Synopsis Simvastatin (epistatin; synvinolin; MK 733), an HMG-CoA reductase inhibitor, acts by decreasing cholesterol synthesis and by increasing low density lipoprotein (LDL) catabolism via increased LDL receptor activity. In patients with heterozygous familial and nonfamilial hypercholesterolaemia, orally administered simvastatin 10 to 40mg once daily reduces plasma total and LDL-cholesterol concentrations by about 30 to 45%. It also produces a beneficial moderate decrease in plasma triglycerides and a small, although significant, increase in high density lipoprotein (HDL)-cholesterol. Like many other hypocholesterolaemic agents simvastatin does not appear useful in patients with homozygous familial hypercholesterolaemia who lack LDL receptors. The hypocholesterolaemic activity of simvastatin is greater than that of the bile acid sequestrants, probucol and the fibrates. Combined administration of simvastatin with bile acid sequestrants results in further reductions in plasma cholesterol levels beyond those seen with either drug alone. Simvastatin appears well tolerated in the short to medium term, but its long term tolerability needs to be confirmed. No comparisons of simvastatin and other HMG-CoA reductase inhibitors have been reported. As yet there have been few investigations to determine the impact of simvastatin or other HMG-CoA reductase inhibitors on cardiovascular events relative to their hypocholesterolaemic effects, but at least one such trial is ongoing. Simvastatin, like other HMG-CoA reductase inhibitors, has considerable potential advantages over other classes of hypocholesterolaemic agents, i.e. the magnitude of its cholesterol-lowering effect and convenience of administration. If further study confirms long term tolerability and an impact on cardiac mortality and morbidity, then simvastatin and others of its class should offer a significant new approach to the treatment of hypercholesterolaemia. Pharmacodynamic Properties Simvastatin, after absorption and hydrolysis in the liver to form the active β-hydroxyacid metabolite, acts as a potent reversible, competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, an early and rate limiting enzyme in the biosynthesis of cholesterol. In vitro cell culture studies show that simvastatin is a potent inhibitor of cholesterol synthesis. Various studies in vivo in rabbits and dogs have confirmed the ability of simvastatin to reduce plasma cholesterol levels, and there is some evidence the drug reduces the production of atherosclerotic lesions in rabbits. HMG-CoA reductase inhibition may decrease LDL synthesis and increase receptor-mediated LDL catabolism. The former mechanism appears to predominate in patients with non-familial hypercholesterolaemia and the latter in patients with heterozygous familial hypercholesterolaemia. The degree of cholesterol reduction is apparently similar in the 2 groups of patients. During therapy of hypercholesterolaemic patients with simvastatin there is an approximate 25 to 35% decrease in the mean plasma concentration of apolipoprotein B, the major LDL protein. Some studies have noted a mean increase of about 10% in apolipoproteins AI and AII, the major HDL proteins. In humans, simvastatin does not appear to influence adrenocortical function which theoretically might be affected as a result of HMG-CoA reductase inhibition reducing cholesterol concentrations. The cholesterol saturation index of gallbladder bile was significantly reduced in hypercholesterolaemic patients treated with simvastatin, suggesting the drug is unlikely to enhance cholesterol gallstone development. Pharmacokinetic Properties Simvastatin is a prodrug which undergoes rapid hydrolysis after absorption to form a number of active metabolites in humans. The major metabolite, β-hydroxyacid-simvastatin, is the most potent with respect to HMG-CoA reductase inhibition. After absorption in humans, simvastatin undergoes extensive first-pass metabolism in the liver, the primary site of action, with subsequent excretion of drug in bile. The systemic bio-availability of the drug is therefore low: the absolute bioavailability of β-hydroxyacid-simvastatin is less than 5%. The area under the plasma concentration-time curve for total HMG-CoA reductase inhibitors in the circulation is clearly related to dose over the range from 5 to 120mg in humans after the administration of single oral doses of simvastatin. Plasma inhibitor concentration is unaffected by coadministration of food with simvastatin. No accumulation appears to occur with repeated administration of normal therapeutic doses. Both simvastatin and β-hydroxyacid-simvastatin are >95% protein bound in human plasma. Distribution studies in rats indicate that simvastatin and lovastatin appear more selective for liver tissue than pravastatin. After oral administration of a radiolabelled dose of simvastatin, 13% of radioactivity is recovered in urine and 60% in faeces, the latter representing unabsorbed drug and that excreted as metabolites in bile. Therapeutic Use Dose-finding studies have