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Experience with atromid in various hypercholesterolaemic states and diabetes mellitus
JOURNAL OF ATHEROSCLEROSIS RESEARCH
EXPERIENCE
WITH
HYPERCHOLESTEROLAEMIC
ATROMID
689
IN VARIOUS
STATES AND DIABETES
MELLITUS
R. R. DE MOWBRAY Queen Mary's Hospital for the East End, Stratford, London (England)
DESIGN OF STUDY T h i r t y p a t i e n t s w e r e s t u d i e d , all of w h o m w e r e i n c l u d e d in t h e m u l t i c e n t r e t r i a l p r e s e n t e d a t t h e s y m p o s i u m . A n a n a l y s i s of t h e i r clinical f e a t u r e s a n d s e r u m chole s t e r o l levels is g i v e n in T a b l e I. S e v e n t e e n of t h e p a t i e n t s w e r e d i a b e t i c s a n d an TABLE I ANALYSIS OF THE WHOLE
Dmgnosis
Number of pat,ents
Myocardial infarction diabetic 3 non-diabetic 7 total 10 Angina with ischaemic ECG but no infarction* diabetic 3 non-diabetic 3 total 6 Claudication* diabetic 4 non-diabetic 2 total 6 Xanthomatosis* xanthoma tuberosum 1 xanthelasma 1 Symptomless idiopathic hypercholesterolaemia 2
SERIES OF 30 PATIENTS
Sex
Serum cholesterol (rag~ 7O0 ml)
Age
male
#male
range
mean
range
mean
2 7 9
1 0 1
42-67 40-63 40-67
54 48 50
320-450 280-530 280-530
367 360 362
2 1 3
1 2 3
59-69 47-62 47-69
62 56 59
275-340 385-600 275-600
318 502 410
4 1 5
0 1 1
55-68 60-62 55-68
62 61 62
260-340 385-520 260-520
294 452 347
0 0
1 1
0
2
60 56 32-58
45
520 410 370-380
375
* Combinations of conditions, so marked, occurred in 3 patients. Also systolic BP 180-200 in 6 patients (5 diabetic) and diastolic 110-120 in 3 patients (all diabetic). a d d i t i o n a l a n a l y s i s of t h e m is g i v e n in T a b l e I I . T h r e e of t h e 17 d i a b e t i c p a t i e n t s r e q u i r e d insulin; 9 w e r e c o n t r o l l e d on s u l p h o n y l u r e a s alone; 2 r e q u i r e d a d i g u a n i d e in a d d i t i o n to a s u l p h o n y l u r e a ; 3 w e r e c o n t r o l l e d on d i e t alone. T h e y w e r e n o t adm i t t e d to t h e t r i a l u n t i l t h e i r d i a b e t e s h a d b e e n s t a b i l i s e d as far as possible. All p a t i e n t s w e r e g i v e n A t r o m i d 2 g d a i l y in t h r e e d i v i d e d doses a f t e r m a i n m e a l s J. Atheroscler. Res., 3 (1963) 689-693
690
R. R. DE MOWBRAY TABLE II ANALYSIS
OF ASSOCIATED
CONDITIONS
IN 17 DIABETICS
(DURATION OF DIABETES 1--14 YEARS)
Associated condition
Number of Sex patients male female
Myocardial infarction Angina w i t h ischaemic ECG b u t no infarction* Claudication* Healed gangrene Cerebral t h r o m b o s i s Diabetic r e t i n o p a t h y No a p p a r e n t complication
Age
Serum cholesterol
range
mean
range
mean
3
2
1
42-67
54
320-450
367
3 4 2 1 1 4
2 4 1 0 0 1
1 0 1 1 1 3
59-69 55-68 55-62
62 62 58 61 72 59
275-340 260-340 285-370
318 294 327 345 360 320
54-70
285-387
* See footnote to Table I.
