Pharmacotherapy of Disorders of Plasma Lipoprotein Metabolism Norman E. Miller, MD, Pharmacologic intervention for altering plasma lipoproteins is aimed principally at reducing atherogenesis and thereby preventing coronary artery disease. These drugs should be prescribed only after nonpharmacologic interventions (reduction of saturated fat and cholesterol consumption, weight reduction, aerobic exercise, cessation of cigarette smoking) have failed to achieve an adequate effect. The plasma concentration of the atherogenic low-density lipoprotein (LDL) may be reduced in hypercholesterolemic patients by increasing hepatic LDL receptor synthesis (bile acid sequestering resins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) or by reducing hepatic very low density lipoprotein synthesis (gemfibrozil, nicotinic acid). LDL concentration may also be reduced by treatment with one of the fibrates (e.g., fenofibrate). Several classes of lipid-lowering drugs also increase the plasma high-density lipoprotein (HDL) cholesterol concentration. In the case of the flbrates, this appears to be principally mediated through an increase in lipoprotein lipase activity. Gemfibrozil additionally stimulates apolipoprotein Al synthesis. The increase in HDL cholesterol produced by nicotinic acid is due primarily to decreased clearance of HDL particles from the circulation. The increase in HDL concentration produced by gemfibrozil was shown in the Helsinki Heart Study to make a major contribution to a reduced incidence of coronary artery disease, independently of that made by the decrease in LDL. The Cholesterol-Lowering Atherosclerosis Study demonstrated that combined therapy with a resin (colestipol) and nicotinic acid can reduce the progression of coronary atherosclerosis and the development of graft lesions in patients who have undergone coronary artery bypass graft surgery. (Am J Cardiol 1990;66:16A-19A)
From the Department of Medicine, Section of Endocrinology and Metabolism, The Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina. Address for reprints: Norman E. Miller, MD, DSc, Department of Medicine, Section of Endocrinology and Metabolism, The Bowman Gray School of Medicine, Wake Forest University, 300 South Hawthorne Road, Winston-Salem, North Carolina 27104.
16A
THE AMERICAN JOURNAL OF CARDIOLOGY
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DSC
I
n discussing the pharmacotherapy of disordered lipoprotein metabolism, it is convenient to consider 2 principal modesof action of theseagents.One mode is their effectson thoselipoproteins whoseprincipal function is to transport cholesterol,triglycerides, or both, from the splanchnic region (i.e., the liver and intestine) to peripheral tissues.Theselipoproteins contain apolipoprotein (apo) B-apo B48 in the caseof chylomicrons and apo BlOO in the caseof the very low density, intermediate-density and low-density lipoproteins (VLDL, IDL and LDL, respectively). Most researchinto lipid-lowering drugs has centered on apo B loo-containing lipoproteins. The other mode of action of these drugs is their effectson high-density lipoproteins (HDL), which play a central role in the movementof cholesterolfrom peripheral tissues back to the liver-a processusually referred to as reverse cholesterol transport. EFFECTS OF DRUGS ON APOLIPOPROTEIN B-CONTAINING LIPOPROTEINS What do we know about the metabolism of these particles and how they influence atherogenesis?The triglyceride-rich VLDLs are synthesized and secretedby the liver and are then converted to IDL in peripheral tissuesthrough the action of endothelium-bound lipoprotein lipase (Fig. 1). The IDL particles can then undergo 1 of 2 fates: (1) They can be taken up and catabolized by the liver through apo B 100,Ereceptors,or (2) they can be converted to the cholesteryl ester-rich LDL, which is then also removed from the circulation, again primarily by hepatic apo B 100,Ereceptors.A proportion of LDL is also catabolized through apo BlOO,Ereceptorsin peripheral tissues. There is increasing evidence that the LDL particle itself may not be directly atherogenic.Rather, it must be converted to modified forms that exhibit atherogenicactivity.’ Much attention has been directed toward this process,particularly the oxidation of the polyunsaturated fatty acids in LDL. This leadsto secondarychangesin the apo BlOO of the particles, which render them recognizable by so-called scavenger receptors present in arterial macrophages.This is probably the major route by which LDL enters the macrophagesin developing atherosclerotic lesions.Other forms of modified LDL have also been described (e.g., glycated forms), which may also contribute in an important way to atherogenesis. The principal goal of lipid-lowering treatment has beento prevent coronary artery disease(CAD) by reducing the plasma concentration of LDL. Basically, there are 4 ways in which lipid-lowering agentsexert their effects on the apo BlOO-containing lipoproteins: (1) stimulation of LDL clearance by increasedsynthesisof apo B100,E
FIGURE 1. Metabolism of apolipoprotein BlO+containing lipoproteins and sites of phannacolo$ie intervention. The numbers 1 zL4 indicate the following: (1) inhibition secreth (nicothdc acid, gemfibro61); (2) stimulation of apo BlOD,E receptor stabm in liver (resins, HMG-CoA reductase inhibitors); (3) inhibition of LDL modification (probuol); (4) stimulation of lipoprotein lipase (gemffbrozil, fibrates). IDL = intermediitedensity lipoprotein; LDL = low-density lipoprotein; VLDL = very low density lipoprotein. (Reprinted with permission from Adis Ress Ltd, Auckland, New Zealand.)
