Clinical evaluation of a new hypolipidemic drug, CIBA 13,437-Su

Journal of A therosclerosis Research

235

Elsevier Publishing Company, Amsterdam - Printed in The Netherlands

CLINICAL EVALUATION OF A NEW HYPOLIPIDEMIC DRUG, CIBA 13,437-Su

G. HARTMANN AND G. F O R S T E R

Medizinische Universitiitsklinih, Basle, and Medizinische Universittits-Poliklinih, Zurich (Switzerland) (Revised, received April 1st, 1969)

SUMMARY

The first clinical trials with a new aryloxy-type of hypolipidemic compound, the tetralin-derivative CIBA 13,437-Su, are reported. Various hyperlipidemic syndromes were treated in a total of 88 patients for periods up to 22 months. With daily doses of 4-10 mg/kg, i.e. 300-600 mg per day, serum triglycerides and cholesterol were markedly lowered. The most pronounced effect was observed in hyperlipidemias of Types In, IV, and V of the Fredrickson-Lees classification. The pre-/5-fraction appeared to be more readily lowered than the/5-fraction, although the rather resistant hypercholesterolemia of Type II responded in all cases, yet to a lesser degree, and these patients received the higher doses. Slight transient increases in serum transaminases were observed in 7 out of 88 patients. The compound was very well tolerated subjectively. The results demonstrate that 13,437-Su is a very potent hypolipidemic agent.

Key words:

Clinical evaluation - Hyperlipidemias

- Hypolipidemic

agent - Tetralin-

derivative

Of the many compounds suggested as hypolipidemic agents only very few are in current clinical use. Among these, clofibrate (ethyl-a-[p-chlorophenoxy]-isobutyrate) has attracted most interest, although it is not devoid of side-effects and has to be administered in rather large doses. A new compound from the series of substituted aryloxy acids, 2-methyl-2[p-(1,2,3,4-tetrahydro-l-naptlthyl)-phenoxy]propionic acid (CIBA 13,437-Su) has proved to be very active and well tolerated in various animal species as shown by HESS AND BENCZE1. In the experimental animals it lowers both serum cholesterol and triglyceride. J. Atheroscler. Res., 1969, 10:235-246

236

G. HARTMANN, G. FORSTER

The present report summarizes the results of the first clinical trials which now extend to periods of treatment of up to 22 months. The results of two clinics are combined. PATIENTS

A total of 88 patients has so far been treated with the new compound; this includes a few preliminary studies designed to establish the minimal effective dose and general tolerability. The patients' age and sex distribution is shown in Fig. 1. Whereas the first investigations were conducted under hospital conditions, most of the longterm treatments were carried out in out-patients with or without initial periods of hospitalization. All patients were instructed to continue their customary diet without change or restriction and to keep their weight as stable as possible. They did not alter their normal way of life. Most of the patients had some form of atherosclerotic vascular disease (see Table 1), usually coronary heart disease. Xanthomas were present in 7 instances and xanthelasmas in 4 others. METHODS

All serum samples were taken in the morning before breakfast. As a rule, control examinations were performed on the same day of the week on each occasion. In Group A (Basle) total lipids were determined by the method of SPERRY2 until summer 1967 and subsequently b y calculation from the other fractions; total and free cholesterol were estimated by the SPERRY-WEBB modification 3 of the SCHOENHEIMER AND SPERRY procedure, phospholipids b y the method of ZILVERSMIT

49~' 395

25-

20-

i . z 10-

2 0 30 4 0 5 0 6 0 70 8 0

Age

Fig. 1. Age and sex distribution o5 patients treated with 13,437-Su. J. Atheroscler. Res., 1969, I0:235-246

CLINICAL EVALUATIONOF A NEW HYPOLIPIDEMICDRUG, CIBA 13,437-Su

237

TABLE 1 PRINCIPALDIAGNOSIS(88 PATIENTS) Coronary heart disease Periph. vascular occlusion Cerebral vascular disease Diabetes Hypothyroidism Nephrotic syndrome Chronic bronchitis Xanthomatosis Xanthelasmas Hyperlipidemia alone

