Practical significance of serum triglycerides and radioactive fat tolerance

Practical

Significance

of Serum

and Radioactive Their

Relation

to Current

Fat Tolerance

Therapy

DONALD BERKOWITZ, M.D., JOHN J. SPITZER, Philadelphia,

T

HE CONCEPT linking an error in fat metabolism to the genesis of atherosclerosis has been viewed with increasing favor during the Included among the investigative past decade. details supporting this theory is the observation that specific types of atherosclerosis may be accompanied by increased blood levels of various lipid fractions, most particularly cholesterol, phospholipids and beta-lipoproteins. More recently, data have been presented suggesting that abnormal triglyceride concentrations’ and radioactive fat tolerance are well correlated with clinical atherosclerosis.3-19 The requirement to restore to normal the lipid biochemical changes associated with this condition has thus been a natural and obvious implication. Currently certain chemical substances capable of reducing blood cholesterol levels are available for clinical application. triparanol, nicotinic acid, include These d-thyroxine, mytatriencdiol and oxymetholone. This report summarizes the results of treatment with these drugs on the serum triglyceride levels and radioactive fat tolerance concomitantl) with their hypocholesterolemic effects in patients with hypercholesterolemia or coronary arter! disease or both. METHOD Ninety patients whose cholesterol levels during a three-month control interval were consistently greater than 275 mg. per 100 mg. were selected for study. Fifty-seven were female and 33 male. Their ages nor ranged from 28 to 80. None had hypothyroidism nephrosis. Forty-three individuals had well documented evidence of coronary atherosclerosis. Ten patients were treated with triparanol (250 mg. daily) and 10 with nicotinic acid (3 to 5 gm. daily). * From the Hahnemann Medical Centers, Philadelphia, Pennsylvania. sylvania, and the U.S. Pulic Health

Triglycerides

for Hypercholesterolemia*

M.D.

and

WILLIAM LIKOFF, M.D., F.A.C.C.

Pennsylvania

Twenty-five received d-thyroxine (4 to 8 mg. daily) ; 20 received mytatrienediol (10 to 15 mg. daily) ; and another 25 were treated with oxymetholone (7.5 mg. daily). All patients were seen at three to four week intervals. Blood samples were withdrawn in the fasting state for the determination of the serum cholesterol (method of Zak13) and triglycerides (method of Van Handel and Zilversmitl4). Fat tolerance following an oral test meal of 113’ triolein3 was measured before and after the period of drug administration. No dietary restrictions were imposed in any case. The period of treatment extended for at least six months.

RESULTS (TABLE I) The cholesterol levels fell in 9 of 10 patients treated with this preparation, the Triglyceraverage change being 17.2 per cent. ide levels remained essentially unaffected in 6 and increased in the other 4. Radioactive fat tolerance was improved in only 1 case. The remainder continued to demonstrate impairment even when the cholesterol had become normal Tri$aranoL:

(Fig. 1).

.Vxotinic Acid: Nicotinic acid produced a fall in the blood cholesterol in each of the 10 patients treated, the average decrease being 13 per cent. The triglycerides were significantly reduced in only 1 case. Radioactive fat tolerance showed no improvement regardless of the decrease in the cholesterol (Fig. 2). d-Thyroxine:t A decrease in the cholesterol level occurred in each patient treated. In 19 patients (76 per cent) this was equal to 15 or more per cent of the initial value. In addition, a reduction in the triglyceride concentration t Choloxin, Baxter Laboratories, Morton Grove, Illinois.

College and Hospital and the Albert Einstein and Sidney Hillman Medical Supported in part by grants from the Heart Association of Southeastern PennService

(H-3976).

198

THE

AMERlCAN

JOURNAL

OF

CARDIOLOGY

Therapy with Hypercholesterolemic 20

-

Setore Rx Khd. = 440,

-

After

3 mm.

TGr210)

Rx (CM.*270.

Agents

z

TG.240)

199

A

?I5 Y 0 9 IO

Before R lCHOL.390. Afts

6nos.

TG1240)

R (CHOL. 250. TG:

761

A 5

1 IB 5

IO

15

HOURS AFTER

s

IO

HOURS

IS

AFTER

TEST

20

20

TEST

24

MEAL

FIG. 4. Case 25. Radioactive fat tolerance tests before and after treatment with d-thyroxine. RA = radioactive.

