Diabetic Retinopathy in Non-Insulin-Dependent Diabetes Mellitu~’ Patients: The Role of Gliclazide YASUO AKANUMA, M.D.,
KINORI
Tokyo, Japan,
FUKUDA,
MASATOSHI
KOSAKA, M.D., YASUNORI KANAZAWA, M.D., and MASATO KASUGA, M.D., M.D.,
Okinawa, Japan, SHIGENOBU
Diabetic retinopathy is the most common cause of human blindness between the ages of 30 and 67 in the indusfrialized world. Retinopathy has a multifactori+4 etiology. Standard treatment has aimed at correcting only disturbed glucose metabolism, but this may lead only to the partial amelioratiov of certain hemobiologic factors. In addition to its metabolic action, gliclazide has been shown to have specific hemobiologic properties; studies with gliclazide in animals and humans have shown significant impravements of platelet abnormalities, stimulation of prostaglandin I2 synthesis, and enhancement of fibrinolytic activity. In humans, open-label studies have shown that gliclazide treatment leads to stabilization of background retinopathy in non-insulindependent diabetics and, more recently, these beneficial effects have been confirmed in controlled studies lasting up to 3’7 months in which other sulfonylureas were used. The Japanese Diabetic Retinopathy Program studied the progression of retinopathy over a &year period, comparing gliclazide with other sulfonylureas and with placebo. This study showed that, with equivalent metabolic control, there was a trend toward a lower rate of deterioration and a significantly lower incidence of preproliferative retinopathy in the group receiving gliclazide compared with those receiving other sulfonylureas. Overall, the specific hemobiologic actions of gliclazide appear to offset or retard the progression of diabetic retinopathy and may have the advantage of lowering the incidepce’of preproliferative retinopathy. From lnstltute for Diabetes Care and Research (YA), Asahi Life Foundation, Tokyo, Japan; Toranomon Hospital (KK), Tokyo, Japan; Third Department of Internal Medicine (MK), Faculty of Medicine, llnlverslty of Tokyo, Tokyo, Japan; Department of Ophthalmology (MF), School of Medicine, University of the Ryukyus, Okinawa, Japan; and Department of Public Health (SA), School of Medicine, Gunma University. Maebashi, Japan. Requests for reprints should be addressed to Yasuo Akanuma, M.D., Institute for Diabetes Care and Research, Asahl Life Foundation, 1-6-1 Marunouchi, Chlyoda-Ku, Tokyo 100, Japan.
6A-746
June 24, 1991
The Amencan Journal of Medicine
AOKI,
M.D.,
Maebashi, Japan
iabetic retinopathy is the most common cause of blindness in the 30- to 64-year-old age group in the industrialized world [l] and remains a significant complication, which has yet to be resolved, in the treatment of diabetes mellitus. Nonproliferative retinopathy accounts for 90% of diabetic retinopathies and causes legal blindness in 15% of cases after 5 years [4]. Proliferative retinopathy occurs in 10% of patients with diabetic retinopathy and results in bilateral blindness after 5 years in 50% of these patients [2,3]. Retinopatby is uncommon in patients with insulin-dependent diabetes mellitus (IDDM) of less than 5 years’ duration, but it develops in approximately 75% of IDDM patients within 20 years. The incidence of diabetic retinopathy is more difficult to assess in non-insulin-dependent diabetes mellitus (NIDDM), since it may be present at diagnosis. Diabetic retinopathy develops as part of diabetic microangiopathy, which affects the body as a whole after diabetes has been present for several years. The preclinical stages are characterized by reduced retinal perfusion and increased capillary permeability with thickening of the basal membrane. The early, characteristic signs of background or nonproliferative retinopathy are microaneurysms and dot hemorrhages. As the retinopathy progresses, hard exudates, venous dilation, arteriovenous shunts, dilation of segments of veins, and intra-retinal microvascular abnormalities develop. In a small proportion of diabetics, retinopathy progresses to the most advanced stage, proliferative retinopathy, resulting in marked loss of vision and eventual blindness. Ophthalmologic surgery, particularly photocoagulation by laser, has enabled the progression of proliferative retinopathy to be substantially reduced and remains the most effective method for the prevention of early blindness in diabetic retinopathy. Nevertheless, it is vital that measures to prevent the development and progression of diabetic retinopathy are taken before the retina becomes involved. To date, the treatment of diabetic retinopathy has consisted of correcting only one of the m&y factors involved in its development, namely, dis-
Volume 90 (suppl 6A)
SYMPOSIUM
