Tohoku J. exp. Med., 1983, 141, Suppl., 693-706

Comparison of and Treatment in Non- -Dependent

SHIGEAKI BABA, SHOICHI NAKAGAWA,* KAZUO TAKEBE,•õ

YOSHIO GOTO•ö, HIDENORI MAEZAWA•˜, RYOYU TAKEDA//,

NOBUO SAKAMOTO•÷ and IWAO FUKUI//

The Second Dept. of Internal Medicine, Kobe University,

School of Medicine, Kobe 650, *The Second Dept. Of

Internal Medicine, Hokkaido University, School of

Medicine, Sapporo 060, •õ The Third Dept. of Internal

Medicine, Hirosaki University, School of Medicine, Hirosaki

036, •öThe Third Dept. of Internal Medicine, Tohoku

University, School of Medicine, Sendai 980, •˜The Third Dept. of Internal Medicine, Tokyo Medical and Dental

University, School of Medicine, Tokyo 113, //The Second

Dept. of Internal Medicine, Kanazawa University, School

of Medicine, Kanazawa 920, •÷The Third Dept. of Internal

Medicine, Nagoya University, School of Medicine, Nagoya

466, //Central Laboratory for Clinical Investigation, Kyoto

Prefectural University of Medicine, Kyoto 602.

BABA,S., NAKAGAWA,S., TAKEBE,K., GOTO,Y., MAEZAWA,H., TAKEBA,R., SAKAMOTO,N. and FUKUI, I. Comparison of Gliclazide and Glibenclamide Treatment in Non-Insulin-Dependent Diabetes. Tohoku J. exp. Med., 1983, 141, Suppl., 693-706 - Gliclazide has been reported to decrease platelet function and to inhibit the progression of diabetic retinopathy in addition to having a hypogly cemic effect. To confirm these effects we performed a double-blind randomized study using glibenclamide as a reference drug. Thirty-eight hospitals from eight university groups in Japan performed the study on type II diabetic subjects. Evaluation of blood glucose control, platelet adhesiveness, platelet aggregation and blood lipids over 24 weeks were assessed by the central committee. Two hundred and eighty-nine patients were enrolled in the study. Twelve were excluded and 277 were statistically analysed. Homogeneity between the two diabetic groups was demonstrated for background factors. Forty mg of gliclazide was comparable to 2.5mg of glibenclamide in the potency of hypoglycemic efficacy. Funduscopic aggravations were observed in a statistically smaller number of cases in the gliclazide group than in the glibenclamide group and in evaluation of serum lipids, the gliclazide group was also superior to the glibenclanide group. No significant differnce between the two groups was found in platelet adhesiveness and aggrega tion. Gliclazide is a useful drug in the therapy of diabetes mellitus. oral hypoglycemic drug ; glielazide ; glibenclamide ; diabetes mellitus ; randomized study 693 694 S. Baba et al.

Gliclazide (SE-1702) is a new hypoglycemic drug, developed by

Laboratoires Servier in France. It shows a platelet adhesiveness and aggregation reducing activity in addition to hypoglycemic activity, in vivo and in vitro1-8).

From these findings, we expect it to prevent the further advancement of diabetic retinopathy9-10). In order to assess the efficacy of gliclazide, a double-blind randomized study was conducted for the treatment of patients with type II diabetes mellitus, employing glibenclamide as an active control drug. This study was carried out in thirty-eight hospitals from 8 university groups in Japan.

MATERIALS AND METHODS

Test drugs. Gliclazide (S), 1-(3-azabicyclo •u3. 3.0•v oct-3-yl)-3-(p-tolylsulfonyl) urea was used as a test drug (Fig. 1). In order to assess the efficacy of the drug, we adopted

glibenclamide (G) as an active control drug.

Fig. 1. Bliclazide (SE-1702).

Design of double-blind study. The subjects were type II diabetes mellitus patients

with FBS over 130mg/100ml after diet therapy for one to two weeks, in the case of patients

who had received no other medication before the trial, or in the case of patients transferred

from other drugs, they were changed to the test drug on the first day of the study. The treatment lasted 24 weeks. We applied the variable dose schedule method in which dosage

is adjusted according to the patient's response up to 4 tablets per day. Gliclazide and

glibenclamide tablets contain 40mg and 2,5mg of active ingredient, respectively. Gliben clamide tablets bioequivalent to the commercial product were prepared.

