Use of 3-Hydroxy-31Methylglutaryl Coenzyme A Reductase Inhibitors Various Forms of Dyslipidemia
in
Scott M. Grundy, MD, PhD, Gloria Lena Vega, PhD, and Abhimanyu Garg, MD
The inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase are highly effective in treating severe elevations of serum cholesterol, and are being widely used for this purpose. In our laboratory, these drugs have been used for the treatment of other forms of dyslipidemia including primary moderate hypercholesterolemia, primary mixed hyperlipidemia, diabetic dyslipidemia, hyperlipidemia of the nephrotic syndrome, and primary hypoalphalipoproteinemia. In these conditions, the HMG CoA reductase inhibitors proved effective in substantially decreasing levels of both low-density lipoproteins and very low density lipoproteins, as well as apolipoprotein B. In some patients, they may even increase levels of high-density lipoproteins. The primary mode of action of HMG CoA reductase inhibitors appears to be to increase the synthesis of hepatic receptors for lipoproteins containing apolipoprotein B, although a reduction in synthesis of these lipoproteins has not been ruled out with certainty. Regardless of mechanisms, drugs of this type appear to have the potential for effective therapy of various forms of dyslipidemia beyond primary severe hypercholesterolemia. (Am J Cardiol 1990;66:3 1 B-38s)
-From the Center for Human Nutrition, Departments of Internal Medicine, Biochemistry, and Clinical Nutrition, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. Address for reprints: Scott M. Grundy, MD, PhD, Center for Human Nutrition, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 752359052.
he inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase are a new class of drugs that are highly effective for the treatment of hypercholesterolemia. The first drug of this class to be released in the United States was lovastatin. Recently, an analog, simvastatin, has been approved for use in several European countries. Because of their high efficacy, use of these drugs has increased rapidly, and already more than a million people are taking lovastatin in the United States alone. Although the HMG CoA reductase inhibitors have been recommended primarily for treatment of severe hypercholesterolemia, in clinical practice they undoubtedly are being used in patients with various other forms of dyslipidemia. Even so, their potential value for treatment of different forms of dyslipidemia, other than severe hypercholesterolemia, has not been investigated systematically in large numbers of well-defined patients. For this reason, we have performed a series of studies in patients with various types of dyslipidemia to explore the range of potential value of HMG CoA reductase inhibitors. None of our findings can be called definitive, but they do provide insights into possible utility of these drugs. In most of our studies, lovastatin was the drug investigated, but our findings almost certainly can be extended to other HMG CoA reductase inhibitors as well. Investigations in our laboratory also have been directed toward learning the mechanisms whereby HMG CoA reductase inhibitors produce a reduction in plasma cholesterol levels. Studies in tissue culture and laboratory animals strongly suggest that the primary action of these agents is to increase the synthesis of low-density lipoprotein (LDL) receptors.’ This response results from their action to inhibit cholesterol synthesis. Our isotope-kinetic investigations support this general mechanism. Our data, however, do not rule out the possibility that a lesser action of HMG CoA reductase inhibitors is to partially inhibit the synthesis of lipoproteins by the liver. Both mechanisms are consistent with the observation that reductase inhibitors lower serum concentrations of both LDL and very low density lipoproteins (VLDL). It must be recalled that VLDL particles, which contain apolipoprotein (apo) E as well as apo B, actually have a greater affinity for LDL receptors than LDL itself, which has only apo B. The action of HMG CoA reductase inhibitors to reduce VLDL levels, as well as LDL, may expand their potential use. Finally, there are reports that these agents will increase high-density lipoprotein (HDL) cholesterol concentrations in some patients. In the discussion to follow,
THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 18, 1990
A SYMPOSIUM:
HMG CoA REDUCTASE
INHIBITORS
TABLE I Plasma Lipid and Lipoprotein Levels in Eight Patients with Heterozygous Familial Hypercholesterolemia
Total cholesterol Triglycerides LDL cholesterol HDL cholesterol
Control (w/d)
Lovastatin + Colestipol (w/d0
367 f 31 142 f 19 321 f 32 27zk3