30 15 5 12 1 1 2 7 4 29

AND DAVIS4, triglycerides by difference calculation in the early stages of the study, and, after the summer of 1967, by the enzymatic procedure of KREUTZ AND EGGSTEIN5, and total fl-lipoproteins by the method of BURSTEIN AND SAMAILLE6. The enzymatic triglyceride method was also adopted in Study Group B (Zurich). In most of the patients of Study Group A electrophoresis on agarose with lipid-staining was carried out according to the technique of HOUTSMULLER7 and in some cases lipoprorein lipase was determined by the method of FREDRICKSON et al. 8. In Group B, total cholesterol was measured according to LEVlNE AND ZAK9 and total esterified fatty acids by the method of FRIED AND HOEFLMAYR10. On the basis of the above mentioned methods, plus serum turbidity determinations, glucose tolerance tests and examination of siblings, the hyperlipidemias could be classified in many cases in accordance with the system of FREDRICKSONAND LEES. However, in several patients assignment to a certain type is merely a description of the plasma lipid or lipoprotein pattern present. Among the predominant hypercholesterolemias cases with a concomitant increase in triglycerides, relatively higher phospholipids compared with Type II and a broad r-band with or without a marked pre-flfraction in the agarose electrophoresis were classified as Type III. In most patients additional laboratory tests were done, including SGOT and SGPT, cholinesterase, alkaline phosphatase, bilirubin, bromsulphalein retention, urea, uric acid, blood glucose, prothrombin, hemoglobin, RBC and WBC, platelets and complete urinalysis. In a few selected patients liver biopsies were carried out. DOSAGE AND DESIGN OF THERAPEUTICEVALUATION CIBA 13,437-Su was available in the form of tablets of 20 and 50 mg at the beginning of the study, and of 100 mg in the later stages. The preparation was given in three divided daily doses. The minimal effective dose proved to be 1-1.5 mg/kg body weight or 80-120 mg per day. Most patients were treated with 300 mg per day, corresponding to an average of 2.5-4.5 mg/kg per day. Variations in the dosage were mostly determined by the type of hyperlipidemia, Type II requiring the highest doses to elicit a significant J. Atheroscler. Res., 1969, 10:235-246

238

G. H A R T M A N N , G. F O R S T E R

response. During the last 6 months, all these patients received 600 mg per day, i.e. up to 10 mg/kg. Treatment was started once 2-3 control values had been determined. Blood samples were taken at intervals of 2 4 weeks in the early stages of treatment and every 4-6 weeks later on. Only 23 patients received the drug for less than 2 months. Twelve patients have been under treatment for more than 1 year. So far, 13,437-Su has been administered for about 2200 patient-weeks or 507 patient-months. The results are presented separately for the different types of hyperlipidemia. The criteria separating hyperlipidemias from normal values are shown in Table 2 and the prevalence of the various types in Table 3. Predominant hypercholesterolemia was present in 57 cases. The response to treatment was evaluated separately for the first 4 weeks, when the drug achieves its near maximum effects, whereas in the subsequent periods the reliability of the drug's lipid-lowering action was assessed. In 28 patients the effect of treatment was substantiated by comparison with values obtained during placebo periods; further details of these studies will be presented elsewhere. In several cases, drug-free periods were included.

TABLE 2 CRITERIA FOR HYPERLIPIDEMIA (MEN)

The values below correspond to a percentile 90 of a normal sample (Basle Studya), calculated separately for age groups of 10 years.

Age Lipids

15-24 years

45-54 years (mg/lO0 ml)

Cholesterol Phospholipids Triglycerides Total tipids

227 233 227 746

309 295 253 966

a In the Basle Study about 2400 individuals of both sexes, employed in the chemical industry, have been examined for all lipid fractions.

TABLE 3 DISTRIBUTION

OF H Y P E R L I P I D E M I A S

Type I Type II Type III Type IV Type V Symptomatic (second.) Within normal range Not determined Total

A C C O R D I N G TO T Y P E

1 22 37 8 5 2 2 11 88

j . Atheroscler. Res., 1969, 1O: 235-246

CLINICAL EVALUATION OF A NEW HYPOLIPIDEMIC DRUG, C I B A 13,437-Su

I=oo 1

"OOm,/..

239

[

TG rngllOOml

1=.I

2000-

!

1973

Chol.

m~ lOOml ldQ90

1453

~'==~ ~

1000237

:300

1036 1188 ~mle

21o 207. . . . . .