Body weight, blood glucose (FBS, blood glucose 2hours after meal), and platelet

adhesiveness were examined 2 times before medication and 6 times in total each 4 week after

medication. Serum lipids (total , triglyceride, HDL-cholesterol) and platelet aggregation were examined 4 times before and after medication. Funduscopic examina

tions were carried out before and after medication. Additionally, urine examination (sugar,

protein, ketone body), hematological examination (WBC, RBC, Ht, Hb), and renal function test (GOT, GPT, Al-P, ƒÁ-GTP, total protein, BUN, creatinine), blood pressure,

ECG, subjective symptoms, adverse effects, hypoglycemic symptoms, compliance with diet

and exercise therapy, drinking and smoking were also observed. Criteria of blood glucose control by the committee. Blood glucose control evaluation at

each observation time was made according to the classification ranging from excellent to

poor shown in Table 1. Blood glucose control was judged the committee to be excellent in cases where 60% or more of the blood glucose evaluations were excellent after administra

tion, good in cases where 60% or more of the blood glucose evaluations were good or

excellent after administration, fair in cases where 60% or more of the blood glucose

evaluations were fair, good or excellent after administration, and all other cases were

considered as poor.

Criteria for platelet adhesiveness control by the committee. Criteria for platelet adhesi

veness at the time of observation are summarized. Cases where 80% or more of platelet

adhesiveness evaluations were normal (platelet adhesiveness : 10.0-56.2%) after administra

tion were considered good. Cases where 60% or more of platelet adhesiveness evaluations

were normal after administration were considered fair, and cases where 59% or less of Comparison of Gliclazide and Glibenclamide 695

TABLE1. Criteria of blood glucosejudgement

TABLE2. Criteria of serum lipid judegement (compared with the value before study)

platelet adhesiveness evaluations were normal after administration were considered poor. Criteria of serum lipid evaluation by the committee. The average difference between the value for premedication and that for post-medication was calculated, and evaluated according to Table 2.

RESULTS and DISCUSSION Diabetic patients taking part in the study Of 289 patients given the drugs, 3 subjects in the glibenclamide group were excluded due to a FBS of 78mg/dl on the first day of administration, a diagnosis of hepatoma 4 weeks after administration and death from heart disease 4days after administration, respectively. Two hundred and eightysix eligible cases, excluding the above 3 cases, were subjected to the safety assessment. Nine more cases were excluded due to difficulty in evaluating the efficacy- patients with a duration of administration of less than 8 weeks could not be considered equivalent to subjects of 24 weeks administration. But subjects who dropped out due to lack of effect, adverse effects or hypoglycemic symptoms were included. As a result, 277 eligible cases were subjected to the efficacyevaluation.

Background of patients As shown in Table 3, there was a slight difference in the number of each sex between the groups. The gliclazide group had a higher percentage of males than 696 S. Baba et al.

TABLE3. Background of patients Comparison of Gliclazide and Glibenclamide 697

U, Mann-Whitney U-test ; x2, x2 test. *** p <0.001 , ** p <0.01, * p <0.05, + p <0.10, NS, not significant. 698 S. Baba et al. the glibenclamide group (p <0.1). But, there were no significant differences in age, obesity index, duration of DM, premedication and control of DM before the study between the two groups. Hypertention as a complication was observed in more cases in the gliclazide group (p <0.05). But there were no significant differences in diabetic complications, hyperlipidemia or heart disease between the two groups.

Patient's situation during the study Hospitalization, drinking, smoking, compliance with diet and exercise the- rapy, changes in body weight and number of tablets taken daily were examined (Table 4). Among them, only the number of tablets taken daily in the gliclazide group tended to be slightly higher than in the glibenclamide group (minimum and final p <0.01).

Blood glucose Fasting and 2 hr blood glucose profiles during the study were markedly reduced in both groups. Two hour blood glucose is shown in Fig. 2. The results of the evaluation of blood glucose by the central committee are shown in Table 5. Eighteen percent of cases in the gliclazide group were judged as excellent, and 17% in the glibenclamide group. Forty-nine percent in the gliclazide group and 50% in the glibenclamide group were judged as good or excellent, and 71% in the gliclazide group and 76% in the glibenclamide group were judged as fair, good or excellent. Poor cases were 27% in the gliclazide group and 21% in the glibenclamide group. As a whole, there was no significant difference between the two groups.

Platelet adhesivenessand aggregation Platelet adhesiveness levels decreased over 4-20 weeks after medication in both groups. There was no significant difference between the two groups. According to the evaluation of the central committee, 31% of cases in the gliclazide group were good, and 30% in the glibenclamide group. Forty-seven percent were fair or good in the gliclazide group and 52% in the glibenclamide group, and 40% in the gliclazide group and 35% in glibenclamide group were poor. As a whole, there was no significant difference between the two groups (Table 6). Bearing in mind that only a small number of cases were investigated, there was no significant difference in platelet aggregation between the two groups.

Serum lipids For the serum lipids, interesting findings were obtained. Total cholesterol(Fig. 3, Table 7). Total cholesterol levels were significantly reduced at the 8th and 16th weeks after medication in the gliclazide group but only at the 24th week in the glibenclamide group, and the gliclazide group Comparison of Gliclazide and Glibenclamide 699

TABLE 4. Patient's situation during the study 700 S. Baba et al.

