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Zocor

 

ZOCOR (simvastatin, MSD) is a lipid-lowering agent derived synthetically from a fermentation product of Aspergillus terreus.


After oral ingestion, ZOCOR, an inactive lactone, is hydrolyzed to the corresponding beta-hydroxyacid form. This is a principal metabolite and an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes an early and rate-limiting step in the biosynthesis of cholesterol. Clinical studies show ZOCOR to be highly effective in reducing total plasma cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and very-low-density lipoprotein cholesterol (VLDL-C) concentrations, and increasing high-density lipoprotein cholesterol (HDL-C) in heterozygous familial and non-familial forms of hypercholesterolemia, and in mixed hyperlipidemia when elevated cholesterol was cause for concern and diet alone has been insufficient. Marked responses are seen within 2 weeks, and maximum therapeutic responses occur within 4-6 weeks.


The response is maintained during continuation of therapy. When therapy with ZOCOR is stopped, cholesterol and lipids return to pretreatment levels. The active form of simvastatin is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate.


Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway of cholesterol, therapy with ZOCOR would not be expected to cause an accumulation of potentially toxic sterols. In addition, HMG-CoA is also metabolized readily back to acetyl-CoA, which participates in many biosynthetic processes in the body.


In animal studies, after oral dosing, simvastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues. Simvastatin undergoes extensive first-pass extraction in the liver, the primary site of action, with subsequent excretion of drug in the bile. Systemic exposure of the active ton of simvastatin in man has been found to be less than 5% of the oral dose. Of this, 95% is bound to human plasma proteins.


In the Scandinavian Simvastatin Survival Study (4S), the effect on total mortality of therapy with ZOCOR for a median of 5.4 years was assessed in 4,444 patients with coronary heart disease (CHD) and baseline total-C 212-309 mg/dL (5.5-8.0 mmol/L). In this multicenter, randomized, double-blind, placebo-controlled study, ZOCOR reduced the risk of death by 30%, of CHD death by 42%, and of having a hospital-verified non-fatal myocardial infarction by 37%. ZOCOR reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37%. In patients with diabetes mellitus the risk of a major coronary event was reduced by 55%. Furthermore, ZOCOR significantly reduced the risk of fatal plus non-fatal cerebrovascular events (stroke and transient ischemic attacks) by 28%.


In the Heart Protection Study (HPS), the effects of therapy with ZOCOR for a mean duration of 5 years were assessed in 20,536 patients, with or without hypedipidemia, who were at high risk of coronary heart disease (CHD) events because of diabetes, history of stroke or other cerebrovascular disease, peripheral vessel disease, or CHD. At baseline, 33% had LDL levels below 116 mg/dL; 25% had levels between 116 mg/dL and 135 mg/dL; and 42% had levels greater than 135 mg/dL.


In this multicenter, randomized, double-blind, placebo-controlled study, ZOCOR 40 mg/day compared with placebo reduced the risk of total mortality by 13%, due to a reduction in CHD deaths (18%). ZOCOR also decreased the risk of major coronary events (a composite endpoint comprising non-fatal MI or CHD deaths) by 27%. ZOCOR reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) and peripheral and other non-coronary revascularization procedures by 30% and 16%, respectively. ZOCOR reduced the risk of stroke by 25%. Furthermore, ZOCOR reduced the risk of hospitalization for angina pectoris by 17%.


The risks of major coronary events and major vascular events (a composite endpoint comprising major coronary events, stroke, or revascularization procedures) were reduced by about 25% in patients with or without CHD, including diabetics and patients with peripheral or cerebrovascular disease.


In addition, within the subgroup of patients with diabetes, ZOCOR reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21%. The risk reductions produced by ZOCOR in both major vascular events and major coronary events were evident and consistent regardless of patient age, gender, baseline LDL-C, HDL-C, TG, apolipoprotein A-l, or apolipoprofein B level, presence or absence of hypertension, creatinine levels up to the entry limit of 2.3 mg/dL presence or absence of baseline cardiovascular medications (i.e., aspirin, beta blockers, angiotensin converting enzyme (ACE) inhibitors, or calcium channel blockers), smoking status, alcohol intake, or obesity. By 5 years, 32% of patients in the placebo group were faking a statin (outside of the study protocol), so that the observed risk reductions underestimate the real effect of simvastatin.


