Appraisal and reappraisal of cardiac therapy Edited by Arthur C. DeGraff and Julian Frieden

Drug treatment of hyperlipidemia

Paul Samuel, M.D. New York. N. Y.

During the past decade we have witnessed one of the major controversies of modern pharmacology in the field of drugs used for the treatment of hyperlipidemia. First, as is frequently the case, the lapse of time, improved methodology, and the advent of large clinical trials have demonstrated significant and hitherto unsuspected side effects of a number of drugs widely used in the field: clofibrate was shown to induce gallstone forma- tion,‘, 2 d-thyroxin caused significant cardiac arrhythmias3 estrogens increased thromboem- bolic complications,3 just to mention a few. Sec- ond, the validity of drug intervention itself has become the subject of controversy and has been seriously questioned. The results of the Coronary Drug Project’ and of the World Health Organiza- tion trial” showing no difference in cardiovascular mortality rate between patients in the control and drug treatment groups, have raised concerns about the validity and efficacy of drug treatment in this field.

Justifiably the question has to be asked: what are we treating, numbers or people?

And yet, despite the controversy, we are faced with more and more evidence which indicates that increased plasma lipid levels are a significant health hazard and ought to be reduced by what- ever means. The epidemiologic evidence is over- whelming, indicating increased risk of cardiovas- cular disease as plasma lipids go up. Concerning the clinical trials, the reduction of plasma choles- terol levels in the CDP’ was only 6% with clofi-

From The Rockefeller University, New York City, and The Long Island Jewish-Hillside Medical Center, New Hyde Park, N. Y.

Supported in part by United States Public Health Service grants HL-22567 and HI-06222 from the National Heart, Lung, and Blood Institute, and by grant No. FR-00102 from the General Clinical Research Center’s Branch of the Division of Research Resources.

Received for publication June 6, 1980.

Reprint requests: Paul Samuel, M.D., The Rockefeller University, 1230 York Ave., New York, N. Y. 10021.

Table I. Aver,age plasma cholesterol concentra- tions and 95th percentiles according to age

Age Mean plasma

(years) cholesterol

95th percentile

(w. W

12.17* 176 228 21.29** 193 260 30-39** 212 270 40.49** 228 280 50-59” * 230 290

- *U.S. Dept. of HEW.

**Center for the Prevention of Premature Arteriosclerosis; Rockefeller University.

brate; one would really not expect too much of that. Conversely, in the WHO study,2 there was a significant reduction in the incidence of nonfatal myocardial infarction; yet, this result was obtained with only a 9% reduction of serum cholesterol levels. (Similar results were seen with nicotinic acid in the CDP.‘) Moreover, in the WHO study -the reduction of myocardial infarc- tion in the clofibrate-treated group was most marked in men who experienced the largest reductions in plasma cholesterol levels. Thus, the results of the WHO study offer the first clear-cut support for the “lipid hypothesis,” which postu- lates that reducing plasma cholesterol, by what- ever means, should lead to a lower incidence of cardiovascular morbidity and mortality.

Whom to treat?

The primary treatment of hyperlipidemia is dietary. The preceding article describes its modal- ities in detail. But who should be treated with drugs and with what drugs? At the outpatient clinic of The Rockefeller University Hospital, our guideline is to initially institute dietary treatment for not less than three months. If at the end of that period plasma lipid levels have failed to

0002~8703/80/100573 + 05$00.50/O 0 1980 The C. V. Mosby Co. American Heart Journal 573

reach or decrease below the 95th percentile of the age group of the patient, we procee treatment. Our mean values for pla 01 levels and the 95th percentile cuttin given in Table I. Our 95th percentile triglycerides is 200 mg. %.

times daily (or two capsules twice a day). January, 1980, the cost to oa~pha~~a~y was $6. per 100 capsules.

holestyramine and coiestipol. Virtually unabsorbable high molecular weight anion exchange resins.

The drugs presently availab are few in number, have limited

n the market

have multiple side effects. Instead of being com- plete or exhaustive, I shall restrict myself to the description of those drugs that are the most effective or the most widely used for the treat- ment of hyperlipidemia.

indicator. The drug of choice in hypercholes- terolemia and the drug to be used in children when drug treatment is indicated.

Ciofibrate (CPIB). Ethyl-p-chlorophenoxyso- butyrate (CPIB) is a branched-chain fatty acid ester.

E,&ct. These compounds reduce plasma choles- terol levels by about 20% to 30%. Plasma triglyc- erides may moderately increase during drug administration. LDL cholesterol is decreased, VLDL triglycerides may moderately increase, and HDL remains unchanged.7, 8

Indications. Clofibrate is the drug of choice in the treatment of hypertriglyceridemia. Many patients with combined hyperlipidemia also re- spond.

