Disodium ascorbyl phytostanol phosphate. A new cholesterol-lowering drug?

Abstract

The Adult Treatment Panel III (ATP III) Guidelines [1] have revised the treatment goals for the reduction of lowdensity lipoprotein (LDL)-cholesterol in patients. For those patients at a moderate to high risk, the target goal is a LDLcholesterol level of <2.6 mmol/L(=<100 mg/dL); for those at a very high risk, the target goal is <1.8 mmol/L (=<70 mg/dL) The most potent cholesterol drugs in current use are the statins [2], but not all patients using these drugs are reaching the ATP III goal. Therefore, new cholesterollowering compounds are necessary in addition to the statins so that more patients will achieve their target/treatment goal. It is beleived that an increased number of patients would be able to approach the ATP III goal if ezetimibe were to be added to ongoing statin therapy [3]. Ezetimibe is a drug which diminishes intestinal cholesterol absorption [4]. However, the recent study published by the leading author of the present article (ref. Nr. 6 old, 7 new) (Kastelein) showed that although the addition of ezetimibe to Simvastatin (80 mg/day) was followed by a significant further reduction in LDL-cholesterol compared to Simvastatin alone, no further reduction in the intima-media thickness of the walls of the carotid and femoral arteries was observed [5]. Additional cholesterol reduction can also be achieved when dietary food enriched with plant sterols or stanols is ingested (up to 2 g/day) [6]. In this issue of the European Journal of Clinical Pharmacology, Vissers et al. [7] demonstrate that a dose of 400 mg/day of the synthetic disodium ascorbyl phytostanol phosphate (FM-VP4) resulted in a slight but significant reduction in LDL-cholesterol (−6.5%) in healthy male subjects with mild hypercholesterolemia. A dose of 100, 200 or 800 mg/day, however, had no significant effect (+2.9, −4.2 and −4.6%, respectively). This is the first study in humans showing that the water-soluble compound FMVP4 has a small serum cholesterol-lowering effect in subjects with mild hypercholesterolemia. It has been established that food enriched with plant stanols, such as sitostanol, which is incorporated in this new drug, is able to reduce serum cholesterol when the plant stanols-enriched food is given in a dose of approximately 1 up to 2 g/day by 7–15% [6]. Studies in humans have also clearly demonstrated that sitostanol consumption reduces plasma sterol concentrations by inhibiting the intestinal absorption of sterols [8–11]. Furthermore, the reduction in plasma sterol concentrations (e.g. campesterol and sitosterol) is much more pronounced than that of cholesterol because plant sterols can not be synthesized in the human body. In contrast, Visser et al. found no reduction in either campesterol or sitosterol in their study [see Table 3 of 7] . Thus, the mechanism of action of FMVP4 in humans is unlikely to be due to an inhibition of the absorption of sterols by the intestine, although, based on the results of animal studies, it has been claimed that cholesterol absorption is reduced by FM-VP4 [12]. It is of interest that in a single-dose escalation study of FM-VP5, a dose-dependent increase in the serum concentration of both DASP (disodium ascorbyl sitostanol phosphate) and DACP (disodium ascorbyl campestanol phosphate), both present in FM-VP5, was observed (Table 2 in [7]), indicating that these compounds are absorbed in humans. In addition, campestanol and sitostanol also increased significantly in the plasma of the subjects, indicating that part of the Eur J Clin Pharmacol (2008) 64:649–650 DOI 10.1007/s00228-008-0491-9