Acta Medica Scandinavica. Vol. 169, fam. 2,1961

From the Department of Medicine (Head: H. Malmros, M. D.): University Hospital, Lund, Sweden

Assessment of Treatment with Tolbutamide

in Diabetes Mefitus1

BY LARS BRANDT, AKE NORD~N and BENGT SWAHN

The literature on the use of oral therapy in the treatment of diabetes is voluminous. Recent reviews have been published by Marble and Krall (1959), Williams et al. (1959) and Duncan and Baird (1960). In most reports favourable results have been achieved in anything up to 80 per cent of the patients. Failure has usually been ascribed to too wide a selection of patients for the type of treatment. Some authors have observed that after some time the patient will no longer respond to the oral drug.

Our experience of prolonged oral treatment in a small group of patients has been less favourable than could be expected from most published reports. We feel that our findings may justify a warning that oral therapy is frequently not the optimal type of treatment. This may also hold for some patients without glycosuria. 1 Presented in part at the meeting of the Swedish Society for Internal Medicine at Lund, May 7, 1960.

Submitted for publication August 29, 1960.

Material and methods

The material consisted of 66 cases in which treatment was started during the time between January 1, 1956 and December 31, 1957. In the beginning carbutamide was used in some cases but was later replaced by tolbutamide. Most patients were seen at regular intervals by one of us (A. N.) until March 1960. The patients were selected according to the generally accepted criteria : elderly patient, diabetes of short duration, small require- ments of insulin, not controllable on diet only. They were all on a regulated diet with a low-fat content. All the patients were first studied in hospital for their response to tolbutamide. Oral treatment was only con- tinued if it produced a normal fasting blood sugar and no glycosuria. The dosage has varied between 0.5 and 4 grams per day. I n cases showing glycosuria the effect of an increase of the dose was usually studied before going over to insulin. The increase only seldom produced a better result.

Ambulatory controls were carried out at intervals of at most 3 months. The patients were instructed to check their urine daily a t home with chitest@ tablets and to present their records when visiting the clinic. They were also instructed to contact us if glycosuria

193

194 LARS BRANDT, AKE NORDBN AND BENGT SWAHN

Neuro- pathy

+

T a b b I . Grading of complications in diabetes mellitus

Hyper- tension

1. Microaneurysms .............................. 2. Microaneurysms + exudate.. .................. 3. Microaneurysms + exudate + hemorrhages . . , . 1. Palanesthesia,. ................................ 2. Palanesthesia + reflex abnormalities ............ 3. Palanesthesia + reflex abnormalities + paresis or

anesthesia .................................... 1. Arterial diastolic blood pressure 90-100 mm Hg 2. Arterial diastolic blood pressure 105-120 mm H g 3. Arterial diastolic blood pressure 125- mm Hg 1. Proteinuria .................................. 2. Proteinuria + decreased clearing teat. ........... 3. Proteinuria + decreased clearing test + increased

NPN ........................................

occurred and persisted for more than two days. Every follow up examination com- prised ophthalmoscopy, measurement of the blood pressure, neurological examination in- cluding determination of vibratory sense with a bio-thesiometer (Steiness, 1957). In the event of retinal changes not previously observed the patient was referred to the Department of Ophthalmology. Laboratory studies included testing of the urine for reducing substance, protein, urobilinogen and acidosis. AlbustixB was used to dif- ferentiate true proteinuria from the excretion product of tolbutamide. Blood sugar deter- minations were performed according to Hage- dorn et al. (1935) in order to detect hyper- glycemia in the absence of any glycosuria.

Criteria for acceptable results were : general feeling of wellbeing, normal working capacity €or age, no glycosuria, no signs of progress of complications.

A simple system was used for recording complications (table 1 ). Classification of renal involvement offered the greatest difficulties because the patients were treated mainly on an ambulatory basis. Renal function tests were only performed on patients admitted to hospital for complicating disease. The NPN was determined when considered necessary.

Retino- pathy

+ +-I-

+. + f

++ + i- +

Renal lesion

+ ++

+++

Results Oral anti-diabetic drugs were given to

66 patients selected according to the above-mentioned criteria. During the trial 6 of the 66 patients died, three of them during treatment i n hospital. Post- mortem examination showed pancreatic carcinoma in two of them. The third patient died following amputation of one leg. The cause of death was pulmonary embolism. Microscopic examination of the pancreas and liver by routine methods revealed nothing of interest. In one patient still alive laparotomy disclosed pancreatic carcinoma, thus making a total of three patients with this type of tumour.

Fig. 1 illustrates the difficulties in controlling patients with no sugar in the urine but with an increased blood sugar sufficient to prevent healing of gangrene of the foot. T h e patient, a 67-year-old woman, had been treated by her phy- sician with tolbutamide for “several years” and had shown no glycosuria.

