ZETIA(R) co-administered with fenofibrate provided complementary lipid lowering efficacy

11/08/04

Ezetimibe and fenofibrate treatment well-tolerated over 12 weeks

NEW ORLEANS, November 8, 2004 – Results from a new study showed that coadministration of ZETIA® (ezetimibe) and fenofibrate significantly reduced LDL ("bad") cholesterol (LDL-C), non-high density lipoprotein cholesterol (non-HDL-C) and apo B in patients with mixed hyperlipidemia and high LDL cholesterol when compared to fenofibrate alone. The study, presented today at the 2004 American Heart Association Scientific Sessions, also showed that significant increases in HDL cholesterol and decreases in trigycerides (TG) similar to those seen with fenofibrate alone were seen in patients on ZETIA co-administered with fenofibrate. The treatment with ZETIA and fenofibrate for 12 weeks was also well-tolerated with a safety profile comparable to fenofibrate monotherapy. The label for ZETIA indicates that the safety and effectiveness of ZETIA with fibrates have not been established, therefore co-administration with fibrates is not recommended.

"This is the first large study to indicate that co-administration of ZETIA and fenofibrate significantly lowers LDL cholesterol and non-HDL cholesterol more than fenofibrate alone in a mixed hyperlipidemia population. This study revealed that when diet changes alone were not sufficient in mixed hyperlipidemia, the co-administration of ezetimibe and fenofibrate significantly lowered LDL cholesterol, compared to fenofibrate alone. ZETIA co-administered with fenofibrate also improved HDL cholesterol and triglyceride levels similar to fenofibrate alone," said Mason Wright Freeman, M.D., chief, Lipid Metabolism Unit, Massachusetts General Hospital. "Mixed hyperlipidemia is a metabolic disorder characterized by elevated LDL cholesterol, non HDL-C and TG and reduced levels of HDL cholesterol. Co-administration of ZETIA and fenofibrate is not indicated for use in the label for ZETIA, however further studies in these populations are certainly warranted to confirm these findings."

ZETIA co-administered with fenofibrate provided significant LDL cholesterol reduction compared to fenofibrate alone

In a multicenter, randomized, double-blind, placebo-controlled, parallel arm trial, 619 patients were randomized in a 3:3:3:1 ratio to one of four daily treatments for 12 weeks: ZETIA 10 mg (n=185), fenofibrate 160 mg (n=188), ZETIA 10 mg plus fenofibrate 160 mg (n=183) and placebo (n=63). The study population was comprised of 619 patients, ages 18 to 75 with mixed hyperlipidemia after a six to eight week washout and dietary run-in period. Baseline LDL cholesterol levels ranged from 130 to 220 mg/dL (100 to 180 mg/dL for patients with type 2 diabetes) and triglycerides (TG) from 200 to 500 mg/dL; patients with a history of coronary heart disease (CHD), CHD-equivalent disease (except for type 2 diabetes) or CHD risk greater than 20 percent (except for type 2 diabetes) as defined by NCEP ATP III criteria were excluded.

The primary endpoint of this study compared the LDL cholesterol lowering efficacy of ZETIA plus fenofibrate versus fenofibrate alone. After 12 weeks, the co-administration of ZETIA and fenofibrate significantly reduced LDL cholesterol, non-HDL cholesterol, and apo B to a greater extent than ZETIA alone or fenofibrate alone (p<0.001). ZETIA and fenofibrate co-administration and fenofibrate alone both significantly increased HDL cholesterol levels by 19 percent and significantly reduced TG levels by 44 percent. Treatment with ZETIA coadministered with fenofibrate, ZETIA alone, and fenofibrate alone were all well-tolerated. Treatment with ZETIA with fenofibrate was well tolerated over the 12 week study.

Important information about ZETIA

ZETIA is a prescription medication 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 women who are nursing or pregnant or who may become pregnant, or by anyone with active liver disease. Statins should not be taken by anyone with these conditions. If you have ever had liver problems or are pregnant or nursing, your doctor will decide if ZETIA is right for you. Your doctor may do blood tests to check your liver before you start taking ZETIA with a statin and during treatment. The effects of ZETIA, either alone or in addition to a statin, on the risk of cardiovascular morbidity and mortality have not been established.

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. 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. 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 has not been established; therefore, co-administration with fibrates is not recommended until further investigation justifies their concomitant use.

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. Caution should be exercised when initiating ZETIA in patients treated with cyclosporine, particularly in patients with severe renal insufficiency, due to increased blood levels of ZETIA.

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).

ZETIA, marketed by Merck/Schering-Plough Pharmaceuticals, is the first in a class of cholesterol-lowering agents that inhibits the intestinal absorption of cholesterol through a unique mechanism of action. ZETIA is complementary to the class of cholesterol-lowering agents known as statins, which work in the liver to reduce the production of cholesterol. ZETIA, along with diet, is indicated for use either by itself or together with statins in patients with high cholesterol to reduce LDL "bad" cholesterol and total cholesterol when the response to diet and exercise has been inadequate. ZETIA has been proven to significantly improve LDL cholesterol levels.

Source: Eurekalert & others

Last reviewed: By John M. Grohol, Psy.D. on 21 Feb 2009
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