Ape B,E Peripheral cells
Modified
forms
Macrophages in Atherosclerotic lesions
(e.g., oxidized]
receptors in the liver (e.g., bile acid-binding resins [cholestyramine, colestipol], 3-hydroxy-3-methyl-glutaryl coenzyme A [HMG-CoA] reductase inhibitors [lovastatin])2x3; (2) inhibition of VLDL secretion by the liver, which has a secondary effect on LDL production from VLDL (e.g., nicotinic acid, gemfibrozil)4J; (3) inhibition of LDL modification (e.g., antioxidants [probucol])$ and (4) stimulation of lipoprotein lipase activity (e.g., gemfibrozil, fibrates).5,7 Hepatic apo B100,E receptors are a major determinant of plasma LDL concentration8 and the stimulation of receptor synthesis is an effective mode of action in patients with hypercholesterolemia. The primary action of the bile acid sequestrants is to inhibit the reabsorption of bile acids in the terminal ileum, thereby reducing their enterohepatic recirculation. This in turn increases the activity of cholesterol-7-alpha-hydroxylase, which is suppressedby bile acids. Because this enzyme is rate-limiting in the conversion of cholesterol to primary bile acids, cholesterol oxidation to bile acids is increased. Although this is associated with a compensatory increase in cholesterol synthesis within hepatocytes, it is not sufficient to prevent an increase in the synthesis of apo B 100,E receptors, which is under feedback suppression by the unesterified cholesterol content of the cells. This in turn increases the rate of uptake of LDL from the circulation and decreases the plasma LDL concentration. The HMG-CoA reductase inhibitors also increase apo B 100,E receptor activity in hepatocytes. By reducing the activity of the rate-limiting enzyme for cholesterol synthesis, they reduce the intracellular pool of unesterified cholesterol and hence increase receptor synthesis. The combination of a bile acid-sequestering resin and an HMG-CoA reductase inhibitor can be particularly effective in lowering LDL concentration by taking advantage of these agents’ different modes of action on cholesterol metabolism. Nicotinic acid and gemfibrozil reduce LDL levels through primary effects on the hepatic synthesis of VLDL. In the case of nicotinic acid, this is secondary to decreased delivery of free fatty acids to the liver from adipocytes, in which nicotinic acid inhibits the lipolysis of stored triglyceride. The mechanism of action of gemfibrozil on VLDL is not yet clear, although metabolic studies in patients with hypertriglyceridemia have shown that it involves a reduction in the rate of VLDL triglyceride synthesis.
