Effects of atorvastatin on serum lipids of patients with familial hypercholesterolaemia

Authors


MD Nicoline Hoogerbrugge Dr University Hospital Dijkzigt Dr Molewaterplein 40, 3015 GD Rotterdam, the Netherlands (fax: +31 10 4633268; e-mail: hoogerbrugge@inw3.azr nl).

Abstract

Hoogerbrugge N (University Hospital Dijkzigt, Rotterdam, the Netherlands). Effects of atorvastatin on serum lipids of patients with familial hypercholesterolaemia. J Intern Med 1998; 244: 143–7.

Objectives

The effects of atorvastatin, a new synthetic HMG-CoA reductase inhibitor, were investigated in patients with familial hypercholesterolaemia (FH), with high LDLc levels whilst on standard treatment.

Design

Open treatment with 40 mg atorvastatin daily for 6 weeks, followed by another 6 weeks with 80 mg atorvastatin.

Setting

Outpatient lipid clinic of a tertiary referral centre.

Subjects

FH was diagnosed when the untreated LDLc concentration was higher than 6 mmol L−1, tendon xanthomas were present at the participant or a first degree relative, and the family history for hypercholesterolaemia was positive. The FH patients were selected for an LDLc above 5.0 mmol L−1 whilst on standard therapy for at least 3 months. Standard therapy consisted of a diet and 40 mg simvastatin, either alone (n= 17), or in combination with 8–12 g colestyramin (n= 12), or 1800 mg nicotinic acid (n= 12).

Main outcome measure

Effects on LDLc concentration.

Results

LDLc concentration significantly decreased during treatment with 80 mg atorvastatin as compared to LDLc levels on 40 mg simvastatin alone or in combination with 8–12 g colestyramin, by 24 ± 14% (P < 0.01) and 19 ± 22% (P < 0.01), respectively. LDLc concentration was comparable during treatment with 80 mg atorvastatin or 40 mg simvastatin in combination with 1800 mg nicotinic acid. Atorvastatin was tolerated well, no side-effects were observed.

Conclusions

Atorvastatin is a valuable addition to the treatment possibilities of patients with serious hypercholesterolaemia, like FH.

Introduction

A high serum cholesterol concentration is a major risk factor for coronary heart disease [ 1]. Treatment with 3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins like simvastatin, pravastatin lowers cholesterol concentration and has established beneficial effects on coronary heart disease (CHD) [ [2][3][4]2–5]. As a group statins are potent, highly specific and reversible competitive inhibitors of HMG CoA reductase. The inhibition of endogenous cholesterol synthesis in the liver increases the expression of low-density lipoprotein (LDL) receptors on hepatocytes; this results in increased clearance of LDL particles from serum and a fall in LDL cholesterol concentrations. Statins may reduce the serum LDLc concentration to a maximum of ≈40% [ [4][5]4–6]. Additionally they increase high-density lipoprotein cholesterol (HDLc) concentration by 5–10% and decrease serum triglyceride (TG) concentration by 10–20% [ [4][5]4–6]. Worldwide millions of hypercholesterolaemic patients have been treated successfully with these drugs over the past 10 years.

Familial hypercholesterolaemia (FH) is an autosomal dominant hereditary disease typically characterized by high levels of serum LDLc, tendon xanthomas in a large proportion of affected subjects, and the occurrence of premature coronary artery disease by the third or fourth decade. One of a number of defects in the LDL receptor gene is responsible for reduced, absent, or abnormal cell surface LDL receptors and results in a lowered clearance of LDL particles from plasma. In FH patients total serum cholesterol often ranges between 8 and 12 mmol L−1, with an LDLc concentration of 6–10 mmol L−1 [ 7, 8]. For a number of FH patients a decrease in the LDLc concentration of 40%, will not be enough to decrease the LDLc level to a goal level, which varies between 3 and 4.5 mmol L−1 [ 9]. Additional therapies, in which an HMG-CoA reductase inhibitor is combined with colestyramin or nicotinic acid are often necessary to induce a further decrease in the LDLc level. These additional drugs are effective, but are known for side-effects [ 10].

Recently atorvastatin, a synthetic HMG-CoA reductase inhibitor, has been introduced. In controlled studies with various groups of hyperlipidaemic patients, this drug was shown to reduce LDLc by up to 60% [ 11, 12]. The effective ability of atorvastatin to lower LDLc probably reflects its greater uptake and longer duration of action in the liver [ 13].

