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Zetia (Ezetimibe) Plus Simvastatin Provided More than Twice the Reduction of C-reactive protein in Patients with High Cholesterol Compared to Simvastatin Alone: Presented at AHA

ORLANDO, FL -- November 13, 2003 -- Data from a new analysis showed that Zetia(TM) (ezetimibe) co-administered with simvastatin provided more than twice the reduction of C-reactive protein (CRP), an inflammatory marker associated with coronary heart disease (CHD), compared to simvastatin alone in patients with hypercholesterolemia (elevated cholesterol). The analysis, presented at the 2003 American Heart Association Scientific Sessions, combined the results of two similarly designed studies, one of which will be published in the Dec. 15 issue of American Journal of Cardiology. Results from the analysis showed that Zetia with simvastatin reduced levels of the marker CRP significantly more than simvastatin administered alone (33.3 percent compared with 14.3 percent, respectively; p<0.01). Zetia is marketed by Merck/Schering-Plough Pharmaceuticals.

CRP is considered an emerging risk marker for CHD. In an American Heart Association/Centers for Disease Control Scientific Statement published in the January 2003 issue of Circulation, high-sensitivity CRP was recognized as a potentially valuable marker and an optional adjunct to major risk factors in the assessment of risk for coronary disease in patients at moderate cardiovascular risk. The relationship between reductions in CRP and reduction of CHD risk has not been established.

"Zetia, when co-administered with simvastatin, provided a greater than two-fold reduction in CRP versus simvastatin alone, in addition to significant incremental reductions in LDL or 'bad' cholesterol," said Christie M. Ballantyne, M.D., FACC, FACP, director of the Center for Cardiovascular Disease Prevention and professor of medicine at Baylor College of Medicine/The Methodist DeBakey Heart Center in Houston. "This study demonstrated that co-administering Zetia with simvastatin provided additional reductions in CRP compared to simvastatin alone in these patients." Zetia with simvastatin provided more than twice the reduction of CRP

The randomized, double-blind, placebo-controlled studies included a total of 1,113 patients with primary hypercholesterolemia. Following a recommended cholesterol-lowering diet, patients were randomized to one of the following drug regimens administered daily for 12 consecutive weeks: Zetia 10 mg (n=109), simvastatin 10, 20, 40 or 80 mg (pooled n=443), Zetia 10 mg co-administered with simvastatin 10, 20, 40 or 80 mg (pooled n=443) or placebo (n=118). Results from the analysis showed that Zetia with simvastatin reduced levels of the marker CRP by 33.3 percent compared to simvastatin administered alone (14.3 percent; p<0.01).

In addition, patients taking Zetia co-administered with simvastatin experienced an LDL cholesterol (LDL-C) reduction of 45 to 60 percent across the dosage range, compared to a reduction of 31 to 44 percent in patients taking simvastatin alone (p<0.01), consistent with other clinical trial results. Zetia demonstrated an excellent overall safety and tolerability profile in clinical studies

Zetia has been evaluated for safety in more than 4,700 patients in completed clinical trials. Clinical studies of Zetia (administered alone or with a statin) demonstrated that Zetia was generally well tolerated. The overall incidence of clinical adverse events reported with Zetia was similar to that reported with placebo, and the overall discontinuation rate due to adverse events was also similar for Zetia and placebo.

When Zetia was co-administered with a statin, consecutive elevations in liver enzymes, more than three times the upper limit of normal, were slightly higher than those with the statin alone (1.3 percent vs. 0.4 percent). These elevations were generally asymptomatic and returned to baseline after discontinuation of therapy or with continued treatment. Because of significantly increased blood levels of Zetia in one patient on multiple medications including cyclosporine, patients who take both Zetia and cyclosporine should be carefully monitored. In clinical trials, there was no increased incidence of myopathy or rhabdomyolysis associated with Zetia. However, myopathy and rhabdomyolysis are known adverse reactions to statins and other lipid-lowering drugs.

For monotherapy, the most frequent adverse events reported with greater incidence than placebo, regardless of causality, were back pain (4.1 percent vs. 3.9 percent) and arthralgia (3.8 percent vs. 3.4 percent). In co-administration with a statin, the most frequent adverse events reported with greater incidence for Zetia plus statin versus statin or placebo alone, regardless of causality, were back pain (4.3 percent vs. 3.7 percent vs. 3.5 percent, respectively) and abdominal pain (3.5 percent vs. 3.1 percent vs. 2.3 percent, respectively). Important Information about Zetia

Zetia, along with diet, is indicated for use either alone or together with statins in patients with high cholesterol to reduce LDL-C and total cholesterol when the response to diet and exercise has been inadequate. The effects of Zetia, either alone or in addition to a statin, on the risk of cardiovascular morbidity and mortality have not been established. Zetia is a prescription medicine and should not be taken by people who are allergic to any of its ingredients. When Zetia is prescribed with a statin, it should not be taken by anyone with active liver disease or unexplained persistent liver enzyme elevations. When Zetia is used with a statin, liver function tests should be performed at the start of therapy and after that in accordance with the label for that statin. Liver function tests are not required when Zetia is used alone. Due to the unknown effects of increased exposure to Zetia in patients with moderate or severe hepatic insufficiency, Zetia is not recommended in these patients.

All statins are contraindicated in pregnant or nursing women. When Zetia is administered with a statin in a woman of childbearing potential, refer to the pregnancy category and product labeling for the statin. There are no adequate and well-controlled studies of Zetia in pregnant women. Zetia should not be used in pregnant or nursing women unless the benefit outweighs the potential risks.

The safety and effectiveness of Zetia with fibrates have not been established; therefore, co-administration with fibrates is not recommended.


SOURCE: Merck/Schering-Plough Pharmaceuticals

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