turbed glucose metabolism. Correction of hemobiologic abnormalities-such as increased blood viscosity, agglutination of the red cells, or formation of the platelet aggregates that constitute intracapillary microthrombi-has yet to be addressed. There is ample evidence of the involvement of hemostatic abnormalities and platelet hyperactivity in diabetic vasculopathy [5,6]. The possibility that good glycemic control may improve some of the hemobiologic abnormalities has already been considered [7]; however, drugs that display favorable hemobiologic properties could be useful in the prevention of diabetic vasculopathy. Laboratory studies have shown that gliclazide, apart from its hypoglycemic effect, suppresses platelet function [8], has an antithrombotic action [g-11], stimulates prostaglandin I2 synthesis in the vascular wall [12], and enhances fibrinolytic activity [13]. Examination of serial photographs taken during the passage of fluorescein through the retinas of normal or pancreatomized dogs reveals a protective effect of gliclazide (10 mg/kg intravenously) against capillary obstruction induced by a constant adenosine diphosphate infusion [ 141. Similar beneficial effects of gliclazide on platelet activity and the fibrinolytic system have been demonstrated in humans [15-171. These findings have led to studies of treatment with gliclazide in patients with diabetic retinopathy. An open trial over a 2.5-year monitoring period reported stability in the progression of retinopathy in 47 of the 60 eyes examined, while 11 of the 13 eyes with established retinopathy at entry into the trial showed no deterioration [ 181. Several recent, controlled studies (some comparing gliclazide with other sulfonylureas) using multiple methods of assessment (e.g., retinography and fluorescein angiography) suggest a lesser progression of retinopathy with gliclazide in the short term (6 months) [19,20] and medium term (18 to 37 months) [Zl-251. A significantly slower rate of deterioration in those patients treated with gliclazide (24%) compared with a control group receiving other hypoglycemics (55%) was reported after 18 to 32 months of therapy [23]. Furthermore, in this study significantly more gliclazide patients (43%) showed an improvement in the status of their retinopathy compared with those in the control group (19%). A study over a 3-year period reported that retinopathy improved or remained stable in 11 of 12 patients receiving gliclazide, 80 mg daily, in contrast to nine of 13 patients receiving glibenclamide, 5 mg daily 1241. In the Diabetic Retinopathy Program, a Z-year double-blind study, three methods of evaluation
ON GLICLAZIDE l AKANUMA
ET AL
were used to quantify the progress of diabetic retinopathy [ZZ]. The results varied with the method used. The rate of deterioration of retinopathy was lower in the gliclazide group (109 assessments) than in the group receiving other sulfonylureas (177 assessments) or in the group treated with diet alone (120 assessments), when estimated according to the severity of the disease. However, there was no difference between the groups when evaluated by a paired comparison method. In addition, the rate of deterioration of retinopathy as estimated by ranking of photofluorographic findings was slightly higher in the gliclazide group (29.0%) than in either the sulfonylurea group (26.0%) or the diet group (18.0%). Although these results differed according to the method of evaluation used, the study did show that gliclazide and other sulfonylureas are comparable with respect to both hypoglycemic effect and safety. Retinal changes in the patients from the Diabetic Retinopathy Program were observed for a further 3 years to ascertain whether gliclazide might be effective in preventing the long-term development and deterioration of diabetic retinopathy. Patients undergoing diet therapy alone were also followed as a control group. After a 5-year follow-up period, changes in fundoscopy were assessed by examining the degree of severity of retinopathy. All three groups showed an increase in the incidence of retinopathy; however the increase in the gliclazide group (7.1%) was not as great as that in either the sulfonylurea (13.6%) or diet (21.7%) groups. These results indicate that gliclazide does not prevent the development of diabetic retinopathy. However, the gliclazide and diet groups showed no increase in the incidence of moderate diabetic retinopathy, in contrast to the sulfonylurea group in which cases of mild retinopathy (simple retinopathy: Scott Ia or II) increased by 5.5% and moderate retinopathy (advanced simple retinopathy: Scott IIIa) increased by 2.7%. This suggests that gliclazide may be superior to other sulfonylurea drugs in delaying the progress of retinopathy. As a further assessment of retinal changes in the study patients, a comparison of the appearance of preproliferative retinopathy among the three groups was undertaken. Patients who showed progression to preproliferative retinopathy received photocoagulation and/or changed to other drug therapy (insulin), which often led to their withdrawal from the study. These patients were included in the assessment of the preproliferative retinopathy despite their withdrawal from the study, and thus all cases of preproliferative retinopathy were accounted for. The drop-out rate in the three treatment groups was not significantly different.
