Risk Factors Associated with Severe Proliferative ... - Diabetes Care

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isk Factors Associated with Severe Proliferative Retinopathy in Insuliii'dependent Diabetes Mellitus H. J. BODANSKY, A. G. CUDWORTH, P. L. DRURY, AND EVA M. KOHNER

The natural history of disease and suspected risk factors for bad prognosis were investigated in 40 subjects with insulin-dependent diabetes mellitus who had severe retinopathy and in 22 patients with a similar duration of diabetes without evidence of complications. The retinopathy group showed a marked excess of men (ratio 2:1). Examination of the data in the literature also showed a striking excess of men, 61% (P < 0.001) in patients with insulin-dependent diabetes and severe microvascular disease. In addition, proliferative retinopathy was found to have significant associations with current poor diabetic control, hypertension, and previous treatment with once-daily insulin regimens, particularly with protamine zinc i n s u l i n . DIABETES CARE 5: 97-100, MARCH- APRIL 1982.

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he development of long-term complications now constitutes the major hazard for patients with diabetes mellitus. For example, diabetic retinopathy is the most common cause of blindness in the 3 0 65-yr-old age group and was the most common cause of newly registered blind for the years 1963 to 1968 in England and Wales.1 It is now well-established that the major types of diabetes have different etiologies.2 However, while blindness and other forms of tissue damage may occur in all types of diabetes, it is possible that these complications may have certain factors common to their etiology, such as endothelial cell damage and tissue hypoxia. There is increasing evidence that the evolution of microvascular disease is related to poor diabetic control.3'4 However, many clinicians have the experience of patients who, despite having always appeared to be well-controlled, nevertheless develop complications.5 In contrast, some patients, poorly controlled for many years, appear to escape complications, suggesting that hyperglycemia may not be the only factor involved.6 We have therefore attempted to identify some aspects of the natural history of diabetes that may be associated with the presence of one type of microvascular disease, severe proliferative retinopathy, in patients with type I or insulin-dependent diabetes mellitus (IDDM). We compared a group of patients with this complication to a second group with the same type and duration of diabetes but without evidence of complications.

METHODS AND RESULTS

Two groups of Caucasoid patients with IDDM were studied. The first group of 40 patients was ascertained consecutively from two specialist retinal clinics. Its members were selected for the presence of severe proliferative retinopathy with neovascularization either on the optic disc or peripheral retina assessed by direct and indirect ophthalmoscopy and by fluorescein angiography. The control group was ascertained consecutively from our diabetic clinic, and its members were selected for their clinical absence of complications. In particular, they had no evidence of diabetic retinopathy when their fundi were examined by experienced diabetologists using direct ophthalmoscopy through dilated pupils. Both groups were assessed with particular reference to current diabetic control as measured by glycosylated hemoglobin (HbA!%), the prevalence of hypertension, renal impairment, cigarette smoking, and the type of their previous insulin treatment. The details of the patients studied are shown in Table 1. Sex incidence. There was a striking preponderance of men in the retinopathy group (ratio 2:1) as shown in Table 1, although this was not significantly different from the ratio in the control group (X2 with Yates's correction =2.02). However, a similar increase in men may be seen in other series of IDDM patients with microvascular disease. The available data in the literature where the sex ratio is given are shown

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TABLE 1 Characteristics of the patients studied

jects in the retinopathy group had biochemical evidence of renal impairement (serum creatinine > 0.1 mmol/L, range 0.11-0.31 mmol/L). None of the patients without compliMean duration of Sex of patients cations had abnormal renal function. Mean age (yr) diabetes (yr) ± Cigarette smoking. Patients were counted as current ± SD SD Men Women smokers if they smoked five or more cigarettes daily at the Retinopathy time of the study. On this basis 20% of both groups were patients smokers. (N ^ 40) 39 ± 8 24 ± 9 27 13 Previous insulin treatment. Information on the different Patients types of insulin the patients had used, their frequency of inwithout jection, and the duration of each type of regimen was ascercomplications tained from the patients and their records. The period ana(N = 22) 40 ± 12 21 ± 8 10 12 lyzed in the retinopathy group was before the known development of complications, i.e., from the diagnosis of diabetes to the first detection of retinopathy. That analyzed in in Table 2. Men comprise 61% of the combined subjects, a the complication-free group consisted of the total duration of finding which is significantly different from the expected diabetes. Thirty five patients with retinopathy and all 22 paequal sex ratio (P < 0.001). tients without complications were able to supply this inforCurrent diabetic control. Glycosylated hemoglobin (HbAx) mation. The data were analyzed with respect to the number was measured by a micro-scale chromatographic technique of years each type of treatment had been used and the peron venous blood.11 This method takes account of both stable cent of duration to which this corresponded in each patient and labile fractions. The range for healthy young adults is (Figure 1). Significance was assessed with a two-tailed 6.5-9.5%, the intraassay variation 4%, and the interassay Mann-Whitney U test. The patients without complications variation 3.5%. The mean HbAx (±SD)% was 12.4 ± had been treated for significantly longer (P < 0.005) and for 1.9% in the proliferative retinopathy group and 10.8 ± a greater percent of their diabetes duration (P < 0.05) with 1.5% in the patients without complications (P < 0.001 Student's t test). Hypertension and renal impairment. Arterial blood pressure