Effect. Clofibrate reduces plasma triglyceride levels by about 30% to 40%, and plasma cholester- ol levels by 5% to 15%. In hypertriglyceridemic patients, LDL and HDL concentrations increase and VLDL decreases.4 The response in hypercbo- lesterolemia is poor.

Mechanism of action. Sterol balance measure- ments indicated a significant increase of the fecal excretion of cholesterol end products (neutral s.terols),j and a decrease of cholesterol absorption during clofibrate administration, inducing a “neg- ative sterol balance” (more cholesterol end prod- ucts coming out than cholesterol going in). The action on triglycerides seems to be both a decrease of VLDL production and acceleration of its catabolism to LDL. Or simply endogenous triglycerides are synthesized slower by the liver and once made they are broken down faster.

hanism of action. Cholestyramine and co pol bind bile acids in the gastrointestinal tract, thereby interrupting the enterohepatic cir- culation. Bile acids are an important en of cholesterol metabolism, and their fecal excretion leads to a more rapid conversion o cholesterol to bile acids which significantly decreases the plasma cholesterol con Cholesterol absorption is somewhat but only if the drug is taken before meals6

Side effects. Constipation is the most frequent- ly seen complication, sometimes improved with the use of stool softeners. The taste and consis-

are not soluble in water,

Drug interactions. It may reduce the abso tion of a number of compounds (digitalis soluble vitamins, iron, thyroid preparations, tetracycline, thiazides, etc.). It is recommende that any other medication be taken at least a hour before the resins.

Side e/fee&. Nausea and diarrhea may rarely occur. We have seen a few cases of myalgia with elevated CPK levels returning to normal after cessation of drug administration. It has been shown that the drug produces lithogenic bile, and both the CDP’ and the WH0 study2 demon- strated increased rates of cholelithiasis and dis- eases of the biliary tract in patients receiving clofibrate.

Dose and costs. Begin with one 4 sachet before each meal (three times daily), a his dose may be doubled or even tripled in adults. In January, 1980, the cost to our pharmacy was

18 per 100 sachets.

Drug interactions. Clofibrate increases the effect of coumarin anticoagulants Patients should be carefully monitored on both medica- tions.

icotinic acid. This is a vitamin of the B grou (niacin) which prevents pellagra, given in much larger doses to reduce plasma lipids.

Indications. Nicotinic acid is the only lowering drug which is highly effective in reducing both plasma cholesterol and triglyceride levels. It is indicated in hypercholesterolemia, hypertri- glyceridemia, and combined hyperlipidemia, pos- sibly in combination with other drugs (see Table III).

Dose and costs. Dose is 500 mg. capsules four Efect. Nicotinic acid lowers plasma cholesterol

574

Drug treatment of hyperlipidemia

Table II. Effect of clofibrate, neomycin and colestipol therapy on body masses of cholesterol

Study

Control Clofibrate Difference (%)

(Ref. 5)

Control Neomycin Difference (%)

(Ref. 16) Control Colestipol Difference (‘70)

(Ref. 17)

Ma* (gm.)

38 28 10 (26)

36 22 14 (39)

24 23

lM** (gm.) M-Mat (gm.)

109 71 77 49 32 (29) 22 (31)

103 67 70 48 33 (32) 19 (28)

55 31 55 32

- -

*Ma = Rapidly exchangeable pool of cholesterol (Plasma + RBC + liver + gut). **M = Minimum estimate of total body mass of cholesterol (except CNS). TM-Ma = Slowly turning over masses or tissue cholesterol.

levels by about 8% to 16% and triglycerides by 20% to 30%. It lowers hlasma free fatty acids, VLDL and LDL and it increases HDL levels.9

levels by 20% to 30%, sometimes even in patients with resistent familial hypercholesterolemia.‘O

Mechanism of action. It is frequently stated to be unknown. Nicotinic acid was shown to decrease lipolysis, decrease the hepatic produc- tion of triglycerides, and increase fecal excretion of cholesterol end products (neutral sterols).

Side effects am unfortunately numerous and patient acceptance is poor. It seems to me that for this reason, the drug is only a second-line com- pound. The main problem is intense cutaneous flushing and pruritus. Starting with small doses (100 mg. in the middle of meals) and increasing the dose gradually may somewhat alleviate this symptom. Anorexia, nausea, vomiting, diarrhea, and activation of peptic ulcer have been reported. Glucose intolerance, impaired liver function tests, and hyperuricemia may also occur.