Probucol is also used to decrease LDL levels, although its mode of action is still not clear. Interest is now focused more on probucol’s antioxidant action on LDL. The fact that probucol also decreases HDL cholesterol has raised concern, although the significance of this finding will not be known until its effects on HDL metabolism are understood. The mechanism by which a drug decreases LDL concentration is probably not important for the prevention of CAD. Reductions produced by both cholestyramine and gemfibrozil have been shown to decrease the incidence of CAD in hyperlipidemic men.9,‘” Drugs that reduce LDL production by reducing VLDL synthesis also reduce the concentrations of VLDL and IDL and are therefore of value in the treatment of patients with hypertriglyceridemia and dysbetalipoproteinemia. In addition, VLDL concentrations can be lowered by drugs that increase lipoprotein lipase activity. In some hypertriglyceridemic subjects, the associated increase in the fractional rate of conversion of VLDL to LDL can produce a transient or sustained increase in LDL levels. EFFECTS OF DRUGS ON HIGH-DENSITY LIPOPROTEIN In contrast to the situation with LDL, the mechanism by which drugs alter HDL cholesterol concentration is likely to be important, since a change in concentration need not necessarily be accompanied by a parallel change in reverse cholesterol transport. There are 2 reasons for this: First, cholesterol enters HDL from more than 1 source (i.e., peripheral tissues and triglyceride-rich lipoproteins); second, the concentration of cholesteryl esters in HDL reflects not only the rate of delivery of cholesterol to the particles, but also the fractional rate of catabolism of the particles and the fractional rates of transfer of cholesteryl esters from the particles to the liver and to other lipoproteins.’ ’ Nascent HDL particles are synthesized in several different tissues. The small intestine secretes particles containing apo AI, and the liver secretes particles predominantly containing apo E (Fig. 2). In addition, several peripheral tissues also secrete apo E-containing particles (e.g., macrophages). Unlike the spherical mature HDL particles found in normal plasma, the nascent particles are discoidal because of the absence of cholesteryl esters. When these particles are acted upon by the cholesterolesterifying enzyme 1ecithin:cholesterol acyltransferase
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER4, 1990
17A
A SYMPOSIUM:
HDL CHOLESTEROL
IN CORONARY
ARTERY
DISEASE
CE
FIGURE 2. Metabolism of high4ensity lipoprotein (HDL) and mechanisms by which dnrgoincreoseplasmaHDLehdeaerdconcenbath. Thenumbers1 through3 indiie the following: (1) stbnulation of apo Al synthesis (gemtlbrozil); (2) stimulation of lipolysis of tlfglycs&le-l+ch lipoproteins &!nlfibrozil, fibrates);(3) inhibition of catabolism (nicotinic acid). CE = cholesterol ester; CETP = cholestsryl ester transfer protein; LCAT = lecithinchobtsd acylbansferase; LDL = low-density Ii-n; LPL = lipoprotein lipase; TG = triglycerides; UC = uneskified cholesterd; VLDL = very low density lipoprotsin. (Reprinted wlth permission from Adis Press Ltd, Auckland, New Zealand.)
(LCAT), and acquire additional unesterified cholesterol from tissuesand as a component of the surface remnants of triglyceride-rich lipoproteins, they are converted to the mature spherical forms. However, in humans, most cholesteryl ester molecules are not retained in HDL, but are transferred by way of a transfer protein to the cores of triglyceride-rich lipoproteins such as VLDL. Cholesteryl estersformed in HDL by the LCAT reaction are delivered to hepatocytesvia several routes: (1) as a result of uptake of apo B-containing lipoproteins (chylomicron remnants, IDL and LDL); (2) by clearance of apo E-containing HDL particles from the circulation through apo BlOO,E receptors and apo E receptors; and (3) by direct transfer from HDL to hepatocytesby way of a mechanism that does not involve catabolism of the particles.1i Drugs that increaseHDL cholesterol are known to do so by 1 or more of the following 3 mechanisms:(1) stimulation of the synthesisof apo AI, the major HDL protein (e.g., gemfibrozil, cholestyramine)5J2;(2) stimulation of lipolysis of triglyceride-rich lipoproteins (e.g., gerntibrozil, clolibrate, bezafibrate)5g7J2; and (3) inhibition of the catabolism of HDL particles (e.g., nicotinic acid).4 There is strong evidencethat gemfibrozil increasesthe synthesisof apo AI in hypertriglyceridemic subjects,pre-
Dlug
Ape Al SR
Cholestyramine Gemfibrozll Estrogens Nicotinic acid Fibrates
FCR
LPL
HL
4 44
4
4
+ +
4
FIGURE 3. Effects of soms aUgs and hormones on metabotic determinants of plasma hig%density lipoprotein cholesterol concenkation. Apo AISR = apdipopro&in Al synthesis rate; FCR = apo Al fractional catabolii rate; HL = hepatic lipase activity; LPL = lipoprotein lipase activity.
