Reduction in plasma low-density lipoprotein cholesterol and urinary mevalonic acid by lovastatin in patients with heterozygous familial hypercholesterolemia

Abstract

The effects of lovastatin, an inhibitor of 3-hydroxy-3-methyl glutaryl coenzyme A reductase (HMG CoA reductase), on 24-hour urinary excretion rates of mevalonic acid (an intermediate in cholesterol biosynthesis) and plasma low-density lipoprotein (LDL) cholesterol concentrations were evaluated in patients with heterozygous familial hypercholesterolemia (FH). The mean rates of urinary mevalonate excretion of 28 FH patients were initially higher (2.95 +/- 0.29 (+/- SEM) mumols/d) than in 17 control subjects (1.82 +/- 0.12 mumols/d). Patients with FH were treated with sequentially increasing doses of lovastatin (10, 20, 40, and 80 mg daily, taken as a twice daily dosage) for a period of 6 weeks on each dose. When compared to baseline, LDL cholesterol levels fell by 22%, 26%, 30%, and 35% respectively, on these different doses. The mean daily urinary mevalonate excretion decreased from baseline by 19% after 4 weeks on 10 mg daily of lovastatin, 35% on 20 mg, and 31% on 40 mg and 80 mg daily. Similar decreases in urinary mevalonate excretions were observed when patients with FH were treated directly with 40 mg (20 mg twice daily) or 80 mg (40 mg twice daily) mg of lovastatin daily. The magnitude of decrease in LDL cholesterol did not show any significant correlation with the changes in urinary excretion of mevalonic acid. Lovastatin therapy decreases rates of urinary mevalonate excretion (which has previously been shown to reflect rates of cholesterol synthesis) by up to 35% at doses of 20 to 80 mg/d; such a decrease seems unlikely to compromise other important cellular requirements for mevalonate.