Atromid in the treatment of post-climacteric diabetes

694

JOURNAL OF ATHEROSCLEROSIS RESEARCH

ATROMID IN T H E T R E A T M E N T OF POST-CLIMACTERIC D I A B E T E S R. D. M I L L E R

Hull Royal lnfirmary and Beverley Westwood Hospital, Hull (England)

Post-climacteric diabetes is commonly associated with hypercholesterolaemia and atherosclerosis. When therefore in 1962 THORP AND WARING1 reported that Atromid (ethyl-a-p-chlorophenoxy-isobutyrate (CPIB) in combination with androsterone) reduced the concentration of serum cholesterol in rats, and when OLIVER2 showed that it had a similar action in 19 of 20 hypercholesterolaemic patients with ischaemic heart disease, it appeared rational to study the effect of the mixture on diabetes. This paper reports such a study which was embarked upon in June 1969..

SUBJECTS AND METHODS

The subjects were chosen from amongst those who were already in attendance at or who were subsequently referred to a diabetic clinic. A condition of acceptance was freedom from demonstrable hepatic or endocrine disease or infection, and none had been given steroid therapy at any time. Ten women and 8 men were finally selected for trial their ages ranging from 40-74 (mean 59) years. The period of trial lasted from 1.3 to nearly 11 (mean 6.2) months. Atromid was taken at a 6 hourly dose of 500 mg. No subjective side-effects, other than transient morning nausea, were noted. It was appreciated that it might not be possible to make an abrupt substitution of Atromid for insulin or ethically proper to deny insulin to new patients. Therefore, the individual's sensitivity to sulphonyhirea was determined by an intravenous tolbutamide test and where possible patients were weaned off insulin, to Atromid and insulin or sulphonyhirea, on to Atromid alone. Of the 16 patients so tested, 15 were found to be sensitive whilst 1 was resistant to tolbutamide and to chlorpropamide. Of these only 2 required insulin throughout the trial. The question of diet was somewhat of a problem for it is not ethically proper to deny dietary control to overweight diabetics. Twelve of these patients were overweight and 1 was obese but, as will be shown later, dietary control did not materially affect the issue. Serum cholesterol was estimated by a modification of the method of PEARSON et al. 3. Improvement in diabetes is not easy to assess absolutely. Search was made for some absolute value which would serve as a base-line against which the outcome might be related. The "Increment Index ''4 was chosen but was later discarded because movements of the index were too narrow to give confidence that they were J. Atheroscler. Res., 3 (1963) 6 9 4 - 7 0 0

695

ATROMID IN THE TREATMENT OF POST-CLIMACTERIC DIABETES

significant. F o r this reason t h e s t a n d a r d 50 g oral glucose tolerance test has been a d o p t e d as a base-line. Changes in cholesterol c o n c e n t r a t i o n also were studied.

RESULTS AND DISCUSSION

Cholesterol T a b l e I illustrates t h e levels of fasting s e r u m t o t a l cholesterol in 18 p a t i e n t s . Fig. 1 shows, as an e x a m p l e , g r a p h s of t h e p e r c e n t a g e falls in fasting s e r u m t o t a l cholesterol in cases 1-9. I t i l l u s t r a t e s t h r e e things. T h e r e is a r e m a r k a b l e s i m i l a r i t y a n d none of those here i l l u s t r a t e d shows resistance to A t r o m i d . I n all cases there is a r a p i d decline within the initial 4 - 6 weeks. I n m o s t there is a s e c o n d a r y r e b o u n d in t h e level of cholesterol. TABLE I

CHOLESTEROL LEWLS BEFOR~ AND AFTER ATROMIDTREATMENT

(18 PATIENTS)

Total cholesterol (mg/lO0 ml) Range

Mean

Pre-Atromid

234-610

369

Post-Atromid

165-348

218

T h e t i m e scale, which is in weeks a n d d a t e s from t h e c o m m e n c e m e n t of t r e a t m e n t w i t h A t r o m i d , b e a r s no r e l a t i o n to the calendar. However, analysis of all 18 case records shows t h a t this r e b o u n d occurred: 5 t i m e s in D e c e m b e r a n d J a n u a r y each; a n d 1 t i m e each in F e b r u a r y , N o v e m b e r , March, a n d May. I n 4 cases the d a t a are insufficient. T h u s in 12 o u t of 14 cases t h e r e b o u n d occurred b e t w e e n t h e end of

