Study raises new questions about Merck pill Zetia

Sun Nov 15, 2009 6:16 PM EST
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ORLANDO — A new study raises fresh concerns about Zetia and its cousin, Vytorin — drugs still taken by millions of Americans to lower cholesterol, despite questions raised last year about how well they work.

In the study, Zetia failed to shrink buildups in artery walls while a rival drug, Niaspan, did so significantly. Zetia users also suffered more heart attacks and other problems although the numbers of these events were too small to draw firm conclusions.

Zetia "has been on the market for about seven years and we still haven't proven that it improves clinical outcomes," said Dr. Roger Blumenthal, preventive cardiology chief at Johns Hopkins University. The new results will be "very influential" in getting more doctors to turn to Niaspan, he said.

He wrote an editorial accompanying the results, which were presented Sunday at an American Heart Association conference and published on the Internet by the New England Journal of Medicine.

The study is too limited to warrant changing practice, heart experts said. Patients also should not stop taking any heart medicine without checking with their doctors, they warn.

Statins such as Lipitor and Crestor have long been used to lower LDL, or bad cholesterol, and are known to cut the risk of heart problems. Nevertheless, many statin users still suffer heart attacks, so doctors have been testing adding a second medicine to further lower risk.

One they are trying is Niaspan, a slow-release version of niacin, a type of B vitamin that raises HDL, or good cholesterol. Another is Zetia, which lowers bad cholesterol in a different way than statins do, by blocking its absorption in the gut.

Vytorin is a pill that combines Zetia with a statin. Both are sold by Merck & Co. of Whitehouse Station, N.J. Niaspan is made by North Chicago, Ill.-based Abbott Laboratories. All three of these drugs cost between $3 and $4 a day, though niacin has been sold as a cheap generic for decades. The heart association advises consumers against using over-the-counter vitamin versions in place of prescriptions, though, because they may have purity and potency issues and other risks.

The new study was sponsored by Abbott, and several study leaders have been paid speakers or consultants to the company or to rival drugmakers.

Researchers enrolled 363 people with heart disease or a high risk for it who had been taking statins for six years on average. Many were from Walter Reed Army Medical Center, where study leader Dr. Allen Taylor formerly worked.

Half were given Niaspan and the rest, Zetia. Researchers stopped the study in June, after 208 participants had been on the medicines for 14 months, because one group was faring much better than the other.

Ultrasound images of neck arteries showed that Niaspan shrank buildups by about 2 percent, while Zetia had no effect on this even though it lowered bad cholesterol as expected.

There were two heart attacks, heart-related deaths or other heart-related problems in the 160 people given Niaspan, and nine among the 165 on Zetia.

"It should be better for the arteries and it wasn't," Taylor said of Zetia. "The drug wasn't operating as you otherwise would expect it to," raising concern that its effects are not fully understood, he said.

Merck's research chief, Peter Kim, said the study and number of heart attacks and other problems are too small to be conclusive. More than 25,000 people are in studies testing Zetia now, and independent monitors have found no problems that would lead them to stop the trials.

"We stand behind the safety of this drug," he said.

Kenneth Frazier, Merck's president of global human health, said: "The question is, how important is the study?" Shrinking plaque is no guarantee that heart attacks will be prevented, and not all studies have found a correlation, he said.

However, the difference in plaque that Niaspan made in this study "is precisely the same as the difference" that earlier studies found from statins, which are now known to save lives, said Dr. James Stein of the University of Wisconsin-Madison. He is a leading researcher on imaging artery buildups and in the past consulted for Schering-Plough Corp., which used to market Vytorin with Merck.

Dr. Sidney Smith, a former heart association president from the University of North Carolina at Chapel Hill, said that for people with newly diagnosed cholesterol problems, "the foundation is still statins." The new study "affirms the benefits of niacin" and makes it the next drug to add if people need more help, he said.

Dr. Anthony DeMaria, a past president of the American College of Cardiology from the University of California at San Diego, said the study "doesn't quite put the nail in the coffin" for Zetia, but pushes it way down on the list of things to try.

Last year, a large study found that the combo pill Vytorin was no more effective than Zocor alone, a statin now available as a cheap generic. In August, Merck and Schering-Plough agreed to pay $41.5 million to settle lawsuits claiming they delayed unfavorable study results on the drugs because they would hurt sales.