established that the maximal lipid changes induced by simvastatin occur within the range of 10 to 40mg once daily. Most subsequent studies have used dosages in this range, although in Japanese patients dosages begin at 5mg daily. After appropriate dietary control, monotherapy with simvastatin generally produces the following mean changes in circulating lipids in patients with heterozygous familial and nonfamilial hypercholesterolaemia (Fredrickson types IIa or b): total cholesterol is reduced by 30 to 35% and LDL-cholesterol by about 35 to 45%, triglycerides are reduced by about 20 to 40%, and HDL-cholesterol is increased by about 5 to 15%. With fixed dosages, the maximal effects are reached in about 4 to 8 weeks and are maintained during longer term therapy — up to 2 years in some patients, although most trials did not progress beyond 3 months. In percentage terms, simvastatin-induced changes in lipid levels appear similar in patients with familial and nonfamilial disease, and are not dependent on the severity of hypercholesterolaemia. However, patients with more severe hypercholesterolaemia (usually those with familial disease) are less likely to attain a desirable ‘normal’ level of plasma cholesterol. Limited information in patients with hypercholesterolaemia secondary to diabetes or nephrotic syndrome indicates that simvastatin produces similar lipid changes to those in patients with primary hypercholesterolaemia. Simvastatin may be useful in the treatment of primary dysbetalipoproteinaemia (Fredrickson type III) but is unlikely to offer any benefit in patients with homozygous familial hypercholesterolaemia unless there is some residual LDL-receptor function. In comparative studies, simvastatin produced significantly greater decreases in total and LDL-cholesterol concentrations than probucol, bile acid sequestrants (colestipol and cholestyramine), and the fibrates (bezafibrate, fenofibrate and gemfibrozil). However, the fibrates produced a greater increase in HDL-cholesterol levels, and were more effective in reducing triglyceride concentrations than simvastatin. Simvastatin is not indicated for the treatment of hypertriglyceridaemia, but its ability to reduce triglycerides to a moderate extent in hypercholesterolaemic patients can be considered as a secondary beneficial effect. Unlike probucol, simvastatin did not decrease HDL-cholesterol levels nor did it increase triglycerides levels, unlike cholestyramine. Simvastatin has not been compared with nicotinic acid, or with other HMG-CoA reductase inhibitors. The addition of colestipol or cholestyramine to simvastatin produces further decreases in total and LDL-cholesterol levels compared with simvastatin alone. With combination therapy the reduction in total and LDL-cholesterol may reach 50 to 60%, which means that patients with severe hypercholesterolaemia are more likely to attain a desirable cholesterol level. Adverse Effects Published information on the tolerability of simvastatin indicates that the drug is well tolerated in the short to medium term. Adverse effects are usually mild and transient, leading to drug withdrawal in less than 2% of patients. These most frequently include mild gastrointestinal complaints and more rarely fatigue, headache and rash. Mild, transient increases in serum transaminase levels may occur relatively frequently at the start of therapy, but more persistent, greater increases occur in 1 to 2% of patients and may require drug withdrawal. However, these changes have not been associated with signs or symptoms of hepatic disease. Simvastatin may cause minor increases in serum creatine phosphokinase; this has rarely been associated with myopathy, which appears to be a class-specific effect potentiated by drugs such as gemfibrozil, niacin and cyclosporin. Simvastatin has not demonstrated any cataractogenic potential in the short term. While the tolerability of simvastatin appears favourable compared with the established profiles of other hypocholesterolaemic agents, further monitoring is required to confirm its long term tolerability. Dosage and Administration Simvastatin is indicated for patients with primary hypercholesterolaemia when the response to diet and other nonpharmacological measures alone has proved inadequate. The usual starting dose is 10 mg/day given as a single dose in the evening; in Japanese clinical trials a starting dose of 5 mg/day has been favoured. Depending on the patient’s response the dosage may be increased at 4-week intervals to a maximum of 40 mg/day given as a single dose in the evening. Regular monitoring of serum hepatic enzymes and creatine phosphokinase should be performed during therapy. The use of simvastatin in combination with fibrates, niacin and cyclosporin should be avoided to minimise the risk of myopathy. The drug is contraindicated in patients with active liver disease or unexplained persistent elevations of serum transaminases. Dosage reduction should not be required in patients with renal insufficiency. © 1990, Adis International Limited. All rights reserved.