;:; . . . . . . . . . . . . . . . . .

-~=

'200 "100

~tl

i

i

2~

o

20

,.0

5.0

85

i

|

1~o ,=o

,,o

i

,50

1~o

Days

Fig. 2. Response of triglycerides and cholesterol during treatment of Type I hyperlipidemia with 200 and 300 mg/day of 13,437-Su. - - - - : triglycerides; . . . . : cholesterol. RESULTS

Type I The only case of pure fat-induced hyperlipidemia was a 38-year-old woman. Fig. 2 shows the moderate response of triglycerides and cholesterol during treatment with 200 and 300 rag/day of 13,437 Su. The long-term decrease after the initial 4 weeks was 3 1 % for triglycerides, 23 % for cholesterol, 28 % for total lipids and 1 1 % for phosphatides. The effect of the drug was unequivocal, b u t not very pronounced. Chol. mg/lOOml 500-

oo

200.

*

100-

.

.

.

.

.

t Pretreatment

.

.

.

4 Treatment

'2

5

1

'

'~

1

'

'

20 Weeks

Fig. 3. Response of type II hypercholesterolemia to 13,437-Su. J. Atherosvler. Res., 1969, 10:235-246

240

G. HARTMANN, G. FORSTER

%Decrease 1~period

l

2 a period

-10

-20-

0t

-40-

-

-

-

-

-504

t

!

|

i

!

B

12

16

20

24

Weeks

Fig. 4. Decrease of serum cholesterol in Type III hyperlipidemia during treatment with 13,437-Su. The results of the first period are computed from 2-5 single values, those of the second period from 2-10 single values.

-20.

-30-

8oj Weeks

Fig. 5. Decrease of serum triglycerides in Type [ t [ h yperlipidemia during treatment with 13,437-Su. The results of the first period are computed from 2-5 single values, those ot the second period from 2-10 single values.

j . Ath.eroscler. Res., 1969, 10:235-246

CLINICAL EVALUATION OF A N E W HYPOLIPIDEMIC DRUG, C I B A

No

=o0,~/d.v

_..oo2u! ~-_.~0]

mg/lqOml

13,437-Su

241

3o0,../,,.~

I

I I I

500-

I

400"

;*e

300

I', . /-"4".

200-

_..-'f/

L ~ / ~ / ~

100-

\/

..... - . . . . . . . . . . . . -

\

e

I

I I I | J

I

2.0

6'0

1;0

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% ............

I/

1;,0

.~0

|

=20

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|

=

3o0 340

|

e~~ !

3=)

*;0

4eo~,s

Fig. 6. R e s p o n s e of s e r u m triglycerides a n d cholesterol to 13,437-Su a n d placebo in t y p e I I I hyperlipidemia. : triglycerides; . . . . : cholesterol.

Type II The response of the cholesterol levels in 9 cases is shown in Fig. 3. The decrease seemed to be rather slow and the m a x i m u m effect was not obtained in some individuals until 8 weeks had passed. The mean decrease during the first 4 weeks was --15.3 %, whereas during weeks 5 - I 6 a mean fall of 23.8% was calculated. TABLE 4 VALUES WITH

FOR

SERUM

CHOLESTEROL

IN T Y P E

Ill

HYPERLIPIDEMIAS

BEFORE

AND

DURING

TREATMENT

13,437-Su (mg/100 ml)

Patient

Before treatment

tnitial period 9

N F. Si. B. Be. M. Ja. R. St. M. W e . E. Le. L. B~. H. B1. R. Wi. M. En. A. Gu. J. K6. B. Le. K. Ba. L. Fe.

281 298 302 312 324 329 333 351 382 384 389 402 409 416 668

3 1 2 2 2 2 2 2 3 2 2 4 3 1 2

Long-term period b

N 243 235 210 284 236 305 266 349 333 298 300 306 328 288 335

2 2 2 2 3 2 2 1 2 3 1 3 4 2 3

N 225 238 213 287 -281 298 311 219 286 271 276 334 300 331

2 7 4 2 -2 2 5 5 17 3 7 5 8 5

(5) (28) (7) (6) -(9) (7) (23) (7) (72) (9) (24) (12) (39) (12)

a W e e k s 2-4. b D u r a t i o n of t r e a t m e n t d u r i n g t h i s period in p a r e n t h e s e s (weeks). N = No. of d e t e r m i n a t i o n s .

