Risk of Early-Onset Proliferative Retinopathy in IDDM Is Closely Related to Cardiovascular Autonomic Neuropathy ANDRZEJ S. KROLEWSKI, JOSHUA BARZILAY, JAMES H. WARRAM, BLAISE C. MARTIN, MICHAEL PFEIFER, AND LAWRENCE I. RAND
Determinants of proliferative diabetic retinopathy (PDR) that occur during the 2nd decade of insulin-dependent diabetes mellitus (IDDM) (early-onset PDR) were investigated in a nested case-control study. From an inception cohort of patients with juvenile-onset IDDM that now has 15-21 yr diabetes duration, the patients with PDR (cases, n = 74) were selected for study along with a random sample of the patients in the cohort without PDR (control subjects, n = 88). The risk of PDR was associated with poor glycemic control during the first 12 yr of diabetes. Relative to patients in the first quartile of the index of hyperglycemia, those in higher quartiles and nonattenders had a four- to fivefold risk of developing PDR. A striking relationship with cardiovascular autonomic neuropathy (CAN) was found. Relative to patients without CAN, patients with significant and mild CAN had odds ratios of 77.5 and 34.6, respectively. Patients with albumin excretion rates >30 jig/min had moderately increased risk of PDR (ranging from 4-fold for microalbuminuria to 7-fold for proteinuria). In contrast, patients with impaired renal function had an extremely high risk of PDR. All 20 of these patients were cases, therefore the odds ratio was infinite. All three factors (poor glycemic control, CAN, and various stages of nephropathy) were associated with PDR in multiple logistic regression analysis. However, in models including glycemic control, the association between microalbuminuria or proteinuria and PDR was weakened. In conclusion, our findings are consistent with a hypothesis that the level of glycemia is a primary determinant of early-onset PDR. Autonomic neuropathy, almost universal among
From the Epidemiology and Genetics and Eye Research Sections, Research Division of the Joslin Diabetes Center, Boston, Massachusetts; and the Diabetes Research and Analysis Association, Humana Hospital, Diabetes Center of Excellence, Lexington, Kentucky. Address correspondence and reprint requests to Andrzej S. Krolewski, MD, PhD, Epidemiology and Genetics Section, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Received for publication 25 July 1990 and accepted in revised form 2 January 1992.
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cases, may be a strong risk factor for or a risk indicator of an etiologic process underlying the development of PDR. Conditions associated with advanced diabetic nephropathy, on the other hand, may accelerate the progression of nonproliferative retinopathy to PDR. Diabetes 41:430-37,1992
D
iabetic retinopathy may be divided into two stages: nonproliferative and proliferative. Nonproliferative retinopathy seems to be specific for diabetes and some degree of this complication develops in most juvenile-onset insulin-dependent diabetes mellitus (IDDM) patients during the first 10 yr of diabetes (1,2). During the 2nd decade of IDDM, - 2 5 % of the patients with nonproliferative retinopathy develop proliferative lesions (2,3). The factors causing progression of nonproliferative retinopathy to proliferative diabetic retinopathy (PDR) so soon in the course of IDDM are unknown. Diabetic kidney disease or cardiovascular autonomic neuropathy (CAN), which have developed in many patients during the 1st decade of diabetes, may play a role in the development of PDR (2-6). There is little information regarding the degree of association between earlyonset PDR and these other diabetic complications. This study examines the relationship between the development of early-onset PDR and the presence of diabetic nephropathy and CAN in an inception cohort of juvenile-onset IDDM patients who came to the Joslin Clinic with newly diagnosed diabetes between 1967 and 1972 and were recalled for examination 15-21 yr later. The data from this study are consistent with a hypothesis that the presence of CAN may play a permissive role in the development of early-onset PDR, whereas advanced renal complications may accelerate progression of nonproliferative retinopathy to PDR.
