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Niacin Extended-Release Tablets Combined With Low/Moderate Dosed Statin Achieves Better Total Lipid Control Versus Higher Dose Statin Monotherapy or Simvastatin and Ezetimibe

COMPELL study shows significantly greater reductions in triglycerides and Lp(a), as well as superior 2.5-3.5 fold increases in HDL-C and comparable lowering of LDL-C with Niaspan combination therapy versus Crestor® and Zocor/Zetia

Adding Niaspan to statin therapy achieves better total lipid control for patients at high risk for heart attack

CRANBURY, NJ -- June 22, 2006 -- Kos Pharmaceuticals, Inc. commented on the results from the COMPELL (COMParative Effects on Lipid Levels of Niaspan and Statins Versus Other Lipid Therapies) Phase IV efficacy trial presented at the XIV International Symposium on Atherosclerosis.

The results demonstrated that adding the HDL-boosting therapy Niaspan (niacin extended-release tablets) to statin therapy (HMG-CoA reductase inhibitors) achieved superior raising of high-density lipoprotein cholesterol (HDL-C), or "good" cholesterol, and increased triglyceride lowering, with equivalent lowering of low-density lipoprotein cholesterol (LDL-C), or "bad" cholesterol, for patients compared to treatment with a high dose statin or Zocor/Zetia (simvastatin and ezetimibe).1

COMPELL was a 12-week, randomized, multicenter, open-label study in 292 patients comparing the efficacy of combination therapy with Niaspan and low to moderate doses of Lipitor® and Crestor against moderate to high dose Crestor and Zocor/Zetia (sold as the fixed-dose combination tablet, Vytorin®).

One-half of the patients treated were women, who required LDL-C lowering therapy according to NCEP ATP III guidelines (LDL-C more than 100 mg/dL). McKenney JM, Jones PH, Bays HE, Knopp RH, Kashyap ML, Ruoff GE, Stanek EJ, McGovern ME. Comparative Lipid Effects of Combination Therapy with a Statin and Extended-Release Niacin Versus Statin Plus Ezetimibe Versus a Statin Alone. (Abstract presented at the XIV International Symposium on Atherosclerosis.) The primary endpoint was percent change in LDL-C at week 12 from baseline compared across all treatment groups.2 In a dose-escalation study design, Niaspan 1000 mg with Crestor 10 mg, and 20 mg, or, Niaspan 1000 mg and Lipitor 20 mg, and Niaspan 2000 mg with Lipitor 40 mg were compared with Crestor 20 mg and 40 mg or Zocor/Zetia 20mg/10mg and 40mg/10 mg.

Study results showed that patients given Niaspan in combination with a low to moderate dose of Lipitor or Crestor achieved equivalent reduction in LDL-C (51-58%), 1.2 to 1.9-fold greater decreases in triglycerides and 2.5 to 3.5 fold greater increases in HDL-C, than patients who received high-dose Crestor or Zocor/Zetia.1 Only patients receiving Niaspan experienced significant decreases in lipoprotein (a), referred to as Lp(a), which actually increased in patients on Crestor and Zocor/Zetia.2 Similar numbers of patients reported adverse events and serious adverse events. No drug-related myopathy was observed.

COMPELL was presented by Peter Jones, MD, Associate Professor of Cardiology, Baylor University. "These results are particularly powerful because they demonstrate that we can drive LDL-C levels down to goal and also raise the good cholesterol, HDL-C, without the need for high doses of statin medications," said Dr. Jones. "The patients in the study were at high risk for heart attack. For these patients, achieving optimal goal levels for all lipid parameters, including HDL-C, LDL-C and triglycerides is essential. We found that by combining the prescription form of niacin, called Niaspan, with a low to moderate dose of a statin, we could achieve these results. When heart disease patients achieve these three goals, their risk of heart disease goes down substantially."

"The COMPELL study puts broad dyslipidemic control and efficacy in appropriate perspective. Lowering LDL cholesterol to ultra-low levels may not be enough to protect against heart disease," said Adrian Adams, President and CEO of Kos Pharmaceuticals. "There seems to be a diminishing rate of return in reducing coronary events when LDL is lowered progressively below 100 mg/dL. Most LDL-lowering trials show that two-thirds to three-quarters of statin-treated patients who are at risk in fact progress to a cardiovascular event, despite treatment. This research points to combining statin therapy with Niaspan, the most effective drug available for increasing HDL, as the next clinical advance in risk reduction."

"Patients are currently being enrolled in the AIM-HIGH study, which is a landmark outcomes study sponsored in part by The National Institutes of Health to evaluate the independent effect of treating HDL-C and triglycerides with Niaspan and simvastatin versus simvastatin alone in the prevention of heart attack and stroke. This heightened awareness and recognition bodes extremely well for Kos' highly differentiated cholesterol products, Niaspan and Advicor and positions our optimized Niaspan CF and SimcorTM (Niaspan/simvastatin) well in what we believe is an under penetrated market with a growing emphasis on treating HDL cholesterol," Adams continued.

The HDL-C particle facilitates "reverse cholesterol transport," and is like a "cleaning service", removing bad cholesterol (LDL-C) out of the arteries and back to the liver to be released into the gastrointestinal tract, where it is removed from the body.5 The primary mechanism of statins is reducing levels of LDL-C through inhibition of cholesterol synthesis and output from the liver, but they have a much smaller effect on HDL-C levels.6 Importantly, lowering LDL-C alone has only reduced events related to coronary artery disease by approximately 30 – 35%.7

Previous studies have provided evidence that supports the role of HDL-C in reducing risks associated with heart disease.