TABLE5. Evaluation of blood glucose control by Committee

( ) : %, a : Good and excellent, b : Fair, good and excellent.

Fig. 2. 2 hr blood glucose

TABLE6. Evaluation of platelet adhesiveness control by Committee

( ) : %, a : Fair and good. Comparison of Gliclazide and Glibenclamide 701 attained the significantly lower level than the glibenclamide group at the 8th week (p <0.05). According to the evaluation of the central committee, 27% of the cases in the gliclazide group but only 17% in the glibenclamide group showed a moderate decrease (p <0.05). Triglyceride(Fig. 4, Table 8). Triglyceride levels were significantly reduced at the 8th week in the gliclazide group, but there was no significant difference between the two groups. In the central committee evaluation 21% of subjects in the gliclazide group and 31% in the glibenclamide group showed an increase in the level of triglyceride (p<0.1).

* : p <0 .05 (Mann-Whitney U-test, comparison between the two groups). Fig. 3. Total cholesterol.

TABLE7. Evaluation of total cholesterol by Committee

( ) : %, a : Slight and moderate decrease. * : p <0 .05 (Fisher exact probability test). 702 S. Baba et al. HDL-cholesterol (Fig. 5, Table 9). HDL-cholesterol levels increased signifi cantly at the 24th week in the gliclazide group, but no significant difference was observed between the two groups. In the central committee evaluation, 19% of cases in the gliclazide group showed a decrease in HD.L-cholesteroland 31% in the glibenclamide group. The gliclazide group had significantly less cases with a decrease in HDL-cholesterol (p <0.05). These findidgs suggest that the test drug, gliclazide has a favorable effect on

: p <0.1 (Mann-Whitney U-test, comparison between the two groups).

Fig. 4. Triglyceride.

TABLE8. Evaluation of triglyceride by Committee

{ ) : %, a : Slight and moderate decrease. + : p <0 .1 (Fisher exact probability test).

•õ Comparison of Gliclazide and Glibenclamide 703

fi : p <0.1 (Mann-Whitney U-test, comparison between the two groups). Fig. 5. HDL-cholesterol.

TABLE9. Evaluation of HDL-cholesterol by Committee

( ) : %, a : Moderate and marked increase, b : Slight, moderate and marked increase. * : p <0 .05 (Fisher exact probability test). the lipid metabolism of diabetes mellitus, when compared with glibenclamide.

Evaluation of the funduscopic examination Funduscopic examination was performed by ophthalmologic specialists, and we adopted Scott's classification in the right and left eyes for the evaluation. As shown in Table 10, there were no significant differences in improved cases of the right or left eye, or overall between the two groups. On the other hand, the gliclazide group afforded a significantly smaller number of aggravated cases in both right and left eyes, and the overall (p <0.05). In the evaluation carried out by doctors (Table 11), 7% of cases in the 704 S. Baba et al.

gliclazide group improved, and 11% in the glibenclamide group. There was no significant difference between the two groups. But 3% of the gliclazide group and 11% of the glibenclamide group were aggravated (p <0.1).

Summarized evaluation by doctors Final global inprovement rating (FGIR) was evaluated by overall judgement of the condition of diabetes. Marked improvement was seen in 23% of the gliclazide group and 24% of the glibenclamide group. Moderate or marked improvement was seen in 57% of the gliclazide group and 55% of the glibencla mide group. Slight, moderate or marked improvement was seen in 73% of the gliclazide group and 79% of the glibenclamide group. Aggravated cases were 5% in the gliclazide group and 2% in the glibenclamide group. There was no significant difference between the two groups.

TABLE10. Change of Scott's classification

* * : p<0 .01, * : p<0.05 (Fisher exact probability test).

TABLE11. Evaluation of funduscopic findings

: p

+ Comparison of Gliclazide and Glibenclamide 705

Final overall safety rating (FOSR) was evaluated based on adverse effects, hypoglycemic symptoms and laboratory findings. Not safety cases were 11% in gliclazide group and 9% in the glibenclamide group. There was no significant difference between the two groups. Global utility rating (GUR) was evaluated by overall judgement of FGIR and FOSR. Marked useful cases were 26% in the gliclazide group and 25% in the glibenclamide group. Useful and marked useful cases were 73% in the gliclazide group and 77% in the glibenclamide group. Four percent of the cases in the gliclazide group and 3% in the glibenclamide group were unfavorable. There was no significant differenie between the two groups.