In a multicenter, placebo-controlled clinical study in 404 patients using quantitative coronary angiography, ZOCOR slowed the progression of coronary atherosclerosis and reduced the development of both new lesions and new total occlusions, whereas coronary atherosclerotic lesions steadily worsened over four years in patients receiving standard care.


Subgroup analyses from 2 studies including a total of 147 patients with hypertriglyceridemia (Fredrickson type IV hypedipidemia) demonstrated that ZOCOR at doses of 20 to 80 mg/day reduced TO 21 to 39% (placebo: 11 to 13%), LDL-C 23 to 36% (placebo: +1 to +3%), non-HDL-C 26 to 43 (placebo: 1 to 3%), and raised HDL-C by 9 to 14% (placebo: 3%).


In another subgroup analysis of 7 patients with dysbetalipoproteinemia (Fredrickson type III hyperipidemie), ZOCOR at a dosage of 80 mg/day reduced LDL-C including intermediate-density lipoproteins (IDL) by 51% (placebo: 8%) and VLDL-C+IDL by 60% (placebo: 4%).


CLINICAL PHARMACOLOGY
PHARMACODYNAMICS
ZOCOR Is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate. However, at therapeutic doses, the enzyme is not completely blocked, thereby allowing biologically necessary amounts of mevalonate to be available. Because the conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway of cholesterol, therapy with ZOCOR would not be expected to cause an accumulation of potentially toxic sterols. In addition, HMG-CoA is metabolized readily back to acetyl-CoA, that participates in many biosynthetic processes in the body.


Although cholesterol is the precursor of all steroid hormones, simvastatin has not been shown to have any clinical effect on steroidogenesis. Simvastatin caused no increase in biliary lithogenicity and, therefore, would not be expected to increase the incidence of gallstones.


CLINICAL STUDIES
ZOCOR has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from VLDL and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-C lowering effect of ZOCOR may involve both reduction of VLDL-cholesterol concentration and induction of the LDL receptor, leading to reduced production and increased catabolism of LDL-C. Apo B also falls substantially during treatment with ZOCOR. Since each LDL particle contains one molecule of Apo B, and since little Apo B is found in other lipoproteins, this strongly suggests that ZOCOR does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, ZOCOR increases HDL-C and reduces plasma TG. As a result of these changes the ratios of total-C to HDL-C and LDL-C to HDL-C are reduced.


The involvement of LDL-C in atherogenesis has been well-documented in clinical and pathological studies, as well as in many animal experiments.


Epidemiological studies have established that high total-C, LDL-C, and apo B are risk factors for coronary heart disease, while high HDL-C and apo A-I are associated with decreased risk.


In 4S, the effect of therapy with ZOCOR on total mortality was assessed in 4,444 patients with CHD and baseline total cholesterol 212-309 mg/dL (5.5-8.0 mmol/L(. In this multicenter, randomized, double-blind, placebo-controlled study, patients with angina ore previous myocardial infarction (MI) were treated with diet and standard care and either ZOCOR 20-40 mg daily (n=2,221) or placebo (n=2,223) for a median duration of 5.4 years. Over the course of the study, treatment with ZOCOR led to mean reductions in total-C, LDL-C, and TO of 25%, 35%, and 10%, respectively, and a mean increase in HDL-C of 8%. ZOCOR reduced the risk of death (Figure 1) by 30%, p=0.0003 (182 deaths in the ZOCOR group vs 256 deaths in the placebo group).


The risk of CEO death was reduced by 42%, p=0.00001 (111 vs 189). ZOCOR also decreased the risk of having major coronary events (CHD death plus hospital-verified and silent non-fatal MI) (Figure 2) by 34%, p<0.00001 (431 patients vs 622 patients with one or more events). The risk of having a hospital-verified non-fatal MI was reduced by 37%. ZOCOR reduced the risk for undergoing myocardial revascularization procedures (coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 37%, p<0.00001 (252 patients vs 383 patients). Furthermore, ZOCOR significantly reduced the risk of fatal plus non-fatal cerebrovascular events (stroke and transient ischemic attacks) by 28%, (p=0.033, 75 patients vs 102 patients).