24

YEAL

1. Case I. Radioactive fat tolerance tests before and after treatment with triparanol. WB = whole blood; LB = lipid bound. FIG.

-

*Or

Bc‘orc Rx (Chob390

-After

2SO

TG.172)

4 mar. Rx (Chob260

T6.150)

2I’E

I cmtrot

’

,J mgnw. *w

. I

2

I

2.3

4

6

6

7

S

9

MONTHS

FIG. 5. Case 46. Effects of treatment with mytatrienedial on cholesterol and triglycerides.

w5

10

HOUR5

IS

AFTER

TEST

20 MEAL

24

2. Case 16. Radioactive fat tolerance tests before and after treatment with nicotinic acid. FIG.

20 r

-

Wore

-

A,,.?, 6 “~6.

Rr (Chol.= 350, TG* 166) RI Khol.*250,

TG..IOJ)

‘00*, SERUM

3Do

CHOL.

SERUM TG.

2oo ~~

^

c

5

op

“OURS

10 AFTER

20 I5 TEST MEAL

24

FIG. 6.

Case 46. Radioactive fat tolerance tests before and after treatment with mytatrienediol.

MONTHS

-2

! Sod._+Thyroxine

6 mgms. Daily

0

6

2

4

8

, IO

FIG. 3. Case 25. Serum cholesterol and triglyceride levels during treatment with sodium d-thyroxine.

occurred concomitantly except in one patient Radioactive fat tolerance was sig(Case 23). nificantly improved in each patient whose triglycerides were lowered. In over 50 per cent, normal tolerance was actually achieved (Fig. A significant hypocholesterolemic 3 and 4). effect during treatment with d-thyroxine has been reported previously.*5-1g

Mytatrienediol: * Mytatrienediol [3 methoxy16-alpha-methyl-1,3,5(10) -estratriene-l6-beta, 17-beta-diol] is a modified synthetic estrogen which Marmorston and her associates have shown to be effective in lowering serum lipid levels in patients with coronary artery disease.zW22 In our experience it was possible to produce a significant fall in the cholesterol concentration in 50 per cent of those treated, together with a reduction in the triglyceridemia and improvement in the fat tolerance (Fig. 5,6).

* Anvene@, G. D. Searle and Co., Chicago.

Berkowitz,

200

Spitzer TABLE

Effects of Treatment with Various Hypocholesterolemic

and Likoff 1

Agents on Serum Cholesterol and Triglyceride

Cholesterol

Triglycerides

(mg. %J

(mg. %)

Before Treatment

After Treatment

Change

Change

%

Before Treatment

After rreatment

2 3 4 5 6 7 8 9 10

42, 52, 38, 52, 49, 58, 62, 60, 39, 43,

F M F M M F F M F F

362 440 292 298 372 312 306 390 400 320

302 270 267 278 338 280 312 290 192 300

- 60 -170 - 25 -- 20 - 34 - 32 + 6 -100 -208 - 20

-17 -39 -8 -7 -9 -10 +2 -26 _ 52 -6

264 210 186 108 412 310 284 366 582 440

246 240 168 114 486 390 342 412 648 520

11 12 13 14 15 16 17 18 19 20

62, 54, 58, 50, 60, 45, 53, 48, 43, 42.

M F M M F M F F F M

322 308 296 289 374 390 362 418 372 302

290 282 276 285 302 250 298 380 320 278

- 32 - 26 - 20 4 - 72 -140 - 64 - 38 - 52 - 24

-10 -8

-19 -36 -18 -9 -14 -8

412 682 306 212 142 172 152 206 106 186

406 294 309 364 306 330 331 364 390 427 336 296 325 330 309 387 300 307 320 309 320 312 342 306 334

219 169 219 292 270 200 282 240 250 333 280 276 240 303 207 224 200 214 230 230 252 277 298 197 292

-186 -125 - 90 - 72 - 36 -130 - 49 -124 -140 - 94 - 56 - 20 - 85 - 27 -102 -163 -100 - 93 - 90 - 79 - 68 - 35 - 44 -109 - 42

-46 -43 -29 -20 -12 -40 -15 -34 -36 -22 -17 -7 -26 -8 -33 -42 -33 -30 -28 -26 -21 -11 -13 -36 -13

360 148 58 110 64 140 133 214 240 162 170 258 164 89 123 153 150 112 106 170 257 88 76 102 170

