Elsevier

Atherosclerosis

Volume 131, Issue 1, May 1997, Pages 17-23
Atherosclerosis

Review article
A brief review paper of the efficacy and safety of atorvastatin in early clinical trials

https://doi.org/10.1016/S0021-9150(97)06066-8Get rights and content

Abstract

Preclinical and clinical data on atorvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, indicate that it has superior activity in treating a variety of dyslipidemic disorders characterized by elevations in low-density lipoprotein cholesterol (LDL-C) and/or triglycerides. Results for patients randomized in early efficacy and safety studies were combined in one database and analyzed. This analysis included a total of 231 atorvastatin-treated patients (131 with hypercholesterolemia (HC), 63 with combined hyperlipidemia (CH), 36 with hypertriglyceridemia (HTG), and 1 with hyperchylomicronemia (Fredrickson Type V)). Patients were treated with a cholesterol-lowering diet (National Institutes of Health National Cholesterol Education Program Step 1 diet or a more rigorous diet) and either 2.5, 5, 10, 20, 40, or 80 mg/day of atorvastatin or placebo. Efficacy was based on percent change from baseline in total cholesterol, total triglycerides, LDL-C, very low-density lipoprotein cholesterol (VLDL-C), high-density lipoprotein cholesterol (HDL-C), apolipoprotein B (apo B), and non-HDL-C/HDL-C. Safety was assessed in all randomized patients. Atorvastatin seemed to preferentially lower those lipid and lipoprotein component(s) most elevated within each dyslipidemic state: LDL-C in patients with HC, triglycerides and VLDL-C in patients with HTG, or all 3 in patients with CH. Atorvastatin was well-tolerated with a safety profile similar to other drugs in its class.

Introduction

While there is no cure for atherosclerosis, it is well recognized that lipids and the family of lipoproteins play a significant role in the formation and progression of atherosclerotic disease. The National Cholesterol Education Program (NCEP) and the European Atherosclerosis Society guidelines continue to stress the importance of adequate lipid control in the treatment of coronary heart disease (CHD) 1, 2. The results of several studies conducted world-wide since 1984, 3, 4, 5, 6, 7, 8, 9, 10have led to target levels of low-density lipoprotein cholesterol (LDL-C) for cholesterol reduction. In addition, although specific target levels are not identified, triglycerides are often cited as a marker for increased risk of CHD 11, 12. There is accumulating evidence that disorders characterized by high levels of small, cholesterol enriched very-low-density lipoprotein (VLDL), triglyceride-rich LDL, and/or hypoalphalipoproteinemia, including familial dysbetalipoproteinemia [13]and familial combined hyperlipidemia 14, 15are associated with an increased risk for CHD, as are many of the diseases associated with hypertriglyceridemia, such as diabetes mellitus and chronic renal disease.

Currently, a variety of therapies are available for the diverse dyslipidemic population. Present standards recommend a change in lifestyle—weight reduction, increased physical activity, abstinence from smoking, and diet (reduced alcohol consumption and restriction in saturated fat)—as the first line of therapy for reducing elevated LDL-C or triglycerides. Thereafter, guidelines recommend drug therapy when risk-benefit assessment is favorable 1, 2. For dyslipidemic states characterized by hypercholesterolemia, bile acid sequestering resins (resins) and inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (reductase inhibitors) are the first choice of therapy [1]. Fibric acid derivatives and nicotinic acid are recommended for patients with hypertriglyceridemia [1]. When single-agent therapy is insufficient in severe hypercholesterolemia or combined hyperlipidemia, 2 or more drugs are often recommended but rarely used due to concerns with cost, tolerability, lack of efficacy, or uncertainty of the benefits of therapy.

Currently available drugs target either hypercholesterolemia or triglyceridemia, with no single compound adequately able to treat both abnormalities and sometimes not even able to treat a single abnormality. In a population of patients with primary hypercholesterolemia (HC) and combined hyperlipidemia (CH) atorvastatin, at a dose of 80 mg/day, reduced LDL-C more than any other reductase inhibitor, and reduced LDL-C and triglycerides to a greater extent in a comparative study of pravastatin and simvastatin 16, 17. Atorvastatin also significantly reduced triglycerides and LDL-C in a population characterized by hypertriglyceridemia (CH or hypertriglyceridemia (HTG)). [18]Although these effects indicate that atorvastatin is an effective treatment for various forms of dyslipidemia, each study was small. Therefore, a pooled analysis of atorvastatin was performed on the results of 6 early efficacy and safety studies to determine the effect of this new reductase inhibitor in a variety of dyslipidemic patients.

Section snippets

Patients and contributing studies

Results for patients from 6 early efficacy and safety studies were combined and analyzed (Table 1). The studies were conducted world-wide: 3 in North America, 1 in South Africa, 1 in Australia, and 1 in Europe. Patients were recruited at 33 study centers (22 in the USA, 3 in Canada, 2 in Australia, 4 in Germany, 1 in the Netherlands, and 1 in South Africa). An appropriate institutional review board approved the study at each center.

Patient inclusion criteria varied according to the population

Patient characteristics

A total of 377 patients completed 6 early efficacy and safety studies. 5 Patients withdrew prior to the collection of lipid values. There were 232 (62%) men and 145 (38%) women in the studies. The median age was 55 years with a range 19–79 years. The patient population was 91 white, 2 black, 2 asian, and 5% other. The mean BMI was 26±3. Of the 231 patients who received atorvastatin, 131 had HC including 22 patients with heterozygous familial hypercholesterolemia, 63 had CH, 36 had HTG, and 1

Discussion

Based upon the data presented, atorvastatin seems unique in its ability to preferentially lower those components most elevated within each dyslipidemic category: LDL-C (HC), triglycerides and VLDL-C (HTG), or all 3 (CH). Fig. 1 summarizes the effect of atorvastatin on LDL-C and triglycerides as a function of the baseline ratio of these parameters. Patients with higher baseline triglycerides relative to LDL-C have a greater change in triglycerides relative to their change in LDL-C; likewise,

Acknowledgements

The Authors gratefully acknowledge the other investigators that participated in these 6 Phase II studies: Virgil Brown, MD; Frances Broyles, MD; Michael Davidson, MD; Jean Davignon, MD; Robert Goldstein, MD; Jonathan Issacsohn, MD; Peter Jones, MD; Leonard Keilson, MD; Paul Lupien, MD; Gerhard Mahla, MD; James McKenney, PharmD; Valery Miller, MD; D. Muller, MD; Geoffrey Nicholson, MBBS; H. Pentrup, MD; Helmut Schrott, MD; Erich Schutz, MD; Sherwyn Schwartz, MD; Allan Sniderman, MD; Dennis

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