacin as a growth hormone stimulant should take it on an empty stomach (glucose and insulin also inhibit growth hormone, as well as fatty acids).

b3

Side Effects and Contraindications to High-Dose Niacin

High dose niacin is very safe. Its most frequent “adverse effect” is a harmless flushing of the skin, accompanied by itching. This effect usually resolves over a few days or weeks of use. Taking an aspirin 30 minutes or so before the niacin also helps to reduce this effect. Another way to minimize the flushing is to start with low doses (50-100 mg) and gradually increase the dose as tolerated. Finally, inositol hexanicotinate (IHN)—another non-flushing form of niacin—can also be used. IHN, while a bit more costly than niacin, is effective in somewhat lower doses, thereby remaining cost effective.

Another side effect is the potential for elevation of liver enzymes or liver toxicity. Liver toxicity is rare, and occurs most frequently with timed release preparations. Anyone contemplating high dose niacin therapy probably should have their liver enzymes checked within several months of achieving therapeutic levels (1,500-3,000 mg).

The only absolute contraindication to niacin therapy is insulin-dependent diabetes. Niacin aggravates blood sugar problems in insulin dependent diabetics, further worsening their lipid problems, usually causing their triglycerides to skyrocket. Alternatively, I recommend niacinamide (also contained in Optimum D) in doses up to three grams daily for insulin dependent diabetics. Although niacinamide does not normally effect lipid levels in non-diabetics, because of its glucose-stabilizing effect in diabetics, it tends to normalize their blood lipids—especially, the triglycerides.

Conclusion

Niacin once again emerges as a low-cost, highly effective agent to reduce cholesterol, raise HDL, and lower LDL and triglycerides. In addition, it has the added benefits of lowering apolipoproteins a and b, and fibrinogen, and raising growth hormone. Muntoni (1974) stated that “lipostatic” substances are the agents of choice to retard aging, and niacin may very well be the best substance in this class (Dilman and Dean, 1992).

References:

  1. Canner, P.L., Berge, K.G., Wenger, N.K., et al. Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin. J Am Coll Cardiol, 1986, 8: 1245-1255.
  2. Dilman, V., and Dean, W. The Neuroendocrine Theory of Aging and Degenerative Disease, 1992, The Center for Bio-Gerontology, Pensacola.
  3. Guyton, John R., Blazing, Michael A., Hagar, James, et al. Extended-release niacin vs Gemfibrozil for the treatment of low levels of high density lipoprotein cholesterol. Arch Intern Med, 2000, 160: 1177-1184.
  4. Horowitz, N. Link niacin to longevity after an MI. Medical Tribune, 1985, 26: 12, pp. 1, 17.
  5. Muntoni, S. Inhibition of fatty acid oxidation by biguanides: implication for metabolic physiopathology. Adv Lipid Res, 1974, 12: 311-377.
  6. Quabbe, H.J., Ramek, W., and Luyckx, A.S. Growth hormone, cortisol and glucagon concentration during plasma free fatty acid depression. Different effects of nicotinic acid and an adenosine derivative. J Clin Endocr Metab, 1983, 57: 410-414.





USDA PARTNERS IN HEART DISEASE STUDY

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RECENT STUDIES HAVE FOCUSED ON NIACIN…A SIMPLE NUTRITIONAL SUPPLEMENT.

USDA: Feature on partners in heart disease
2/21/2011

Heart disease causes one quarter of the deaths in the United States. USDA and Tufts University are studying ways to understand, prevent and treat heart disease.

A new feature is available on the USDA FTP site

Filename: heart study feature

YouTube: http://www.youtube.com/watch?v=nd2jsW7_xyU

FEATURE – USDA PARTNERS IN HEART DISEASE STUDY

INTRO: Heart disease causes one quarter of the deaths in the United States. The USDA’s Bob Ellison has more on a joint study between USDA and Tufts University to understand, prevent and treat heart disease. (1:38)

DOCTOR ERNIE SCHAEFER BECAME INTERESTED IN HEART DISEASE VERY EARLY IN HIS MEDICAL CAREER.

Dr. Ernie Schaefer, USDA ARS Funded Researcher for Tufts University: It started when I was a medical resident in New York City at Mount Sinai Hospital and three patients died in the coronary care unit and I decided that this was a disease that should be studied.

SINCE THEN DOCTOR SCHAEFER HAS STUDIED HEART DISEASE AT TUFTS UNIVERSITY IN BOSTON IN PARTNERSHIP WITH THE U-S DEPARTMENT OF AGRICULTURE’S AGRICULTURAL RESEARCH SERVICE. MUCH OF HIS WORK WITH TUFTS AND U-S-D-A HAS INVOLVED INCREASING H-D-L, OR GOOD CHOLESTEROL AND DECREASING L-D-L, OR BAD CHOLESTEROL.