1

-

I

-

1

Change

Levels

%

Change

+ -

18 30 18

;I: -10

: + + + + +

7: 80 58 46 66 80

$1: +26 f20 +13 +11 +I8

388 700 300 190 136 150 178 240 98 192

+ + +

24 18 6 22 6 22 26 34

286 84 39 58 62 89 54 143 78 140 140 208 150 60 63 82 79 88 68 95 222 62 82 54 150

- 74 - 64 - 19 - 52 2 - 51 - 79 - 71 -162 - 22 - 38 - 50 - 14 - 29 - 60 - 71 - 71 - 24 - 38 - 75 - 35 - 26 + 6 - 48 - 20

I

“6

I’; -2 -10 -4 -13 +17 +17 -8 +3

d-Thyroxine 21

51, F

22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45

48, 62, 58, 65, 80, 46, 52, 65, 51, 70, 61, 65, 49, 52, 56, 58, 56, 46, 62, 66, 70, 52, 58, 28,

F F F F F F F F M M F F F M M M F F F F M M F M

THE

AMERICAN

JOURNAL

OF

-21 -43 -33 -47 -1 -36 -59 -33 -67 -14 -21 -19 -8 -33 -50 -46 -48 -21 -36 -44 -14 -30 +8 -47 -12

CARDIOLOGY

Therapy

with Hypercholesterolemic TABLE

Age, Sex

Case

__

I (Continued)

Triglycerides (mg. %)

Cholesterol (mg. %) Before Treatment

After Treatment

201

Agents

Change

% Change

Before Treatment

After Treatment

Change

% Change

Mytatrdenediol 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65

52, F 46, M 43, M 36, F 64, M 63, F 50, M 52, M GO, F 39, F 60, M 52, M 50, F 48, M 46, F 52, M 57, F 56, M 49, F 44, F

312 296 294 350 346 382 316 340 290 298 306 314 362 412 372 360 298 306 314 330

264 300 290 250 290 360 260 328 235 306 246 324 340 302 406 328 242 294 256 262

- 48 + 4 4 -100 - 56 - 22 - 56 - 12 - 55 + 8 - 60 + 10 - 22 -110 + 34 - 32 - 56 - 12 - 58 - 68

-13 -13 -12 -29 -16 -6 -18 -4 -19 +3 -20 +3 -6 -27 $9 -9 -19 -4 -18 -21

312 102 196 185 418 112 512 98 286 96 184 88 112 200 146 99 188 192 242 306

260 110 198 105 212 100 362 112 180 114 96 96 102 89 158 106 168 170 180 142

-

49, 52, 54, 52, 58, 52, 46, 52, 43, 50, 62, 52, 48, 62, 36, 60, 65, 45, 60, 52, 46, 54, 46, 54, 64,

430 300 325 315 350 340 390 350 418 319 314 364 350 470 288 295 325 350 310 303 375 334 340 346 317

459 441 288 294 280 215 280 280 527 354 425 290 285 377 352 238 287 284 274 260 269 302 351 280 218

+ 29 +141 - 37 - 21 - 70 -125 -110 - 70 f109 + 35 +111 - 74 - 65 - 93 + 64 - 57 - 38 - 66 - 36 - 43 -106 - 32 + 11 - 66 - 99

:4: -11 -7 -20 -37 -28 -20 1-26 +11 +35 -20 -19 -20 f22 -19 -12 -19 -12 -21 -28 -10 f3 -19 -31

177 70 92 110 110 220 208 251 350 190 112 320 285 416 95 161 206 241 110 182 50 120 167 342 133

150 80 67 70 125 85 146 132 300 170 186 160 125 212 100 80 80 130 120 106 54 80 120 201 62

- 27 + 10 - 25 - 40 + 15 -135 - 62 -119 - 50 - 20 + 74 -160 -150 -204 + 5 - 81 -126 -114 + 10 - 76 + 4 - 40 - 47 -141 - 71

-17 +8

52

:; - 80 - 206 - 12 -150 + 14 -106 + 20 - 78 + 8 - 10 -111 + 12 + 7 - 20 - 22 - 62 -164

i-43 -49 -10 -29 +14 -37 f21 -47 +9 -9 -22 :; -11 -11 -26 -53

Oxyrnetholone 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90

F F F F F F M M M F F M M M F F F F F F F F F M F

The occurrence of undesirable side effects, notably breast enlargement and loss of libido in males was the limiting factor in reaching a satisfactory AUGUST

1962

hypolipemic

response

from

the drug.