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sumably leading to an increasein the synthesisof nascent HDL particles. The site of this action (i.e., liver or intestine) is not known. Cholestyramine also stimulates apo AI synthesis in humans, but to a lesserextent than does gemfibrozil. The increase in HDL cholesterol produced by gemfibrozil is alsodue in part to an increasein lipoprotein lipase activity. This appearsto be the principal mechanism by which clofibrate and bezafibrateincreaseHDL cholesterol. In addition to increasing the rate of transfer of unesterified cholesterol from triglyceride-rich lipoproteins to HDL, an increase in lipoprotein lipase activity may also reduce the transfer of cholesteryl estersfrom HDL to VLDL by reducing the residencetime of the latter in plasma. The increase in HDL cholesterol produced by nicotinic acid is due to a reducedfractional rate of catabolism of apo A-containing HDL particles, although the mechanismof this effect hasnot beenstudied. Nicotinic acid has not been found to increasethe rate of synthesisof apo AI or apo AII. The known effectsof some agentson HDL metabolism are summarizedin Figures 2 and 3. The effects on reversecholesterol transport and atherogenesis of different drug-induced modifications of HDL metabolism are likely to attract considerableattention over the next few years. Current information is not sufficient to permit any generalizations.However, it is of interest that the 2 drugs demonstrating increasedapo AI synthesis(i.e., cholestyramine and gemlibrozil) havealso been shown to reduce the incidence of CAD in prospective clinical trials (the Lipid ResearchClinics Coronary Primary Prevention Trial [LRC-CPPT] and the Helsinki Heart Study) through a mechanismrelated in part to the increase in HDL cholesterol.9~i0In addition, an increase in apo AI synthesis has been describedin women taking estrogens,the use of which was found in the LRC-CPPT to be associatedwith a low incidence of cardiovascular diseasein postmenopausalwomen.*3 Statistical analyses indicated that this protective effect was partly explained by the associatedincrease in HDL cholesterol.t3These observations, coupled with evidence from other sources (studies of familial hypoalphalipoproteinemia, experimental studies in animals) supporting the likely impor-
tance of apo AI synthesisin conferring protection against atherosclerosis,suggest that drug-induced increases in HDL cholesterol resulting from stimulation of apo AI production are likely to have beneficial effects on reverse cholesterol transport and atherogenesis.
CJ,
Miller
NE,
eds. Pharmacological
Control
of Hyperlipidemia.
Barcelona,
Spain: JR Prous Science Publishers, 1986:171-186. 6. Cwynne lesterolemia:
JT, Schwartz examining
CJ, eds. Second International Conference on Hyperchonew data on probucol after a decade of use. Am J Car&o/
1988;62(3):4XB-5/B. 7. Shepherd J. Packard CJ. An overview of the effects of p-chlorophenoxyisobutyric acid derivatives on lipoprotein metabolism. In: Fears R, Levy RI, Shepherd J. Packard CJ. Miller NE. eds. Pharmacological Control of H)perlipidemia. Barre-
lonu. Spain: JR Prom .Sciencr Publishem. /986.-l 3S-144.