2

4

6

8

10

12

14 i

Weeks 16 18 i

20

22

24

26

28

30

i

i

32

"6 10 2c

~

4o

= 60

~a 70 8o Fig. 1. Percentage fall in c o n c e n t r a t i o n of fasting s e r u m total cholesterol during t r e a t m e n t w i t h Atromid. Cases 1-9.

j . Atheroscler. Res., 3 (1963) 694-700

696

R.D. MILLER

November and the beginning of February. It is not yet possible to determine whether a second and comparable seasonal rebound will be demonstrable around the summer solstice. This observation is in conformity with THORP AND WARING'S1 findings that in the rat there is a seasonal variation in the concentration of serum total cholesterol which corresponds inversely with periods of adrenal and thyroid activity. I t would appear that a similar seasonal pattern obtains in manS. This bi-annual "resistance" to the cholesterol-lowering property of CPIB was in THORP AND WARING'S experience ironed out b y the addition to CPIB of the chosen adrenal steroid, namely androsterone, even when given b y mouth. It would appear that this is not invariably so at least in post-climacteric diabetics. In view of this remarkable lowering of the serum concentration of total cholesterol and the concurrent improvement, subjective and objective, in the diabetic state of the majority some correlation was sought between the cholesterol and blood sugar levels before and after treatment. The data were submitted to DR. J. HOUGH, Department of Physics, University of Hull, who kindly examined them and reported that with one exception no significant correlation was found between either the absolute or the percentage fall in cholesterol and blood sugar level estimated before or after treatment or any decrement in blood sugar level which followed treatment. The exception is that when the post-trial cholesterol is plotted against the post-treatment apogee level of blood sugar, there is a correlation r 0.57 being regarded as significant at the 5 % level and nearly so at the 1 % level.

Diabetes With Atromid, it has been possible to maintain or even enhance control of diabetes on a reduced dose of insulin and in m a n y cases to discontinue insulin. Fig. 2 illustrates two parameters which represent the means of 18 glucose tolerance tests taken prior to and at the end of the trial. The second shows a shrinkage of 22.7 %. This reduction is considerable but it acquires added significance when it is appreciated that the lower parameter illustrates responses to a load of 50 g glucose in 18 diabetic patients 16 of whom have taken no recognised hypoglycaemic agent for a period which has ranged from 1.3--11 months. The result of the trial is summarised schematically in Fig. 3. The vertical line represents the adjusted point in time at which treatment of the 18 cases with Atromid commenced; it is not a calendar date. To the left of the vertical line are those cases who were in attendance and who were being given insulin or sulphonylurea prior to the trial. The blacked-out parallels to the left of the vertical line represent treatment with insulin alone and to the right of the vertical line treatment with insulin and Atromid, in other words the weaning period. The clear parallels represent the periods of treatment with Atromid alone. I t will be seen that the material consisted of 13 insulin-requiring old cases of diabetes and 5 new cases. Of the latter all were considered to require insulin at a greater or lesser dose.

J. Atheroscler. Res., 3 (1963) 694-700

ATROMID IN THE TREATMENT OF POST-CLIMACTERIC DIABETES

697

Weaning off insulin was not possible in 2 cases and throughout the period of observation they continued on their pre-trial dose. Of the remaining 16 it was possible to make an abrupt change to or start on Atromid in 6 cases but in 10 a period of 320 98C 24C O

9 eoc 03

E

16C

,/

shrinkoge 22.7%

12c

u

C9

8C 40 I

I

I

I

i

Time (h) Fig. 2. P a r a m e t e r s of m e a n s of 18 glucose tolerance test p a r a m e t e r s t a k e n before ( - - - - ) after (. . . . ) t r e a t m e n t w i t h Atromid.

1

2

Time (months) 3 4 5 Atr'omid

6

7

8

9

10

and

11

+

H,S.

±

J.G, M.M, G.M. R.R L.R. T.C ~L.

tg:

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M.O. M.T. W.K. M.C. C.R D.W.

