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Current Medical Research and Opinion

Vol. 6,No. 1, 1979

Glipizide (‘Glibenese’) in maturity-onset diabetes mellitus

C. H. L. Klaassen, M.D.

Cum. Med. Res. Opin., (1979), 6,8.

Rode Kruis Ziekenhuis, Beverwijk, The Netherlands

Received: 30th November 1978

Summary A clinical evaluation was carried out in 19 maturity-onset diabetics to assess the e8ectiveness of glipizide in the treatment of newly diagnosedpatients ( I 1) not responding to diet alone and of patients (8) who had been inadequately controlled on other oral antidiabeticagents. Patients were studied over a period of 6 months. AN of the I 1 newly diagnosedpatients were adequately controlled with glipizide in a dose of 5 to 15 mglday (mean 9.6,3.7 mglday), as were 5 of the 8previously treatedpatients with a dose of 10 to 25 mglday (mean 18f6.7 mglday). None of the patients became hypoglycaemic nor did the blood sugar levels indicate hypoglycaemia in the fasting state. Serum triglyceride levels did not change significantly during glipizide therapy, neither did the patients’ weight. No side-efects were reported. Key words: Glipizide - hypoglycaemic agents - diabetes mellitus

Introduction Diet is important in the treatment of the diabetic patient. The aim should be to achieve the ideal patient body weight, and a reduction in dietary sugars is essential. Diet alone, however, may not be effective and if hyperglycaemia persists, oral antidiabetics can be given in order to obtain a further lowering of the blood sugar level. Several sulphonylureas of the so-called second generation are available. Glipizide (‘Glibenese’t) is a new sulphonylurea derivative’ and studies in humans have shown that it is completely absorbed from the gastro-intestinal tract and is metabolized by the liver. The metabolites, which have little or no hypoglycaemic activity, are excreted by the kidney.2 The plasma insulin level increases rapidly after the administration of glipizide and again many hours later in response to a glucose l0ad.4 Clinical experience with this drug has been favourable and there have been a number of published reports which show that it is an effective hypoglycaemic agent.3.5-* In order to evaluate the effectiveness of glipizide, 11 patients who had not yet been treated with oral antidiabetic agents and 8 patients who had been inadequately controlled on other sulphonylureas (alone or in combination with a biguanide) were studied over a period of 6 months. ttrade mark, Pfizer 8

C . H.L. Klaassen

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Patients and methods Patients were selected who were suffering from maturity-onset diabetes mellitus which was inadequately controlled by diet alone and, in some cases, by diet combined with oral antidiabetic agents. Patients with ketoacidosis, either actual or in their history, were excluded. Also excluded were patients with a hypersensitivity to glipizide, and pregnant women. Nineteen patients (12 female and 7 male) with a mean age of 60 years (range 36 to 82 years) were included in the trial. In 11 patients, an additional diagnosis was made: hypertension (1 patient), old myocardial infarction and angina pectoris (2 patients), angina pectoris (1 patient), chronic bronchitis (1 patient), uterine myomatosis (1 patient), neurofibroma (1 patient), BZresection because of duodenal ulcer (1 patient), and osteoarthrosis of the knee or hip (3 patients). Eleven patients had not previously received hypoglycaemic drug treatment. Eight patients were already being treated with other sulphonylureas, in 2 cases in combination with a biguanide. The patients were subjected to a general medical investigation at the beginning of the trial and after 6 months. On these occasions a routine haematological and biochemical investigation was carried out. Before the start of drug treatment and after 3 and 6 months, blood glucose and serum triglyceride levels were determined in the morning before breakfast and 2 hours after every meal (10.00 hrs, 14.00 hrs and 19.00 hrs). The amount of glucose in a 24-hour sample of urine was determined. Dose titration was done on the basis of the 2-hours’ post-prandial blood glucose levels and the urine glucose level. Glipizide treatment was initiated with a dose of 5 mg/day. The maximum dosage was 30 mg/day.