REFERENCES 1. Steinberg D. Parthasarathy S, CareTE, Khoo JC. Witztum JL Beyond cholesterol: Modifications of lox density lipoprotein that incrcasc its. atherogenitit). N Engl J Med 1989;32@9/5-924. 2. Grundy SM. Bile acid resins: mechanisms of action. In: Fears R. Lev) RI, Shepherd J. Packard CJ. “vliller NE, eds. Pharmacological Control of H)perlipldemia. Barcelona, Spain: JR Prous Scmce Publishers, /986:3 / 9. 3. lllingworth DR. Specific inhibitors of cholesterol biosynthesis as hypucholesterolemic agents in humans: mevinolin and compactm. In: Fears R. Lev) RI, Shepherd J. Packard CJ. Miller NE, eds. Pharmacological Control of Hyperlipidemia. Barcrlona. Spain: JR Prous S&we Publishers, I986 231 ~249. 4. Olsson AG, Walldius G. Wahlberg ti. Pharmacological control of hyperlipidemia: Nicotinic acid and Lts analogues -Mechanisms of action, effects and clinical usage. In: Fears R, Levy RI, Shepherd J, Packard CJ, Miller NE. eds Pharmacological Control of Hyperlipidemia. Barc&ma. Spain: JR Prous Science Publish-
en, 19X6.2/7-230. 5. Newton RS, Krause RR. Mechanisms of action of gemfibrozil. comparison of studies in the rat to clinical efficaq. In: Fears R, Levy RI, Shepherd J. Packard
8. Nanjec MN, Miller NE. Human hepatlc low-density lipoprotein receptors: associations of receptor activities in vitro with plasma lipid and apolipoprotein concentrations in Go. Blochrm Biophys Acra 1989;1002:245m255. 9. Lipid Research Clinics Program Primary Prevention Trial Results: II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. JAMA 1987:251:363- 374. 10. Manninen V, Elo MO, Frick MH, Haapa K, Heinonen OP, Heinsalmi P. Helo P. Huttunen JK, Kaitaniemi P, Koskinen P, et al. Lipid alterations and decline in the incidence of coronary heart disease m the Helsinki Heart Study.
JAM.4
/98N:260:64/ -651,
11. Reich1 D. Miller NE. The anatomy and physiology of reverse cholesterol transport. C/in SC; 1986;70:221-231, 12. Kashyap ML. Effects of drugs on HDL apoprotem metabolism. In: ~Miller NE. ed: High Density Lipoproteins and Atherosclerosis. II. Proceedings of the Second International Workshop on High Density Lipoproteins and Atherosclerosis. Amsterdam. Elseciw, 19X9:199m207. 13. Bush TL, Barrett-Connor E, Cowan LD. ct al. Cardiovascular mortality and non-contraceptive use of estrogen in women: results from the Lipid Rwxrch Clinic% Program Follow-up Study. C‘irculotron 1987,75.1lO2~//09.
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER4, 1990
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From the Department of Medicine, Section of Endocrinology and Metabolism, The Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina. Address for reprints: Norman E. Miller, MD, DSc, Department of Medicine, Section of Endocrinology and Metabolism, The Bowman Gray School of Medicine, Wake Forest University, 300 South Hawthorne Road, Winston-Salem, North Carolina 27104.
16A
THE AMERICAN JOURNAL OF CARDIOLOGY
VOLUME 66
DSC
I
n discussing the pharmacotherapy of disordered lipoprotein metabolism, it is convenient to consider 2 principal modesof action of theseagents.One mode is their effectson thoselipoproteins whoseprincipal function is to transport cholesterol,triglycerides, or both, from the splanchnic region (i.e., the liver and intestine) to peripheral tissues.Theselipoproteins contain apolipoprotein (apo) B-apo B48 in the caseof chylomicrons and apo BlOO in the caseof the very low density, intermediate-density and low-density lipoproteins (VLDL, IDL and LDL, respectively). Most researchinto lipid-lowering drugs has centered on apo B loo-containing lipoproteins. The other mode of action of these drugs is their effectson high-density lipoproteins (HDL), which play a central role in the movementof cholesterolfrom peripheral tissues back to the liver-a processusually referred to as reverse cholesterol transport. EFFECTS OF DRUGS ON APOLIPOPROTEIN B-CONTAINING LIPOPROTEINS What do we know about the metabolism of these particles and how they influence atherogenesis?The triglyceride-rich VLDLs are synthesized and secretedby the liver and are then converted to IDL in peripheral tissuesthrough the action of endothelium-bound lipoprotein lipase (Fig. 1). The IDL particles can then undergo 1 of 2 fates: (1) They can be taken up and catabolized by the liver through apo B 100,Ereceptors,or (2) they can be converted to the cholesteryl ester-rich LDL, which is then also removed from the circulation, again primarily by hepatic apo B 100,Ereceptors.A proportion of LDL is also catabolized through apo BlOO,Ereceptorsin peripheral tissues. There is increasing evidence that the LDL particle itself may not be directly atherogenic.Rather, it must be converted to modified forms that exhibit atherogenicactivity.’ Much attention has been directed toward this process,particularly the oxidation of the polyunsaturated fatty acids in LDL. This leadsto secondarychangesin the apo BlOO of the particles, which render them recognizable by so-called scavenger receptors present in arterial macrophages.This is probably the major route by which LDL enters the macrophagesin developing atherosclerotic lesions.Other forms of modified LDL have also been described (e.g., glycated forms), which may also contribute in an important way to atherogenesis. The principal goal of lipid-lowering treatment has beento prevent coronary artery disease(CAD) by reducing the plasma concentration of LDL. Basically, there are 4 ways in which lipid-lowering agentsexert their effects on the apo BlOO-containing lipoproteins: (1) stimulation of LDL clearance by increasedsynthesisof apo B100,E
FIGURE 1. Metabolism of apolipoprotein BlO+containing lipoproteins and sites of phannacolo$ie intervention. The numbers 1 zL4 indicate the following: (1) inhibition secreth (nicothdc acid, gemfibro61); (2) stimulation of apo BlOD,E receptor stabm in liver (resins, HMG-CoA reductase inhibitors); (3) inhibition of LDL modification (probuol); (4) stimulation of lipoprotein lipase (gemffbrozil, fibrates). IDL = intermediitedensity lipoprotein; LDL = low-density lipoprotein; VLDL = very low density lipoprotein. (Reprinted with permission from Adis Ress Ltd, Auckland, New Zealand.)
Ape B,E Peripheral cells
Modified
forms
Macrophages in Atherosclerotic lesions
(e.g., oxidized]
receptors in the liver (e.g., bile acid-binding resins [cholestyramine, colestipol], 3-hydroxy-3-methyl-glutaryl coenzyme A [HMG-CoA] reductase inhibitors [lovastatin])2x3; (2) inhibition of VLDL secretion by the liver, which has a secondary effect on LDL production from VLDL (e.g., nicotinic acid, gemfibrozil)4J; (3) inhibition of LDL modification (e.g., antioxidants [probucol])$ and (4) stimulation of lipoprotein lipase activity (e.g., gemfibrozil, fibrates).5,7 Hepatic apo B100,E receptors are a major determinant of plasma LDL concentration8 and the stimulation of receptor synthesis is an effective mode of action in patients with hypercholesterolemia. The primary action of the bile acid sequestrants is to inhibit the reabsorption of bile acids in the terminal ileum, thereby reducing their enterohepatic recirculation. This in turn increases the activity of cholesterol-7-alpha-hydroxylase, which is suppressedby bile acids. Because this enzyme is rate-limiting in the conversion of cholesterol to primary bile acids, cholesterol oxidation to bile acids is increased. Although this is associated with a compensatory increase in cholesterol synthesis within hepatocytes, it is not sufficient to prevent an increase in the synthesis of apo B 100,E receptors, which is under feedback suppression by the unesterified cholesterol content of the cells. This in turn increases the rate of uptake of LDL from the circulation and decreases the plasma LDL concentration. The HMG-CoA reductase inhibitors also increase apo B 100,E receptor activity in hepatocytes. By reducing the activity of the rate-limiting enzyme for cholesterol synthesis, they reduce the intracellular pool of unesterified cholesterol and hence increase receptor synthesis. The combination of a bile acid-sequestering resin and an HMG-CoA reductase inhibitor can be particularly effective in lowering LDL concentration by taking advantage of these agents’ different modes of action on cholesterol metabolism. Nicotinic acid and gemfibrozil reduce LDL levels through primary effects on the hepatic synthesis of VLDL. In the case of nicotinic acid, this is secondary to decreased delivery of free fatty acids to the liver from adipocytes, in which nicotinic acid inhibits the lipolysis of stored triglyceride. The mechanism of action of gemfibrozil on VLDL is not yet clear, although metabolic studies in patients with hypertriglyceridemia have shown that it involves a reduction in the rate of VLDL triglyceride synthesis.
