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Pharmacologic Therapy for the Hyperlipidemic Patient
Pharmacologic Therapy for the Hyperlipidemic Patient
DONALD B. HUNNINGHAKE, M.D. ~mneapoHs, ~innesom
Drug therapy should be Instituted only after appropriate diet treatment has been started and adequate baseline lipid and lipoprotein values are established. Nicotinic acid Is useful In treating most lipoprotein disorders and the cutaneous flushing that develops during the early part of treatment Is usually alleviated by aspirin. Cholestyramine and colestlpol are nonabsorbable resins whose use Is limited to type II hyperllpoprotelnemla. Clofibrate Is primarily effective In lowering triglyceride levels, but Its clinical use has considerably declined following the World Health Organization study results that reported Increased morbidity and mortality rates among patients receiving this drug. Based on the finding of Increased mortality among a subset of patients participating In the Coronary Drug Project, dextrothyroxlne Is only recommended for treating patients who do not have clinically evident atherosclerotic heart disease. Probucollowers total and low-density lipoprotein cholesterollevels, but has the undesirable effect of slmu"aneously reducing high-density lipoprotein levels. Although diet remains the first line of therapy, there is a definite place for pharmacologic intervention In selected patients with hyperlipidemia in whom dietary measures do not produce the desired changes in lipid profile. TREATMENT INDICATIONS AND GOALS
From the Department of Medicine and Pharmacology and Lipid Research Clinic. University of Minnesota Medical School, Minneapolis, Minnesota. Requests lor reprints should be addressed to Dr. Donald B. Hunninghake, Department of Pharmacology, 3-260 Millard Hall, University of Minnesota. Minneapolis, Minnesota 55455.
A primary clinical concern is the risk of coronary heart disease. and few would argue against maintaining lipids within an acceptable range. even though the ultimate benefits of intervening on this risk factor have not yet been proven in terms of reduced coronary heart disease morbidity and mortality rates. My personal conviction Is that the younger the patient, the more pronounced the family history of premature coronary heart diseas.e, and the greater the number of associated risk factors, the more aggressive should be the treatment. Patients with markedly elevated triglyceride levels should be treated to reduce the risk of pancreatitis. Furthermore, the majority of persons with elevated triglyceride levels tend to have reduced high-
Ma, 23. 11.3
The AmerIcan Journal of MedIcIne
11
HYPERLIPOPROTEINEMIA SYMPOSIUM-HUNNINGHAKE
Figure 1. Currently approved drugs for the management of hyperllpoproteinemia.
way to establish this is by obtaining adequate baseline lipid levels, and this is most reliably accomplished by making at least three determinations before treatment is started and taking periodic checks during the course of treatment. In the pharmacologic approach to treating hyperlipoproteinemia, one is primarily interested in a drug's effect on high-density lipoprotein cholesterol and low-density lipoprotein cholesterol rather than the effect on total cholesterol levels. The primary mode of action of some of the pharmacologic agents used today is to reduce low-density lipoprotein levels, whereas others act by increasing high-density lipoprotein cholesterol levels. When assessing drug effect it is therefore essential to measure both fractions. Once a drug regimen has been established, it is important to stress to the patient that this does not replace the prescribed diet and the clinician should periodically make certain that the patient is continuing to comply with dietary recommendations. A treatment goal should be set up regarding what one hopes to achieve by adding pharmacologic agents. The desirable amount of lipid reduction will vary from patient to patient, but as a general guideline, one should achieve at least a 15 percent reduction in low-density lipoprotein cholesterol levels and a 30 percent reduction in triglyceride levels to justify continuation of therapy. All the presently available drugs are associated with some degree of morbidity, so the benefits achieved in individual patients should be sufficiently satisfactory to outweigh the possible adverse side effects of pharmacologic intervention. CONSIDERATIONS IN CHOOSING A DRUG
In general. the currently approved lipid-lowering drugs are more effective in decreasing low-density lipoprotein levels than in increasing high-density lipoprotein cho-
20
May 23. 1983