Results Patients already receiving drug treatment Eight patients (5 female, 3 male) had already received oral hypoglycaemic agents. The average duration of this earlier treatment was 4 years (range 4 months to 6.5 years). The treatment always consisted of diet supplemented with an oral hypoglycaemic drug: tolbutamide (6 patients), glibenclamide + buformin (1 patient), tolbutamide + glibenclamide + buformin (1 patient). The mean age of this group of patients was 61 years (range 47 to 74 years). The mean height was 163.5 cm (range 153 to 172 cm) and the mean weight 7 1.4 kg (range 60 to 93 kg). The treatment of these patients was changed to glipizide because the previous therapy gave unsatisfactory results. One of the patients had to be hospitalized soon after the initiation of drug therapy for further treatment with insulin. Two more patients were not adequately controlled with glipizide treatment. Of the remaining 5 patients, excellent results were obtained in 1 patient, good results in 3 patients, and a moderate result in 1 patient (Table I). The mean fasting blood glucose level declined from 17f1.5 mmol/l to 7.251.05 mmol/l. The blood sugar levels at 10.00 hrs, 14.00 hrs, and 19.00 hrs showed a comparable decline, which was maintained 9

G lipizide (‘Glibenese’) in maturity-onset diabetes mellitus

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during the 6-month trial period (Figure 1). The glucose content of the 24-hour urine declined from 331f132 mmo1/24 hr to 34.2&32 mmo1/24 hrs (range 0 to 86 mmo1/24 hrs). Table I. Criteria for assessment of response to treatment ~ _ _ _ _ _ _

Response

Glycaemia (mmol/l)

Excellent Good Moderate Poor None

Glucosuria (mmo1/24 hrs)

Fasting

2-hours’ postprandial

~6

< 1.2 G 8.3 Q 10.0 G 13.9 > 13.9

< 1.2 ~ 8 . 3 Q 12.2 > 12.2

0

< 21.8 ~ 5 5 . to 6 111.2 G 166.8 to 222.4 > 222.4

Figure 1. Mean (IS.E.M.) blood glucose levels before and after treatment in 8 patients already receiving oral hypoglycaemic agents 25

T

120.3

19.5

20 118.8 117.0

15

-

>

2E

10

r9.2

Po 5

3

Fasting

10.00hrs

14.00 hrs

Note: 1 =pre-treatment, 2 = 3 months, 3 = 6 months of treatment 10

19.00 hrs

C . H.L. Klaassen

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The mean dose of glipizide was 18h6.7 mg/day (range 10 to 25 mg/day). The 3 patients not responding to the treatment were given 25,30 and 35 mg/day, respectively. The serum triglyceride levels did not change significantly during glipizide therapy (Figure 2). Figure 2. Mean (i S.E.M.) serum triglyceride levels before and after treatment in 8 patients already receiving oral hypoglycaemic agents

T

T

Fasting

10.00 hrs

14.00 hrs

19.00 hrs

The mean body weight at the end of the observation period was 70.3A9.4 kg. This was not significantly different from the pre-treatment values. None of the patients experienced side-effects from the treatment. Haematological testing as well as blood biochemistry did not show any deviations other than those caused by the diabetes itself. No changes in the cardiovascular status occurred.

New patients Eleven patients were newly diagnosed and had not received prior treatment for their diabetes mellitus with an oral hypoglycaemic agent. The mean age of these patients was 59 years (range 36 to 82 years). The mean height was 167 cm (range 156 to 183 cm) and the mean weight 74 kg (range 60 to 105 kg). A special diet given for 2 weeks had failed to control these patients' diabetes. It was because of this that glipizide was prescribed. The treatment results, as judged by the criteria given in Table I, were good for 4 patients and moderate for 6 patients. In 1 patient the results were good if evaluated on the basis of the blood sugar level, and moderate if judged by the glucosuria. The mean fasting blood sugar level declined from 16.2k3.8 mmol/l pre-treatment to 7.6f0.6 mmol/l post-treatment (Figure 3). The '2-hour post-prandial values declined from 21.2A5.5 mmol/l (lunch) and 20.1 1 3 . 9 mmol/l (dinner) pre-treatment to 7.7h0.9 mmol/l (lunch) and 7.5h0.7 mmol/l (dinner) post-treatment. The glucosuria also diminished considerably in all patients. The mean glucose content of the 24-hour urine pre-treatment amounted to 297 mmo1/24 hrs (range 31 to 525 mmo1/24 hrs). By the end of the observation period, no glucose could be demonstrated in the urine in 6 patients. 11