(phase I and V) was measured with a mercury sphygmomanometer with the patients recumbent after 5 min rest. The mean of five readings taken at 1-min intervals was used for analysis. Eight patients with retinopathy and none of the patients without complications were receiving antihypertensive therapy. Mean blood pressures in the retinopathy group were 134/78 mm Hg compared with 120/71 mm Hg in the complications-free group (P < 0.0005 systolic and P < 0.025 diastolic; Wilcoxon unpaired rank test). Twelve sub-

TABLE 2 Sex incidence in IDDM and microvascular disease*

100 % duration of diabetes on once daily insulin

T

80

i

60 40

i

20 0 100 % duration of diabetes on twice daily insulin

80 60 40 20

Author

Complication 7

Barbosa et al. Deckert et al.8 Jonest Bodansky et al.9 Barbosa et al.10 Tunbridget

Nephropathy Proliferative retinopathy Nephropathy Proliferative retinopathy Proliferative retinopathy Nephropathy

Men

Women

67

43

110

7 23

8 13

15 36

91

42

133

114

86 32 224

200

45 347 (61%)

77 571 Total

* P < 0.001. t Personal communication (see text). t British Diabetic Association Medical Services Study Group: Deaths in diabetics under 50 yr of age, 1980.

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±

Total 100 80 % duration of diabetes on PZI

60 40 20 0

MHIMMIMMIM Retinopathy patients

Diabetics without complications

FIG. I. Duration of treatment with once-daily, twice-daily, and protamine zinc insulin regimens expressed as percentage duration of diabetes free of complications in type 1 diabetic subjects with proliferative retinopathy (N = 35) and without complications (N =22).

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twice-daily insulin than the retinopathy patients. Conversely, the retinopathy group had been treated for a significantly greater percent of their duration of diabetes with once-daily insulin (P < 0.05) compared with the complications-free group. Seventeen of the retinopathy group (49%) had received treatment with protamine zinc insulin (PZI) compared with only five (23%) of the healthy patients. Consequently, the retinopathy patients had been treated for a significantly greater percent of their diabetes duration (P < 0.05) with PZI than the complication-free group.

DISCUSSION

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retinopathy found in other studies.15'16 It is difficult to attribute the cause of the hypertension in the retinopathy group to renal disease alone because none of this group had severe nephropathy. Indeed, only four patients had nephropathy of a moderate degree, their serum creatinine exceeding 0.16 mmol/L, a finding similar to that of Pell et al.17 Whether hypertension plays a causal role in the pathology of microangiopathy is difficult to determine. There is general agreement that smoking is harmful, particularly for patients with diabetes,18 but its exact relationship to microvascular disease is controversial. Our results are in accordance with a recent study that did not find a relationship between smoking and microvascular disease.19 Our data were based on current smoking habits because we found it difficult to elicit reliable retrospective smoking histories. One such study on cumulative effects has shown, however, that smoking is possibly deleterious.20 It is known that glycosylated hemoglobin levels tend to be higher in poorly controlled diabetic patients than in those who are well-controlled.21 Diverse glycosylation of body proteins may be an important cause of diabetic tissue damage, e.g., basement membrane thickening.22 There was a significantly higher HbAj in the patients with retinopathy than in the patients without complications, suggesting that the latter were better controlled at the time of study. HbAj levels reflect short-term metabolic control and therefore cannot give an accurate reflection of many years of varying glucose homeostasis. These results lend support to the opinion that hyperglycemia plays a role in the etiology of microvascular complications, although not all are in agreement with this.3 Prospective, randomized trials may help to decide this issue. Evidence that the type of insulin used and the frequency of injections may be important in the development of complications is provided by the analysis of previous insulin regimens. It has been suggested that patients who remained on the original regimen of multiple injections of regular insulin were less likely to develop long-term complications than those on once-daily injections.5"23 This concept is supported by studies suggesting that good diabetic control may prevent or delay the progression of microvascular disease24"28 and that multiple daily insulin injections can improve control,29"32 thus delaying the progression of retinopathy.33~35 In our retrospective analysis of previous insulin treatment, the patients without complications had been treated for significantly longer with twice-daily insulin than the patients with complications. Therefore, multiple daily insulin injections in the long-term may help to protect against diabetic microangiopathy. In relation to the type of long-acting insulin used, it is also of interest that patients in the retinopathy group had been treated for significantly longer with protamine zinc insulin (PZI). This is of theoretical concern because PZI is more immunogenic than other conventional insulins.36

