Effect of a new HMG-CoA reductase inhibitor, atorvastatin, on lipids, apolipoproteins and lipoprotein particles in patients with elevated serum cholesterol and triglyceride levels

doi:10.1016/S0021-9150(97)00119-6

Atherosclerosis

Volume 133, Issue 1, August 1997, Pages 123-133

https://doi.org/10.1016/S0021-9150(97)00119-6 Get rights and content

Abstract

The effects of atorvastatin (lipitor) on cholesterol-rich and triglyceride-rich lipoproteins were evaluated in this multicenter trial. Following a 6-week baseline period, 47 patients with elevated cholesterol and triglyceride levels were treated with atorvastatin 10 mg once daily (QD) for the initial 12 weeks (Period 1) increasing to 20 mg QD for the following 12 weeks (Period 2). At both the 10 and 20 mg doses, atorvastatin treatment resulted in significant reductions compared to pretreatment levels in low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), very low-density lipoprotein cholesterol (VLDL-C), apolipoprotein (apo) B, apoB in LDL (LDL-apo B), apo B in VLDL (VLDL-apo B), lipoprotein (Lp)B, lipoprotein B-complex (LpB_c), triglycerides (TG), low-density lipoprotein triglycerides (LDL-TG), very low-density lipoprotein triglyceride (VLDL-TG), high-density lipoprotein triglycerides (HDL-TG), and apo C-III. Atorvastatin 10 and 20 mg QD also resulted in significant increases in high-density lipoprotein cholesterol (HDL-C), apo AI, and LpAII:B:C:D:E. Due to its unique ability to normalize both cholesterol-rich and triglyceride-rich particles, atorvastatin is a promising candidate for monotherapy in a broad range of patients including those with varying degrees of hypercholesterolemia and hypertriglyceridemia.

Introduction

Hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors are most often prescribed for lowering plasma cholesterol levels in those patients with primary hypercholesterolemia. These agents, including lovastatin, pravastatin, simvastatin and fluvastatin very effectively treat patients with primary hypercholesterolemia, but have a limited ability to decrease triglyceride (TG) levels 1, 2, 3. For the patient presenting with concomitant elevations in total cholesterol (TC) and TG levels, treatment options are limited. The co-administration of an HMG-CoA reductase inhibitor with an agent such as nicotinic acid or a fibric acid derivative can often reduce both cholesterol and triglycerides in this population; however, this combination therapy results in higher cost to the patient, more difficulties with compliance, and an increased risk of myositis and renal failure [4].

It has recently been shown that atorvastatin (lipitor), a newly developed HMG-CoA reductase inhibitor, reduces total plasma cholesterol up to 45% and LDL-cholesterol up to 60% in a dose dependent manner when administered to patients with primary hypercholesterolemia [5]. Additionally, the triglyceride lowering property of atorvastatin has been demonstrated in patients with primary hypercholesterolemia 5, 6, 7, 8and in those with primary hypertriglyceridemia [9]. Because of these differential effects of HMG-CoA reductase inhibitors on the concentrations of cholesterol-rich and triglyceride-rich lipoproteins and because of the already documented substantial triglyceride-lowering effect of atorvastatin, it was of considerable interest and importance to further evaluate atorvastatin's effect on cholesterol-rich and triglyceride-rich lipoprotein particles in a dyslipidemic population that would benefit from this dual effect.

Section snippets

Patients

Seven centers in Canada participated in this open-label trial. Eligible patients were aged 18–80 years old with a body mass index ≤32 kg/m² (Table 1). Patients were ineligible if they were pregnant or nursing, had active liver disease or hepatic dysfunction; nephrotic syndrome or renal insufficiency; uncontrolled hypertension, hypothyroidism or diabetes; were consuming more than 10 alcoholic drinks per week, or had a history of drug abuse. Additionally, patients were screened for Type III

Patient characteristics and disposition

A total of 47 patients (33 men, 14 women) were treated with atorvastatin. Forty-six patients had data for Period 1 and 45 had data for Period 2. Ninety-four percent of the patients were white and the mean patient age was 50 years. Based on investigator assessments (pill count), atorvastatin compliance ranged from 93–100%. According to their baseline lipid levels, patients were categorized as having combined hyperlipidemia (CHL) (LDL≥3.5 mmol/l (134 mg/dl) and TG≥2.3 mmol/l (200 mg/dl)) or

Discussion

Results of this study demonstrate that atorvastatin has the capacity to lower significantly the plasma concentrations of the characteristic cholesterol-rich and triglyceride-rich lipoprotein constituents in patients with elevated levels of both cholesterol and triglycerides. It has been previously reported that in CHL patients, 10 or 20 mg atorvastatin resulted in significantly greater reductions in LDL-C, apo B, TC, LDL-apo B and LpB compared to 300 mg fenofibrate treatment [22]. The degree of

Acknowledgements

This study was supported by Parke-Davis Pharmaceutical Research, Division of Warner Lambert Co, Ann Arbor, Mich. The authors would like to thank R.E. Laskey, PhD, for assistance in manuscript preparation, and C. Knight-Gibson, J.D. Fesmire, C. Quiroga and S. Bryant for their technical assistance.