June 24, 1991
The American Journal of Medicine
Volume 90 (suppl 6A)
6A-75s
SYhlPOSIUM
ON GUCLAZIDE
I AKANUMA
ET AL
The gliclazide group showed a significantly lower incidenceof progressionto preproliferative retinopathy comparedwith that of the sulfonylureagroup (p ~0.05); the diet group also displayeda lower incidence than the sulfonylurea group (p = 0.03). These results indicate the efficacy of gliclazide in limiting the increasein severity of diabetic retinopathy. During this 5-year observation period, no instancesof hypoglycemia or significant adverse reactions were encountered. In addition, no significant abnormal laboratory data were observed. Theseresults indicate that gliclazide is a safe drug, suitable for the long-term treatment of diabetes mellitus. Although additional long-term studies are required to support these encouraging findings with gliclazide treatment, this drug is a suitable alternative to other sulfonylureas in preventing or delaying the progress of diabetic retinopathy, and its use may well have distinct advantages,suchas a lower incidenceof preproliferative retinopathy. REFERENCES 1. Grey RHB, Morris A. Ophthalmic survey of a diabetic clinic II. Requirements of treatment of retinopathy. Br J Ophthalmol 1986; 70: 804-7. 2. Caird F, Burditt AF, Drapes GJ. Diabetic retinopathy a further study of prognosis for vision. Diabetes 1968; 17: 121-3. 3. Deckert T, Simonsen SE, Poulsen JE. Prognosis of proliferative retinopathy in juvenile diabetics. Diabetes 1967; 16: 728-33. 4. Caird F, Garrett CJ. Prognosis for vision in diabetic retinopathy. Diabetes 1963;
12: 389-97. 5. Almer LO, Pandolfi M. Oxferlin S. The fibrinolytic system in patients with diabetes mellitus with special reference to diabetic retinopathy. Ophthalmologica 1975; 170:
191-203. 10. Rubinjoni Z, Turk Z, Coce F, Mustovic C, Maitre D. Effect on platelet adhesiveness in diabetics after long term treatment wrth a new oral hypoglycaemic agent, gliclazide. Curr Med Res Ophthalmol 1978; 5: 625-31. 11. Duhault J, Boulanger M, Lonchampt M. Gliclazide and the microvascular system. In: Keen H, Caldwell ADS, Murphy M, Bowker C, eds. Gliclazide and the treatment of diabetes. lnternabonal congress and symposium series no. 20. Proceedings of International Sympostum, London April 1979. London: Academic Press and Royal Society of Medicine, 1980; 9-19. 12. Fujitani B, Maeda J, Tsuboi T, et a/. Effect of gliclazide on aortic prostaglandin I2 formation in normal and streptozotocin-induced diabetic animal. Jpn J Pharmacol
1983; 33: 965-70. 13. Desnoyers P, Labaume J, Anstett M. The pharmacology
of S1702, a new highly effective oral antidiabetic drug with unusual properties. Part 3: Antisickness activity, fibrinolybc properties and haemostatic parameters study. Arzneimittelforschung
1972; 22: 1691-5. 14. Duhault J, Lebon F. The pharmacology
of S1702, a new highly effective oral antidiabetic drug with unusual properties. Part 2: Protective activity of S1702 on the microvascular system in normal and diabetic rats. Arzneimittelforschung 1972; 22:
1686-90. 15. Kuwashima J, Tsuboi T, Komiya M, et al. Inhibitory effect of gliclazide on platelet adhesiveness and aggregation in alloxan diabetes rabbits. Yakugaku Zasshi 1979; 99:
59-64. 16. Tsuboi T, Fujitani 8. Inhibitory mechanism of antiplatelet effect of gliclazide. Blood vessels 1981; 12: 211-4. 17. Nagafushi Y, Tanaka K. Effects of 1-(4.methyl-benzensuIfonyl)-3,3-azabicyclo (3,3,0) octyl urea (gliclazide) on platelet function and thrombus formation induced by argon-gas laser in rat aorta. J Jpn Coil Angiol 1983; 23: 115-21. 18. Lesbre FX, Canicave JC. Metabolic and ophthalmological effects of gliclazide after 2% year administration. Gaz Med France 1984; 1: 51-4. 19. Baba S, Nakagawa S, Takebe K, Goto Y, Maezawa H, Takeda R. Double-blind randomized control study with gliclazide. Clin Eval 1983; 11: 51-94. 20. Chan TK, Chan V, Teng CS, Yeung Rll. Effects of gliclazide and glibenclamide on platelet function, fibrinolysis and metabolic control in diabetic patients with retinop athy. Sem Hop Paris 1982; 58: 1197-1200. 21. Regnault F. Prognosis of non-proliferative diabetic retinopathy during treatment with gliclazide. In: Keen, et al, eds. Gliclazide and the treatment of diabetes. International congress and symposium series no. 20. Proceedings of International Symposium, London, April 1979. London: Academic Press and Royal Society of Medicine,
353-61.
1980: 249-59.
6. Colwell JA, Halushka PV, Sarji K, Levine J, Sage1 J. Nair RMB. Altered platelet function in diabetes mellitus. Diabetes 1976; 25 (Suppl 1): 826-31. 7. Peterson CM, Jones RL, Koenig RJ, Melvin ET, Lehrman ML. Reversible haematologlc sequelae of diabetes mellitus. Ann Intern Med 19n; 86: 425-9. 8. Paton RC, Kemofl PBA, Wales JK, McNicol GP. Effects of diet and gliclazide on the haemostatic system in maturity-onset diabetes. In: Keen M, Caldwell ADS, Murphy M, Bowker C, eds. Gliclazide and the treatment of diabetes. International Congress Symposium series No. 20. Proceedings of International Symposium, London, April 1979. London: Academic Press and Royal Society of Medicine, 1980: 193-9. 9. Ponari 0, Givardi E, Megha S, Pina M, Portioli D, Dettori AG. Antiplatelet effects of long term treatment with gliclazide in diabetic patients. Thromb Res 1980; 16:
22. Kosaka K, Hirata Y, Akanuma Y, et al. Comparative clinical study on the therapeutic effects of oral hypoglycaemic agents in patients with diabetic retinopathy. J Jpn Diabetes Sot 1983; 26: 531-70. 23. Charbonnel 8. Un nouvel abord therapeutique de la maladie diabetique. Bilan a long terme. Volume Therapeutique des Entretiens de Bichat 19n 187-92. 24. Minami N, Matsuba I, Saito S, et al. The effect of long-term treatment with gliclazide on diabetic retinopathy. Jikeikai Med J 1981; 28: 127-31. 25. Cabral BV, Fernando R, IcasasCabral E, Villegas-Cinco L, Cinco L. Gliclazide in the treatment of early diabetic retinal microvascular changes. In: Alberti et al, eds. Eleventh Congress of the International Diabetes Federation Abstracts. Amsterdam: Excerpta Medica, 1982: 7.