TREATMENT WITH TOLBUTAMIDE IN DIABETES MELLITUS 195

insulin lolbutamide

Fasting blood 160. sugar 1~ mg U o q Per cent 130.

m Izo. 110. I

I I I I c I Glycosuria per cent

15 20 25 30 vl0 10 15 20 25 3q0 5 10 15 20

Fig. 1. 67-year-old woman. (K.H. 920524). Diabetes since “several years”; treated with tolbutamide. Gangrene of left foot since 3 months.

She was admitted to hospital with gangrene involving two thirds of the lateral part of left foot. During observa- tion her morning fasting blood sugar was between 130 and 180 mg per 100 ml. The gangrene increased and amputation seemed inevitable. The institution of insulin kept the fasting blood sugar at a level of 90 to 110 mg per 100 ml and was followed by rapid improvement and final healing of the foot.

Fig. 2 illustrates the type of treatment given after 25 to 30 months to 66 patients originally treated with tolbutamide. Two types of changes are obvious. As time passes more and more patients on tol- butamide will require insulin and fewer and fewer will be under satisfactory control. In the course of the trial a few patients were found not to require tolbutamide as long as they observed the dietary restriction. Thirty patients were followed for more than 25 months.

Table I1 gives data on 14 patients followed up for 25 to 29 months, during which they were treated with tol- butamide. The diabetic complications observed at the beginning and end of the period were recorded. Some increase was noted, but it was not impressive enough to justify replacement by insulin.

The reasons why tolbutamide was replaced by insulin in 8 out of the 14 patients are summarized in table 111. In seven there was persistent glycosuria and in the eighth retinopathy appeared to have progressed.

In 16 patients observed for 30 to 44 months the diabetic neuropathy appeared to have progressed. Some of these patients had severe nocturnal leg pain. Nothing suggested toxic neuritis due to tolbutamide. When given insulin, these patients reported rapid improvement and they were able to sleep all night. The data are given in table IV. In 8 patients

196 LARS BRANDT, AKE N O R D ~ N AND BENOT SWAHN

TOTAL NUMBER

TO L BU TA MI 0 E

0 5 10 15 20 25 30 MONTHS

Fig. 2. Type of treatment in 66 patients started on tolbutamide during the following 25-30 months. Six patients died during this period.

in this group of 16, tolbutamide treat- ment was replaced by insulin for reasons given in table V.

Discussion In the control of diabetes criteria

have varied, perhaps more than in any other type of treatment presumably due to the fact that the patient may feel comfortable a t a degree of control which is insufficient to prevent the develop- ment of late complications (Johnsson, 1960). In the old age group, which seems to benefit from oral treatment more than other groups the length of

survival even without diabetes is limited, and it may seem reasonable to use a less restricted schedule for treatment. We have illustrated the importance of the difference between a normal and a slightly elevated blood sugar without glycosuria in the treatment of gangrene of the foot. When the blood sugar was normalized with insulin there was a rapid improvement and amputation, which had seemed inevitable, became unnecessary. The foot healed completely. Such cases are not uncommon.

An observation which has impressed us even though it is difficult to measure, is the mental changes which may follow adequate control of the patient’s diabe-

TREATMENT WITH TOLBUTAMIDE IN DIABETES MELLITUS 197

Tabk II. Evaluation of complications in 14 patients with diabetes mellitus a f w treatment with tolbutamide for 25 to 29 months

Pat. no.

Dead. a Now on insulin treatment

Duration Reasons for insulin Dosage of treat- treatment of ment insulin with Per tol- day butamide I. u.

tes. Loss of memory, difficulties in understanding instructions given, e- motional instability may all seem to be symptoms typical of old age. Frequently these symptoms fade away when un- controlled diabetes is regulated. This may imply that the patient can return to his own home and again be able to take care of himself and also carry out testing of the urine for sugar and, if necessary, administer insulin. Attempts are being made to devise an objective system for grading these symptoms. In some cases they seemed important enough to be considered in the evaluation of the treatment under discussion and were an additional reason for replacing oral therapy by insulin. The improvement has usually been obvious to the patient and only a single patient requested to go back again to oral treatment.

20 22 23

26 28

29 30 31

24monthr

29 ))

28 ))

27 ))

27 >)

Persistent glycosuria . . Persistent glycosuria, . Persistent glycosuria +

retinopathy. . . . . . . . Penistent glycosuria , . Persistent glycosuria +

gangrene .......... Persistent glycosuria. . Persistent glycosuria. . Re t inopath y . . . . . . . .

20 38

28 18

28 40 20 20

In several patients severe nocturnal pains in the legs with neurological signs of polyneuritis promptly disappeared

198 LARS BRAN^, AKE N O R D ~ N AND BENGT SWAHN

Table IV. Evaluation of complications in 16 patients with diabetes mellitus afhr treatmmt with tolbutamide for 30 to 44 months

no.

1 69 116 68 16 74 '7 79 14 61 17 79

'11 57 2 67

I 1 5 58 10 71 '5 60 18 69 19 58 3 51

12 54 13 70

I Now on insulin treatment

Table V, Eight cases in which insulin was given after 30 to 41 months' treatment zvilh tolbutamide

Pat. no.