Mechanism of action. Neomycin decreases cho- lesterol absorption and increases fecal cholesterol end product (neutral sterol) excretion, leading to a negative sterol balance.” Its effect may be mediated through its action on the intestinal bacterial flora (markedly decreased 7cu-dehydrox- ylase activity of intestinal bacteria), or by inter- fering with micelle formation in the lumen of the gastrointestinal tract.

Drug interactions. May potentiate the effect of vasodilator drugs or hyperuricemic diuretics.

Dose and costs. Begin with 100 mg. tablets three times daily, and increase gradually to one gram (two 500 mg. tablets) in the middle of three meals (3 gm. per day). In January, 1980, the cost to our pharmacy was $1.50 per 100 (500 mg.) tablets.

Side effects. One third to half of patients on neomycin have transitory diarrhea or abdominal cramps that usually subside after 1 or 2 weeks. Lomotil is helpful for this symptom. The small amounts of n.eomycin absorbed from the gut are excreted by the kidney; thus normal renal func- tion is an absolute prerequisite for using the drug. Ototoxicity has been reported in very rare cases; we perform periodic hearing tests in patients treated with neomycin. At higher dose levels (12 gm. daily) steatorrhea, renal damage, staphylo- coccus enterocolitis, moniliasis, and multiresis- tant coliform overgrowth have been reported; however, we have not observed these complica- tions with the small doses used for cholesterol reducing purposes.12

Neomycin. Neomycin is a broad-spectrum, Drug interactions. Digoxin should be adminis- aminoglycoside antibiotic, poorly absorbed from tered one hour before neomycin is given, inas- the gastrointestinal tract (< 3%). It lowers plas- much as there may be interference with its ma cholesterol levels at very low doses of admin- absorption. The possibility exists that coumarin istration (0.5 to 2 gm. daily). anticoagulants may be potentiated by the drug.

Indications. Hypercholesterolemia. Dose and costs. Tablets of 0.5 gm. of neomycin Effect. The drug reduces plasma cholesterol sulfate, three or four times daily after meals (two

American Heart Journal 575

Table Ii 1. Drug treatment of hy~erlipidemia

Hyperlipidemia

Hypercholesterolemia (-1

Cholestyramine (12-32 g.) Or

Colestipol (S-30 g.)

Neomycin (1.5-2 g.) or

Nicotinic acid (3 g.) or

Frobucol (1 gm.)

Hypertrigl.yceridemia (III, IV)

Clofibrate (2 g.) Nicotinic acid (3 g.)

Combined hyperlipidemia (IIb, III, IV, V)

Clofibrate (2 g.) Nicotinic acid (3 g.) or

Neomycin (1.5-2 g.) or

Probucoi (1 gm.)

Add to primary Rx if unsatisfactory.

tablets twice a day), In January, 1980, the cost to our pharmacy was $13.85 for 109 tablets.

Probucol. Probucol is a substituted dithioace- tEd.

Indicatio&. Moderate hypercholesterolemia. Effect. Probucol reduces plasma cholesterol

levels by about 10% to 15%, with variable effect on plasma triglycerides. It lowers both LDL and

L with no effect on VLDL.‘” Mechanism of action is unknown. It has been

suggested that the drug may decrease cholesterol biosynthesis by an unknown mechanism.

Side effects. Probucol has minimal clinical side effects. Diarrhea, flatulance, and occasional ele- vation of triglycerides have been reported. Large amounts of the drug accumulate in adipose tissue and may be stored for long periods, the potential side effects of which are not known. In monkeys on high dose levels, the drug may cause interval changes, ventricular tachycardia fibrillation; thus the drug should not be given to patients with cardiac arrhythmias.

Drug interactions. None known. Dose and costs. Probucol is available in tablets

of 250 mg. The usual dose is 500 mg. twice daily. In January, 1980, the cost to our pharmacy was $15.67 per 100 tablets.

Rationale for drug treatment

he crucial question in attempting to lower the level of plasma lipids is a simple one-are we doing any good for our patients? It is very difficult for the clinical investigator to come to grips with this essential question. Since one of the clinical com-