for periods of 2-45 (mean 26{) weeks. Two control estimations of serum cholesterol were made at an interval of one week or more before starting treatment and further estimations were made after two weeks' treatment and thereafter at monthly intervals. RESULTS
Effects on s e r u m cholesterol
In the series of 30 patients, the mean serum cholesterol level fell from a control level of 359 mg/100 ml to 256 mg/100 ml, representing a mean fall of 29 %. This new level was reached within 6 weeks of treatment, as judged b y the overall mean, and, although there were subsequent fluctuations, no progressive fall or rise in the mean level occurred subsequently. The absolute fall in cholesterol level was in general roughly proportional to the initial height of cholesterol concentration in the serum. There were, however, considerable individual variations in this pattern. The mean fall in serum cholesterol level varied in individual patients from 17 mg/100 ml (6 %) to 290 mg/100 ml (56 %). Whereas the eventual mean level was reached within 6 weeks in the series as a whole, it was attained within the first two weeks in about half the patients. On the other hand, 2 patients with symptomless idiopathic hypercholesterolaemia took ten weeks to reach their ultimate level and 3 patients with myocardial ischaemia or infarction took 10-22 weeks. In 24 patients (80 %) the mean serum cholesterol level fell below 275 mg/100 mt and in 15 patients (50 %) to 250 mg or less. The most dramatic response occurred in the woman aged 60 years with familial hypercholesterolaemic xanthomatosis, associated with xanthoma tuberosum, a persistently hyperlipaemic serum, angina pectoris and intermittent claudication. In this patient the mean level of serum cholesterol fell from 520 to 230 mg/100 ml. The only really disappointing response was in a man aged 43 years who had suffered myocardial infarction 5 years previously and whose mean serum cholesterol level fell from 530 to only 480 mg/100 ml. J. Atheroscler. Res., 3 (1963) 689-693
ATROMID
IN
HYPERCHOLESTEROLAEMIA
o
AND
DIABETES
691
MELLITUS
~ A o°~ ~ g
~
8
a2
+o
~
~
g, ca
0
"i "6
,~ ~o
'o- ' +
0 o
@
i A~
Z
~ ~o~
"~
"~
o ~*~ ..Qa2
~+ 0
o ¢6 o
o v
o~
~
o9
4-~ ~
O
,1O ca O
.j.
J. Atheroscler. Res., 3 1963) 689-693
692
R. R. DE MOWBRAY
Effect on body weight In 15 of 23 cases the body weight increased by 3-14 pounds (1.4-6.4 kg) in the course of 6 weeks to 6 months, though in 4 of these it subsequently tended to fall again. In 6 cases the weight showed no significant change and in 2 it fell slightly. The weight changes were however difficult to assess, owing to fluctuations.
Side effects These were minimal. Dyspeptic symptoms occurred in 2 diabetic patients. In one of these they were mild and transient. In the other they were associated with drowsiness, which necessitated withdrawal of treatment. A third diabetic patient complained of transient paraesthesias during the first 2 weeks of treatment.
Improvement in symptoms Angina pectoris appeared to improve in 3 out of 10 patients and in none of them did it become more severe. Claudication improved in 3 out of 6 patients. Several patients reported an increase in well-being.
Effect on anti-coagulant therapy In 3 out of 4 patients on long-term dindevan following myocardial infarction the dose of dindevan had to be reduced on account of prolongation of the prothrombin time.
Effect on diabetes mellitus In none of the 17 patients did the diabetes become unstabilised during treatment with Atromid. In none of them were the requirements of insulin or oral hypoglycaemic agents altered and no patient previously treated with diet alone required any additional treatment. The mean random blood sugar level did not change significantly, being 158 nag/100 ml initially and 145 mg/100 ml during treatment. No hypoglycaemic attacks occurred.