.±

InSulin

I=mlnsulin & otromid

~Atromid

+ Insulin reqd. +_ . . . . (minimal dose) Fig. 3. Schematic s u m m a r y of t r e a t m e n t w i t h A t r o m i d of 18 cases of diabetes. F o r f u r t h e r explanations see text.

weaning was required which extended over a mean period of 2.03 months (range 0.5-4.5 months). With the exception of the 2 cases referred to, no insulin or any recognised hypoglycaemic drug was taken b y any patient over a period which ranged from 1.3 to 11.0 months. On the conclusion of the trial the following assessment has been made. Of the 18 patients who submitted to trial 9 will require insulin. In 2 the dose will be full; in 5 it will be less than formerly and in 2 it will be minimal and might well be dispensed J. Atheroscler. Res., 3 (1963) 694-700

698

R . D . MILLER

with. In 9 cases carbohydrate tolerance would appear to have been restored or materially improved and it is considered that there is no need for them to take any hypoglycaemic substance, other than Atromid. GRAVES 1963

1962 Chol. 400 39C F. acid S G.O.T 16 S.G.R T. 13 Uric acid

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Fig. 4. Illustrated history of case described in text.

A criticism might be that a similar improvement might well have been attained by dietetic restriction alone. The diet was restricted for overweight patients to fat which was unsaturated and a carbohydrate intake which at the start averaged 30 g daily and latterly was raised to 120 g daily. It is true that the majority lost weight under this treatment. However, the universal application of this criticism is denied b y the case which is illustrated in Fig. 4 and on which brief comment is made. J. Atheroscler. Res.,

3 (1963) 694-700

ATROMID IN THE TREATMENT OF POST-CLIMACTERIC DIABETES

699

An obese m a n of 58 y e a r s w a s referred in April 1962 a n d f o u n d to be diabetic. H e w e i g h e d 98.4 kg a n d his f a s t i n g s e r u m t o t a l cholesterol m e a s u r e d 400 m g / 1 0 0 ml. No t r e a t m e n t w a s i n s t i t u t e d o t h e r t h a n w e i g h t reduction. H i s prescribed diet c o n t a i n e d c a r b o h y d r a t e a t 10 g/24 h a n d f a t w h i c h w a s e x c l u s i v e l y u n s a t u r a t e d . After 1 m o n t h , his s e r u m cholesterol r e m a i n e d a t 390 rag/ 100 m l a l t h o u g h his w e i g h t w a s falling (figure n o t available). As he w a s c o m p l a i n i n g b i t t e r l y his c a r b o h y d r a t e allowance w a s raised to 50 g/24 h. B y J u l y 1962 his w e i g h t h a d d r o p p e d to 89.4 kg, a fall of 9.0 kg, b u t his s e r u m cholesterol c o n c e n t r a t i o n r e m a i n e d a t 410 m g / 1 0 0 m l a n d his carboh y d r a t e i n t o l e r a n c e w a s v i r t u a l l y u n c h a n g e d . I n O c t o b e r 1962, he w a s g i v e n A t r o m i d 500 m g 6 - h o u r l y a n d his s u b s e q u e n t progress is set o u t in Fig. 4 w h i c h s h o w s t h a t w i t h i n 4 w e e k s t h e c o n c e n t r a t i o n of his f a s t i n g s e r u m t o t a l cholesterol fell f r o m 410 to 264 m g / 1 0 0 m l a n d t h a t t h i s fall w a s s u s t a i n e d e x c e p t for a s e a s o n a l r e b o u n d in D e c e m b e r . T h e progressive fall in his glucose t o l e r a n c e t e s t p a r a m e t e r s s h o u l d be n o t e d a n d in p a r t i c u l a r t h a t a l t h o u g h on M a r c h 31st 1963 his c a r b o h y d r a t e a l l o w a n c e w a s i n c r e a s e d to 120 g/24 h his glucose tolerance p a r a m e t e r of M a y 2 0 t h 1963 is a l m o s t physiological.