Probucol is also used to decrease LDL levels, although its mode of action is still not clear. Interest is now focused more on probucol’s antioxidant action on LDL. The fact that probucol also decreases HDL cholesterol has raised concern, although the significance of this finding will not be known until its effects on HDL metabolism are understood. The mechanism by which a drug decreases LDL concentration is probably not important for the prevention of CAD. Reductions produced by both cholestyramine and gemfibrozil have been shown to decrease the incidence of CAD in hyperlipidemic men.9,‘” Drugs that reduce LDL production by reducing VLDL synthesis also reduce the concentrations of VLDL and IDL and are therefore of value in the treatment of patients with hypertriglyceridemia and dysbetalipoproteinemia. In addition, VLDL concentrations can be lowered by drugs that increase lipoprotein lipase activity. In some hypertriglyceridemic subjects, the associated increase in the fractional rate of conversion of VLDL to LDL can produce a transient or sustained increase in LDL levels. EFFECTS OF DRUGS ON HIGH-DENSITY LIPOPROTEIN In contrast to the situation with LDL, the mechanism by which drugs alter HDL cholesterol concentration is likely to be important, since a change in concentration need not necessarily be accompanied by a parallel change in reverse cholesterol transport. There are 2 reasons for this: First, cholesterol enters HDL from more than 1 source (i.e., peripheral tissues and triglyceride-rich lipoproteins); second, the concentration of cholesteryl esters in HDL reflects not only the rate of delivery of cholesterol to the particles, but also the fractional rate of catabolism of the particles and the fractional rates of transfer of cholesteryl esters from the particles to the liver and to other lipoproteins.’ ’ Nascent HDL particles are synthesized in several different tissues. The small intestine secretes particles containing apo AI, and the liver secretes particles predominantly containing apo E (Fig. 2). In addition, several peripheral tissues also secrete apo E-containing particles (e.g., macrophages). Unlike the spherical mature HDL particles found in normal plasma, the nascent particles are discoidal because of the absence of cholesteryl esters. When these particles are acted upon by the cholesterolesterifying enzyme 1ecithin:cholesterol acyltransferase
THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER4, 1990
17A
A SYMPOSIUM:
HDL CHOLESTEROL
IN CORONARY
ARTERY
DISEASE
CE
FIGURE 2. Metabolism of high4ensity lipoprotein (HDL) and mechanisms by which dnrgoincreoseplasmaHDLehdeaerdconcenbath. Thenumbers1 through3 indiie the following: (1) stbnulation of apo Al synthesis (gemtlbrozil); (2) stimulation of lipolysis of tlfglycs&le-l+ch lipoproteins &!nlfibrozil, fibrates);(3) inhibition of catabolism (nicotinic acid). CE = cholesterol ester; CETP = cholestsryl ester transfer protein; LCAT = lecithinchobtsd acylbansferase; LDL = low-density Ii-n; LPL = lipoprotein lipase; TG = triglycerides; UC = uneskified cholesterd; VLDL = very low density lipoprotsin. (Reprinted wlth permission from Adis Press Ltd, Auckland, New Zealand.)
(LCAT), and acquire additional unesterified cholesterol from tissuesand as a component of the surface remnants of triglyceride-rich lipoproteins, they are converted to the mature spherical forms. However, in humans, most cholesteryl ester molecules are not retained in HDL, but are transferred by way of a transfer protein to the cores of triglyceride-rich lipoproteins such as VLDL. Cholesteryl estersformed in HDL by the LCAT reaction are delivered to hepatocytesvia several routes: (1) as a result of uptake of apo B-containing lipoproteins (chylomicron remnants, IDL and LDL); (2) by clearance of apo E-containing HDL particles from the circulation through apo BlOO,E receptors and apo E receptors; and (3) by direct transfer from HDL to hepatocytesby way of a mechanism that does not involve catabolism of the particles.1i Drugs that increaseHDL cholesterol are known to do so by 1 or more of the following 3 mechanisms:(1) stimulation of the synthesisof apo AI, the major HDL protein (e.g., gemfibrozil, cholestyramine)5J2;(2) stimulation of lipolysis of triglyceride-rich lipoproteins (e.g., gerntibrozil, clolibrate, bezafibrate)5g7J2; and (3) inhibition of the catabolism of HDL particles (e.g., nicotinic acid).4 There is strong evidencethat gemfibrozil increasesthe synthesisof apo AI in hypertriglyceridemic subjects,pre-
Dlug
Ape Al SR
Cholestyramine Gemfibrozll Estrogens Nicotinic acid Fibrates
FCR
LPL
HL
4 44
4
4
+ +
4
FIGURE 3. Effects of soms aUgs and hormones on metabotic determinants of plasma hig%density lipoprotein cholesterol concenkation. Apo AISR = apdipopro&in Al synthesis rate; FCR = apo Al fractional catabolii rate; HL = hepatic lipase activity; LPL = lipoprotein lipase activity.