The American Journal of Medicine
lesterol levels (Figure 1). Gemfibrozil, clofibrate, and nicotinic acid are the only drugs on the market today that lower triglyceride levels. and they also tend to increase high-density lipoprotein cholesterol levels. Clofibrate and nicotinic acid are proven effective agents in the management of type III hyperlipoproteinemia. If the primary therapeutic objective is to lower lowdensity lipoprotein cholesterol levels. one should be aware of differences in the percentage reductions and side effects that can be expected with various agents. Probucol, dextrothyroxine. and clofibrate generally produce modest reductions in the range of 15 percent, but are also associated with relatively few adverse side effects. The two bile acid sequestrants-cholestyramine and colestipol-and nicotinic acid produce greater percentage reductions in low-density lipoprotein cholesterollevels, but at the expense of a higher incidence of undesirable side effects. As for the cost of therapy, nicotinic acid is the least expensive and cholestryamine and colestipol are the most expensive of the lipidlowering agents. Nicotinic Acid. In clinical use for many years, this agent favorably alters parameters considered to decrease the risk of coronary heart disease (Figure 2). It decreases total and low-density lipoprotein cholesterol levels, increases high-density lipoprotein cholesterol levels. and decreases triglyceride levels. Of all the lipid-lowering drugs, nicotinic acid probably produces the greatest elevations in high-density lipoprotein cholesterol levels, with many studies reporting rises of between 10 and 15 mg/dl. When given within the usual daily dosage range of 3 to 6 g, most studies report between 20 and 30 percent reductions in low-density lipoprotein cholesterol levels. Nicotonic acid is particularly well suited for combination therapy with bile acid sequestrants because of
HYPERLIPOPAOTEINEMIA SYMPOSIUM
HUNNINGHAKE
Nicotinic acid - Tends to affect all parameters favorably Decreases total and lDl cholesterol Increases HDL cholesterol Decreases triglycerides -Inhibitor of lipoprotein synthesis -Cheap - 500-mg tablets • Dose-titrate FIgure 2. acid.
Characteristics of nicotinic
3-6 gm/day in divided dose
a complementary mode of action. Nicotinic acid is an inhibitor of lipoprotein synthesis. and bile acid sequestrants increase the breakdown of lipoproteins (increase low-density lipoprotein catabolism). The combination of the two types of agents produces synergistic effects very favorable for lowering of lowdensity lipoprotein cholesterol levels. When beginning therapy with nicotinic acid, the daily dosage should be increased gradually so that the establishment of the appropriate dosage level can be guided by the patient's response. All patients experience flushing at the start of nicotonic acid therapy. but tolerance develops rather quickly. It has recently been demonstrated that this skin response is related to prostaglandin-mediated dilation of cutaneous capillaries and can be ameliorated by the administration of prostaglandin synthesis inhibitors like aspirin or indomethacin. We believe that aspirin is a safer drug. and have found that one aspirin given about one-half hour before each scheduled dose is helpful in patients in whom flushing is a distressing or persistent problem.
Other side effects of nicotinic acid include upper gastrointestinal disturbances. but these can usually be avoided by taking the medication before meals. The clinician should be aware that abnormal liver function test results are occasionally seen following administration of this drug, and we consider serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase levels the best predictors of this problem. If the liver function test results return to normal following a reduction in the drug dosage. it is frequently possible to increase the dosage at a later time without incurring the same effect. Other biochemical abnormalities to watch for are hyperuricemia and hyperglycemia, but these occur infrequently. Bile Acid Sequestrants. Colestipol and cholestyramine are the two currently available bile acid sequestrants. They lower total and low-density lipoprotein cholesterol levels. interrupt enterophepatic circulation of bile acids, and increase low-density lipoprotein catabolism (Figure 3). In terms of lipid-lowering effect. 5 g of colestipol is equivalent to 4 9 of cholestyramine.
Bile acid sequestrants - lower total and lDl cholesterol -Interrupt enterohepatlc circulation of bile aclda and Increase catabolism of lDl - Administer bid In proximity to meala FIgure 3. Characteristics of bile acid sequestrants.