The drugs remain blockbusters: Vytorin had nearly $2 billion in sales in the United States in 2008; Zetia, more than $1.5 billion, according to IMS Health, a health care information and consulting company.

However, that's down substantially: Zetia prescriptions fell 22 percent, from nearly 16.5 million in 2007 to less than 13 million in 2008. Vytorin fell 24 percent in that time, from about 22 million in 2007 to 16.5 million in 2008. Vytorin sales were down another 36 percent in the first half of this year.

Niaspan has been gaining but lags far behind — 5.8 million prescriptions in 2008, up 11 percent from 2007.

Its main drawback is a prickly hot sensation called flushing that many people find intolerable. The extended-release version is supposed to minimize this, but a third of study participants still suffered it. The problem tends to go away with longer use and can be blunted by taking the medicine with aspirin, at bedtime, or with a low-fat snack, doctors say.

© 2009 The Associated Press. All rights reserved. This material may not be published, broadcast, rewritten or redistributed.
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{"commentId":10693507,"authorDomain":"gozounlimited"}
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Niaspam is manufactured for Abbott Laboratories by Norwich Pharmaceuticals, Inc. Norwich, NY. Niaspan is marketed as a slow-release version of niacin, a type of B vitamin (Nicotinic Acid) that raises HDL, or good cholesterol.

The following adverse *reactions have been identified during post-approval use of NIASPAN: Hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, flushing, dyspnea, tongue edema, larynx edema, face edema, peripheral edema, laryngismus, and vesiculobullous rash; maculopapular rash; dry skin; tachycardia; palpitations; atrial fibrillation; other cardiac arrhythmias; syncope; hypotension; postural hypotension; blurred vision; macular edema; peptic ulcers; eructation; flatulence; hepatitis; jaundice; decreased glucose tolerance; gout; myalgia; myopathy; dizziness; insomnia; asthenia; nervousness; paresthesia; dyspnea; sweating; skin discoloration, and migraine. (* Not a complete list).

High dosage of Nicotinic Acid such as 2,000 to 3,000 mg per day, should only be used on the advice of a health professional.

It is recommended that persons using supplemental Nicotinic Acid for managing their Cholesterol levels, consume their dosage at nightime (as most persons sleep during the "flushing period"; in addition this timing is likely to produce better results as most endogenous Cholesterol is produced by the Liver during the night).

Nicotinic Acid (2,000 - 3,000 mg per day) may lower serum Cholesterol: Peer-Reviewed Professional Journals

· Altschul, R., et al. Influence of nicotinic acid on serum cholesterol in man. Archives of Biochemistry and Biophysics. 54:558-559, 1955.

· Dorner, V. G., et al. The influence of inositol hexanicotinate ester on serum lipids and lipoproteins. Arzneimittelforsch. 11:110-113, 1961.

· El-Enein, A. M. A., et al. The role of nicotinic acid and inositol hexaniacinate as anticholesterolemic and antilipemic agents. Nutr Reports Int. 28:899-911, 1983.

· Kruse, W., et al. Nocturnal inhibition of lipolysis in man by nicotinic acid and derivatives. Eur J Clin Pharmacol. 16(1):11, 1979.

This study demonstrated that the inositol hexanicotinate form of nicotinic acid was more effective in reducing endogenous cholesterol production than regular nicotinic acid.

· Miettinen, et al. Decrease in serum cholesterol by 25 percent and triglycerides by 30 percent in human subjects after two weeks on 3 grams of niacin per day. Acta Med. Scand, 186: 247-253, 1969.

· Parsons, W. B., et al. Changes in concentration of blood lipids following prolonged administration of large doses of nicotinic acid to persons with hyperlipidemia. Proceedings May Clinic. 31:377-390, 1961.

· Parsons, W. B. Studies of nicotinic acid use in hypercholesterolemia. Archives of Internal Medicine. 107:653-667, 1961.

Laypersons' Publications

· Pearson, D. & Shaw, S. Life Extension: A Practical Scientific Approach. Warner Book, New York, NY, USA. 1982: 327.

The authors explain that 3,000 mg of nicotinic acid per day reduces serum cholesterol levels by 26% after one year of daily supplementation.

