Long Term Clinical Tolerance of Lovastatin (Mevinolin) and Simvastatin (Epistatin)

Abstract

Cholesterol is essential for the normal function of the human body. This sterol is an important constituent of cell membranes and a metabolic precursor for steroid hormones, bile acids and vitamin D. Cells of the body synthesise cholesterol from acetyl coenzyme A through a metabolic pathway which is also important for the generation of ubiquinone, dolichol and isopentenyl adenine. Cells also obtain cholesterol by taking up low density lipoprotein (LDL) from the extracellular fluid via the LDL receptor pathway. Lovastatin (mevinolin) and simvastatin (epistatin) inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the principal rate-limiting enzyme in cholesterol biosynthesis. When this enzyme is inhibited, the cells express more LDL receptors to obtain the cholesterol they require from the plasma LDL-cholesterol pool. When LDL receptor activity is stimulated in vivo, plasma LDL-cholesterol levels may decrease 25 to 40%. Toxic effects from lovastatin and simvastatin therapy may theoretically be related to inhibition of cholesterol biosynthesis and/or direct toxic effects of the drugs. With regard to inhibition of cholesterol biosynthesis, therapy with HMG CoA reductase inhibitors has not affected serum ubiquinone-10 levels; no data are available regarding in vivo effects on dolichol formation or isopentenyl adenine levels. Adrenal steroidogenesis is not significantly altered by therapeutic doses of lovastatin. During 4 months of continuous lovastatin treatment in 16 men, no changes were seen in testicular function, including serum testosterone levels and sperm counts. Therapeutic doses of lovastatin limit mevalonic acid production only moderately and have not caused the faecal output of neutral and acidic steroids to drop below the normal range, indicating that cholesterol synthesis is not severely affected by standard doses of the drug. Information on long term experience with the drug in large groups of patients is still being accumulated. Of 744 patients enrolled in a long term safety study with lovastatin, now entering its fourth year of follow-up, only 2.2% (n = 16) of the subjects withdrew because of drug-attributable adverse events. The most severe of these events related to effects on liver and/or skeletal muscle. Raised transaminases requiring withdrawal of lovastatin treatment occurred in 1.3% of the patients (n = 10). Skeletal muscle myopathy occurred in only 1 of 744 patients (0.1%), but has occurred in about 0.5% of all patients taking lovastatin in clinical trials. Most of these patients had complex medical problems and were taking other medications including immunosuppressants (especially cyclosporin), gemfibrozil, nicotinic acid (niacin) or erythromycin. No long term sequelae have been reported in these patients after lovastatin was discontinued. Other adverse effects leading to discontinuation of therapy were infrequent and included rash (0.3%), gastrointestinal symptoms (0.3%) and insomnia (0.1%). To date, there are no data to indicate that lens opacities occur with a greater prevalence in lovastatin-treated patients than in age-matched controls. In summary, only a small number of patients have continuously received lovastatin for periods of 5 years or more. Large numbers of patients in various clinical trials have been observed for > 3 years, and the indications are that lovastatin is generally well tolerated. In early clinical experience, the pattern and frequency of side effects with simvastatin are similar to those for lovastatin.