Serum lipoprotein Lp(a) concentrations are not influenced by an HMG CoA reductase inhibitor

Abstract

The recent elucidation of the structure of apo(a), the characteristic apoprotein of the lipoprotein Lp(a), has revealed a high homology to human plasminogen [6, 8]. This similarity provides a tentative link between the plasma lipoproteins and the clotting system and may give further insight into the role of Lp(a) in atherosclerosis [2]. Numerous studies have demonstrated a strong association between high levels of Lp(a) and coronary heart disease [1, 3, 10]. Furthermore, there is an additive effect of LDL and Lp(a) such that the relative risk for angiographically documented coronary artery disease at Lp(a) concentrations of 30 mg/dl and greater increases from twofold to fivefold when LDL are also elevated [1]. Whereas both LDL and Lp(a) levels can be lowered by neomycin and niacin [4], bile-acid resins such as cholestyramine do not affect Lp(a) concentrations [11]. The HMG-CoA reductase inhibitors, have proven to be extremely effective in lowering plasma LDL and apo B levels [5, 9], presumably through inhibition of intracellular cholesterol synthesis with a concomitant increase in the livers LDL receptors [7]. In order to establish whether Lp(a) levels are also After a wash-out phase of 4 weeks in which all previous lipid-lowering therapy, with the exception of diet, was stopped, serum total cholesterol, LDL-cholesterot, apoB and Lp(a) concentrations were determined. Total cholesterol was measured with an enzymatic test kit, (Boehringer, Mannheim), LDL-cholesterol by a specific precipitation method (Quantolip-LDL, Immuno, Heidelberg), apoB by rate nephelometry and Lp(a) with a specific non-competitive ELISA. All individuals were administered a single daily dose of 10 mg Simvastatin for 6 weeks and this was then raised to 20 mg once daily for a further 6 weeks. Lipid and lipoprotein parameters betbre and after therapy are summarised in table 1. Simvastatin caused a significant reduction in mean total cholesterol (32%), LDL-cholesterol (38%) and apoB (26%) concentrations. No consistent effect was observed on serum Lp(a) concentrations and both the mean and median remained unchanged after 12 weeks treatment. These results confirm that Lp(a) levels are not altered by increasing the LDL-receptor activity.

Relationship between apolipoprotein(a) phenotype, lipoprotein(a) concentration in plasma, and low density lipoprotein receptor function in a large kindred with familial hypercholesterolemia due to the pro664----leu mutation in the LDL receptor gene.

“…In one family, an FH heterozygote and his FH homozygote daughter, each with apo(a) phenotype 51/48, there appeared to be a possible gene dosage relationship between the defective LDL receptor allele and plasma Lp(a) concentration. However, an unaf- (26), and secondly, early studies on the turnover of Lp(a) in human subjects have suggested that Lp(a) concentration in plasma correlates strongly with its production rate but not with its fractional catabolic rate (27). In a recent study, we also observed no difference in the fractional catabolic rate for Lp(a) between a group ofnormal and FH heterozygotes with matched apo(a) phenotype (28).…”

Lipoprotein (a). Heterogeneity and biological relevance.

“…Drugs like bile acid sequestrants, niacin, or fibrates when used alone have been attended by mixed results (75). The same applies for HMGCoA reductase inhibitors (39,40). In fact, in a recent study, lovastatin (41) has been reported to raise Lp(a) in -30% ofthe cases, suggesting that this HMGCoA reductase inhibitor might increase the hepatic synthesis of Lp(a).…”

“…This, however, has not proven to be the case. For instance, 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors have been shown either to have no significant effect (39,40) or in one case, to raise plasma Lp(a) levels (41).…”

“…This, however, has not proven to be the case. For instance, 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors have been shown either to have no significant effect (39,40) or in one case, to raise plasma Lp(a) levels (41).We have also recently shown that members of a rhesus monkey pedigree with a genetically based familial hypercholesterolemia exhibit no correlation between LDL receptor function and plasma Lp(a) levels (42, 43). Thus, there are uncertainties regarding the genetics ofLp(a) and the role that the apo(a) gene plays in determining apo(a) size polymorphism and plasma Lp(a) levels.…”

Lipoprotein (a) – An Overview

“…These drugs have proven to be extremely effective in lowering plasma LDL and apo-B levels presumably through inhibition of intracellular cholesterol synthesis concomitant with an increase of the LDL receptors in the liver [97]. Although Lp(a) and LDL are very similar especially concerning the content of cholesterol, inhibitors of HMG-CoA-reductase, the regulating enzyme of cholesterol biosynthesis, show no influence [98,99], only modest reduction of about 10% [100,101] or even an increase of serum Lp(a) levels [102]. Altogether the limited magnitude of decrease of Lp(a) by HMG-CoA-reductase inhibitors confirms the assumption that the LDL-receptor does not seem to play a major role in Lp(a) clearance from plasma [103].…”