Complications and outcome In 6 out of the 17 diabetic patients presumed or proven myocardial infarction occurred during treatment with Atromid. Four of these patients died immediately or at a later date (see Table III). The table shows that these patients were "poor risks" in any case and it is impossible to say whether the fatal outcome was in any way attributable to Atromid. No such complications or fatalities occurred among the non-diabetic patients. SUMMARY
Thirty hypercholesterolaemic patients, mostly with atherosclerosis and 17 of them diabetic, were given Atromid 2 g daily for 2-45 (mean 26.5) weeks. The mean serum cholesterol level fell from 359 to 256 mg/100 ml (29%). The absolute fall was roughly proportional to the initial level but varied from 17 mg/100 ml J. Atheroscler. Res., 3 (1963) 689-693
A T R O M I D IN H Y P E R C H O L E S T E R O L A E M I A
AND DIABETES MELLITUS
693
(6%) to 290 mg/100 ml (56%), being maximal within 2-22 (mean 6) weeks. The most dramatic response was in a patient with xanthomatosis and a lipaemic serum. Side effects were minimal. Angina appeared to improve in 3 of 10 patients and claudication in 3 of 6. Dosage of dindevan had to be reduced in 3 of 4 patients. Treatment and stabilisation of diabetes was not affected. Presumed or proven cardiac infarction occurred during treatment in 6 of 17 diabetic patients, 4 of whom died, but in none of the 13 non-diabetics.
R]~SUM]~
Trente sujets hypercholest6rol6miques, la plupart avec ath6roscl6rose, et 17 avec diab~te, ont reCu de l'Atromide pendant 2-45 (en moyenne 26.5) semaines ~t la dose de 2 g par j our. Le taux moyen du cholest6rol s6rique a baiss6 de 359 ~ 256 rag/100 ml (29%). La baisse absolue a 6t~ approximativement proportionnelle au taux de d6part, mais elle a vari6 de 17 rag/100 ml (6%) ~ 290 rag/100 ml (56%) atteignant son m a x i m u m dans les 2-22 (6 en moyenne) semaines. La r6action la plus frappante a ~t6 celle d'un sujet avec xanthomatose et un s~rum lip6mique. Les effets secondaires ont 6t6 minimes. I1 apparut que l'angine am61iorait chez 3 sur 10 suiets, la claudication chez 3 sur 6. L'administration de dindevan devait fitre r6duite chez 3 sur 4 malades. Le traitement et la stabilisation du diab~te ne furent pas affect~s. Un infarctus du myocarde, prouv6 ou pr6sum6, est survenu au cours du traitement chez 6 sur 17 malades diab6tiques, dont 4 sont morts; aucun infarctus chez les 13 non diab6tiques.
ZUSAMMENFASSUNG
Dreissig hypercholesterin~imische Patienten, gr6sstenteils mit Atherosklerose, wovon 17 Diabetiker, wurde w~thrend 2-45 (Durchschnitt 26.5) Wochen t~iglich 2 g Atromid verabreicht. Der Durchschnitt des Serumcholesterinspiegels fiel yon 359 auf 256 mg/100 ml (29%). Die absolute Senkung stand ungef~thr im Verh~iltnis zu dem Ausgangsspiegel, wechselte aber von 17 mg/100 ml (6%) bis 290 mg/100 ml (56%), wobei das Maximum innerhalb 2-22 (Durchschnitt 6) Wochen erreicht wurde. Die am meisten dramatische Reaktion trat bei einem Patient mit Xanthomatose und lip~imischem Serum auf. Nebenwirkungen waren minimal. Angina schien sich bei 3 yon 10 Patienten zu bessern und Hinken bei 3 von 6. Die Dosierung von Dindevan musste bei 3 von 4 Patienten vermindert werden. Die Behandlung und Stabilisierung der Diabetes blieb unbeeinflusst. Vermuteter oder bewiesener Herzinfarkt trat bei 6 von 17 Diabetikern w~ihrend der Behandlung auf, von denen 4 starben. Die 13 Nicht-Diabetiker blieben aber verschont. j . Atheroscler. Res., 3 (1963) 689-693