There was no statistically significant difference between groups in non-cardiovascular mortality. ZOCOR reduced the risk of major coronary events to a similar extent across the range of baseline total and LDL-C levels. The risk of death in patients ≥60 years of age was decreased by 27% and in patients <60 years of age by 37% (p<0.01 in both age groups). Because there were only 53 female deaths, the effect of ZOCOR on mortality in women could not be adequately assessed. However, ZOCOR lessened the risk of having major coronary events by 34% (p=0.012, 60 women vs 91 women with one or more event). In patients with diabetes mellitus the risk of major coronary events was reduced by 55%, p=0.002 (24 patients vs 44 patients).

 

 

High Risk of Coronary Heart Disease (CHD) or Existing-Coronary Head Disease
In HPS, the effects of therapy with ZOCOR were assessed in 20,536 patients, with or without hyperllpidemia, who were at high risk of coronary head disease (CHD) events because of diabetes, history of stroke or other cerebrovascular disease, peripheral vessel disease, or CHD. In this multicenter, randomized, double-blind, placebo-controlled study, 10,269 patients were treated with ZOCOR 40 mg/day and 10,267 patients were treated with placebo for a mean duration of 5 years. At baseline, 6,793 patients (33%) had LDL-C levels below 116 mg/dL, 5,063 patients (25%) had levels between 116 mg/dL and 135 mg/dL; and 8,680 patients (42%) had levels greater than 135 mg/dL.


Treatment with ZOCOR 40 mg/day compared with placebo reduced the risk of total mortality by 13% (p=0.0003) due to an 18% reduction in CHD deaths (p=0.0005). ZOCOR also decreased the risk of major coronary events (a composite endpoint comprised of non-fatal MI or CHD death) by 27% (p<0.00001).


ZOCOR reduced the need for undergoing coronary revascularization procedures (including coronary artery bypass grafting or percuteneous transluminal coronary angioplasty) and peripheral and other non-coronary revascularization procedures by 30% (p<0.0001) and 16% (p=0.006), respectively. ZOCOR reduced the risk of stroke by 25% (p<0.0001), attributable to a 30% reduction in ischemic stroke (p<0.00001). Furthermore, ZOCOR reduced the risk of hospitalization far angina pectoris by 17% (p<0.00001). The risks of major coronary events and major vascular events (a composite endpoint comprising major coronary events, slicks, or revascularization procedures) were reduced by about 25% in patients with or without CHD, including diabetics and patients with peripheral or cerebrovascular disease. In addition, within the subgroup of patients with diabetes, ZOCOR reduced the risk of developing macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers by 21% (p=0.0293). The risk reductions produced by ZOCOR in both major vascular events and major coronary events were evident and consistent regardless of patient age, gender, baseline LDL-C, HDL-C, TG, apolipoprotein A-I, or apolipoprotein B level, presence or absence of hypertension, creatinine levels up to the entry limit of 2,3 mg/dL, presence or absence of baseline cardiovascular medications (i.e., aspirin, beta blockers, ACE inhibitors, or calcium channel blockers), smoking status, alcohol intake, or obesity. By 5 years, 32% of patients in the placebo group were taking a statin (outside of the study protocol), so that the observed risk reductions underestimate the real effect of simvastatin.


In the Multicenter Anti-Atheroma Study, the effect of therapy with ZOCOR on coronary atherosclerosis was assessed by quantitative coronary angiography in hyperchotesterolemic men and women with coronary heart disease. In this randomized, double-blind, controlled clinical trial, 404 patients with total cholesterol values of 212 to 308 mg/dL (5.5 to 8.0 mmol/L) and a mean baseline LDL value of 170 mg/dL (4.4 mmol/L) were treated with conventional measures and with ZOCOR 20 mg/day or placebo. Angiograms were evaluated at baseline, too and four years. A total of 347 patients had a baseline angiogram and et least one follow-up angiogram. In the patients who received placebo, coronary atherosclerolic lesions worsened in a rear-linear manner. In contrast, ZOCOR significantly slowed the progression of lesions as measured in the final angiogram by the mean change per-patient in minimum (p=0.005) and mean (p=0.026) lumen diameters (co-primary endpoints, indicating focal and diffuse disease, respectively), as well as in percent diameter stenosis (p=0.003). ZOCOR also significantly decreased the proportion of patients with new lesions (13% ZOCOR vs 24% placebo, p=0.009)
and with new total occlusions (5% vs 11%, p=0.04). The mean change per-patient in mean and minimum lumen diameters calculated by comparing angiograms in the subset of 274 patients who had matched angiographic projections at baseline, two and four years is presented below (Figures 3 and 4).

 

 

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