Nicotinic Acid may increase HDL Cholesterol by 33:

Research Summary

Author Study Type Intervention Results
Birjmohun, 2005 Meta-Analysis Previous studies were reviewed. Nicotinic acid increases HDL cholesterol by an average of 16% (compared with 10% for fibrates).
Bays, 2003 Human Subjects with decreased HDL (less than 45 mg/dL in men and less than 50 mg/dL in women) cholesterol levels received either atorvastatin, simvastatin or 1,000 mg extended-release nicotinic acid + 40 mg lovastatin for 16 weeks. Extended-release nicotinic acid + lovastatin increased HDL cholesterol significantly more than atorvastatin or simvastatin at all compared doses.

Taylor, 2004 Human:double-blind,randomized,placebo-controlled study Extended-release nicotinic acid (1,000 mg per day) or placebo was added to patients' statin therapy for 1 year. HDL levels increased by an average of 8 mg/dL (21%) with extended-release nicotinic acid therapy. HDL levels were unchanged with placebo.

Duvall, 2002 Human:open-label, uncontrolled, retrospective cohort study Patients using combined statin-nicotinic acid therapy were monitored over a 6.5 year period. At nicotinic acid doses of at least 1,000 mg per day, HDL cholesterol levels increased by 20%. Moderate doses of combined nicotinic acid + statins increased HDL cholesterol levels by 29%. Nicotinic acid doses less than 1,000 mg per day increased HDL cholesterol levels by 13%.

Elam, 2000 Human: prospective, randomized placebo-controlledclinical trial Peripheral artery disease and diabetes mellitus patients received 3,000 mg of nicotinic acid (or placebo) per day for 28 months. Nicotinic acid treatment increased HDL cholesterol levels by 29%.

Guyton, 2000 Human Subjects with low HDL (less than 40 mg/dL) received either extended-release nicotinic acid (375 mg per day, progressively increasing to 2,000 mg per day) or gemfibrozil (1,200 mg per day) for 8 weeks. Extended-release nicotinic acid increased HDL cholesterol levels by over 25% compared to an increase of 13.3% by gemfibrozil.


Crouse, 1996 Review None. Short-acting nicotinic acid at a dosage of 1,500 mg per day is effective for increasing HDL cholestrol levels.

Ganji, 2003 Review None. The mechanism of action for nicotinic acid to raise HDL is by decreasing the fractional catabolic rate of HDL-apo AI without affecting the synthetic rates.

McKenney, 2004 Review None. Nicotinic acid reduces the amount of apolipoprotein A-I extracted and catabolized from HDL during the hepatic uptake of cholesterol, thus preserving the structural and functional integrity of HDL particles. As a result, cholesterol-deficient apolipoprotein A-I–containing HDL particles are recirculated from the liver to peripheral cells, maintaining HDL levels and enhancing reverse cholesterol transport. Nicotinic acid is the most effective pharmacologic agent currently on the market for raising HDL-C levels, with increases of 15% to 35%. It follows a relatively flat dose-response curve so most of the rise in HDL-C with nicotinic acid occurs at daily doses of 1,000 mg to 1,500 mg.

Miller, 2003 Review None. Nicotinic acid substantially increases HDL cholesterol levels.

Rader, 2003 Review None. Nicotinic acid is the most potent currently available agent for increasing HDL cholesterol.


Sprecher, 2000 Review None. In a head-to-head comparison study, 2,000 mg per day of nicotinic acid increased HDL cholesterol more than 1,200 mg per day of gemfibrozil , and decreased the total cholesterol:HDL-cholesterol ratio
Peer-Reviewed Professional Journals

· Bays, H. E., et al. Comparison of once-daily, niacin extended-release/lovastatin with standard doses of atorvastatin and simvastatin (the ADvicor Versus Other Cholesterol-Modulating Agents Trial Evaluation [ADVOCATE]). American Journal of Cardiology. 91(6):667-672, 2003.

Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky, USA.

This study compared the relative efficacy of a once-daily niacin extended-release (ER)/lovastatin fixed-dose combination with standard doses of atorvastatin or simvastatin, with a special emphasis on relative starting doses. Subjects (n = 315) with elevated low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein (HDL) cholesterol blood levels (defined as LDL cholesterol blood levels > or =160 mg/dl without coronary artery disease, or > or =130 mg/dl if coronary artery disease was present, and HDL cholesterol.

Derived from InteleHealth

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  • 1 vote
Reply#1 - Sun Nov 15, 2009 7:25 PM EST
{"commentId":10705279,"authorDomain":"StephanieRN"}
Stephanie, RN

Clipped to Nurses on the Vine.

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Reply#2 - Mon Nov 16, 2009 2:58 PM EST
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