DIABETES, VOL. 41, APRIL 1992
A.S. KROLEWSKI AND ASSOCIATES
RESEARCH DESIGN AND METHODS From 1986 to 1988, we conducted a case-control study nested in an inception cohort of IDDM patients to determine factors associated with the development of earlyonset PDR. The inception cohort was selected from a roster of all individuals 30 |xg/min were considered to have diabetic nephropathy (15,16). During the 3-h urine collection, patients were interviewed about their medical history and antihypertensive medication. This was followed by the physical examination. Height and weight were measured in light clothing without shoes. Index of hyperglycemia and past blood pressure levels. All blood glucose determinations during the first 12 yr of attendance at the Joslin Clinic were abstracted from patients' records, and the index of hyperglycemia was estimated with a previously described method (17). The index is the proportion (expressed as percentage) of clinic visits in which severe hyperglycemia was present
431
EARLY-ONSET PROLIFERATIVE RETINOPATHY
out of all visits to the clinic during the first 12 yr. The index was computed if a patient had at least nine clinic visits. Patients with fewer visits were considered clinic nonattenders. Severe hyperglycemia was considered to be present if blood glucose values were >10 (fasting), >13.3 (postprandial 12.2 (postprandial 1.52.4 h), >11.1 (postprandial 2.5-3.4 h), and >10 mM (postprandial >3.4 h) (17). Similarly, all blood pressure measurements recorded in the medical records during attendance at the Joslin Clinic were abstracted to determine mean arterial pressure for each visit. For patients with IDDM diagnosed after age 13 yr, mean arterial pressures were computed for the first 7 yr of attendance to the clinic. For those with IDDM diagnosed before age 14 yr, the mean blood pressure was computed for 7 yr of attendance to the clinic after age 13 yr. Eye examination. Stereophotographs of seven standard fields of both eyes of each patient were taken at the end of the special examination. The photographs were graded by a trained technician according to the modified Airlie House classification (18). A patient was considered to have PDR if there was evidence of preretinal new vessels or fibrous proliferation in any stereoscopic photograph of the seven standard fields in either eye. If the pictures were unsatisfactory for grading or were not taken, documentation of Diabetic Retinopathy Study "high-risk characteristics" (18) from a previous ophthalmological examination was accepted as confirmation of PDR. If there were no lesions in the standard stereoscopic photographs, the patient was considered to have no retinopathy. If the worst eye had only hemorrhages and microaneurysms or hard exudates, the patient was considered to have mild nonproliferative retinopathy. If the worst eye exceeded the criteria for mild retinopathy but did not have any evidence of PDR, the patient was considered to have moderate-to-severe nonproliferative retinopathy. Definition of cases. Among the 60 patients who were selected as cases on the basis of their self-report of a diagnosis of PDR and who came for the special examination, all but 2 had confirmation of PDR in stereoscopic photographs obtained at the time of examination or from the medical records. Among the patients who did not report PDR and who were selected as control subjects, 16 patients had evidence of neovascularization in the stereoscopic photographs. They were added to the group of cases of PDR; therefore, 74 individuals ([60 - 2] + 16 = 74) were considered as cases in this study. Definition of control subjects. Among the 102 patients selected as control subjects and who participated in the special examination (16 were mentioned previously who had PDR), there were 75 with moderate-to-severe nonproliferative retinopathy, 6 with mild nonproliferative retinopathy, and 6 without retinopathy. The 2 patients who reported PDR but were later found not to have proliferative lesions had severe nonproliferative retinopathy and were included in the control group. All together, there were 88 patients ([102 - 16] + 2 = 88) who were considered control subjects in this study.