208 f 18” 14Of24 154 f 19” 35*5+
* p
in
Scott M. Grundy, MD, PhD, Gloria Lena Vega, PhD, and Abhimanyu Garg, MD
The inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase are highly effective in treating severe elevations of serum cholesterol, and are being widely used for this purpose. In our laboratory, these drugs have been used for the treatment of other forms of dyslipidemia including primary moderate hypercholesterolemia, primary mixed hyperlipidemia, diabetic dyslipidemia, hyperlipidemia of the nephrotic syndrome, and primary hypoalphalipoproteinemia. In these conditions, the HMG CoA reductase inhibitors proved effective in substantially decreasing levels of both low-density lipoproteins and very low density lipoproteins, as well as apolipoprotein B. In some patients, they may even increase levels of high-density lipoproteins. The primary mode of action of HMG CoA reductase inhibitors appears to be to increase the synthesis of hepatic receptors for lipoproteins containing apolipoprotein B, although a reduction in synthesis of these lipoproteins has not been ruled out with certainty. Regardless of mechanisms, drugs of this type appear to have the potential for effective therapy of various forms of dyslipidemia beyond primary severe hypercholesterolemia. (Am J Cardiol 1990;66:3 1 B-38s)
-From the Center for Human Nutrition, Departments of Internal Medicine, Biochemistry, and Clinical Nutrition, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas. Address for reprints: Scott M. Grundy, MD, PhD, Center for Human Nutrition, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 752359052.
he inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase are a new class of drugs that are highly effective for the treatment of hypercholesterolemia. The first drug of this class to be released in the United States was lovastatin. Recently, an analog, simvastatin, has been approved for use in several European countries. Because of their high efficacy, use of these drugs has increased rapidly, and already more than a million people are taking lovastatin in the United States alone. Although the HMG CoA reductase inhibitors have been recommended primarily for treatment of severe hypercholesterolemia, in clinical practice they undoubtedly are being used in patients with various other forms of dyslipidemia. Even so, their potential value for treatment of different forms of dyslipidemia, other than severe hypercholesterolemia, has not been investigated systematically in large numbers of well-defined patients. For this reason, we have performed a series of studies in patients with various types of dyslipidemia to explore the range of potential value of HMG CoA reductase inhibitors. None of our findings can be called definitive, but they do provide insights into possible utility of these drugs. In most of our studies, lovastatin was the drug investigated, but our findings almost certainly can be extended to other HMG CoA reductase inhibitors as well. Investigations in our laboratory also have been directed toward learning the mechanisms whereby HMG CoA reductase inhibitors produce a reduction in plasma cholesterol levels. Studies in tissue culture and laboratory animals strongly suggest that the primary action of these agents is to increase the synthesis of low-density lipoprotein (LDL) receptors.’ This response results from their action to inhibit cholesterol synthesis. Our isotope-kinetic investigations support this general mechanism. Our data, however, do not rule out the possibility that a lesser action of HMG CoA reductase inhibitors is to partially inhibit the synthesis of lipoproteins by the liver. Both mechanisms are consistent with the observation that reductase inhibitors lower serum concentrations of both LDL and very low density lipoproteins (VLDL). It must be recalled that VLDL particles, which contain apolipoprotein (apo) E as well as apo B, actually have a greater affinity for LDL receptors than LDL itself, which has only apo B. The action of HMG CoA reductase inhibitors to reduce VLDL levels, as well as LDL, may expand their potential use. Finally, there are reports that these agents will increase high-density lipoprotein (HDL) cholesterol concentrations in some patients. In the discussion to follow,
THE AMERICAN JOURNAL OF CARDIOLOGY SEPTEMBER 18, 1990
A SYMPOSIUM:
HMG CoA REDUCTASE
INHIBITORS
TABLE I Plasma Lipid and Lipoprotein Levels in Eight Patients with Heterozygous Familial Hypercholesterolemia
Total cholesterol Triglycerides LDL cholesterol HDL cholesterol
Control (w/d)
Lovastatin + Colestipol (w/d0
367 f 31 142 f 19 321 f 32 27zk3
208 f 18” 14Of24 154 f 19” 35*5+
* p