J. Atheroscler. Res., 1969, 1 0 : 2 3 5 - 2 4 6

242

G. HARTMANN, G. FORSTER

TABLE 5 VALUES FOR TRIGLYCERIDE IN TYPE

III

H Y P E R L I P I D E M I A S B E F O R E A N D D U R I N G T R E A T M E N T \VITI-I

13,437-Su (mg/100 ml) Patient

Before treatment

Initial period a

N B. Le. M. En. B. Be. E. Le. L. Bgt. H. B1. M. We. F. Si. J. KS. M. Ja. R. Wi. A. Gu. K. Ba. L. Fe.

214 245 250 261 265 292 380 390 428 460 472 610 756 952

3 2 1 2 2 2 2 3 4 2 3 2 1 2

Long-term period b

N 98 166 165 165 176 206 85 144 165 140 104 300 273 326

4 3 2 2 2 1 3 2 3 2 2 1 2 3

N 148 84 141 159 143 126 -142 147 169 204 385 371 251

5 17 7 2 2 5 -2 7 4 5 3 8 5

(12) (72) (28) (9) (6) (23) (3) (5) (24) (7) (7) (9) (39) (12)

a Weeks 2-4. b Duration of treatment during this period in parentheses (weeks). N = No. of determinations. Type HI E v a l u a t i o n of 14 cases (Figs. 4, 5) showed an average decrease of 20.5 % in cholesterol d u r i n g t h e initial 4 weeks a n d of 24.3 ~o d u r i n g the s u b s e q u e n t period. Triglycerides were lowered to a more m a r k e d e x t e n t - - i . e . 50.2 % d u r i n g t h e first 2-4 weeks a n d 52.1 ~o in the l a t e r stages. Tables 4 a n d 5 present t h e a c t u a l values of this g r o u p before a n d d u r i n g t r e a t m e n t . T h e percentage fall in cholesterol a n d less in triglycerides seems to d e p e n d from the s t a r t i n g level. The time-course of the effect on b o t h lipid fractions in a t y p i c a l case is shown in Fig. 6. (The results of the S t u d y G r o u p B (Zurich) of T y p e I I I are n o t i n d i c a t e d in the figures a n d tables, because in these cases t o t a l f a t t y acids were d e t e r m i n e d i n s t e a d of triglycerides. F o r the same reason, only p a r t of t h e T y p e I V a n d V cases are r e p r e s e n t e d in the following figures.) Type IV Fig. 7 shows the m e a n decrease in cholesterol, p h o s p h o l i p i d s a n d t r i g l y c e r i d e s in 4 patients, 2 of w h o m were borderline cases. Following an average fall of 55.5 % t h e triglycerides r e v e r t e d to n o r m a l in 2 cases. Type V I n 4 s u b j e c t s the m e a n falls over an average of 30 weeks were as follows: cholesterol 29.2 %, p h o s p h a t i d e s 27.8 %, a n d triglycerides 72.8 % (Fig. 8). T h e m e a n response of all p r i m a r y h y p e r l i p i d e m i a s , where all lipid fractions were d e t e r m i n e d , is shown in T a b l e 6 for the initial period a n d in T a b l e 7 for t h e l a t e r stages of continuous t r e a t m e n t . J. Atheroscler. Res., 1969, 10:235-246

CLINICAL EVALUATION OF A NEW HYPOLIPIDEMIC DRUG, C I B A -%

Cholesterol

Phosphotlplds

13,437-Su

243

Trlglycerldes

-1Z4 80-

60-

il

40-

20-

0

2-4

>4

0

2-4

>4

0

-54.5

-553

2-4

~4

Weeks

Fig. 7. Response of type IV hyperlipidemia to 13,437-Su. The pretreatment level is set at 100 %. The mean differences in % are computed from the means for each individual and each period,

Phospholipids

Cholesterol

Triglycerides

100,

80. -25.2

60.

-59D 40,

20.

0

2- 4

10-74

0

2- 4

~0-74

0

2-4

13 -74

Weeks

Fig. 8. Response of type V hyperlipidemia to 13,437-Su. Mean differences as in Fig. 7.