6A-766
June 24, 1991
The American Journal of Medicine
Volume 90 (suppl 6A)
KINORI
Tokyo, Japan,
FUKUDA,
MASATOSHI
KOSAKA, M.D., YASUNORI KANAZAWA, M.D., and MASATO KASUGA, M.D., M.D.,
Okinawa, Japan, SHIGENOBU
Diabetic retinopathy is the most common cause of human blindness between the ages of 30 and 67 in the indusfrialized world. Retinopathy has a multifactori+4 etiology. Standard treatment has aimed at correcting only disturbed glucose metabolism, but this may lead only to the partial amelioratiov of certain hemobiologic factors. In addition to its metabolic action, gliclazide has been shown to have specific hemobiologic properties; studies with gliclazide in animals and humans have shown significant impravements of platelet abnormalities, stimulation of prostaglandin I2 synthesis, and enhancement of fibrinolytic activity. In humans, open-label studies have shown that gliclazide treatment leads to stabilization of background retinopathy in non-insulindependent diabetics and, more recently, these beneficial effects have been confirmed in controlled studies lasting up to 3’7 months in which other sulfonylureas were used. The Japanese Diabetic Retinopathy Program studied the progression of retinopathy over a &year period, comparing gliclazide with other sulfonylureas and with placebo. This study showed that, with equivalent metabolic control, there was a trend toward a lower rate of deterioration and a significantly lower incidence of preproliferative retinopathy in the group receiving gliclazide compared with those receiving other sulfonylureas. Overall, the specific hemobiologic actions of gliclazide appear to offset or retard the progression of diabetic retinopathy and may have the advantage of lowering the incidepce’of preproliferative retinopathy. From lnstltute for Diabetes Care and Research (YA), Asahi Life Foundation, Tokyo, Japan; Toranomon Hospital (KK), Tokyo, Japan; Third Department of Internal Medicine (MK), Faculty of Medicine, llnlverslty of Tokyo, Tokyo, Japan; Department of Ophthalmology (MF), School of Medicine, University of the Ryukyus, Okinawa, Japan; and Department of Public Health (SA), School of Medicine, Gunma University. Maebashi, Japan. Requests for reprints should be addressed to Yasuo Akanuma, M.D., Institute for Diabetes Care and Research, Asahl Life Foundation, 1-6-1 Marunouchi, Chlyoda-Ku, Tokyo 100, Japan.
6A-746
June 24, 1991
The Amencan Journal of Medicine
AOKI,
M.D.,
Maebashi, Japan
iabetic retinopathy is the most common cause of blindness in the 30- to 64-year-old age group in the industrialized world [l] and remains a significant complication, which has yet to be resolved, in the treatment of diabetes mellitus. Nonproliferative retinopathy accounts for 90% of diabetic retinopathies and causes legal blindness in 15% of cases after 5 years [4]. Proliferative retinopathy occurs in 10% of patients with diabetic retinopathy and results in bilateral blindness after 5 years in 50% of these patients [2,3]. Retinopatby is uncommon in patients with insulin-dependent diabetes mellitus (IDDM) of less than 5 years’ duration, but it develops in approximately 75% of IDDM patients within 20 years. The incidence of diabetic retinopathy is more difficult to assess in non-insulin-dependent diabetes mellitus (NIDDM), since it may be present at diagnosis. Diabetic retinopathy develops as part of diabetic microangiopathy, which affects the body as a whole after diabetes has been present for several years. The preclinical stages are characterized by reduced retinal perfusion and increased capillary permeability with thickening of the basal membrane. The early, characteristic signs of background or nonproliferative retinopathy are microaneurysms and dot hemorrhages. As the retinopathy progresses, hard exudates, venous dilation, arteriovenous shunts, dilation of segments of veins, and intra-retinal microvascular abnormalities develop. In a small proportion of diabetics, retinopathy progresses to the most advanced stage, proliferative retinopathy, resulting in marked loss of vision and eventual blindness. Ophthalmologic surgery, particularly photocoagulation by laser, has enabled the progression of proliferative retinopathy to be substantially reduced and remains the most effective method for the prevention of early blindness in diabetic retinopathy. Nevertheless, it is vital that measures to prevent the development and progression of diabetic retinopathy are taken before the retina becomes involved. To date, the treatment of diabetic retinopathy has consisted of correcting only one of the m&y factors involved in its development, namely, dis-
Volume 90 (suppl 6A)
SYMPOSIUM