Oxymetholone:* Oxymetholone droxy-methylene-17-alpha-methyl

-15 +14 -27 -37 +14 -61 -30 -47 -14 -22 +66 -50 -53 -49 +5 -50 -61 -47 +9 -42 +8 -33 -28 -41 -53

(HMD) (2-hy17-heta-hy-

* Anadrol@, Syntex Laboratories, Adroydm, Parke Davis and Co., Detroit.

New

York.

Berkowitz,

202

Spitzer

Mgms.y_ 400 t

and 20

Likoff

r

-

Before

-

After

IO

5 HOURS

AFTER

20

15 TEST

I

I

I

2

I

2345670 MONTHS

FIG. 7. Case 71. Effects of treatmrnt with oxynxtholone on weight, cholesterol and triglycerides.

droxy-3-androstanone) is a recently introduced steroid with active anabolic properties.“3t’4 Depression of cholesterol was significant in 52 per cent of those treated: it was usually associated with a fall in the triglyceride levels and a concomitant improvement in the radioactive fat tolerance. In an additional number of cases a reduction in the triglycerides occurred without an associated lowering of levels of cholesterol. Striking results were obtained particularly in underweight hyperlipemic individuals in whom therapy with this preparation produced a decrease in cholesterol and triglyceride levels along with an increase in body weight (Fig. 7 and 8). DISCUSSION The data presented in this report would seem to demonstrate two important points. First, there are apparently a number of agents, unrelated chemically and pharmacologically, that can produce a reduction in the serum cholesterol. On the other hand, the ability to decrease this lipid fraction is not necessarily associated with any alteration in serum triglycerides or fat tolerance. Thus, triparanol and nicotinic acid, though effective hypocholestero-

TG=BS)

24

MEAL

I~rc. 8. Case 71. Radioactive fat tolerance and after treatment with oxymetholone.

I

TG=ZZO)

Rx (Chol.= 340,

3 rims. Rx (Chot=215

tests before

lemic preparations, did not reduce the triglyceride concentration or improve fat tolerance, in contradistinction to d-thyroxine, mytatrienediol and oxymetholone, which did. With these latter agents the most significant reduction of cholesterol occurred in patients who initiall) had hypertriglyccridemia, and the least reduction in those cases \\-ith normal neutral fat levels. This, together with the observation that a normalization of the hypertriglyceridemia resulted in certain patients without an accompanying fall in the cholesterol, suggests that the hypocholesterolemic effect was secondary to the lowcxring of the triglycerides. Lt’hether or not the restoration to normal of an)- or all of these abnormalities when present will influence the pathogenesis of atherosclerosis remains to be established. Nonetheless, these extended achievements, namely, the lowering of the cholesterol and triglycerides and improvement in fat tolerance, would appear to be a more rational and complete objective to seek in any potentially beneficial pharmacologic agent, rather than a hypocholesterolemic effect alone. SUMMARY 1. The effects of triparanol, nicotinic acid, d-thyroxine, mytatrienediol and oxymetholone on the serum cholesterol, triglycerides and fat tolerance have been determined in a group of 90 patients with hypercholesterolemia. 2. Triparanol and nicotinic acid produced a decrease in the serum cholesterol without any significant changes in the triglycerides and fat tolerance. The other agents were effective in lowering the cholesterol in over 50 per cent of the treated patients with a concomitant reduction in the triglycerides and improvement in the fat tolerance. THE

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3. It is postulated that normalization of the triglycerides and fat tolerance, in addition to the cholesterol, is a more rational pharmacologic objective to seek than one directed solely toward lowering the serum cholesterol.

11.

12.

ACKNOWLEDGMENT We acknowledge with thanks the invaluable assistance of OUT technicians, Miss Margaret Williams and Mrs. Gloria Sword. Clinicians participating in these studies were Drs. Philip Lisan, Fred Shechter and Harry Rasansky.

REFERENCES I. ANTONIS, A. and BERSOHN, I.

2.

3.

4.

5.

G.

7.

8.

9.

10.