n many previous studies of diabetic complications, patients with different types of diabetes and combinations of different complications have been considered together. Such heterogeneity makes interpretation difficult because the development of complications in the various types of diabetes may be influenced by different pathogenetic factors in addition to the long-term effects of hyperglycemia. In this study all the patients had classic IDDM, and the complications group was specifically selected for the presence of severe proliferative retinopathy. The two groups of subjects were matched as closely as possible for age and duration of diabetes. The mean duration of diabetes of the complication-free group was 3 yr less than that of the retinopathy group and, although this difference was not statistically significant, it is possible that the members of the complicationfree group may still develop retinopathy in the future. We found an unexpected excess of men in the retinopathy group (M:F = 27:13) compared with the group without complications (M:F = 10:12). Although a degree of selection bias cannot be excluded, it is of interest that we found a similar excess of men in a larger series of subjects with IDDM and severe proliferative retinopathy (N = 133, M = 93, F = 40) that we have studied.9 Furthermore, in a different series of type I diabetic subjects with end-stage diabetic nephropathy, collected at another center, there was also an excess of men (M = 23, F = 13, Dr. R. H. Jones, personal communication). A significant excess ol; men in groups of subjects examined for the presence of IDDM and microvascular disease is demonstrated by the combined analysis (Table 2). We are not aware that this disturbance in the sex ratio has been previously noted. Some previous series of subjects with microvascular disease have had an excess of women because both insulin-dependent and non-insulin-dependent diabetic subjects have been included. There is a 12—20% excess of men in subjects with juvenile-onset insulin-dependent diabetes12'13 (type la) and a slight excess of men may thus be seen in some studies of subjects free of complications. However, this would not explain the greater excess of men with severe microvascular disease. In conclusion, we found that proliferative retinopathy in The finding by Deckert et al.14 that female patients had a significantly lower mortality than male patients with juvenile- subjects with type I diabetes is associated with the male sex, hypertension, and lengthy previous treatment with onceonset diabetes lends support to our findings. We have confirmed the association of hypertension and daily insulin, particularly PZI. Treatment with twice-daily

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insulin may afford some protection. The latter finding supports the concept that diabetic control in terms of blood glucose may be the primary factor influencing which patients will develop complications. It remains puzzling, however, that not all patients fit this simple hypothesis. Genetic and other unknown factors could be involved, and in this respect the high prevalence of men may provide a clue. ACKNOWLEDGMENTS: We thank Dr. D. J. Galton, J. H. Dobree, and R. A. F. Whitelocke for permission to study their patients. We also thank Dr. S. G. Welch and Christine Swindlehurst for the HbAx estimations.