- Dose-dependent reduction In LOL
May 23, 1"3
The American Journal of Medicine
21
HYPERLIPOPROTEINEMIA SYMPOSIUM-HUNNINGHAKE
These compounds are nonabsorbable resins and, therefore, are not subject to the usual problems of systemic side effects or toxicity. The side effects that patients complain about are restricted to the gastrointestinal tract. Upper gastrointestinal complaints include eructation, heartburn, and a feeling of fullness. Advising patients to take the medication more slowly may be helpful since this reduces the amount of air swallowed. Cutting down on the total volume of the vehicle also eases these complaints in many patients, and separating the time of administration from a heavy meal may be helpful. Lower gastrointestinal complaints include increased volume of stool, constipation, and diarrhea. Some of these are transient side effects. Increasing the bulk in the diet may help decrease constipation. There is not much difference In patient acceptance between these two drugs. Some prefer colestipol because it is unflavored, can be taken In smaller volume, and has antacid properties. Another consideration in choosing between these agents is that colestlpol is less likely to interfere with the absorption of co-administered drugs. Cholestyramine is a more highly charged molecule, containing quaternary amines, and Is therefore more likely than colestipol to affect the absorption of drugs like thiazide diuretics, warfarin, and other anionic agents. Dosage scheduling of bile acid sequestrants is an important consideration in their clinical efficacy. It has been shown that the evening dose is the most effective in terms of reduction in low-density lipoprotein cholesterol levels, and we recommend that patients take their medication in divided doses twice a day. In our experience, one can get as much as a 30 percent reduction in low-density lipoprotein cholesterol levels using bile acid sequestrants. Compared to other lipidlowering agents, these are very costly drugs. Clofibrate. The World Health Organization Clofibrate' Trial showed that significant increases in morbidity and mortality rates were associated with the administration of clofibrate, and these findings have considerably reduced its widespread use [1]. In the treatment of patients with type lib, and some patients with type IV hyperlipoproteinemia, an increase rather than a decrease in low-density lipoprotein cholesterol levels has resulted. Prior to the advent of gemfibroZil, clofibrate and nlcotonic acid were the only two available agents for
lowering triglyceride levels, but today gemfibrozll offers a very acceptable alternative. Clofibrate produces only modest decreases in low-denslty lipoprotein cholesterol levels in the range of 10 to 15 percent. and similarly minimal Increases in high-denslty lipoprotein cholesterol levels in the range of 5 to 8 mg/dl. Dextrothyroxlne. This agent lowers both total and low-density lipoprotein cholesterol levels, but its effect on hlgh-density lipoprotein is questionable. In the Coronary Drug Project [2], a subset of patients, who probably had more severe atherosclerotic heart disease than the remaining patients, had an increased mortality rate. Based on this finding, dextrothyroxine is only recommended for treating patients who do not have clinically evident atherosclerotic heart disease. The dosage range usually recommended is between 4 and 6 mg a day. but our own studies suggest that 3 mg a day is a more acceptable dosage. All the patients we have treated within this dosage range showed suppression of the hypothalmic anterior pituitary axis. At this dosage, the thyrotrophin-releasing hormone-Induced release of thyroid-stimulating hormone from the anterior pituitary gland is completely suppressed, suggesting that higher dosages are probably associated with a hypermetabolic state. One can only speculate whether the latter might increase the risk of cardiac arrhythmias. Probucol. This agent lowers total and low-density lipoprotein cholesterol levels by between 10 and 15 percent, but it has the added tendency to lower highdensity lipoprotein cholesterol levels by between 20 and 25 percent, and to increase the low-density Iipoprotein/high-denslty lipoprotein cholesterol ratio. The latter property has raised the question that probucol might increase the risk of coronary heart disease. Probucol has a very long half-life, and the standard dose is 500 mg twice daily. A preliminary report from a Finnish prospective study comparing diet alone, diet plus probucol, and diet plus clofibrate shows that morbidity and mortality were lower in the probucol group than among patients treated with diet alone [3]. Another study suggests that probucol may cause a reduction in xanthomas [4]. The primary conclusion one can draw from the various study results is that It is extremely important to monitor lipid levels during therapy with lipid-lowering drugs.
REFERENCES 1.
2.
22
Report from the Committee of Principal Investigators: A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J 1978; 40: 1069-1118. The Coronary Drug Project: Findings leading to further modification of its protocol with respect to dextrothyroxlne. The coronary drug project research group. JAMA 1972; 220
May 23, 1983 The American Journal of Medicine
3. 4.
[suppI7): 996-1008. Miettinin TA. HuttunenJK. Strandberg T. Naukkarlnen V. Mattila S, Kumlin T: Lowered HDL cholesterol and Incidence of ischemic heart disease [letter]. Lancet 1981; II: 478. Baker SG, Joffe BI, Mendelshon D. Settel HD: Treatment of homozygous familial hypercholesterolaemla with probucol. S Afr Med J 1982; 62 [suppl 11: 7-11.