EXPERIENCE
WITH
HYPERCHOLESTEROLAEMIC
ATROMID
689
IN VARIOUS
STATES AND DIABETES
MELLITUS
R. R. DE MOWBRAY Queen Mary's Hospital for the East End, Stratford, London (England)
DESIGN OF STUDY T h i r t y p a t i e n t s w e r e s t u d i e d , all of w h o m w e r e i n c l u d e d in t h e m u l t i c e n t r e t r i a l p r e s e n t e d a t t h e s y m p o s i u m . A n a n a l y s i s of t h e i r clinical f e a t u r e s a n d s e r u m chole s t e r o l levels is g i v e n in T a b l e I. S e v e n t e e n of t h e p a t i e n t s w e r e d i a b e t i c s a n d an TABLE I ANALYSIS OF THE WHOLE
Dmgnosis
Number of pat,ents
Myocardial infarction diabetic 3 non-diabetic 7 total 10 Angina with ischaemic ECG but no infarction* diabetic 3 non-diabetic 3 total 6 Claudication* diabetic 4 non-diabetic 2 total 6 Xanthomatosis* xanthoma tuberosum 1 xanthelasma 1 Symptomless idiopathic hypercholesterolaemia 2
SERIES OF 30 PATIENTS
Sex
Serum cholesterol (rag~ 7O0 ml)
Age
male
#male
range
mean
range
mean
2 7 9
1 0 1
42-67 40-63 40-67
54 48 50
320-450 280-530 280-530
367 360 362
2 1 3
1 2 3
59-69 47-62 47-69
62 56 59
275-340 385-600 275-600
318 502 410
4 1 5
0 1 1
55-68 60-62 55-68
62 61 62
260-340 385-520 260-520
294 452 347
0 0
1 1
0
2
60 56 32-58
45
520 410 370-380
375
* Combinations of conditions, so marked, occurred in 3 patients. Also systolic BP 180-200 in 6 patients (5 diabetic) and diastolic 110-120 in 3 patients (all diabetic). a d d i t i o n a l a n a l y s i s of t h e m is g i v e n in T a b l e I I . T h r e e of t h e 17 d i a b e t i c p a t i e n t s r e q u i r e d insulin; 9 w e r e c o n t r o l l e d on s u l p h o n y l u r e a s alone; 2 r e q u i r e d a d i g u a n i d e in a d d i t i o n to a s u l p h o n y l u r e a ; 3 w e r e c o n t r o l l e d on d i e t alone. T h e y w e r e n o t adm i t t e d to t h e t r i a l u n t i l t h e i r d i a b e t e s h a d b e e n s t a b i l i s e d as far as possible. All p a t i e n t s w e r e g i v e n A t r o m i d 2 g d a i l y in t h r e e d i v i d e d doses a f t e r m a i n m e a l s J. Atheroscler. Res., 3 (1963) 689-693
690
R. R. DE MOWBRAY TABLE II ANALYSIS
OF ASSOCIATED
CONDITIONS
IN 17 DIABETICS
(DURATION OF DIABETES 1--14 YEARS)
Associated condition
Number of Sex patients male female
Myocardial infarction Angina w i t h ischaemic ECG b u t no infarction* Claudication* Healed gangrene Cerebral t h r o m b o s i s Diabetic r e t i n o p a t h y No a p p a r e n t complication
Age
Serum cholesterol
range
mean
range
mean
3
2
1
42-67
54
320-450
367
3 4 2 1 1 4
2 4 1 0 0 1
1 0 1 1 1 3
59-69 55-68 55-62
62 62 58 61 72 59
275-340 260-340 285-370
318 294 327 345 360 320
54-70
285-387
* See footnote to Table I.