From the Department of Diabetes, Medical Unit, St. Bartholomew's Hospital, London, England, and the Department of Medicine, Hammersmith Hospital, London, W12 OHS, England. Address reprint requests to H. J. Bodansky. Department of Diabetes, Medical Unit, St. Bartholomew's Hospital, London, EC1 7BE, England. REFERENCES 1 Sorsby, A.: The incidence and causes of blindness in England and Wales 1963-1968. Report on Public Health and Medical Subjects no. 128, 1973, H.M.S.O. 2 Cudworth, A. G.: Type 1 diabetes mellitus. Diabetologia 14: 281-91, 1978. 3 Tchobroutsky, G.: Relation of diabetic control to development of microvascular complications. Diabetologia i5: 143-52, 1978. 4 Pirart, J.: Diabetes mellitus and its degenerative complications: a study of 4,400 patients observed between 1947 and 1973. Diabetes C a r e l : 168-88, 252-63, 1978. 5 Lawrence, R. D.: Treatment of 90 severe diabetics with soluble insulin for 20-40 years: effect of diabetic control on complications. Br. Med. J. 2: 1624-25, 1963. 6 Pyke, D. A., and Tattersall, R. B.: Diabetic retinopathy in identical twins. Diabetes 22: 613-18, 1973. 7 Barbosa, J., Noreen, H., and Emme, L., et al.: Histocompatibility (HLA) antigens and diabetic microangiopathy. Tissue Antigens 7: 233-37, 1976. 8 Deckert, T., Egeberg, J., Frimodt-M^ller, C , Sander, E., and Svejgaard, A.: Basement membrane thickness, insulin antibodies and HLA antigens in longstanding insulin dependent diabetics with and without severe retinopathy. Diabetologia 17: 91-96, 1979. 9 Bodansky, H. J., Drury, P. L , Medbak, S., and Kohner, E. M.: HLA, Aspects of control and residual beta-cell function in the development of microantiopathy. Diabetologia 19: 259, 1980. 10 Barbosa, J., Ramsay, R. C., Knobloch, W. C., Cantrill, W. L., Noreen, H., and Kings, R.: Histocompatibility antigen frequencies in diabetic retinopathy. Am. J. Opthalmol. 90: 148-53, 1980. 11 Welch, S. G., and Boucher, B. J.: A rapid micro-scale method for the measurement of hemoglobin Al (a + b + c). Diabetologia 14: 209-11, 1978. 12 Bloom, A., Hayes, T. M., and Gamble, D. R.: Register of newly diagnosed diabetic children. Br. Med. J. 3: 580-83, 1975. 13 Ghristau, B., Kroman, H., Ortved-Anderson, O., et al.: Incidence, seasonal, and geographical patterns of juvenile-onset insulin-dependent diabetes mellitus in Denmark. Diabetologia 13: 281-84, 1977. 14 Deckert, T., Poulsen, J. E., and Larsen, M.: Prognosis of diabetics with diabetes onset before the age of thirty one. I. Survival,

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K.: Relation of the course of retinopathy to control of diabetes, age and therapeutic agents in diabetic Japanese patients. Diabetes 18: 773-80, 1969. 27 Miki, E., Kuzuya, T . , Ide, T . , and N a k a o , K.: Frequency, d e gree a n d progression with time of proteinuria in diabetic patients. Lancet 1: 922-24, 1972. 28 Takazakura, E., N a k a m o t o , Y., and Hayakawa, H . : O n s e t and progression of diabetic glumerulosclerosis. Diabetes 24: 1 - 9 , 1975. 29 Oakley, W . , Hill, D . , and Oakley, N . : C o m b i n e d use of regular and crystalline protamine ( N P H ) insulin in the treatment of severe diabetes. Diabetes 15: 2 1 9 - 2 2 , 1966. 30 Forsham, P. H . : Insulin twice a day suggested for control. J A M A 26: 202, 1967. 31 Kopf, A . , Tchbroutsky, G , and Eschwege, E.: Serial post prandial blood glucose levels in 309 subjects with and without diabetes. Diabetes 22: 8 3 4 - 4 6 , 1973. 32 Tchbroutsky, G . , Charitanski, D., Blouquit, Y., Papoz, L., Soria, J., and Rosa, J.: Diabetic control in 102 insulin treated out patients. Diabetologia 18: 4 4 7 - 5 2 , 1980. 33 Johnsson, S.: Retinopathy and nephropathy in diabetes mellitus: comparison of the effects of two forms of treatment. Diabetes 9: 1 - 8 , 1960. 34 Job, D., Eschwege, E., Guyot-Argenton, C , Aubry, J-P., and Tchobroutsky, G : Effect of multiple daily insulin injections on the course of diabetic retinopathy. Diabetes 25: 4 6 3 - 6 9 , 1976. 35 Eschwege, E., Job, D., Guyot-Argenton, C , Aubry, J-P., and Tchobroutsky, G.: Delayed progression of diabetic retinopathy by divided insulin administration: a further follow-up. Diabetologia 16:

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