Adverse effects,hypoglycemic symptoms and laboratory findings Adverse effects were seen in 7% of the gliclazide group and 4% of the glibenclamide group. There was no significant difference between the two groups. When the adverse effects observed before medication or due to complications or diet were eliminated, they were seen in 3% of the gliclazide group (2: gastro intestinal symptoms, 2 : allergic symptoms, 1 : stiffness of leg, total 5 cases) and 1% of the glibenclamide group (1 : gastro-intestinal symptoms, 1 : allergic sym ptoms, total 2 cases). All of them disappeared after continuation or discontinua tion of the medication. Hypoglycemic symptoms were seen in 7% of the gliclazide group and 15% of the glibenclamide group. The gliclazide group had a lower incidence than the glibenclamide group (p <0.10). All symptoms disappeared after continuation or discontinuation of the medication. Abnormal laboratory findings were seen in 6% of the gliclazide group and 5% of the glibenclamide group. There was no significant difference between the two groups. In detail, slight anemia was observed in 3% of subjects in both groups and 3% of subjects in both groups exhibited defects in liver function tests. The present study demonstrated evidence suggesting that funduscopic aggra vations were less numerous in the gliclazide group than in the glibenclamide group, and in the evaluation of serum lipids, the gliclazide group was also superior to the glibenclamide group. However, in the Diabetic Retinopathy Program (DRP) study11) with gliclazide and other together with diet treatment, findings on diabetic retinopathy were not as clear as those demonstrated in our study. These discrepancies may possibly be attributed to the following differences in the backgrounds of the two studies : (a) Our study included a smaller number of cases of over 10 years duration than the DRP study. (b) In diabetic control rating before commencement of the studies, almost all cases were poor to fair in our study but fair to good in DRP. (c) The observation period was 6 months in our study but 24 months in DRP. (d) Observations were simply funduscopic in our study but more sophisticated in DRP, which adopted retinal color pictures 706 S. Baba et al. and fluorescent angiography in addition to funduscopic observation.

Acknowledgments We would like to thank Prof. Naokata Shimizu (The First Dept. of Internal Medicine, Teikyo University, School of Medicine) and Prof. Akira Nakajima (The Dept. of Ophthal mology, Juntendo University, School of Medicine) for their statistical analyses and excellent suggestions.

References 1) Shimizu, M., Kuwashima, J., Ishikawa, K., Matsui, Y. Sohmura, Y. & Yoshida, K. (1976) Pharmacological studies on gliclazide (1) hypoglycemic activity of gliclazide and its stimulation of insulin secretion. Pharmacometrics, 12, 289-294. 2) Shimizu, M. Tsuboi, T., Fujitani, B., Yoshida K. & Tamura, Y. (1976) Pharmacolo gical studies on gliclazide (2) effect of gliclazide on platelet aggregation, adhesion and blood coagulation. Pharmacometrics, 12, 295-302. 3) Tsuboi, T., Fujitani, B., Maeda, J., Yoshida, K. & Shimzu, M. (1981) Effect of gliclazide on prostaglandin and thromboxane synthesis in guinea-pig platelets. Thrombosis Research, 21, 103-110. 4) Rubinjoni, Z., Coce, F., Mustovic, D., Maitre, D. & Skrabalo, Z. (1981) Effect on platelet adhesiveness in diabetics after long-term treatment with a new oral hypogly cemic agent, gliclazide. Curr, Med. Res. Opin., 5, 625-631. 5) Duhault, J. & Lebon, F. (1972) The Pharmacology of S1702, a now highly effective oral antidiabetic drug with unusual properties, part 2 : protective activity of S1702 on the microvascular system in normal and diabetic rats. Arzneim. Forsch., 22, 1686 -1690. 6) Duhault, J., Regnault, F., Boulanger, M. & Tisserand, F., (1975) Prevention of experimental obstructions in the retinal microcirculation, arterial fluorescein studies. Ophthalmologica, 170, 345-352. 7) Lagarde, M., Dechavenne, M., Thouverez, J-P. & Verry, M. (1975) Effects of glicla zide, a new antidiabetic agent, on the platelet release reaction, rele of adenylate cyclase. Thromb. Res., 6, 345-355. 8) Vainer, H. & Verry, M. (1974) Effects "in vitro" du gliclazide, nouvel agent hypogly cemiant, sur les plaquettes humaines normales. Thromb. Res., 4, 523-538. 9) Regnault, F. (1979) Gliclazide in the treatment of diabetic retinopathy. Advance in Exp. Med. and Biology, 119, 443-448. 10) Riveline, B. (1974) Etude a long terrme d'un nouvel agent antidiabetique sur une population de 1183 cas. Sem. Hop. Paris (Ther.), 50, 133-139. 11) Diabetic Retinopathy Program Research Group (1983) Clinical comparative study on the therapeutic effects of oral hypoglycemic agents in patients with diabetic retinopathy. J. Japan Diab. Soc., 26 (5), 531-570.