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THE AMERICAN JOURNAL OF CARDIOLOGY
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sumably leading to an increasein the synthesisof nascent HDL particles. The site of this action (i.e., liver or intestine) is not known. Cholestyramine also stimulates apo AI synthesis in humans, but to a lesserextent than does gemfibrozil. The increase in HDL cholesterol produced by gemfibrozil is alsodue in part to an increasein lipoprotein lipase activity. This appearsto be the principal mechanism by which clofibrate and bezafibrateincreaseHDL cholesterol. In addition to increasing the rate of transfer of unesterified cholesterol from triglyceride-rich lipoproteins to HDL, an increase in lipoprotein lipase activity may also reduce the transfer of cholesteryl estersfrom HDL to VLDL by reducing the residencetime of the latter in plasma. The increase in HDL cholesterol produced by nicotinic acid is due to a reducedfractional rate of catabolism of apo A-containing HDL particles, although the mechanismof this effect hasnot beenstudied. Nicotinic acid has not been found to increasethe rate of synthesisof apo AI or apo AII. The known effectsof some agentson HDL metabolism are summarizedin Figures 2 and 3. The effects on reversecholesterol transport and atherogenesis of different drug-induced modifications of HDL metabolism are likely to attract considerableattention over the next few years. Current information is not sufficient to permit any generalizations.However, it is of interest that the 2 drugs demonstrating increasedapo AI synthesis(i.e., cholestyramine and gemlibrozil) havealso been shown to reduce the incidence of CAD in prospective clinical trials (the Lipid ResearchClinics Coronary Primary Prevention Trial [LRC-CPPT] and the Helsinki Heart Study) through a mechanismrelated in part to the increase in HDL cholesterol.9~i0In addition, an increase in apo AI synthesis has been describedin women taking estrogens,the use of which was found in the LRC-CPPT to be associatedwith a low incidence of cardiovascular diseasein postmenopausalwomen.*3 Statistical analyses indicated that this protective effect was partly explained by the associatedincrease in HDL cholesterol.t3These observations, coupled with evidence from other sources (studies of familial hypoalphalipoproteinemia, experimental studies in animals) supporting the likely impor-
tance of apo AI synthesisin conferring protection against atherosclerosis,suggest that drug-induced increases in HDL cholesterol resulting from stimulation of apo AI production are likely to have beneficial effects on reverse cholesterol transport and atherogenesis.
CJ,
Miller
NE,
eds. Pharmacological
Control
of Hyperlipidemia.
Barcelona,
Spain: JR Prous Science Publishers, 1986:171-186. 6. Cwynne lesterolemia:
JT, Schwartz examining
CJ, eds. Second International Conference on Hyperchonew data on probucol after a decade of use. Am J Car&o/
1988;62(3):4XB-5/B. 7. Shepherd J. Packard CJ. An overview of the effects of p-chlorophenoxyisobutyric acid derivatives on lipoprotein metabolism. In: Fears R, Levy RI, Shepherd J. Packard CJ. Miller NE. eds. Pharmacological Control of H)perlipidemia. Barre-
lonu. Spain: JR Prom .Sciencr Publishem. /986.-l 3S-144.
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THE AMERICAN JOURNAL OF CARDIOLOGY
SEPTEMBER4, 1990
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