for periods of 2-45 (mean 26{) weeks. Two control estimations of serum cholesterol were made at an interval of one week or more before starting treatment and further estimations were made after two weeks' treatment and thereafter at monthly intervals. RESULTS
Effects on s e r u m cholesterol
In the series of 30 patients, the mean serum cholesterol level fell from a control level of 359 mg/100 ml to 256 mg/100 ml, representing a mean fall of 29 %. This new level was reached within 6 weeks of treatment, as judged b y the overall mean, and, although there were subsequent fluctuations, no progressive fall or rise in the mean level occurred subsequently. The absolute fall in cholesterol level was in general roughly proportional to the initial height of cholesterol concentration in the serum. There were, however, considerable individual variations in this pattern. The mean fall in serum cholesterol level varied in individual patients from 17 mg/100 ml (6 %) to 290 mg/100 ml (56 %). Whereas the eventual mean level was reached within 6 weeks in the series as a whole, it was attained within the first two weeks in about half the patients. On the other hand, 2 patients with symptomless idiopathic hypercholesterolaemia took ten weeks to reach their ultimate level and 3 patients with myocardial ischaemia or infarction took 10-22 weeks. In 24 patients (80 %) the mean serum cholesterol level fell below 275 mg/100 mt and in 15 patients (50 %) to 250 mg or less. The most dramatic response occurred in the woman aged 60 years with familial hypercholesterolaemic xanthomatosis, associated with xanthoma tuberosum, a persistently hyperlipaemic serum, angina pectoris and intermittent claudication. In this patient the mean level of serum cholesterol fell from 520 to 230 mg/100 ml. The only really disappointing response was in a man aged 43 years who had suffered myocardial infarction 5 years previously and whose mean serum cholesterol level fell from 530 to only 480 mg/100 ml. J. Atheroscler. Res., 3 (1963) 689-693
ATROMID
IN
HYPERCHOLESTEROLAEMIA
o
AND
DIABETES
691
MELLITUS
~ A o°~ ~ g
~
8
a2
+o
~
~
g, ca
0
"i "6
,~ ~o
'o- ' +
0 o
@
i A~
Z
~ ~o~
"~
"~
o ~*~ ..Qa2
~+ 0
o ¢6 o
o v
o~
~
o9
4-~ ~
O
,1O ca O
.j.
J. Atheroscler. Res., 3 1963) 689-693
692
R. R. DE MOWBRAY
Effect on body weight In 15 of 23 cases the body weight increased by 3-14 pounds (1.4-6.4 kg) in the course of 6 weeks to 6 months, though in 4 of these it subsequently tended to fall again. In 6 cases the weight showed no significant change and in 2 it fell slightly. The weight changes were however difficult to assess, owing to fluctuations.
Side effects These were minimal. Dyspeptic symptoms occurred in 2 diabetic patients. In one of these they were mild and transient. In the other they were associated with drowsiness, which necessitated withdrawal of treatment. A third diabetic patient complained of transient paraesthesias during the first 2 weeks of treatment.
Improvement in symptoms Angina pectoris appeared to improve in 3 out of 10 patients and in none of them did it become more severe. Claudication improved in 3 out of 6 patients. Several patients reported an increase in well-being.
Effect on anti-coagulant therapy In 3 out of 4 patients on long-term dindevan following myocardial infarction the dose of dindevan had to be reduced on account of prolongation of the prothrombin time.
Effect on diabetes mellitus In none of the 17 patients did the diabetes become unstabilised during treatment with Atromid. In none of them were the requirements of insulin or oral hypoglycaemic agents altered and no patient previously treated with diet alone required any additional treatment. The mean random blood sugar level did not change significantly, being 158 nag/100 ml initially and 145 mg/100 ml during treatment. No hypoglycaemic attacks occurred.