Serum triglyceride levels in South Africans, Europeans, and Bantus and in ischemic heart disease. Lancet, 1: 998, 1960. ALBRINK, M. J., MEIGS, J. W. and MAN: E. B. Serum lipids, hypertension, and coronary artery disease. Am. J. Med., 31: 4, 1961. LIKOFF, W., BERKOWITZ,D., WOLDOW, A., JACOBS, A. G. and SKLAROFF, D. Radioactive fat absorptive patterns: their significance in coronary artery atherosclerosis. Circulation, 18: 1118, 1958. BERKOWITZ, D., SKLAROFF, D., WOLOOW, A., JACOBS,A. G. and LIKOFF, W. Blood absorption patterns of isotopically labeled fat and fatty acid. Ann. Znt. Med., 50: 247, 1959. BERXOU’ITZ, D., SKLAROFF, D. and IJKOFF, W. Radioactive fat absorption patterns in the geriatric patient. J. Am. Geriatrics SW., 7: 941, 1959. SELLER. R. H., BRACHFELD,J., SANDBERG,H. and BELLET, S. The use of 1’3’ labeled fat in the study of lipid handling in patients with coronary artery disease. Am. J. Med., 27: 231, 1959. BERKOWITZ, D., SPITZER, J. J., LIKOFF, W. and SKLAROFF, D. Radioactive fat tolerance studies in coronary artery disease. South. M. J., 53: 468, 1960. HALL, G. V., GEORGE, E. P. and HICKIE, J. B. Studies of fat metabolism in atherosclerosis by isotopic methods. Australasian Ann. Med., 8: 307, 1959. TIETZ, N. W., BORDEN,T. A., HAMILTON, J. C. and MURPHEY, N. L. The influence of pancreatic secretions on the fat tolerance of humans. Circulation Res.. 8: 214: 1960. METZ, J., ANTONIS, A. and BERSOHN, I. Studies with Ii3i triolein in South African, Bantu and

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white subjects, and in patients with myocardial infarction. &it. M. J., 5208: 1270, 1960. BROWN, D. F., HESLIN, A. S. and DOYLE, J. T. Post-prandial lipemia in health and in ischemic heart disease. New England J. Med., 264: 733, 1961. BERKOWITZ, D., SKLAROFF, D. and LIKOFF, W. The effects of sitosterol, nicotinic acid, and triparanol on fat tolerance. Am. J. Clin. :Vutulritzon, 10: 107, 1962. ZAK, B. Simple rapid microtechnic for serum total cholesterol. Am. J. Clin. Path., 27: 583, 1957. VAN HANDEL, E. and ZILVERSMIT, D. B. Micromethod for the direct determination of serum triglycerides. J. Lab. @Y Clin. Med., 50: 152, 1957. BOYD, G. S. and OLIVER, M. F. Effect of certain thyroxin analogues on sernm lipids in human subjects. J. Endocrinol., 21 : 33, 1960. BENUA, R. S., LEEPER, R. D., KUMAOKA, S. and RAWSON, R. W. Metabolic effects of thyroxin analogues in human myxedema. Ann. New York Acad. SC., 86: 563, 1960. STARR, P., ROEN, P., FREIBURG,L. and SCI~LEISSNER, L. A. Reduction of serum cholesterol by sodium Arch. Znt. Med., 105: 830, dextro-thyroxine. 1960. BEST, M. M. and DUNCAN, C. H. Comparative effects of thyroxin analogues as hypocholesteremic agents. Circulation, 24: 58, 1961. Sodium dextroJONES, R. J. and COHEN, L. thyroxine in coronary disease and hypercholesterolemia. Circulation, 24: 164, 1961. MARMORSTON, J., MOORE, F. J., MAGIDSON, O., Kuz~.~A: 0. and LEWIS, J. J. Effects of long-term estrogen therapy on serum cholesterol and phospholipids in men with myocardial infarction. Ann. Znt. Med., 51 : 972, 1959. MARMORSTON, J., MOORE, F. J., LEWIS, J. J.: MAGIDSON,0. and KUZMA, 0. Estrogen therapy in men with myocardial infarction: occurrence of lipid changes before feminization. Cll?l. Pharmacol. @ Theroj., 1: 449, 1960. MARMORSTON,J., MAGIDSON, 0.: KUZMA. 0. and MOORE, F. J. Estrogen therapy in men with myocardial infarction. J.A.M.A., 174: 241, 1960. BERKOWITZ,D. The treatment of post-gastrectomy weight loss with two new anabolic agents. Clin. Res., 8: 199, 1960. MYERSON, R. M. Clinical and metabolic studies on Am. .I a new anabolic steroid, oxymetholone. M. SC., 241: 732, 1961.