plications of hyperlipidemia is lipid deposition in tissues, and specifically the arterial wall, perhaps the only approach available at present is the measurement of cholesterol pool sizes in the body, by input-output** or by compartmental’j ana- lyses. Data on these measurements are available on three drugs: clofibrate, neomycin, and colesti- pol (Table II). The size of the total exchangeable body mass of cholesterol (excluding the brain) was decreased by 29% by clofibrate,” was decreased 32% by neomycin,*G and was unchange by colestipol.” The negative result in the case of the resin may be due to technical problems of measurement (the turnover of cholesterol is too rapid, and the method may give surreptitiously high results during resin administration), inas- much as decreased sizes or disappearance of visi- ble xanthomas have been reported during resin administration. Table II shows the results of these pool size measurements. Most of the choles- terol efllux, in the case of clofibrate and neomy- cin, originates from body tissue; we do not know whether any comes from the arterial wall. We do know that we can lower plasma cholesterol by as much as 20% or 30% and triglycerides by 30% or 40% with single drug therapy. The combined administration of these compounds may give us even more effective decreases. Table III presents a practical schedule for drug therapy, ~c~~d~g possible combinations. It is perhaps in good order to caution the practitioner-the contents of Table III must be interpreted and applied with flexibil- ity. There are many exceptions to the rule, and individual patients may respond differently. The

October, 1980, Vol. 100, No. 4

Drug treatment of hyperlipidemia

necessity of individual judgment in this field is eminent.

It is clear from the foregoing that in most patients we can lower plasma lipids by drugs, drugs which may have side effects. Thus the risk and benefits must Ibe carefully weighed.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

The Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease, J.A.M.A. 231:360, 1975. Committee of Principal Investigators: A cooperative trial in the primary prevention of ichaemic heart disease using clofibrate, Br. Heart J. 40:1069, 1978. The Coronary Drug Project Research Group: Initial findings leading to modifications of its research protocol, J.A.M.A. 214.~1303, 1970.

Wilson, D. E., and Lees, R. S.: Metabolic relationship among the plasma lipoproteins, J. Clin. Invest. 51:1051,

1972. Grundy, S. M., Ahrens, E. H., Jr., Salen, G., Schreibman, P. H., and Nestel, P. J.: Mechanism of action of clofibrate on cholesterol metabolism in patient with hyperlipide- mia, J. Lipid Res. 13:531, 1972. Davidson, N. O., McNamara, D. J., Samuel, P., and Ahrens, E. H., Jr.: Cholesterol absorption (%) is altered by lipid-lowering drugs but not by diet, Circulation 59 and GO(Supp1. II):II-32, 1979. Glueck, C. J., Ford, S., Jr., Scheel, D., and Steiner, P.: Colestipol and cholestyramine resin: comparative effects in familial Type II hyperlipoproteinemia, J.A.M.A. 222:676, 1972. Witztum, J. L., Sclhonfeld, G., and Weldman, 9. W.: The

9.

10.

11.

12.

13.

14.

15.

16.

17.

effect of colestipol on the metabolism of very-low-density lipoproteins in man, J. Lab. Clin. Med. 88:1008, 1976. Sheaherd. J.. Packard. C. J.. Patsch. J. R.. Gotto. A. M.. Jr., and T&ton, 0. D.: Effects of nicotinic acid therapy on plasma higlh density lipoprotein subfraction distribu- tion and composition and on apolipoprotein A metabo- lism, J. Clin. Invest. 63:858, 1979. Samuel, P., Holtzman, C. &I., and Goldstein, J.: Long- term reduction of serum cholesterol levels of patients with atherosclerosis by small doses of neomycin, Circula- tion 35:938, 1967. Sedeghat, H., Samuel, P., Crouse, J. R., and Ahrens, E. H., Jr.: Effect of neomycin on absorption, synthesis, and/or flux of cholesterol in man, J. Clin. Invest. 55:12, 1975. Samuel, P.: Current Concepts: Treatment of hypercho- lesterolemia with neomycin. A time for reappraisal, New Engl. J. Med. 301:595, 1979. Lelorier, J., Dubreuil-Quidoz, S., Lussier-Cacan, S., Huang, Y. S., and Davignon, J.: Diet and probucol in lowering cholesterol concentrations, Arch. Intern. Med. 137:1429, 1977. Samuel, P., and Lieberman, S.: Improved estimation of body masses and turnover of cholesterol by computerized input-output analysis, J. Lipid Res. 14~189, 1973. Goodman, D. S., Noble, R. P., and Dell, R. B.: Three- pool model of the long-term turnover and plasma choles- terol in man, 6. Lipid Res. 14:178, 1973. Samuel, P., Holtzman, C. M., Meilman, E., and Perl, W.: Effect of neomycin on exchangeable pools of cholesterol in the steady state, J. Clin. Invest. 47:1806, 1968. Goodman, D. )S., Noble, R. P., and Dell, R. B.: The effects of colestipol resin and of colestipol plus clofibrate on the turnover of plasma cholesterol in man, J. Clin. Invest. 52:2646,1973,

American Heart Journal 577