Lipid-Lowering Combination May Be More Effective Than High-Dose Atorvastatin

Peggy Peck

March 12, 2004

March 12, 2004 (New Orleans) — Results of a head-to-head trial suggest that combining two drugs that lower cholesterol by two different mechanisms of action appears to be a more effective dyslipidemia treatment than high-dose atorvastatin.

Christie Ballantyne, MD, professor of medicine at Baylor College of Medicine in Houston, presented the findings at the 53rd annual scientific session of the American College of Cardiology.

"The coadministration of ezetimibe plus simvastatin provided additional improvements in lipid profiles across a wide range of doses compared with titration of atorvastatin monotherapy," Dr. Ballantyne said.

Patients titrated to receive 80 mg of atorvastatin achieved a low-density lipoprotein (LDL) cholesterol reduction of 52.5%, but when high-dose simvastatin (80 mg) was combined with 10 mg of ezetimibe, the average decrease in LDL cholesterol level was 59.4%, a "statistically significant difference," Dr. Ballantyne said.

Both ezetimibe and simvastatin are being reformulated into one tablet in a joint manufacturing program between Schering-Plough, which makes ezetimibe, a cholesterol-lowering medication that works to reduce the amount of cholesterol absorbed from the digestive tract, and Merck, which manufactures simvastatin. An application for approval of the combined product, which will be marketed as Vytorin, is under review by the U.S. Food and Drug Administration.

Dr. Ballantyne's study was funded by Merck/Schering-Plough Pharmaceuticals, the company established to develop and market Vytorin.

"It is very helpful to add ezetimibe to almost any dose of statin," said Anne Goldberg, MD, associate professor of medicine at Washington University in St. Louis, Missouri. "I usually see a 15% or greater decrease in my patients when ezetimibe is added." She said the combination product would be helpful in getting patients to remain on medication, but market forces such as the price of the new medication could determine how well it will be accepted in clinical practice. Dr. Goldberg was not involved in the study.

Dr. Ballantyne and colleagues recruited 788 patients with high LDL cholesterol levels and assigned them to receive either a starting dose of atorvastatin 10 mg; 10 mg of simvastatin and 10 mg of ezetimibe; or 20 mg simvastatin and 10 mg of ezetimibe. The patients were titrated over 24 weeks to receive final doses of 80 mg atorvastatin or 40 mg simvastatin plus 10 mg ezetimibe or 80 mg simvastatin plus 10 mg of ezetimibe.

"We now know it is important to go very low in LDL cholesterol," Dr. Ballantyne said, suggesting that the addition of ezetimibe allows physicians to reduce blood cholesterol levels below the threshold at which atherosclerosis appears to begin — around 70 mg of LDL cholesterol.

The study did not, however, assess clinical end points. The primary end point was the difference in LDL cholesterol lowering seen after six weeks of treatment with the starting doses. During that period, the combination doses showed decreases of 46% to 50%, while atorvastatin monotherapy on average reduced LDL cholesterol by 37%.

"We continued to see a greater cholesterol-lowering benefit with the combination at every dose of atorvastatin," Dr. Ballantyne said. In addition, he reported that at the highest-dose levels, there was a 12.3% increase in high-density lipoprotein (HDL) cholesterol in patients receiving the drug combination compared with a 6.5% increase in HDL in patients receiving atorvastatin. That difference was statistically significant ( P < .01).

A representative of Merck/Schering-Plough said approval of the combination product is expected by the end of 2004.

ACC 53rd Annual Scientific Session: Abstract 1084-176. Presented March 8, 2004.

Reviewed by Gary D. Vogin, MD

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