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| |  ACC: Zocor (Simvastatin) Increases HDL And apo A-I More Than Lipitor (Atorvastatin) ANAHEIM, CA -- March 15, 2000 -- The first study comparing the highest recommended doses of Merck's cholesterol-modifying medicine Zocor(R) (simvastatin 80 mg) with Lipitor(R) (atorvastatin 80 mg), manufactured by Warner-Lambert, showed that Zocor increased levels of both "good" (HDL) cholesterol and a key component of good cholesterol called apolipoprotein (apo A-I) to a greater degree than Lipitor. Low HDL has been identified as a risk factor for heart disease. The study, presented today at the 49th Annual Scientific Session of the American College of Cardiology, also showed for the first time differences between the medicines at their highest doses in the rate of discontinuations due to elevated liver enzymes -- a sensitive indication of liver side effects. "Several studies have proven that HDL levels are consistently increased with Zocor, regardless of the dose," said Dr. John R. Crouse III, one of the principal study investigators and professor of medicine and public health sciences at Wake Forest University School of Medicine, Winston-Salem, N.C. "This study confirms statistically significant differences between the two drugs in their effect on HDL and apo A-I seen in an earlier study." The earlier study compared the HDL and apo A-I increases achieved with Zocor 40 mg vs. Lipitor 20 mg and Zocor 80 mg vs. Lipitor 40 mg. Zocor should be used in addition to diet to modify cholesterol levels after diet and other non-drug measures have failed to achieve target levels. In patients with high cholesterol and coronary heart disease (CHD), Zocor is indicated to help save lives by reducing coronary mortality, and to help prevent heart attacks, strokes or mini-strokes and coronary revascularization procedures such as bypass and angioplasty. The recommended usual starting dose is Zocor 20 mg. The 36-week, double-blind study included 826 patients with high cholesterol enrolled in a four-week diet run-in period then randomized to treatment with Zocor or Lipitor. In the first six weeks, patients were treated with Zocor 40 mg or Lipitor 20 mg, similarly potent doses for lowering "bad" (LDL) cholesterol. For the next six weeks, patients were treated with Zocor 80 mg or Lipitor 40 mg, also similarly potent doses for lowering LDL. Patients were then treated with Zocor 80 mg or Lipitor 80 mg for the final 24 weeks of the study. Results were compared at 6, 12 and 18/36 weeks, a time point representing the last 24 weeks of the study and reflecting the average of values obtained at weeks 18, 24, 30 and 36. At the start of the study, patients had average HDL levels of 50.2 mg/dL (Zocor) and 51.4 mg/dL (Lipitor), apo A-I levels of 150.3 mg/dL (Zocor) and 153.6 mg/dL (Lipitor), LDL levels of 209.1 mg/dL (Zocor) and 205.8 mg/dL (Lipitor) and median triglyceride levels of 165.5 mg/dL (Zocor and Lipitor). Zocor 80 mg increased levels of HDL-cholesterol significantly more than Lipitor 80 mg. At the 18/36-week time point, patients treated with Zocor 80 mg had average HDL increases that were more than double the HDL increases seen in those treated with Lipitor 80 mg (7.6 percent with Zocor vs. 3.1 percent with Lipitor; p<0.001). The clinical significance of these comparative differences has not been established, and the independent effect of raising HDL cholesterol on cardiovascular morbidity and mortality has not been established. Results showed that on average, patients treated with Zocor 80 mg significantly increased their levels of apo A-I (+2.5 percent), compared to patients treated with Lipitor 80 mg who decreased their levels of apo A-I (-3.5 percent) at 18/36 weeks (p<0.001). Patients in both treatment groups had significant decreases in their levels of LDL cholesterol and triglycerides (TGs). At 18/36 weeks, when doses that were not similarly potent for lowering LDL were compared, average reductions with Zocor 80 mg were -48.4 percent in LDL and -23.6 percent in TGs, compared to average reductions with Lipitor 80 mg of -54.0 percent and -31.4 percent, respectively (p<0.001). Zocor should not be used by anyone allergic to any of its components, with liver disease, or by women who are pregnant, breast-feeding or likely to become pregnant. Muscle pain or weakness in patients taking Zocor should be reported to a doctor, because these could be signs of a serious side effect. Doctors may perform blood tests before and periodically during treatment with Zocor to check for liver problems. Patients taking the 80 mg strength of Zocor should receive an additional liver function test at three months. Patients should tell their doctors about other medications they are taking in order to avoid possible drug interactions. In clinical trials, adverse reactions usually have been mild and transient. Most commonly reported side effects, regardless of cause, included headache (3.5 percent), abdominal pain (3.2 percent), and constipation (2.3 percent). In this study, 17 patients were taken off therapy because of two consecutive measures of clinically relevant elevations in liver enzymes, a pre-specified endpoint of the study. Of those patients, 3.8 percent (n=15/392) had been treated with Lipitor 80 mg and 0.5 percent (n=2/384) had been treated with Zocor 80 mg (p<0.001). More women treated with Lipitor 80 mg (n=12/202 women; 5.9 percent) stopped therapy due to elevated liver enzymes than women treated with Zocor 80 mg (n=1/162; 0.6 percent). Discontinuations in men treated with Lipitor 80 mg were three in 190 (1.6 percent) vs. one in 122 (0.5 percent) discontinuations in men treated with Zocor 80 mg. The clinical significance of these results are not known. Further studies are needed to confirm the findings of this observation. There were no clinically significant liver enzyme elevations seen with either drug during the first two treatment periods. Total discontinuations due to elevations in creatine kinase (CK), another pre-specified endpoint, occurred at a similar rate (less than one percent) for both drugs. Both products were well tolerated. Analyses of other safety parameters are ongoing. Large epidemiological studies have shown a strong association between decreased levels of HDL cholesterol and an increased cardiovascular risk. The National Cholesterol Education Program (NCEP) of the National Institutes of Health has identified low HDL (less than 35 mg/dL) as a risk factor for heart disease. Apo A-I is one of the key components of HDL and it facilitates the movement of cholesterol into the HDL particle. In 1999, Zocor was approved by the U.S. Food and Drug Administration (FDA) to increase HDL cholesterol in patients with high LDL cholesterol. Merck & Co., Inc. (NYSE: MRK) is a global, research-driven pharmaceutical company that discovers, develops, manufactures and markets a broad range of human and animal health products, directly and through their joint ventures, and provides pharmaceutical benefit services through Merck-Medco Managed Care. Zocor(R) is the Merck registered trademark for simvastatin. Related Links: Zocor, Merck & Co., Inc, Lipitor, Warner-Lambert Co.
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