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Blood Glucose Control and Vision Outcome in Diabetes
Editorial
Blood Glucose Control and Vision Outcome in Diabetes In these tumultuous times for medicine in the United States, we must seize every opportunity to be proactive on behalf of our patients and enhance professional interaction with our non-ophthalmologist physician colleagues. A recent group of publications reinforces the timeliness of the American Academy of Ophthalmology's Diabetes 2000 program. At long last, there is compelling evidence that tight control of blood glucose levels in diabetes decreases the risk of microvascular disease, including retinopathy.l" The Diabetes Control and Complications Trial (DCCT) Research Group, initiated in 1982, is comprised of diabetologists and their patients recruited from 29 centers across the country. ' This clinical trial has reported data on 1441 patients with insulin-dependent diabetes (100M), ranging in age from 13 to 39 years, with follow-up of 3 to 9 years.' Retinopathy, monitored by fundus photography, was the principal measure of outcome. The "primary-prevention cohort" included 726 patients with 100M who were free of retinopathy at baseline ; the "secondary-prevention cohort" included 715 patients with mild retinopathy. Patients were randomized to either " standard" or " intensive" insulin therapy groups. The intensive treatment group received multiple daily insulin injections or insulin infusion by pump, with continual adjustment of insulin dosage. The standard treatment group received one or two daily injections ofinsulin with conventional monitoring ofblood glucose levels. Seven-field fundus photographs at 6-month intervals were graded for retinopathy by masked readers according to the Early Treatment of Diabetic Retinopathy Research Study criteria.' Change in retinopathy was defined as at least three steps of progression from baseline that persisted for at least 6 months. The appearance of proliferative retinopathy or severe non proliferative retinopathy triggered referral for possible photocoagulation. Other outcomes measured included nephropathy, neuropathy, neuropsychologic disorders, macrovascular disease, and quality-of-life. Data analyses at all time intervals clearly indicated statistically significant differences in average glycosylated hemoglobin and blood glucose levels between study groups, and verified that intensive therapy better controlled blood glucose than did standard therapy. Most importantly, the risk of progression of retinopathy was definitely less in the intensive therapy group than in the control, standard therapy group after 36 months of study. After 5 years, the risk of retinopathy in the intensive treatment group was 50% lower than that in the standard treatment group!" Intensive therapy substantially reduced the risk of nephropathy, neuropathy, and, probably, macrovascular disease. Adverse effects of intensive therapy were relatively minor except for an increased rate of hypoglycemia. This and previous trials did note transient "early worsening" ofretinopathy with intensive insulin therapy in the secondary treatment cohort during the first year of treatment.4 Soft exudates and intraretinal microvascular changes increased early on in intensively treated patients but tended to regress toward baseline by 18 months. The incidence of visionthreatening complications of diabetes, including macular edema and neovascularization, was decreased dramatically by intensive insulin therapy." By life-table anal ysis, sustained microaneurysms were noted in only 70% of intensively treated patients but in 90% of patients who received standard treatment. Intensive treatment lowered the risk of progression of retinopathy in patients with either longstanding (>2.5
703
Ophthalmology Volume 102, Number 5, May 1995 years) or short-duration «2.5 years) diabetes. The 9-year incidence of new vessels on the disc or elsewhere was 24% among patients who received standard treatment but only 8% among patients who received intensive treatment. The relative risk of macular edema after 9 years was 44% and 27% among standard and intensively treated groups, respectively. In the secondary intervention cohort, 5.5% of patients receiving intensive treatment and 14.2% of patients receiving standard treatment also received laser. In the secondary intervention cohort, the intensively treated group needed less than one-half the laser treatments used in the standard treatment group. With regard to retinopathy status after 5 years, 51 % of patients who received intensive treatment in the primary cohort were stable compared with baseline, versus 33% of patients who received standard treatment. In the secondary treatment group, 48% of patients who received intensive treatment were stable compared with baseline, versus 32% among those who received standard treatment. Several useful generalizations derived from the above series of research reports are: the earlier that intensive therapy is begun in the course of diabetic retinopathy, the more effective it will be; advanced retinopathy also profits.from intensive insulin therapy, although at least 3 years of intensive therapy may be necessary to see these benefits; sight-threatening complications, including macular edema and new vessel formation on the disc and elsewhere, are reduced by intensive insulin therapy; the rate of progression of retinopathy among patients who receive conventional therapy increases with time, whereas intensive insulin therapy decreases the rate of progression. As retinopathy is the "model" diabetic vascular disease, ophthalmologists can playa major role in disseminating this information. Improved communication among diabetologists, other primary care givers, and ophthalmologists is essential. Increased costs of more frequent checkups, special equipment such as insulin pumps, and more frequent monitoring of blood glucose or glycosylated hemoglobin determinations will no doubt slow or even prevent the application of intensive insulin therapy to many patients. We encourage ophthalmologists to familiarize themselves with these recent studies and to explore, in cooperation with other physicians, the use of intensive insulin therapy, especially in young patients with diabetes. References
I. Brinchmann-Hansen 0, Dahl-Jegensen K, Sandvik L, Hanssen KF. Blood glucose concentrations and progression of diabetic retinopathy: the seven year results of the Oslo study. Br Med J 1992;304: 19-22. 2. Reichard P, Nilsson B-Y, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993;329:304-9. 3. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. 4. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus: The Diabetes Control and Complications Trial. Arch Ophthalmol 1995; 113:36-51. 5. The Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in The Diabetes Control and Complications Trial. Ophthalmology 1995;102: 647-61. DON MINCKLER, MD
Editor-in-Chief
704