Symptomatic hyperlipidemia A 77-year-old woman with severe hypothyroidism was studied over a 14-day period of treatment. Her initial mean cholesterol level of 357 rag/100 ml was lowered by 10 % with a daily dose of 300 mg. The decrease in triglycerides was more pronounced, the initial level o1507 rag/100 ml being reduced by an average of 46 % (5 samples). J. Atheroscler. Res., 1969, 1O: 235-246

244

G. HARTMANN, G, FORSTER

TABLE 6 MEAN RESPONSE TO 13,437-Su Initial period: 39 hyperlipidemias

% Total lipids Cholesterol Phospholipids Triglycerides

--27.6 --18.7 --17.2 --42.3

Mean observation period 3.3 weeks (2-4) TABLE 7 MEAN RESPONSE TO 13,437-Su Long-term effect: 36 hyperlipidemias

Total lipids Cholesterol Phospholipids Triglycerides

--31.0 --22.0 --20.1 -~9.7

Mean observation period 19.7 weeks (5-80)

In one case of Type III hyperlipidemia (53-year-old womau), gross tuberous, xanthomas of the elbows showed regression after several months of treatment and ii, another case (60-year-old women), xanthomas of the palms disappeared completely. SIDE EFFECTS

The subjective tolerability of CIBA 13,437-Su was remarkably good. A few female patient complained of a slight tendency to constipation, but no other side effects were reported. Objectively, a slight and transient increase in both SGOT and SGPT was observed in 7 patients. In all but 1 treatment was continued. One patient, a 43-year-old woman, had a history of chronic cholangitis and had undergone cholecystectomy. In 2 other subjects, chronic anicteric hepatitis ( a men aged 65) and congestion of the liver of cardiac origin (a woman aged 69) were diagnosed during the study. The course of the chronic hepatitis was not adversely affected by the treatment, since the transaminases became normal during continued administration of 600 mg 13,437-Su per day. In 2 women, 1 aged 38 and 1 39 years, with Type II hyperlipidemia, a reversible elevation of the transaminases was observed. In response to a reduction in dose (200 and 300 mg per day respectively), the enzyme values returned to normal. No other liver function tests yielded pathological results. In these 2 patients the highest transaminase values coincided with the lowest lipid levels. A similar situation was J, Atheroscler. Res., 1969, 10:235-246

CLINICAL EVALUATION OF A NEW ttYPOLIPIDEMIC DRUG,

3 2 PATIENTS

CIBA 13,437-Su

245

MEAN DURATION = 3 3 WEEKS

I I

15-

== u

,~ 1 0 E s.

-7

-6

-3

-1

0 +1

+3

+5

",-7

KG

Fig. 9. B o d y - w e i g h t d u r i n g l o n g - t e r m t r e a t m e n t w i t h 13,437-Su.

encountered in 2 further women who revealed slight rise in transaminases with drop to normal within 1-month while treatment was continued. 13,437-Su had no untoward effect on hemoglobin-concentration, RBC, WBC, platelet count, and renal function. Similar transaminase reactions have been observed with clofibrate and attributed to the metabolic activity of the drug u. INFLUENCE ON BODY WEIGHT, BLOOD COAGULATION AND DIABETES

Body weight appeared not to be influenced by the long-term administration of preparation 13,437-Su, as Fig. 9 illustrates. Weight changes that occurred were relatively moderate and of the same extent in both directions. They were most prominent among obese subjects. Twenty-five of the 88 patients were receiving continuous anticoagulant treatment. None of these patients showed any change in their response to the preparation used (phenprocoumon). No effect on glucose tolerance was detected during long-term treatment with 13,437-Su. The regulation of diabetes was in no case affected. In nondiabetic patients glucose-tolerance was unchanged during the study. COMMENTS AND CONCLUSIONS

The new hypolipidemic agent CIBA 13,437-Su has been tested in a large number of patients with various hyperlipidemic syndromes for a total of more than 2200 patient-weeks. It has proved to be a potent substance for lowering elevated serum lipids with a minimum of side effects. As the results show, all types of hyperlipidemia are influenced, though to a variable degree. Triglycerides are more markedly affected than cholesterol or phospholipids. This indicates that the drug acts mainly on the pre-fl-fraction rather than on the fl-lipoproteins and chylomicron fractions. Consequently, Types III, IV, and V respond best to treatment with the compound. J. Atheroscler. Res., 1969, I 0 : 2 3 5 - 2 4 6