The present study compares the efficacy of atorvastatin 40 and 80 mg with simvastatin 40 mg with and without the addition of either colestyramin or nicotinic acid.

Patients and methods

Study population

The study included males (n= 26) and females (n= 15) with heterozygous familial hypercholesterolaemia (FH) and an LDLc above 5.0 mmol L−1 despite standard therapy for at least 3 months. Standard therapy consisted of a cholesterol-lowering diet and 40 mg simvastatin, either alone (n= 17), or in combination with 8–12 g colestyramin (n= 12), or 1800 mg nicotinic acid (n= 12). FH was diagnosed when there was: (i) untreated LDLc higher than 6 mmol L−1, in combination with (ii) tendon xanthomas at the participant or a first degree relative, as well as (iii) a positive family history for hypercholesterolaemia. In 20 patients fasting blood samples were taken, 3 months before they were given atorvastatin, during dietary treatment, using no lipid-lowering medication for at least 6 weeks. Patients were treated for 6 weeks with 40 mg atorvastatin once daily, followed by another 6 weeks' treatment period with 80 mg atorvastatin once a day. Simvastatin, colestyramin and nicotinic acid were stopped when atorvastatin was started. Fasting blood samples were drawn after 12 h of fasting on standard treatment and after 6 and 12 weeks of treatment. The study was performed according to the rules of the hospital medical ethics committee.

Analytical methods

Cholesterol, HDL-cholesterol and TG were measured using a Hitachi 911 automatic analyser (Boehringer Mannheim BV, Almere, the Netherlands). LDLc was calculated using the Friedewald formula [ 14]. Apolipoprotein B was estimated by an immunoturbidimetric method using the Beckman Array immunochemistry system (Beckman Instruments, Mijdrecht, the Netherlands BV).

@OA.09.C.Head:Statistical analysis All data are presented as mean ± SD. Statistical analysis was done with the Wilcoxon test for paired analysis.

Results

Effects of atorvastatin compared to simvastatin

Treatment with 40 mg atorvastatin induced a 14 ± 11% (P < 0.001) decrease in the total serum cholesterol concentration, as compared to the level during treatment with 40 mg simvastatin. This was due to a 17 ± 13% (P < 0.001) decrease in LDLc concentration ( Table 1). Increasing the atorvastatin from 40 to 80 mg daily resulted in an additional decrease of serum cholesterol, LDLc, and Apo B concentration by 8 ± 10% (P < 0.01), 9 ± 13% (P < 0.01) and 12 ± 11% (P < 0.01), respectively ( Table 1). Compared to treatment levels on 40 mg simvastatin, 80 mg atorvastatin did not change TG and HDLc levels ( Table 1).

Table 1.  Effects of 40 and 80 mg atorvastatin on serum lipid concentrations as compared to the concentrations during treatment with 40 mg simvastatin in 17 patients with familial hypercholesterolaemia whose low-density lipoprotein concentration (LDLc) on simvastatin was higher than 5.0 mmol L−1Thumbnail image of

Effects of atorvastatin compared to simvastatin in combination with nicotinic acid

Treatment with 40 mg atorvastatin did not affect cholesterol and LDLc levels, as compared to these concentrations during treatment with 40 mg simvastatin in combination with 1800 mg nicotinic acid ( Table 2). Treatment with 80 mg atorvastatin resulted in a decrease in cholesterol concentration of 11 ± 17% (P < 0.04), as compared to the level during treatment with simvastatin and nicotinic acid ( Table 2). In comparison to the combined treatment with simvastatin and nicotinic acid, no difference was observed in LDLc, Apo B or TG levels on treatment with 40 or 80 mg atorvastatin. During treatment with 40 and 80 mg atorvastatin HDLc concentration was decreased by 10 ± 11% (P < 0.05) and 15 ± 11% (P < 0.01) as compared to the HDLc concentration on treatment with simvastatin and nicotinic acid.