Complications and outcome In 6 out of the 17 diabetic patients presumed or proven myocardial infarction occurred during treatment with Atromid. Four of these patients died immediately or at a later date (see Table III). The table shows that these patients were "poor risks" in any case and it is impossible to say whether the fatal outcome was in any way attributable to Atromid. No such complications or fatalities occurred among the non-diabetic patients. SUMMARY
Thirty hypercholesterolaemic patients, mostly with atherosclerosis and 17 of them diabetic, were given Atromid 2 g daily for 2-45 (mean 26.5) weeks. The mean serum cholesterol level fell from 359 to 256 mg/100 ml (29%). The absolute fall was roughly proportional to the initial level but varied from 17 mg/100 ml J. Atheroscler. Res., 3 (1963) 689-693
A T R O M I D IN H Y P E R C H O L E S T E R O L A E M I A
AND DIABETES MELLITUS
693
(6%) to 290 mg/100 ml (56%), being maximal within 2-22 (mean 6) weeks. The most dramatic response was in a patient with xanthomatosis and a lipaemic serum. Side effects were minimal. Angina appeared to improve in 3 of 10 patients and claudication in 3 of 6. Dosage of dindevan had to be reduced in 3 of 4 patients. Treatment and stabilisation of diabetes was not affected. Presumed or proven cardiac infarction occurred during treatment in 6 of 17 diabetic patients, 4 of whom died, but in none of the 13 non-diabetics.
R]~SUM]~
Trente sujets hypercholest6rol6miques, la plupart avec ath6roscl6rose, et 17 avec diab~te, ont reCu de l'Atromide pendant 2-45 (en moyenne 26.5) semaines ~t la dose de 2 g par j our. Le taux moyen du cholest6rol s6rique a baiss6 de 359 ~ 256 rag/100 ml (29%). La baisse absolue a 6t~ approximativement proportionnelle au taux de d6part, mais elle a vari6 de 17 rag/100 ml (6%) ~ 290 rag/100 ml (56%) atteignant son m a x i m u m dans les 2-22 (6 en moyenne) semaines. La r6action la plus frappante a ~t6 celle d'un sujet avec xanthomatose et un s~rum lip6mique. Les effets secondaires ont 6t6 minimes. I1 apparut que l'angine am61iorait chez 3 sur 10 suiets, la claudication chez 3 sur 6. L'administration de dindevan devait fitre r6duite chez 3 sur 4 malades. Le traitement et la stabilisation du diab~te ne furent pas affect~s. Un infarctus du myocarde, prouv6 ou pr6sum6, est survenu au cours du traitement chez 6 sur 17 malades diab6tiques, dont 4 sont morts; aucun infarctus chez les 13 non diab6tiques.
ZUSAMMENFASSUNG
Dreissig hypercholesterin~imische Patienten, gr6sstenteils mit Atherosklerose, wovon 17 Diabetiker, wurde w~thrend 2-45 (Durchschnitt 26.5) Wochen t~iglich 2 g Atromid verabreicht. Der Durchschnitt des Serumcholesterinspiegels fiel yon 359 auf 256 mg/100 ml (29%). Die absolute Senkung stand ungef~thr im Verh~iltnis zu dem Ausgangsspiegel, wechselte aber von 17 mg/100 ml (6%) bis 290 mg/100 ml (56%), wobei das Maximum innerhalb 2-22 (Durchschnitt 6) Wochen erreicht wurde. Die am meisten dramatische Reaktion trat bei einem Patient mit Xanthomatose und lip~imischem Serum auf. Nebenwirkungen waren minimal. Angina schien sich bei 3 yon 10 Patienten zu bessern und Hinken bei 3 von 6. Die Dosierung von Dindevan musste bei 3 von 4 Patienten vermindert werden. Die Behandlung und Stabilisierung der Diabetes blieb unbeeinflusst. Vermuteter oder bewiesener Herzinfarkt trat bei 6 von 17 Diabetikern w~ihrend der Behandlung auf, von denen 4 starben. Die 13 Nicht-Diabetiker blieben aber verschont. j . Atheroscler. Res., 3 (1963) 689-693