Lovastatin versus Bezafibrate: Efficacy, Tolerability, and Effect on Urinary Mevalonate

Abstract

Lovastatin and bezafibrate have proved effective in lowering low-density-lipo-protein (LDL) cholesterol and elevating high-density-lipoprotein (HDL) cholesterol. We compared their tolerability, safety, and effects on lipoproteins and urinary mevalonate excretion in a short-term study. Forty patients with primary hypercholesterolemia were enrolled in a single-blind randomized study with a diet/placebo period of 8 weeks and a treatment period of 12 weeks. Twenty patients received lovastatin (final average dose 70.5 mg/day), and 20 patients received bezafibrate 400 mg/day. LDL cholesterol was lowered by 35% (from 323 to 208 mg/dl) with lovastatin and by 8% (from 289 to 264 mg/dl) with bezafibrate. HDL cholesterol increased by 21 and 20% with lovastatin and bezafibrate, respectively. Twenty-four-hour urinary mevalonic acid output decreased by 37% during treatment with lovastatin and by 2% during treatment with bezafibrate. Thus, the lowering of cholesterol by lovastatin, but not by bezafibrate, can be attributed to inhibition of HMG CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase. Both lovastatin and bezafibrate are well tolerated.

The Toxicology of HMG—CoA Reductase Inhibitors: Prediction of Human Risk

“…With the understanding that much of the toxicity of these agents is mechanism-based, it is possible to develop a more rigorous method of assessment of potential human risk by looking at a surrogate marker of the relative biochemical effect in the target species (Beil et al, 1990). The result of this type of evaluation is shown in Figure 13 Gerson, 1990).…”

Quantification of Urinary Mevalonic Acid as A Biomarker of Hmg-Coa Reductase Activity by A Novel Translational LC–MS/MS Method

“…These data conform with published urinary MVA data where a study of healthy volunteers observed increases of 6 to 122% in MVA excretion in eight of 11 volunteers in 12 h urine collected between time points 19:00 and 07:00 compared with 07:00 and 19:00; in the remaining three volunteers this trend was reversed [37]. Correspondingly, plasma MVA was observed to vary fivefold in a 40 year old male with a maximum at 07:00 and a minimum at 22:00 [32].…”

“…With a substantial dynamic range (0.0156-10 µg/ml), the assay is sufficient to determine normal biological and perturbed concentrations of MVA in both rat and human urine. Administration of statins is known to reduce the production of MVA by 30-40% [6,32,33]. Given that the physiological urinary concentration of MVA in humans ranges between 116 and 1227 ng/ml, the validated dynamic range of this assay will comfortably address perturbed MVA biosynthesis.…”

“…The production of MVA, represented by the plasma concentration and urinary excretion, is subject to diurnal variation in humans [14,15,32] and the hepatic microsomal activity of HMG-CoA reductase in rats displays a marked diurnal variation [14,16]. However, early studies were unable to demonstrate a statistically significant diurnal fluctuation of plasma MVA in rats [2].…”

Effects of Bezafibrate—A Hypolipidemic Drug

“…The recommended dose of bezafibrate is 3 X 200 mg of the standard tablet or 1 X 400 mg of the sustained-release Curdiovascular Drug Reviews, Vol. 10 , N o . 3 , 1992 formulation.…”