Table 2.  Effects of 40 and 80 mg atorvastatin on serum lipid concentrations as compared to the concentrations during treatment with 40 mg simvastatin and 1800 mg nicotinic acid (simva + NZ) in 12 patients with familial hypercholesterolaemia whose low-density lipoprotein concentration (LDLc) was above 5.0 mmol L−1 during this combination treatment Thumbnail image of

Effects of atorvastatin compared to simvastatin in combination with colestyramin

The cholesterol, LDLc and Apo B concentrations was comparable during treatment with 40 mg atorvastatin or 40 mg simvastatin plus colestyramin ( Table 3). Atorvastatin 80 mg resulted in a decrease of cholesterol and LDLc concentration, compared to their levels during treatment with simvastatin plus colestyramin, with 17 ± 15% (P < 0.01) and 19 ± 22% (P < 0,01), respectively ( Table 3). Treatment with 80 mg atorvastatin did not change TG and HDLc concentration as compared to their levels during treatment with simvastatin and colestyramin.

Table 3.  Effects of 40 and 80 mg atorvastatin on serum lipid concentrations as compared to the concentrations during treatment with 40 mg simvastatin and 8–12 g colestyramin (simva + Q) in 12 patients with familial hypercholesterolaemia whose low-density lipoprotein concentration (LDLc) was higher than 5.0 mmol L−1 during this combination treatment Thumbnail image of

Efficacy of atorvastatin

Treatment with 40 mg and 80 mg atorvastatin decreased total cholesterol concentration as compared to pretreatment levels by 34 ± 9% (P < 0.001) and 41 ± 7% (P < 0.01), respectively. This was due to a decrease in the LDLc concentration of 37 ± 8% (P < 0.01) and 45 ± 9% (P < 0.01), respectively. Atorvastatin 80 mg decreased LDLc significantly more than 40 mg (P < 0.01) ( Table 4). Atorvastatin did not affect the HDLc concentration ( Table 4). TG concentration decreased during treatment with 40 and 80 mg atorvastatin by 41 ± 17% (P < 0.01) and 44 ± 20% (P < 0.01) ( Table 4).

Table 4.  Effects of 40 and 80 mg atorvastatin on serum lipid concentrations in 20 patients with familial hypercholesterolaemia whose low-density lipoprotein concentration (LDLc) did not reach below 5.0 mmol L−1 during standard cholesterol lowering therapy Thumbnail image of

Side-effects

On treatment with 40 and 80 mg atorvastatin no changes in transaminases (ALAT, ASAT) or creatine phosphokinase (CPK) were measured. No objective or subjective side-effects occurred.

Discussion

This study was aimed at assessing the effectiveness of action of atorvastatin in FH patients chosen because of their refractory hypercholesterolaemia. Despite this circumstance the administration of 80 mg atorvastatin effectively decreased LDLc by 45%. On treatment with 80 mg atorvastatin, 13 out of 41 patients reached an LDLc concentration below 4.0 mmol L−1. LDLc concentration was significantly lower on treatment with 80 mg than on 40 mg atorvastatin. At this moment the maximal recommended doses for simvastatin is 40 mg. Therefore we did not use a higher dose of simvastatin, but cannot exclude that 80 mg of simvastatin might have been more effective than the 40 mg that was used. Previously others have shown that the maximal effect of atorvastatin on LDLc levels is obtained within 2 weeks [ 15]. It is assumed that the higher efficacy of 80 mg over 40 mg atorvastatin cannot be attributed to the fact that 80 mg was given after a previous 6 weeks' treatment with 40 mg of this drug.

Atorvastatin in a dose of 80 mg per day was as effective as standard treatment with 40 mg simvastatin in combination with 1800 mg nicotinic acid. However, atorvastatin was better tolerated, because of the frequent side-effects of nicotinic acid. Atorvastatin did not lead to any complaint or side-effect during the observation period of 12 weeks. During treatment with simvastatin plus nicotinic acid, higher HDLc levels were observed than with atorvastatin. Especially in FH patients with a low HDLc concentration, an increase in the HDLc level can add to risk reduction of coronary heart disease [ 16].

In addition to an LDLc decreasing effect, atorvastatin substantially decreases TG [ 15, 17]. This effect on TG concentration cannot adequately be studied in FH patients, with a primary defect LDLc and not in TG metabolism. However, a drug with a substantial effect on both LDLc and TG concentration deserves our full attention. Atorvastatin is under investigation worldwide. At this time it seems to be a valuable addition to treatment options of patients with serious hypercholesterolaemia, like FH.

Ancillary