Glipizide (‘Glibenese’) in maturity-onset diabetes mellitus

Figure 3. Mean (*S.E.M.) blood glucose levels before and after treatment in 11 newly diagnosed diabetic patients

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25

20

6,.,

T

2

120.0

--16.2 15

-: 2 &

-

I’1

-

10

- 8.2

5

* 5

1

2

3

10.00 hrs 14.00 hrs Fasting Note: 1 =pre-treatment, 2 = 3 months and 3 = 6 months of treatment

19.00 hrs

Figure 4. Mean (kS.E.M.) serum triglyceridelevels before and after treatment in 11 newly diagnosed diabetic patients

T

T

Fasting 10.00 hrs 14.00 hrs Note: 1 =pre-treatment, 2 = 3 months and 3 = 6 months of treatment 12

19.00 hrs

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C. H . L. Klaassen

The mean dose of glipizide in this group of patients was 9.6k3.7 mg/day (range 5 to 15 mg/day). The serum triglyceride level diminished during the observation period, but this decline did not reach statistical significance (Figure 4). The weight also showed a small reduction but this was not significant either. None of the patients became hypoglycaemic, nor did the blood sugar levels indicate hypoglycaemia in the fasting patients. The patients did not suffer from side-effectsdue to treatment, and haematological and blood biochemical tests did not show any deviations from normal values, except those caused by the diabetes itself.

Discussion The results of this investigation show that the sulphonylurea derivative glipizide can cause a significant fall in the hyperglycaemia and the glucosuria in patients with maturity-onset diabetes who were inadequately controlled by diet alone or in combination with other oral hypoglycaemic agents. Iacono et a1.4 showed that serum insulin levels increased during glipizide treatment, and reached almost normal levels if followed during the day. They also showed a significant decrease in serum growth hormone levels. These facts lead to the expectation that glipizide will be a welcome addition to the treatment of diabetes mellitus. Most patients in this trial were overweight. Notwithstanding the prescription of an adapted diet and the explanation to the patients of the necessity to adhere to this diet, the weight did not decrease in the observation period. It is important to give this aspect of the treatment of diabetic patients more attention.

References 1. Ambrogi, V., Bloch, K., Daturi, S., Griggi, P., Logemann, W., Parenti, M. A., Rabini, T., and Tommasini, R., (1971). New oral antidiabetic drugs. Part I. Arzneim. F o r d . , 21,200. 2. Fucella, L. M., Tamassia, V., and Vazzelli, G., (1973). Metabolism and kinetics of the hypoglycaemic agent glipizide in man - comparison with glibenclamide. J. Clin. Phurmucol., 13,68. 3. Fuchs, K., (1973). Glipizide versus tolbutamide in maturity-onset diabetes, an open comparative study. Diubetologiu, 9, Suppl., 351. 4. Iacono, G., Ghionni, A., Colucci, M., Verde, G., and Caputo, G., (1974). A clinical study of the metabolic effect of a new oral hypoglycaemic agent. Znt. J . Clin. Phurmucol. Ther., 9,225. 5 . Johannessen, A., and Fagerberg, S. E., (1973). Glipizide, a new oral antidiabetic agent: report of a controlled clinical study in Sweden. Diubetologiu, 9, Suppl., 339. 6. Lentini, S., Bossini, A., and Colomba Pirola, L., (1972). A controlled clinical trial of a new oral hypoglycaemic agent, glipizide (K 4024). Arzneim. F o r d . , 22,1169. 7. Masbernard, A., Guidicelli, G., and Massey, J., (1973). Clinical experience with glipizide in the treatment of mostly complicated diabetes. Diubetologiu, 9, Suppl., 356. 8. Person, G., (1973). Clinical study with glipizide, a new oral antidiabetic drug. Diubetologiu, 9, Suppl., 348.

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Glipizide ('Glibenese') in maturity-onset diabetes mellitus.

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