DONALD B. HUNNINGHAKE, M.D. ~mneapoHs, ~innesom
Drug therapy should be Instituted only after appropriate diet treatment has been started and adequate baseline lipid and lipoprotein values are established. Nicotinic acid Is useful In treating most lipoprotein disorders and the cutaneous flushing that develops during the early part of treatment Is usually alleviated by aspirin. Cholestyramine and colestlpol are nonabsorbable resins whose use Is limited to type II hyperllpoprotelnemla. Clofibrate Is primarily effective In lowering triglyceride levels, but Its clinical use has considerably declined following the World Health Organization study results that reported Increased morbidity and mortality rates among patients receiving this drug. Based on the finding of Increased mortality among a subset of patients participating In the Coronary Drug Project, dextrothyroxlne Is only recommended for treating patients who do not have clinically evident atherosclerotic heart disease. Probucollowers total and low-density lipoprotein cholesterollevels, but has the undesirable effect of slmu"aneously reducing high-density lipoprotein levels. Although diet remains the first line of therapy, there is a definite place for pharmacologic intervention In selected patients with hyperlipidemia in whom dietary measures do not produce the desired changes in lipid profile. TREATMENT INDICATIONS AND GOALS
From the Department of Medicine and Pharmacology and Lipid Research Clinic. University of Minnesota Medical School, Minneapolis, Minnesota. Requests lor reprints should be addressed to Dr. Donald B. Hunninghake, Department of Pharmacology, 3-260 Millard Hall, University of Minnesota. Minneapolis, Minnesota 55455.
A primary clinical concern is the risk of coronary heart disease. and few would argue against maintaining lipids within an acceptable range. even though the ultimate benefits of intervening on this risk factor have not yet been proven in terms of reduced coronary heart disease morbidity and mortality rates. My personal conviction Is that the younger the patient, the more pronounced the family history of premature coronary heart diseas.e, and the greater the number of associated risk factors, the more aggressive should be the treatment. Patients with markedly elevated triglyceride levels should be treated to reduce the risk of pancreatitis. Furthermore, the majority of persons with elevated triglyceride levels tend to have reduced high-
Ma, 23. 11.3
The AmerIcan Journal of MedIcIne
11
HYPERLIPOPROTEINEMIA SYMPOSIUM-HUNNINGHAKE
Figure 1. Currently approved drugs for the management of hyperllpoproteinemia.
way to establish this is by obtaining adequate baseline lipid levels, and this is most reliably accomplished by making at least three determinations before treatment is started and taking periodic checks during the course of treatment. In the pharmacologic approach to treating hyperlipoproteinemia, one is primarily interested in a drug's effect on high-density lipoprotein cholesterol and low-density lipoprotein cholesterol rather than the effect on total cholesterol levels. The primary mode of action of some of the pharmacologic agents used today is to reduce low-density lipoprotein levels, whereas others act by increasing high-density lipoprotein cholesterol levels. When assessing drug effect it is therefore essential to measure both fractions. Once a drug regimen has been established, it is important to stress to the patient that this does not replace the prescribed diet and the clinician should periodically make certain that the patient is continuing to comply with dietary recommendations. A treatment goal should be set up regarding what one hopes to achieve by adding pharmacologic agents. The desirable amount of lipid reduction will vary from patient to patient, but as a general guideline, one should achieve at least a 15 percent reduction in low-density lipoprotein cholesterol levels and a 30 percent reduction in triglyceride levels to justify continuation of therapy. All the presently available drugs are associated with some degree of morbidity, so the benefits achieved in individual patients should be sufficiently satisfactory to outweigh the possible adverse side effects of pharmacologic intervention. CONSIDERATIONS IN CHOOSING A DRUG
In general. the currently approved lipid-lowering drugs are more effective in decreasing low-density lipoprotein levels than in increasing high-density lipoprotein cho-
20
May 23. 1983
The American Journal of Medicine