turbed glucose metabolism. Correction of hemobiologic abnormalities-such as increased blood viscosity, agglutination of the red cells, or formation of the platelet aggregates that constitute intracapillary microthrombi-has yet to be addressed. There is ample evidence of the involvement of hemostatic abnormalities and platelet hyperactivity in diabetic vasculopathy [5,6]. The possibility that good glycemic control may improve some of the hemobiologic abnormalities has already been considered [7]; however, drugs that display favorable hemobiologic properties could be useful in the prevention of diabetic vasculopathy. Laboratory studies have shown that gliclazide, apart from its hypoglycemic effect, suppresses platelet function [8], has an antithrombotic action [g-11], stimulates prostaglandin I2 synthesis in the vascular wall [12], and enhances fibrinolytic activity [13]. Examination of serial photographs taken during the passage of fluorescein through the retinas of normal or pancreatomized dogs reveals a protective effect of gliclazide (10 mg/kg intravenously) against capillary obstruction induced by a constant adenosine diphosphate infusion [ 141. Similar beneficial effects of gliclazide on platelet activity and the fibrinolytic system have been demonstrated in humans [15-171. These findings have led to studies of treatment with gliclazide in patients with diabetic retinopathy. An open trial over a 2.5-year monitoring period reported stability in the progression of retinopathy in 47 of the 60 eyes examined, while 11 of the 13 eyes with established retinopathy at entry into the trial showed no deterioration [ 181. Several recent, controlled studies (some comparing gliclazide with other sulfonylureas) using multiple methods of assessment (e.g., retinography and fluorescein angiography) suggest a lesser progression of retinopathy with gliclazide in the short term (6 months) [19,20] and medium term (18 to 37 months) [Zl-251. A significantly slower rate of deterioration in those patients treated with gliclazide (24%) compared with a control group receiving other hypoglycemics (55%) was reported after 18 to 32 months of therapy [23]. Furthermore, in this study significantly more gliclazide patients (43%) showed an improvement in the status of their retinopathy compared with those in the control group (19%). A study over a 3-year period reported that retinopathy improved or remained stable in 11 of 12 patients receiving gliclazide, 80 mg daily, in contrast to nine of 13 patients receiving glibenclamide, 5 mg daily 1241. In the Diabetic Retinopathy Program, a Z-year double-blind study, three methods of evaluation
ON GLICLAZIDE l AKANUMA
ET AL
were used to quantify the progress of diabetic retinopathy [ZZ]. The results varied with the method used. The rate of deterioration of retinopathy was lower in the gliclazide group (109 assessments) than in the group receiving other sulfonylureas (177 assessments) or in the group treated with diet alone (120 assessments), when estimated according to the severity of the disease. However, there was no difference between the groups when evaluated by a paired comparison method. In addition, the rate of deterioration of retinopathy as estimated by ranking of photofluorographic findings was slightly higher in the gliclazide group (29.0%) than in either the sulfonylurea group (26.0%) or the diet group (18.0%). Although these results differed according to the method of evaluation used, the study did show that gliclazide and other sulfonylureas are comparable with respect to both hypoglycemic effect and safety. Retinal changes in the patients from the Diabetic Retinopathy Program were observed for a further 3 years to ascertain whether gliclazide might be effective in preventing the long-term development and deterioration of diabetic retinopathy. Patients undergoing diet therapy alone were also followed as a control group. After a 5-year follow-up period, changes in fundoscopy were assessed by examining the degree of severity of retinopathy. All three groups showed an increase in the incidence of retinopathy; however the increase in the gliclazide group (7.1%) was not as great as that in either the sulfonylurea (13.6%) or diet (21.7%) groups. These results indicate that gliclazide does not prevent the development of diabetic retinopathy. However, the gliclazide and diet groups showed no increase in the incidence of moderate diabetic retinopathy, in contrast to the sulfonylurea group in which cases of mild retinopathy (simple retinopathy: Scott Ia or II) increased by 5.5% and moderate retinopathy (advanced simple retinopathy: Scott IIIa) increased by 2.7%. This suggests that gliclazide may be superior to other sulfonylurea drugs in delaying the progress of retinopathy. As a further assessment of retinal changes in the study patients, a comparison of the appearance of preproliferative retinopathy among the three groups was undertaken. Patients who showed progression to preproliferative retinopathy received photocoagulation and/or changed to other drug therapy (insulin), which often led to their withdrawal from the study. These patients were included in the assessment of the preproliferative retinopathy despite their withdrawal from the study, and thus all cases of preproliferative retinopathy were accounted for. The drop-out rate in the three treatment groups was not significantly different.