432
TABLE 1 Descriptive characteristics of the study group with juvenile-onset insulin-dependent diabetes mellitus (IDDM) of 15-21 yr duration according to proliferative diabetic retinopathy status Control subjects (n = 88) Male (%) Age at onset of IDDM (yr) Age at examination (yr) Measurements during adolescence and young adulthood* Clinic nonattenders (%) Index of hyperglycemia (%) Mean arterial pressure (mmHg) Measurements at examination HbA, (%) Hypertension (%) Nephropathy (%) R-R variation Brake index Change in blood pressure on rising (mmHg) Systolic Diastolic
Cases (n = 74)
53
50
11 ±5 29 ±5
11 ± 4 29 ± 4
22
28
42 ±20 84 ±6
51 ± 17t 84 ± 6
11.0 ±2.0
12.0±2.1t
25 26
64* 76±
39 ± 22 32 ±24
18 ± 12± 15 ± 14t
-4 ± 11 +6 ±9
-10 ±17§ - 1 ± 11±
Values are means ± SD. The index is the percentage of clinic visits with severe hyperglycemia (see METHODS). Mean arterial pressure was calculated for all clinic visits at ages 13-20 yr for those with diabetes onset before age 14 yr and the 1st 7 yr of diabetes for those with onset age 14-21 yr. *Nonattenders made
Determinants of proliferative diabetic retinopathy (PDR) that occur during the 2nd decade of insulin-dependent diabetes mellitus (IDDM) (early-onset PDR) were investigated in a nested case-control study. From an inception cohort of patients with juvenile-onset IDDM that now has 15-21 yr diabetes duration, the patients with PDR (cases, n = 74) were selected for study along with a random sample of the patients in the cohort without PDR (control subjects, n = 88). The risk of PDR was associated with poor glycemic control during the first 12 yr of diabetes. Relative to patients in the first quartile of the index of hyperglycemia, those in higher quartiles and nonattenders had a four- to fivefold risk of developing PDR. A striking relationship with cardiovascular autonomic neuropathy (CAN) was found. Relative to patients without CAN, patients with significant and mild CAN had odds ratios of 77.5 and 34.6, respectively. Patients with albumin excretion rates >30 jig/min had moderately increased risk of PDR (ranging from 4-fold for microalbuminuria to 7-fold for proteinuria). In contrast, patients with impaired renal function had an extremely high risk of PDR. All 20 of these patients were cases, therefore the odds ratio was infinite. All three factors (poor glycemic control, CAN, and various stages of nephropathy) were associated with PDR in multiple logistic regression analysis. However, in models including glycemic control, the association between microalbuminuria or proteinuria and PDR was weakened. In conclusion, our findings are consistent with a hypothesis that the level of glycemia is a primary determinant of early-onset PDR. Autonomic neuropathy, almost universal among
From the Epidemiology and Genetics and Eye Research Sections, Research Division of the Joslin Diabetes Center, Boston, Massachusetts; and the Diabetes Research and Analysis Association, Humana Hospital, Diabetes Center of Excellence, Lexington, Kentucky. Address correspondence and reprint requests to Andrzej S. Krolewski, MD, PhD, Epidemiology and Genetics Section, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. Received for publication 25 July 1990 and accepted in revised form 2 January 1992.
430
cases, may be a strong risk factor for or a risk indicator of an etiologic process underlying the development of PDR. Conditions associated with advanced diabetic nephropathy, on the other hand, may accelerate the progression of nonproliferative retinopathy to PDR. Diabetes 41:430-37,1992
D
iabetic retinopathy may be divided into two stages: nonproliferative and proliferative. Nonproliferative retinopathy seems to be specific for diabetes and some degree of this complication develops in most juvenile-onset insulin-dependent diabetes mellitus (IDDM) patients during the first 10 yr of diabetes (1,2). During the 2nd decade of IDDM, - 2 5 % of the patients with nonproliferative retinopathy develop proliferative lesions (2,3). The factors causing progression of nonproliferative retinopathy to proliferative diabetic retinopathy (PDR) so soon in the course of IDDM are unknown. Diabetic kidney disease or cardiovascular autonomic neuropathy (CAN), which have developed in many patients during the 1st decade of diabetes, may play a role in the development of PDR (2-6). There is little information regarding the degree of association between earlyonset PDR and these other diabetic complications. This study examines the relationship between the development of early-onset PDR and the presence of diabetic nephropathy and CAN in an inception cohort of juvenile-onset IDDM patients who came to the Joslin Clinic with newly diagnosed diabetes between 1967 and 1972 and were recalled for examination 15-21 yr later. The data from this study are consistent with a hypothesis that the presence of CAN may play a permissive role in the development of early-onset PDR, whereas advanced renal complications may accelerate progression of nonproliferative retinopathy to PDR.