lesterol levels (Figure 1). Gemfibrozil, clofibrate, and nicotinic acid are the only drugs on the market today that lower triglyceride levels. and they also tend to increase high-density lipoprotein cholesterol levels. Clofibrate and nicotinic acid are proven effective agents in the management of type III hyperlipoproteinemia. If the primary therapeutic objective is to lower lowdensity lipoprotein cholesterol levels. one should be aware of differences in the percentage reductions and side effects that can be expected with various agents. Probucol, dextrothyroxine. and clofibrate generally produce modest reductions in the range of 15 percent, but are also associated with relatively few adverse side effects. The two bile acid sequestrants-cholestyramine and colestipol-and nicotinic acid produce greater percentage reductions in low-density lipoprotein cholesterollevels, but at the expense of a higher incidence of undesirable side effects. As for the cost of therapy, nicotinic acid is the least expensive and cholestryamine and colestipol are the most expensive of the lipidlowering agents. Nicotinic Acid. In clinical use for many years, this agent favorably alters parameters considered to decrease the risk of coronary heart disease (Figure 2). It decreases total and low-density lipoprotein cholesterol levels, increases high-density lipoprotein cholesterol levels. and decreases triglyceride levels. Of all the lipid-lowering drugs, nicotinic acid probably produces the greatest elevations in high-density lipoprotein cholesterol levels, with many studies reporting rises of between 10 and 15 mg/dl. When given within the usual daily dosage range of 3 to 6 g, most studies report between 20 and 30 percent reductions in low-density lipoprotein cholesterol levels. Nicotonic acid is particularly well suited for combination therapy with bile acid sequestrants because of
HYPERLIPOPAOTEINEMIA SYMPOSIUM
HUNNINGHAKE
Nicotinic acid - Tends to affect all parameters favorably Decreases total and lDl cholesterol Increases HDL cholesterol Decreases triglycerides -Inhibitor of lipoprotein synthesis -Cheap - 500-mg tablets • Dose-titrate FIgure 2. acid.
Characteristics of nicotinic
3-6 gm/day in divided dose
a complementary mode of action. Nicotinic acid is an inhibitor of lipoprotein synthesis. and bile acid sequestrants increase the breakdown of lipoproteins (increase low-density lipoprotein catabolism). The combination of the two types of agents produces synergistic effects very favorable for lowering of lowdensity lipoprotein cholesterol levels. When beginning therapy with nicotinic acid, the daily dosage should be increased gradually so that the establishment of the appropriate dosage level can be guided by the patient's response. All patients experience flushing at the start of nicotonic acid therapy. but tolerance develops rather quickly. It has recently been demonstrated that this skin response is related to prostaglandin-mediated dilation of cutaneous capillaries and can be ameliorated by the administration of prostaglandin synthesis inhibitors like aspirin or indomethacin. We believe that aspirin is a safer drug. and have found that one aspirin given about one-half hour before each scheduled dose is helpful in patients in whom flushing is a distressing or persistent problem.
Other side effects of nicotinic acid include upper gastrointestinal disturbances. but these can usually be avoided by taking the medication before meals. The clinician should be aware that abnormal liver function test results are occasionally seen following administration of this drug, and we consider serum glutamic oxaloacetic transaminase (SGOT) and alkaline phosphatase levels the best predictors of this problem. If the liver function test results return to normal following a reduction in the drug dosage. it is frequently possible to increase the dosage at a later time without incurring the same effect. Other biochemical abnormalities to watch for are hyperuricemia and hyperglycemia, but these occur infrequently. Bile Acid Sequestrants. Colestipol and cholestyramine are the two currently available bile acid sequestrants. They lower total and low-density lipoprotein cholesterol levels. interrupt enterophepatic circulation of bile acids, and increase low-density lipoprotein catabolism (Figure 3). In terms of lipid-lowering effect. 5 g of colestipol is equivalent to 4 9 of cholestyramine.
Bile acid sequestrants - lower total and lDl cholesterol -Interrupt enterohepatlc circulation of bile aclda and Increase catabolism of lDl - Administer bid In proximity to meala FIgure 3. Characteristics of bile acid sequestrants.
