Long-term safety is an important consideration in the selection and use of drugs, such as lipid-lowering agents, that are prescribed to reduce the risk of clinical events during long periods.The Scandinavian Simvastatin Survival Study was designed to evaluate the effects of cholesterol lowering with simvastatin on mortality and morbidity in patients with coronary heart disease. The 4444 patients aged 35 to 70 years (mean, 58.9 years) with angina pectoris or previous myocardial infarction and serum cholesterol levels of 5.5 to 8.0 mmol/L (213-310 mg/dL) receiving a lipid-lowering diet were randomly assigned to take double-blind treatment with simvastatin, 20 to 40 mg once daily, or placebo. In addition to previously reported end-point events, detailed clinical and laboratory safety data were collected during a median follow-up period of 5.4 years (range in survivors, 4.9-6.2 years).The only clearly drug-related serious adverse event during the 5.4-year median follow-up period was a single reversible case of myopathy. The frequencies of persistent elevations of hepatic aminotransferase levels above 3 times the upper limit of normal and of nonviral hepatitis in the simvastatin and placebo treatment groups were not significantly different. Examination of the lens showed no between-group differences, and no previously unrecognized adverse effects of the drug were observed. There were no significant between-group differences in adverse events in any body system. In particular, the frequency of adverse events related to the central nervous system was similar in both groups.The safety profile of simvastatin, 20 to 40 mg daily, over 5 years was excellent.
Animal cholesterol synthesis shows a marked diurnal variation, a phenomenon, at the moment, not known to occur in man.Since cholesterol precursors in serum reflect overall cholesterol synthesis in many conditions, a 24-hr profile of squalene and methyl sterols was studied in plasma lipoproteins in order to demonstrate whether these cholesterol precursors could exhibit a diurnal cycling in healthy human subjects.During the 24-hr period, lipoproteins of density < 1.006 g/ml transported 30-50% of the plasma squalene.Free methyl sterols were found mainly in low density lipoproteins (LDL) and esterified methyl sterols in L D L and high density lipoproteins (HDL).Postprandial hyperlipidemia at noon was associated with an inconsistent increase of the squalene and free methyl sterol concentrations in the lipoproteins of density < 1.006 g/ ml.In terms of pg per mg of cholesterol, the precursor contents were, however, low in each lipoprotein during the daytime.During the night and early morning, the values were several times higher.Thus the peak plasma squalene and methyl sterol contents occurred at midnight and 4 AM.The highest variation was found for squalene in the density class < 1.006 g/ml and for lanosterol and diunsaturated dimethyl sterol in L D L and H D L .For different methyl sterols, the mean diurnal variation was 3.5-to 6.9-fold in LDL, 2.0-to 4.5-fold in H D L , and 2.6to 3.6-fold in the density class < 1.006 g/ml.The respective values for squalene were 2.2, 1.4, and 2.9.Esterified methyl sterols varied slightly in the density class < 1.006 g/ml only, whenever present); LDL, low density lipoprotein; HDL, high density lipoprotein; GLC, gas-liquid chromatography.'Some of the results have been presented in the VI1 International
Relationships between biliary bilirubin and lipid secretions were studied in patients with chronic cholestatic liver disease, mainly primary biliary cirrhosis. The bilirubin secretion rate in the patients was not significantly different from that in the controls. However, the bilirubin output per phospholipids, per bile acids, and per phospholipids plus bile acids was high, especially at low bile acid secretion rates. Thus, the bile of the patients with chronic cholestatic liver disease appears to be frequently ‘supersaturated’ with bilirubin. This metabolic abnormality may be associated with an increased risk of pigment stone formation in patients with cirrhosis.