Finally, it is normal diabetic experience to anticipate some primary improvement in the glucose tolerance test parameter of the newly discovered case of diabetes. This is due to the eradication of certain infectious and other pathological processes, to the institution of a more ordered and healthy life and to the administration of insulin. Insulin administration however is nothing else than replacement therapy and following on this early improvement, subsequent tolerance tests, each of which is preceded b y the withholding of insulin and the administration of a load of 50 g glucose, show progressive deterioration or at best minimal improvement. In this series of 18 cases of diabetes all of whom were considered to be insulindependent and from 16 of whom all hypoglycaemic drugs other than Atromid were withheld for 1.3-11 months, none, on the completion of the trial and under a similar load of S0 g glucose, showed a parameter which is worse than it was 12 months ago. In 6 it is similar and in 12 it is lowered to a degree which in all cases is material and in some approaches the physiological in level and shape. This work was embarked upon, namely, to determine whether a prima facie case could be made out t h a t Atromid has a significant part to play in the treatment of postclimacteric diabetes. I t is submitted that such a case has been established. ACKNOWLEDGEMENTS

Grateful acknowledgement is made of the helpfulness and industry of the staffs at the Biochemistry Laboratories at the Hull Royal Infirmary and Beverley Westwood Hospital. SUMMARY

Over a period of 11 months, 18 cases of insulin-requiring diabetes have been treated with Atromid. In all cases there was an early fall in the concentration of fasting serum total cholesterol. This fall was sustained except for a seasonal and temporary rebound at or about the time of the winter solstice. In 16 cases insulin and all recognised hypoglycaemic agents were withheld for a period of 1.3-11 months (mean 6.2 months). J..4theroscler. Res., 3 (1963) 694-700

700

R . D . MILLER

The following assessment of the effects of Atromid can be made. Nine patients will remain insulin-dependent and in 2 the dose is full whilst in 7 it is less than formerly. In the remaining 9 patients there is no need for them to take insulin or any recognised hypoglycaemic substance.

R]~SUM]~

Dix-huit cas de diab&te exigeant l'insuline ont 6t6 trait6s par l'Atromide pendant une p6riode de 11 tools. I1 a 6t6 constat6 dans tous ces cas une chute pr6coce du taux du eholestdrol s6rique total ~ jeun. Cette chute s'est maintenue, ~ part d'un retour saisonnier et temporaire pendant ou vers le solstice d'hiver. Dans 16 cas, l'insuline et tousles agents hypoglyc6miants reconnus ont 6t6 refus aux sujets pendant 1.3-11 mois (6.2 mois en moyenne). Cette expdrience a inspir6 les conclusions suivantes. Neuf sujets resteront sous la d6pendance de l'insuline, deux devront recevoir la dose enti~re, tandis qu'elle sera diminu6e chez sept. Les neuf autres sujets n'ont pas besoin de prendre l'insuline ou une substance hypoglyc6miante reconnue.

ZUSAMMENFASSUNG

Wfihrend einer Periode von 11 Monaten wurden 18 Insulin-bedtirftige Zuckerkranke mit Atromid behandelt. Bei allen F/illen stellte sich bald eine Senkung in der Konzentration des gesamtntichternen Cholesterinspiegels ein. Die Senkung blieb bestehen, einen jahreszeitlichen und vortibergehenden Rtickschlag zur Zeit oder um die Wintersonnenwende ausgenommen. Bei 16 F~llen wurden w~hrend einer Periode yon 1.3-11 Monaten (Durchschnitt 6.2 Monate) Insulin und s~tmtliche anerkannt-hypoglyk~imische Stoffe vorenthalten. tJber die Wirkung von Atromid kann Folgendes ausgesagt werden. Neun Patienten werden abh~ingig von Insulin bleiben, wobei bei 2 die volle, und bei 7 eine kleinere Dosis ben6tigt sein wird. Bei den fibrigen 9 Patienten besteht keine Notwendigkeit, Insulin oder eine andere deutlich hypoglyk~misch wirkende Substanz zu verwenden. REFERENCES 1 j. M. THORPANDW. S. WARING,Nature, 194 (1962) 948. 2 M. F. OLIVER,Lancet, i (1962) 1321. 3 S. PEARSON,S. STERNAND T. ~I. McGAVACK,Anal. Chem., 25 (1953) 813. 4 L. J. P. DUNCAN,Quart. J. Exptl. Physiol., 41 (1956) 85. 5 j. PALOHEIMO,Ann. Med. Exptl. B*ol. Fenniae, 39 (1961) Suppl. 8. J. Atheroscler. Res., 3 (1963) 694-700