- Dose-dependent reduction In LOL
May 23, 1"3
The American Journal of Medicine
21
HYPERLIPOPROTEINEMIA SYMPOSIUM-HUNNINGHAKE
These compounds are nonabsorbable resins and, therefore, are not subject to the usual problems of systemic side effects or toxicity. The side effects that patients complain about are restricted to the gastrointestinal tract. Upper gastrointestinal complaints include eructation, heartburn, and a feeling of fullness. Advising patients to take the medication more slowly may be helpful since this reduces the amount of air swallowed. Cutting down on the total volume of the vehicle also eases these complaints in many patients, and separating the time of administration from a heavy meal may be helpful. Lower gastrointestinal complaints include increased volume of stool, constipation, and diarrhea. Some of these are transient side effects. Increasing the bulk in the diet may help decrease constipation. There is not much difference In patient acceptance between these two drugs. Some prefer colestipol because it is unflavored, can be taken In smaller volume, and has antacid properties. Another consideration in choosing between these agents is that colestlpol is less likely to interfere with the absorption of co-administered drugs. Cholestyramine is a more highly charged molecule, containing quaternary amines, and Is therefore more likely than colestipol to affect the absorption of drugs like thiazide diuretics, warfarin, and other anionic agents. Dosage scheduling of bile acid sequestrants is an important consideration in their clinical efficacy. It has been shown that the evening dose is the most effective in terms of reduction in low-density lipoprotein cholesterol levels, and we recommend that patients take their medication in divided doses twice a day. In our experience, one can get as much as a 30 percent reduction in low-density lipoprotein cholesterol levels using bile acid sequestrants. Compared to other lipidlowering agents, these are very costly drugs. Clofibrate. The World Health Organization Clofibrate' Trial showed that significant increases in morbidity and mortality rates were associated with the administration of clofibrate, and these findings have considerably reduced its widespread use [1]. In the treatment of patients with type lib, and some patients with type IV hyperlipoproteinemia, an increase rather than a decrease in low-density lipoprotein cholesterol levels has resulted. Prior to the advent of gemfibroZil, clofibrate and nlcotonic acid were the only two available agents for
lowering triglyceride levels, but today gemfibrozll offers a very acceptable alternative. Clofibrate produces only modest decreases in low-denslty lipoprotein cholesterol levels in the range of 10 to 15 percent. and similarly minimal Increases in high-denslty lipoprotein cholesterol levels in the range of 5 to 8 mg/dl. Dextrothyroxlne. This agent lowers both total and low-density lipoprotein cholesterol levels, but its effect on hlgh-density lipoprotein is questionable. In the Coronary Drug Project [2], a subset of patients, who probably had more severe atherosclerotic heart disease than the remaining patients, had an increased mortality rate. Based on this finding, dextrothyroxine is only recommended for treating patients who do not have clinically evident atherosclerotic heart disease. The dosage range usually recommended is between 4 and 6 mg a day. but our own studies suggest that 3 mg a day is a more acceptable dosage. All the patients we have treated within this dosage range showed suppression of the hypothalmic anterior pituitary axis. At this dosage, the thyrotrophin-releasing hormone-Induced release of thyroid-stimulating hormone from the anterior pituitary gland is completely suppressed, suggesting that higher dosages are probably associated with a hypermetabolic state. One can only speculate whether the latter might increase the risk of cardiac arrhythmias. Probucol. This agent lowers total and low-density lipoprotein cholesterol levels by between 10 and 15 percent, but it has the added tendency to lower highdensity lipoprotein cholesterol levels by between 20 and 25 percent, and to increase the low-density Iipoprotein/high-denslty lipoprotein cholesterol ratio. The latter property has raised the question that probucol might increase the risk of coronary heart disease. Probucol has a very long half-life, and the standard dose is 500 mg twice daily. A preliminary report from a Finnish prospective study comparing diet alone, diet plus probucol, and diet plus clofibrate shows that morbidity and mortality were lower in the probucol group than among patients treated with diet alone [3]. Another study suggests that probucol may cause a reduction in xanthomas [4]. The primary conclusion one can draw from the various study results is that It is extremely important to monitor lipid levels during therapy with lipid-lowering drugs.
REFERENCES 1.
2.
22
Report from the Committee of Principal Investigators: A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate. Br Heart J 1978; 40: 1069-1118. The Coronary Drug Project: Findings leading to further modification of its protocol with respect to dextrothyroxlne. The coronary drug project research group. JAMA 1972; 220
May 23, 1983 The American Journal of Medicine
3. 4.
[suppI7): 996-1008. Miettinin TA. HuttunenJK. Strandberg T. Naukkarlnen V. Mattila S, Kumlin T: Lowered HDL cholesterol and Incidence of ischemic heart disease [letter]. Lancet 1981; II: 478. Baker SG, Joffe BI, Mendelshon D. Settel HD: Treatment of homozygous familial hypercholesterolaemla with probucol. S Afr Med J 1982; 62 [suppl 11: 7-11.