Simvastatin in severe primary hypercholesterolemia: Efficacy, safety, and tolerability in 595 patients over 18 weeks

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Abstract
We report the results of an open multicenter study which evaluated the efficacy, safety, and tolerability of simvastatin in a large cohort of patients with primary hypercholesterolemia. Against a background of standard dietary advice, the study enrolled 595 patients with total cholesterol ≥ 6.5 mmol/l and triglycerides < 6.0 mmol/l across 20 centers. After 4 weeks on placebo, treatment began with simvastatin 10 mg each night, titrating to 20 mg after 6 weeks, and then to 40 mg after 12 weeks if cholesterol levels still exceeded 5.5 mmol/l. By Week 18, 70% of patients were using 40 mg/day. After 18 weeks of treatment, the mean reductions (95% confidence interval) in total and low density lipoprotein (LDL) cholesterol were 30% (29‐31%) and 38% (37‐39%), respectively. There was a mean increase in high density lipoprotein (HDL) cholesterol of 12% (10‐13%), while triglycerides were reduced by a median 19% (16‐23%). From a mean entry total cholesterol of 9.31 ± 2.15 mmol/l, 52% of patients achieved cholesterol levels ± 6.2 mmol/l on treatment. The changes noted were essentially independent of gender, age, or lipid phenotype (IIa vs. IIb). Compliance with prescribed medication was very good and the drug was well tolerated; only 3% of patients manifested a clinical adverse experience requiring discontinuation or a clinical adverse experience described as serious (associated with hospitalization or serious disability). Isolated laboratory adverse experience required discontinuation in 0.2% of patients. One in 3 patients manifested a clinical adverse experience and 1 in 10 a laboratory adverse experience. Adverse experiences occurred in the digestive system (10% of patients), nervous system/psychiatric (6%), skin/appendages (5%), musculoskeletal (4%), elevated muscle enzymes (5%), and elevated transaminases (2%). In the absence of a parallel control group, the proportion of the events attributable to simvastatin could not be ascertained. Simvastatin appears to be a well tolerated and highly efficacious drug for the management of severe primary hypercholesterolemia.