Blood Glucose Control and Vision Outcome in Diabetes In these tumultuous times for medicine in the United States, we must seize every opportunity to be proactive on behalf of our patients and enhance professional interaction with our non-ophthalmologist physician colleagues. A recent group of publications reinforces the timeliness of the American Academy of Ophthalmology's Diabetes 2000 program. At long last, there is compelling evidence that tight control of blood glucose levels in diabetes decreases the risk of microvascular disease, including retinopathy.l" The Diabetes Control and Complications Trial (DCCT) Research Group, initiated in 1982, is comprised of diabetologists and their patients recruited from 29 centers across the country. ' This clinical trial has reported data on 1441 patients with insulin-dependent diabetes (100M), ranging in age from 13 to 39 years, with follow-up of 3 to 9 years.' Retinopathy, monitored by fundus photography, was the principal measure of outcome. The "primary-prevention cohort" included 726 patients with 100M who were free of retinopathy at baseline ; the "secondary-prevention cohort" included 715 patients with mild retinopathy. Patients were randomized to either " standard" or " intensive" insulin therapy groups. The intensive treatment group received multiple daily insulin injections or insulin infusion by pump, with continual adjustment of insulin dosage. The standard treatment group received one or two daily injections ofinsulin with conventional monitoring ofblood glucose levels. Seven-field fundus photographs at 6-month intervals were graded for retinopathy by masked readers according to the Early Treatment of Diabetic Retinopathy Research Study criteria.' Change in retinopathy was defined as at least three steps of progression from baseline that persisted for at least 6 months. The appearance of proliferative retinopathy or severe non proliferative retinopathy triggered referral for possible photocoagulation. Other outcomes measured included nephropathy, neuropathy, neuropsychologic disorders, macrovascular disease, and quality-of-life. Data analyses at all time intervals clearly indicated statistically significant differences in average glycosylated hemoglobin and blood glucose levels between study groups, and verified that intensive therapy better controlled blood glucose than did standard therapy. Most importantly, the risk of progression of retinopathy was definitely less in the intensive therapy group than in the control, standard therapy group after 36 months of study. After 5 years, the risk of retinopathy in the intensive treatment group was 50% lower than that in the standard treatment group!" Intensive therapy substantially reduced the risk of nephropathy, neuropathy, and, probably, macrovascular disease. Adverse effects of intensive therapy were relatively minor except for an increased rate of hypoglycemia. This and previous trials did note transient "early worsening" ofretinopathy with intensive insulin therapy in the secondary treatment cohort during the first year of treatment.4 Soft exudates and intraretinal microvascular changes increased early on in intensively treated patients but tended to regress toward baseline by 18 months. The incidence of visionthreatening complications of diabetes, including macular edema and neovascularization, was decreased dramatically by intensive insulin therapy." By life-table anal ysis, sustained microaneurysms were noted in only 70% of intensively treated patients but in 90% of patients who received standard treatment. Intensive treatment lowered the risk of progression of retinopathy in patients with either longstanding (>2.5
703
Ophthalmology Volume 102, Number 5, May 1995 years) or short-duration «2.5 years) diabetes. The 9-year incidence of new vessels on the disc or elsewhere was 24% among patients who received standard treatment but only 8% among patients who received intensive treatment. The relative risk of macular edema after 9 years was 44% and 27% among standard and intensively treated groups, respectively. In the secondary intervention cohort, 5.5% of patients receiving intensive treatment and 14.2% of patients receiving standard treatment also received laser. In the secondary intervention cohort, the intensively treated group needed less than one-half the laser treatments used in the standard treatment group. With regard to retinopathy status after 5 years, 51 % of patients who received intensive treatment in the primary cohort were stable compared with baseline, versus 33% of patients who received standard treatment. In the secondary treatment group, 48% of patients who received intensive treatment were stable compared with baseline, versus 32% among those who received standard treatment. Several useful generalizations derived from the above series of research reports are: the earlier that intensive therapy is begun in the course of diabetic retinopathy, the more effective it will be; advanced retinopathy also profits.from intensive insulin therapy, although at least 3 years of intensive therapy may be necessary to see these benefits; sight-threatening complications, including macular edema and new vessel formation on the disc and elsewhere, are reduced by intensive insulin therapy; the rate of progression of retinopathy among patients who receive conventional therapy increases with time, whereas intensive insulin therapy decreases the rate of progression. As retinopathy is the "model" diabetic vascular disease, ophthalmologists can playa major role in disseminating this information. Improved communication among diabetologists, other primary care givers, and ophthalmologists is essential. Increased costs of more frequent checkups, special equipment such as insulin pumps, and more frequent monitoring of blood glucose or glycosylated hemoglobin determinations will no doubt slow or even prevent the application of intensive insulin therapy to many patients. We encourage ophthalmologists to familiarize themselves with these recent studies and to explore, in cooperation with other physicians, the use of intensive insulin therapy, especially in young patients with diabetes. References
I. Brinchmann-Hansen 0, Dahl-Jegensen K, Sandvik L, Hanssen KF. Blood glucose concentrations and progression of diabetic retinopathy: the seven year results of the Oslo study. Br Med J 1992;304: 19-22. 2. Reichard P, Nilsson B-Y, Rosenqvist U. The effect of long-term intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med 1993;329:304-9. 3. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-86. 4. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus: The Diabetes Control and Complications Trial. Arch Ophthalmol 1995; 113:36-51. 5. The Diabetes Control and Complications Trial Research Group. Progression of retinopathy with intensive versus conventional treatment in The Diabetes Control and Complications Trial. Ophthalmology 1995;102: 647-61. DON MINCKLER, MD
Editor-in-Chief
704