Evidence from a smaller clinical trial known as HATS (HDL Atherosclerosis Treatment Study) strongly suggested a correlation between raising HDL-C levels and the slowing or halting of atherosclerosis. HATS compared the combination of niacin and simvastatin versus placebo and showed a 60 to 90 percent reduction in cardiac events.

Another study, known as VA-HIT (VA High Density Lipoprotein Intervention Trial, conducted by the Department of Veteran Affairs), showed that raising HDL-C levels in patients with low HDL-C with a fibrate significantly reduced coronary heart disease events.

The ARBITER 2 (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol) study showed that the combination of Niaspan and a statin slowed disease progression 68 percent more than statin monotherapy as measured by plaque build-up in the carotid artery. Additionally, the combination of Niaspan and statin therapy demonstrated a 60 percent reduction of coronary events compared with a statin used alone.

The findings of ARBITER 3 (Atherosclerosis Regression During Open-label Continuation of Extended-release Niacin following ARBITER 2) showed that raising HDL-C, with a moderate dose of Niaspan (1000 mg) removed existing plaque build-up from the carotid arteries in patients on statin therapy with well-controlled (less than 100 mg/dL) LDL-C. Carotid atherosclerosis was significantly reversed in study patients receiving Niaspan therapy for two years by an average of -0.04mm, which is equal to a 105 percent reduction in the rate of progression. Atherosclerosis regression was measured by the change in carotid intima-media thickness (CIMT), a recognized surrogate outcome marker in which a sub-millimeter increase in arterial wall thickness (plaque build-up) predicts an increase in heart disease risk. ARBITER 3 showed definite atherosclerosis regression 12-24 months following treatment with Niaspan, thereby confirming that sustained increases in HDL-C are independently associated with superior effects on atherosclerosis regression. These results reinforce the benefit of raising HDL-C in patients with well-controlled LDL-C levels.

About Niaspan
Available since 1997, Niaspan is the only FDA-approved, once-daily extended-release prescription formulation of niacin for treating abnormal cholesterol levels. Niaspan is indicated as an adjunct to diet when the response to a diet restricted in saturated fat and cholesterol and other nonpharmacologic measures alone has been inadequate, to reduce elevated total cholesterol, LDL-C, Apo B, and triglyceride levels, and to increase HDL-C in patients with primary hypercholesterolemia and mixed dyslipidemia.

In patients with a history of myocardial infarction and hypercholesterolemia, niacin is indicated to reduce the risk of recurrent non-fatal myocardial infarction or coronary artery disease and hypercholesterolemia. Niacin, in combination with a bile acid binding resin, is indicated to slow progression or promote regression of atherosclerotic disease.

Niaspan is contraindicated in patients with allergies to any of its ingredients, active peptic ulcer disease, significant or unexplained persistent liver dysfunction, or arterial bleeding. Niaspan should not be substituted for equivalent doses of immediate-release niacin. Niaspan should be prescribed with caution in patients who consume substantial amounts of alcohol and/or have a past history of liver disease. Liver function tests should be performed on all patients during therapy with Niaspan. Use of Niaspan with other lipid-altering medications called statins may increase the risk of rhabdomyolysis, a rare condition that causes muscles to breakdown. The most common side effect with Niaspan is flushing of the skin. Other commonly reported side effects include indigestion, headache, pain, abdominal pain, nausea, itching, diarrhea, running nose, vomiting and rash. Patients with diabetes should carefully monitor their blood sugar and report changes to their doctor.8

REFERENCES:
1. McKenney JM, Jones PH, Bays HE, Knopp RH, Kashyap ML, Ruoff GE, Stanek EJ, McGovern ME. Comparative Lipid Effects of Combination Therapy with a Statin and Extended-Release Niacin Versus Statin Plus Ezetimibe Versus a Statin Alone. (Abstract presented at the XIV International Symposium on Atherosclerosis.)
2. McKenney JM, Jones PH, Bays HE, Knopp RH, Kashyap ML, Ruoff GE, Stanek EJ, McGovern ME. Comparative Lipid Effects of Combination Therapy with a Statin and Extended-Release Niacin Versus Statin Plus Ezetimibe Versus a Statin Alone. (Abstract presented at the XIV International Symposium on Atherosclerosis.)
3. McKenney JM, Jones PH, Bays HE, Knopp RH, Kashyap ML, Ruoff GE, Stanek EJ, McGovern ME. Comparative Lipid Effects of Combination Therapy with a Statin and Extended-Release Niacin Versus Statin Plus Ezetimibe Versus a Statin Alone. (Abstract presented at the XIV International Symposium on Atherosclerosis.)
4. McKenney JM, Jones PH, Bays HE, Knopp RH, Kashyap ML, Ruoff GE, Stanek EJ, McGovern ME. Comparative Lipid Effects of Combination Therapy with a Statin and Extended-Release Niacin Versus Statin Plus Ezetimibe Versus a Statin Alone. (Abstract presented at the XIV International Symposium on Atherosclerosis.)
5. The Difference Between LDL and HDL Cholesterol. American Heart Association. 2005. Available at www.americanheart.org; accessed data 6/6/06
6. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. JAMA 2001;285:2486-2497.
7. Bays, H. Existing and investigational combination drug therapy for high-density lipoprotein cholesterol. Am J Cardiol 2002;90(suppl):30K-43K.
8. Niaspan [prescribing information]. Cranbury, NJ: Kos Pharmaceuticals, Inc. 2005


SOURCE: Kos Pharmaceuticals, Inc.

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