DIABETES, VOL. 41, APRIL 1992
A.S. KROLEWSKI AND ASSOCIATES
RESEARCH DESIGN AND METHODS From 1986 to 1988, we conducted a case-control study nested in an inception cohort of IDDM patients to determine factors associated with the development of earlyonset PDR. The inception cohort was selected from a roster of all individuals 30 |xg/min were considered to have diabetic nephropathy (15,16). During the 3-h urine collection, patients were interviewed about their medical history and antihypertensive medication. This was followed by the physical examination. Height and weight were measured in light clothing without shoes. Index of hyperglycemia and past blood pressure levels. All blood glucose determinations during the first 12 yr of attendance at the Joslin Clinic were abstracted from patients' records, and the index of hyperglycemia was estimated with a previously described method (17). The index is the proportion (expressed as percentage) of clinic visits in which severe hyperglycemia was present
431
EARLY-ONSET PROLIFERATIVE RETINOPATHY
out of all visits to the clinic during the first 12 yr. The index was computed if a patient had at least nine clinic visits. Patients with fewer visits were considered clinic nonattenders. Severe hyperglycemia was considered to be present if blood glucose values were >10 (fasting), >13.3 (postprandial 12.2 (postprandial 1.52.4 h), >11.1 (postprandial 2.5-3.4 h), and >10 mM (postprandial >3.4 h) (17). Similarly, all blood pressure measurements recorded in the medical records during attendance at the Joslin Clinic were abstracted to determine mean arterial pressure for each visit. For patients with IDDM diagnosed after age 13 yr, mean arterial pressures were computed for the first 7 yr of attendance to the clinic. For those with IDDM diagnosed before age 14 yr, the mean blood pressure was computed for 7 yr of attendance to the clinic after age 13 yr. Eye examination. Stereophotographs of seven standard fields of both eyes of each patient were taken at the end of the special examination. The photographs were graded by a trained technician according to the modified Airlie House classification (18). A patient was considered to have PDR if there was evidence of preretinal new vessels or fibrous proliferation in any stereoscopic photograph of the seven standard fields in either eye. If the pictures were unsatisfactory for grading or were not taken, documentation of Diabetic Retinopathy Study "high-risk characteristics" (18) from a previous ophthalmological examination was accepted as confirmation of PDR. If there were no lesions in the standard stereoscopic photographs, the patient was considered to have no retinopathy. If the worst eye had only hemorrhages and microaneurysms or hard exudates, the patient was considered to have mild nonproliferative retinopathy. If the worst eye exceeded the criteria for mild retinopathy but did not have any evidence of PDR, the patient was considered to have moderate-to-severe nonproliferative retinopathy. Definition of cases. Among the 60 patients who were selected as cases on the basis of their self-report of a diagnosis of PDR and who came for the special examination, all but 2 had confirmation of PDR in stereoscopic photographs obtained at the time of examination or from the medical records. Among the patients who did not report PDR and who were selected as control subjects, 16 patients had evidence of neovascularization in the stereoscopic photographs. They were added to the group of cases of PDR; therefore, 74 individuals ([60 - 2] + 16 = 74) were considered as cases in this study. Definition of control subjects. Among the 102 patients selected as control subjects and who participated in the special examination (16 were mentioned previously who had PDR), there were 75 with moderate-to-severe nonproliferative retinopathy, 6 with mild nonproliferative retinopathy, and 6 without retinopathy. The 2 patients who reported PDR but were later found not to have proliferative lesions had severe nonproliferative retinopathy and were included in the control group. All together, there were 88 patients ([102 - 16] + 2 = 88) who were considered control subjects in this study.
432
TABLE 1 Descriptive characteristics of the study group with juvenile-onset insulin-dependent diabetes mellitus (IDDM) of 15-21 yr duration according to proliferative diabetic retinopathy status Control subjects (n = 88) Male (%) Age at onset of IDDM (yr) Age at examination (yr) Measurements during adolescence and young adulthood* Clinic nonattenders (%) Index of hyperglycemia (%) Mean arterial pressure (mmHg) Measurements at examination HbA, (%) Hypertension (%) Nephropathy (%) R-R variation Brake index Change in blood pressure on rising (mmHg) Systolic Diastolic
Cases (n = 74)
53
50
11 ±5 29 ±5
11 ± 4 29 ± 4
22
28
42 ±20 84 ±6
51 ± 17t 84 ± 6
11.0 ±2.0
12.0±2.1t
25 26
64* 76±
39 ± 22 32 ±24
18 ± 12± 15 ± 14t
-4 ± 11 +6 ±9
-10 ±17§ - 1 ± 11±
Values are means ± SD. The index is the percentage of clinic visits with severe hyperglycemia (see METHODS). Mean arterial pressure was calculated for all clinic visits at ages 13-20 yr for those with diabetes onset before age 14 yr and the 1st 7 yr of diabetes for those with onset age 14-21 yr. *Nonattenders made