15

16

of treat- treatment

tol- butamide I. u.

I 34months 30 ))

31 ))

41 k

35 ))

34 >)

36 ))

33 )>

Glycosuria .......... Neuropathy ........ Neuropathy . . . . . . . . Glycosuria . . . . . . . . . . Ret inopa thy ........ Retinopathy and

neuropathy ........ Retinopathy and

Glycosuria . . . . . . . . . . neuropathy ........

28 12 32 36 20

20

16 40

I

when treatment with tolbutamide was replaced by insulin. The response was similar to that in untreated or badly controlled diabetes. We have not found any reason to suspect that tolbutamide per se was the cause of the polyneuritis.

Sixty-six patients representing the material under study were followed up for 25-30 months or more. In a group of 16 patients observed for 30 to 44 months, insulin treatment was later re- quired in 8. In another group of 14 observed for 24 to 29 months adequate control required insulin in 8.

When the number of patients treated with tolbutamide was plotted against time, a declining curve was obtained which had almost the characteristics of

TREATMENT WITH TOLBUTAMIDE IN DIABETES MELLITUS 199

a straight line. On extrapolation the line reached the abscissa at 60 months. If such an approximation turns out to be true, it would mean that with the indica- tions for oral treatment used, there would be no patients still on treatment with tolbutamide after 60 months. Joplin et al. (1959) found that 21 out of 24 patients maintained the same response to tolbutamide during an observation period of one year. A comparison with our findings does not permit of any con- clusions owing to the small number of observations in both groups - the tendency, however, was the same.

Williams et al. (1959) assumed that refractoriness was due to increased capac- ity of the body to inactivate the com- pound. If so, tolbutamide should in a given case be replaced by another oral preparation to reveal the specificity of the mechanism inactivating the drug used. This was not done in our series.

Six of our 66 patients are known to be dead. Only 3 were autopsied. The examination showed pancreatic car- cinoma in 2 of them. One patient still living has been subjected to laparot- omy because of obstructive jaundice and in this case, too, a carcinoma of the pancreas was found. In all 3 instances the carcinoma originated from the ex- ocrinepartof the gland. The high figure of three cases of pancreatic carcinoma in a group of 66 patients illustrates the well-known over-representation of this type of malignancy in diabetes. Nothing can be said about the possibility of pancreatic carcinoma in any of the three cases not submitted to post-mortem examination.

In the statistical report from Denmark published by Clemmesen and Serrensen (1959) 3 to 4 cases of pancreatic car- cinoma were found per 10,000 deaths.

In a series of 10,000 cases of proved diabetes, Marble (1959) found malignant disease in 256 cases. In 33 of them pancreas was involved.

So far nothing seems to be known about any influence of tolbutamide on the exocrine part of the pancreas but it may be worth while drawing attention to the stimulatory effect on the islet cells: an increase in islet volume, en- largement of beta cell nucleus, occasional mitosis and new-formation of beta cells (for review see Duncan and Baird, 1960). Are these changes simply manifestations of a high metabolic activity within the normal range?

Summary Tolbutamide was instituted in 66

patients during the period January 1, 1956 to December 31, 1957. The patients were followed up until March of 1960. Six patients died during the investigation - autopsy of 3 of them revealed pan- creatic carcinoma in 2. One patient still alive is known also to have pancreatic carcinoma.

In a group of 14 patients treated for 25 to 29 months, 8 have required insulin treatment for adequate control. In an- other group of 16 patients treated for 30 to 44 months, insulin was necessary in 8.

It appears that with time tolbutamide treatment on medical indications repre- sents adequate treatment for only a few patients. Social indications may never- theless sometimes justify this type of treatment. Close control is necessary and the effect on the patient’s general state of health when tolbutamide is replaced by insulin frequently gives the best illustration of the ineffectiveness of oral treatment.

200 LARS BRANDT, AKE N O R D ~ N AND BENGT SWAHN

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JOHNSJON, S.: Diabetes, 9: 1, 1960. JOPLIN, G. F., FRASER, R. & VALLANCE-OWEN,

J.: Lancet 2: 582, 1959. MARBLE, A. in JOBLIN, E. P., ROOT, H. F.,

WHITE, P. & MARBLE, A.: Treatment of

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diabetes mellitus. 10th ed. Lea and Feabiger, Philadelphia 1959, p. 577.

MARBLE, A. & KRALL, L. P. in JOSLIN, E. P., ROOT, H. F., WHITE, P. & MARBLE, A.: Treatment of diabetes mellitus. 10th ed. Lea and Feabiger, Philadelphia 1959, p. 301.

Moss, J. M., DELAWTER, DEWITT, E. & CANARY, J. J.: Ann. Int. Med. 50: 1407, 1959.

STEINESS, I.: Acta Med. Scand. 158: 327, 1957.

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WILLIAMS, R. H., POLLEN, R. H., TANNER, D. C.