Zocor Mechanism of Action

ZOCOR (simvastatin) 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 β-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 form 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 hyperlipidemia, 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 (3.0mmol/L); 25% had levels between 116 mg/dL (3.0mmol/L) and 135 mg/dL (3.5mmol/L); and 42% had levels greater than 135 mg/dL (3.5mmol/L).
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-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, 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 taking 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 hyperlipidemia) demonstrated that ZOCOR at doses of 20 to 80 mg/day reduced TG 21 to 39% (placebo: 11 to 13%), LDL-C 23 to 35% ( placebo: +1 to +3%), non-HDL-C 26 to 43% (placebo: 1 to 3%), and raised HDL-C by 9 to 14% (placebos: 3%).
In another subgroup analysis of 7 patients with dysbetalipoproteinemia (Fredrickson type III hyperlipidemia), 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%).