Schaefer: This is a normal coronary artery then as we age and as we get exposed to more and more elevations in LDL cholesterol. The cholesterol deposits in the artery wall and HDL is actually important for removing that cholesterol. But if the cholesterol continues to build up there’s also proliferation of smooth muscle cells in the artery and of course the terminal event here can be a clot and then when this happens you have a heart attack.

RESEARCHERS HAVE KNOWN FOR SOME TIME THAT HEALTHIER DIETS, EXERCISE, NOT SMOKING AND TAKING CERTAIN DRUGS LIKE STATINS HELP REDUCE HARMFUL L-D-L CHOLESTEROL. BUT SCHAEFER SAYS RECENT STUDIES HAVE FOCUSED ON NIACIN…A SIMPLE NUTRITIONAL SUPPLEMENT.

Schaefer: Niacin actually markedly increases the ability of HDL to remove cholesterol from cells.

SCHAEFER SAYS WHILE DRUGS AND VITAMINS OFFER HOPE IN TREATING HEART DISEASE HE SAYS LIFE STYLE CHANGE IS THE CORNERSTONE OF THERAPY. FOR THE U-S DEPARTMENT OF AGRICULTURE, I’M BOB ELLISON.

USDA is an equal opportunity provider, employer and lender. To file a complaint of discrimination, write: USDA, Director, Office of Civil Rights, 1400 Independence Ave., SW, Washington, DC 20250-9410 or call (800) 795-3272 (voice), or (202) 720-6382 (TDD).

Niacin Deficiencies and Therapies

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by Sheldon Zerden – Epoch Times

When megavitamin therapy evolved from the early studies, one doctor asked, “If it is so darn good, why isn’t everyone using it?” Dr. Abram Hoffer believes the answer is, it’s so darn good no one believes it!

Niacin (B-3), part of the B-complex, was the vitamin missing from the diets of poor Southerners. Since niacin has been added to processed flour in the United States, pellagra has almost disappeared. Niacin may cause redness and itching when taken in large doses, and niacinamide is often used as an alternative by people who cannot tolerate the red flush.

Dr. Abram Hoffer, a Canadian orthomolecular psychiatrist, has done the definitive work with niacin therapy for schizophrenia. His cure rate is about 85 percent. Niacin therapy usually includes vitamin C and other vitamins and minerals.

Niacin also helps in the treatment of arthritis. Dr. William Kaufman of Bridgeport, Conn., has written two books about his protocol for arthritis and joint dysfunction. In 1941, Kaufman began using niacinamide in large doses for his arthritis patients. He found that joint mobility increased, and pain was alleviated.

In 1955, Kaufman reported on his use of niacinamide on 663 patients. Those who took an adequate dose of the vitamin experienced gains in muscle strength, decreased fatigue, and relief of emotional disorders.

Niacin is also effective in treating some alcoholics. One study by Dr. Russell F. Smith of Lake Orion, Mich., involved 507 alcoholics treated with niacin. Twenty percent of the group maintained complete abstinence, 103 were classified as having excellent results, 240 good, 98 fair, and 96 poor. The study showed that niacin far surpassed all other therapeutic agents commonly used in the treatment of alcoholics.

Niacin keeps blood cholesterol down and helps to increase HDL cholesterol. Dr. Edwin Boyle, research director of the Miami Heart Institute, has used niacin in more than 1,000 cases. In one group of 600 Niacin Deficiencies and Therapies | Health | Epoch Times patients, insurance actuarial mortality tables predicted 62 deaths over a 10-year period. Among these patients, all of whom took large doses of niacin during the period, only six deaths occurred.

In his book, professor Rudi Altschul reviewed the evidence that niacin taken over a period of several years could reverse some of the arteriosclerotic pathology in blood vessels.

Recent studies suggest niacin may be valuable in treating heart attacks. Sludging is the term applied to red blood cells that do not float freely in the blood but adhere to each other. Capillaries are so small that red blood cells pass through in single file. When two or more red blood cells adhere or stick to each other, they cannot traverse the capillaries. These capillaries therefore carry only plasma. With no red blood cells, the tissues fed by these capillaries suffer from anoxia. If many cells are sludged, large areas of tissues are deprived of oxygen. Water-soluble vitamins such as niacin are excreted rapidly. The controlled time-release preparations release vitamin B-3 into the body over an 8- to 24-hour period. The slow-release tablet minimizes side effects, unless one is allergic to the material used in binding slow-release granules.

In summary, niacin is a vitamin that is beneficial in treating alcoholism, schizophrenia, and arthritis. It is also an effective way to lower cholesterol and raise HDL.

The reader should consult a physician for all medical advice.

Sheldon Zerden is an award-winning author. Questions and comments can be sent to Axnoon@yahoo.com.
Niacin Deficiencies and Therapies | Health | Epoch Times

Good cholesterol may mean little for statin users: Research

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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.

Higher HDL Might Lower Cancer Risk

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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.

Niacin can help raise HDL cholesterol levels

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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.

How Can I Prevent Niacin Side Effects?

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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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