June 24, 1991
The American Journal of Medicine
Volume 90 (suppl 6A)
6A-75s
SYhlPOSIUM
ON GUCLAZIDE
I AKANUMA
ET AL
The gliclazide group showed a significantly lower incidenceof progressionto preproliferative retinopathy comparedwith that of the sulfonylureagroup (p ~0.05); the diet group also displayeda lower incidence than the sulfonylurea group (p = 0.03). These results indicate the efficacy of gliclazide in limiting the increasein severity of diabetic retinopathy. During this 5-year observation period, no instancesof hypoglycemia or significant adverse reactions were encountered. In addition, no significant abnormal laboratory data were observed. Theseresults indicate that gliclazide is a safe drug, suitable for the long-term treatment of diabetes mellitus. Although additional long-term studies are required to support these encouraging findings with gliclazide treatment, this drug is a suitable alternative to other sulfonylureas in preventing or delaying the progress of diabetic retinopathy, and its use may well have distinct advantages,suchas a lower incidenceof preproliferative retinopathy. REFERENCES 1. Grey RHB, Morris A. Ophthalmic survey of a diabetic clinic II. Requirements of treatment of retinopathy. Br J Ophthalmol 1986; 70: 804-7. 2. Caird F, Burditt AF, Drapes GJ. Diabetic retinopathy a further study of prognosis for vision. Diabetes 1968; 17: 121-3. 3. Deckert T, Simonsen SE, Poulsen JE. Prognosis of proliferative retinopathy in juvenile diabetics. Diabetes 1967; 16: 728-33. 4. Caird F, Garrett CJ. Prognosis for vision in diabetic retinopathy. Diabetes 1963;
12: 389-97. 5. Almer LO, Pandolfi M. Oxferlin S. The fibrinolytic system in patients with diabetes mellitus with special reference to diabetic retinopathy. Ophthalmologica 1975; 170:
191-203. 10. Rubinjoni Z, Turk Z, Coce F, Mustovic C, Maitre D. Effect on platelet adhesiveness in diabetics after long term treatment wrth a new oral hypoglycaemic agent, gliclazide. Curr Med Res Ophthalmol 1978; 5: 625-31. 11. Duhault J, Boulanger M, Lonchampt M. Gliclazide and the microvascular system. In: Keen H, Caldwell ADS, Murphy M, Bowker C, eds. Gliclazide and the treatment of diabetes. lnternabonal congress and symposium series no. 20. Proceedings of International Sympostum, London April 1979. London: Academic Press and Royal Society of Medicine, 1980; 9-19. 12. Fujitani B, Maeda J, Tsuboi T, et a/. Effect of gliclazide on aortic prostaglandin I2 formation in normal and streptozotocin-induced diabetic animal. Jpn J Pharmacol
1983; 33: 965-70. 13. Desnoyers P, Labaume J, Anstett M. The pharmacology
of S1702, a new highly effective oral antidiabetic drug with unusual properties. Part 3: Antisickness activity, fibrinolybc properties and haemostatic parameters study. Arzneimittelforschung
1972; 22: 1691-5. 14. Duhault J, Lebon F. The pharmacology
of S1702, a new highly effective oral antidiabetic drug with unusual properties. Part 2: Protective activity of S1702 on the microvascular system in normal and diabetic rats. Arzneimittelforschung 1972; 22:
1686-90. 15. Kuwashima J, Tsuboi T, Komiya M, et al. Inhibitory effect of gliclazide on platelet adhesiveness and aggregation in alloxan diabetes rabbits. Yakugaku Zasshi 1979; 99:
59-64. 16. Tsuboi T, Fujitani 8. Inhibitory mechanism of antiplatelet effect of gliclazide. Blood vessels 1981; 12: 211-4. 17. Nagafushi Y, Tanaka K. Effects of 1-(4.methyl-benzensuIfonyl)-3,3-azabicyclo (3,3,0) octyl urea (gliclazide) on platelet function and thrombus formation induced by argon-gas laser in rat aorta. J Jpn Coil Angiol 1983; 23: 115-21. 18. Lesbre FX, Canicave JC. Metabolic and ophthalmological effects of gliclazide after 2% year administration. Gaz Med France 1984; 1: 51-4. 19. Baba S, Nakagawa S, Takebe K, Goto Y, Maezawa H, Takeda R. Double-blind randomized control study with gliclazide. Clin Eval 1983; 11: 51-94. 20. Chan TK, Chan V, Teng CS, Yeung Rll. Effects of gliclazide and glibenclamide on platelet function, fibrinolysis and metabolic control in diabetic patients with retinop athy. Sem Hop Paris 1982; 58: 1197-1200. 21. Regnault F. Prognosis of non-proliferative diabetic retinopathy during treatment with gliclazide. In: Keen, et al, eds. Gliclazide and the treatment of diabetes. International congress and symposium series no. 20. Proceedings of International Symposium, London, April 1979. London: Academic Press and Royal Society of Medicine,
353-61.
1980: 249-59.
6. Colwell JA, Halushka PV, Sarji K, Levine J, Sage1 J. Nair RMB. Altered platelet function in diabetes mellitus. Diabetes 1976; 25 (Suppl 1): 826-31. 7. Peterson CM, Jones RL, Koenig RJ, Melvin ET, Lehrman ML. Reversible haematologlc sequelae of diabetes mellitus. Ann Intern Med 19n; 86: 425-9. 8. Paton RC, Kemofl PBA, Wales JK, McNicol GP. Effects of diet and gliclazide on the haemostatic system in maturity-onset diabetes. In: Keen M, Caldwell ADS, Murphy M, Bowker C, eds. Gliclazide and the treatment of diabetes. International Congress Symposium series No. 20. Proceedings of International Symposium, London, April 1979. London: Academic Press and Royal Society of Medicine, 1980: 193-9. 9. Ponari 0, Givardi E, Megha S, Pina M, Portioli D, Dettori AG. Antiplatelet effects of long term treatment with gliclazide in diabetic patients. Thromb Res 1980; 16:
22. Kosaka K, Hirata Y, Akanuma Y, et al. Comparative clinical study on the therapeutic effects of oral hypoglycaemic agents in patients with diabetic retinopathy. J Jpn Diabetes Sot 1983; 26: 531-70. 23. Charbonnel 8. Un nouvel abord therapeutique de la maladie diabetique. Bilan a long terme. Volume Therapeutique des Entretiens de Bichat 19n 187-92. 24. Minami N, Matsuba I, Saito S, et al. The effect of long-term treatment with gliclazide on diabetic retinopathy. Jikeikai Med J 1981; 28: 127-31. 25. Cabral BV, Fernando R, IcasasCabral E, Villegas-Cinco L, Cinco L. Gliclazide in the treatment of early diabetic retinal microvascular changes. In: Alberti et al, eds. Eleventh Congress of the International Diabetes Federation Abstracts. Amsterdam: Excerpta Medica, 1982: 7.
6A-766
June 24, 1991
The American Journal of Medicine
Volume 90 (suppl 6A)