References (37)

A Endo
The discovery and development of HMG-CoA reductase inhibitors
J Lipid Res
(1992)
M.J Tikkanen et al.
Comparison of low-dose simvastatin and gemfibrozil in the treatment of elevated plasma cholesterol—a multicenter study
Am J Med
(1989)
T.M Heinonen et al.
The lipid-lowering effect of atorvastatin, a new HMG-CoA reductase inhibitor: results of a randomized, double-masked study
Clin Therapeut
(1996)
T.G Cole et al.
High-throughput B-quantification methods
Atherosclerosis
(1994)
P Alaupovic
Apolipoprotein composition as the basis for classifying plasma lipoproteins. Characterization of apo A- and apo B-containing lipoprotein families
Prog Lipid Res
(1991)
P Alaupovic et al.
Isolation and characterization of an apoA-II-containing lipoprotein (LPA-II:B complex) from plasma very low density lipoproteins of patients with Tangier disease and Type V hyperlipoproteinemia
J Lipid Res
(1991)
J.M Bard et al.
Effect of pravastatin, and HMG CoA reductase inhibitor, and cholestyramine, a bile acid sequestrant, on lipoprotein particles defined by their apolipoprotein composition
Metabolism
(1990)
J.M Bard et al.
A multicenter comparison of the effects of simvastatin and fenofibrate therapy in severe primary hypercholesterolemia, with particular emphasis on lipoproteins defined by their apolipoprotein composition
Metabolism
(1992)
Y Arad et al.
Effects of lovastatin therapy on very-low-density lipoprotein triglyceride metabolism in subjects with combined hyperlipidemia-evidence for reduced assembly and secretion of triglyceride-rich lipoproteins
Metabolism
(1992)
R.H Bradford et al.
Expanded clinical evaluation of lovastatin (EXCEL) study results. (1) Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia
Arch Intern Med
(1991)

C East et al.

Combination drug therapy for familial combined hyperlipidemia

Ann Intern Med

(1988)

J.W Nawrocki et al.

Reduction of LDL cholesterol by 25 to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor

Arterioscler Thromb Vasc Biol

(1995)

Black D. Atorvastatin: a step ahead for HMG-CoA reductase inhibitors. In: Woodford FP, Davignon J, Sniderman A,...

T.M Heinonen et al.

Atorvastatin, a new HMG-CoA reductase inhibitor as monotherapy and combined with colestipol

J Cardiovasc Pharmacol Therapeut

(1996)

R.G Bakker-Arkema et al.

Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia

JAMA

(1996)

Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Summary of the second report...

P.S Remmel et al.

Assessing dietary adherence in the Multiple Risk Factor Intervention Trial (MRFIT), I: use of a dietary monitoring tool

JAMA

(1980)

W.T Friedewald et al.

Estimation of the concentration of low density lipoprotein cholesterol in plasma without the use of the preparative ultracentrifuge

Clin Chem

(1972)

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Effect of a new HMG-CoA reductase inhibitor, atorvastatin, on lipids, apolipoproteins and lipoprotein particles in patients with elevated serum cholesterol and triglyceride levels

Abstract

Introduction

Section snippets

Patients

Patient characteristics and disposition

Discussion

Acknowledgements

J Lipid Res

Am J Med

Clin Therapeut

Atherosclerosis

Prog Lipid Res

J Lipid Res

Metabolism

Metabolism

Metabolism

Expanded clinical evaluation of lovastatin (EXCEL) study results. (1) Efficacy in modifying plasma lipoproteins and adverse event profile in 8245 patients with moderate hypercholesterolemia

Arch Intern Med

Combination drug therapy for familial combined hyperlipidemia

Ann Intern Med

Reduction of LDL cholesterol by 25 to 60% in patients with primary hypercholesterolemia by atorvastatin, a new HMG-CoA reductase inhibitor

Arterioscler Thromb Vasc Biol

Atorvastatin, a new HMG-CoA reductase inhibitor as monotherapy and combined with colestipol

J Cardiovasc Pharmacol Therapeut

Efficacy and safety of a new HMG-CoA reductase inhibitor, atorvastatin, in patients with hypertriglyceridemia

JAMA

Assessing dietary adherence in the Multiple Risk Factor Intervention Trial (MRFIT), I: use of a dietary monitoring tool

JAMA

Estimation of the concentration of low density lipoprotein cholesterol in plasma without the use of the preparative ultracentrifuge

Clin Chem