246

G. HARTMANN, G. FORSTER No clear-cut failures to respond were e n c o u n t e r e d in the group as a whole, if one

excludes the few cases in which p a t i e n t reliability was doubtful. The generally resist a n t Type I I was influenced in all cases, though to a lesser degree t h a n the other forms of hypercholesterolemia. The effect on serum lipids was rapid, a l t h o u g h a period of 2-4 weeks was required to achieve a m a x i m u m effect. The action of the drug was sustained. No "escape" or t a c h y p h y l a x i s was observed. W i t h d r a w a l of the drug was n o t followed b y a n y r e b o u n d p h e n o m e n o n , i.e. b y an a b n o r m a l increase in lipid levels to above the i n i t i a l values. As regards the general p a t t e r n of its effect on serum lipids, 13,437-Su resembles clofibrate. However, there are essential differences: it is effective in m u c h lower doses a n d in this s t u d y it was f o u n d to act regularly on T y p e I I hypercholesterolemia. F u r thermore, it has no effect on a n t i c o a g u l a n t r e q u i r e m e n t s a n d provokes v i r t u a l l y no subjective side-effects. I n conclusion, the new p r e p a r a t i o n is capable of n o r m a l i z i n g various types of hyperlipidemia w i t h o u t c o n c o m i t a n t dietary t r e a t m e n t a n d of d i m i n i s h i n g the size of x a n t h o m a s . The differences in the response of the various hyperlipidemias to different dose levels are now being studied. ACKNOWLEDGEMENTS T h e v a l u a b l e advice given b y Dr. R. Hess a n d the cooperation of Dr. N. P u l t is gratefully acknowledged, as well as the technical assistance of M. H i l d e n b r a n d , A. Oberh~insli, H. Zingerli a n d H. Graber.

REFERENCES 1 HESS, R. AND W. L. BENCZE, Hypolipidaemic properties of a new tetralin derivative (CIBA

13,437-Su), Experientia (Basel), 1968, 24: 418. 2 SPERRY, W. M., Lipid analysis. In: E. GLICK (Ed.), Methods of Biochemical Analysis, Vol. 2, Interscience Publ., New York, 1955, p. 98. SPERRY, \V. M. AND M. WEBB, A revision of the Schoenheimer-Sperry method for cholesterol determination. J. biol. Chem., 1950, 187: 97. 4 ZILVERSMIT,D. B. AND A. K. DAVIS,Microdetermination of plasma phospholipids by trichloroacetic acid precipitation, J. Lab. clin. Med., 1950, 35: 155. 5 EGGSTEIN,M. AND F. H. KREUTZ,Eine neue Bestimmungsmethode der Neutralfette im Blutserum und Gewebe, Klin. Wschr., 1966, 44: 262. 6 BURSTEIN, M. AND J. SAMAILLE,Nouvelle m6thode de sdparation et de dosage des lipoprot6ines de faible densit6, Ann. biol. Clin., 1959, 17: 23. 7 HOUTSMULLIgR,A. J., A. I-IuYssoN-HAASDIJK,A. HUVSMANAND E. RINKEL VAN DRIEL, The application of Reinagar for the quantitative separation of a- and fl-lipoproteins, Clin. chim. Acta, 1964, 9: 497. 8 FREDRICKSON,D. S., K. ONO AND L. L. DAVIS, Lipolytic activity of postheparin plasma in hyperglyceridemia, J. Lipid Res., 1963, 4: 24. 9 LEVlNE, J. B. AND B. ZAK, Automated determination of serum total cholesterol, Ctin. chim. Acta, 1964, 101: 381. 10 FRIED, R. AND J. HOEFLMAYR, Vereinfachte Methode zur Bestimmung der veresterten Fetts~uren im Serum, KEn. Wschr., 1963, 41: 727. 11 THORP, J. M., Biochemical aspects of toxicology of Atromid, J. Atheroscler. Res., 1963, 3: 737.

]. Atheroscler. Res., 1969, 10:235-246