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Risk factors for the development of diabetic retinopathy in Japanese type 2 diabetic patients
Diabetes Research and Clinical Practice 51 (2001) 195– 203 www.elsevier.com/locate/diabres
Risk factors for the development of diabetic retinopathy in Japanese type 2 diabetic patients Y. Yoshida *, R. Hagura, Y. Hara, G. Sugasawa, Y. Akanuma The Institute for Diabetes Care and Research, Asahi Life Foundation, 1 -6 -1 Marunouchi, Chiyoda-ku, Tokyo 100 -0005, Japan Received 28 April 2000; received in revised form 13 July 2000; accepted 22 August 2000
Abstract This study investigated the risk factors for development of diabetic retinopathy (DR) in 787 type 2 diabetic patients with no retinopathy at the first visit. The subjects were followed up for at least 3 years (mean, 6.7 years). Among the baseline factors, significant correlations were observed between the development of DR and HbA1c (P B0.0001), the method of therapy (P B 0.005), the duration of diabetes at the first visit (PB 0.005) and the past maximal body mass index (BMI) (PB 0.01). No significant correlation was found with the blood pressure, age, gender, TC or BMI. Among the follow-up variables, the mean HbA1c (PB 0.0001) and duration of diabetes (PB 0.001) correlated significantly with DR development, whereas the blood pressure and age did not. We found that a 1% decrease in HbA1c led to a 35% reduction in the risk of development of DR during the follow-up. The patients whose HbA1c at the first visit was higher than the median value of 8.2% showed a higher probability of development of DR during the next 3 years even when the same blood glucose control was maintained during the follow-up. In conclusion, our study demonstrated that the most important risk factor influencing the development of DR was the blood glucose control. Moreover, we found that the glycemic level at the first visit also influenced the development of DR. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Retinopathy; Blood glucose control; Type 2 diabetes
1. Introduction In contemporary Japan, the increase in microangiopathy is one of the most important problems in the clinical field of diabetes mellitus. The primary cause of acquired blindness is diabetes mellitus, and diabetic nephropathy has recently become the main reason for the introduction of
* Corresponding author. Tel.: +81-3-32016781; fax: + 813-32016881; e-mail address: [email protected]
hemodialysis, surpassing chronic nephritis. The recent UK Prospective Diabetes Study (UKPDS) disclosed that strict control of the blood pressure as well as blood glucose is essential for the prevention of diabetic microangiopathy [1]. While steady increases in blood glucose and body weight were reported by UKPDS [2], our clinical experience seemed somewhat different, i.e. no significant increase in body weight or blood glucose was noted in diabetic patients at our institute. Therefore, we decided to study, using
0168-8227/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 8 - 8 2 2 7 ( 0 0 ) 0 0 2 1 2 - 6
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our follow-up data, the correlations between the development of diabetic retinopathy (DR) and various baseline clinical parameters, such as the body weight, blood glucose control and blood pressure, of patients at their first visit to our institute and also during the follow-up period.
2. Subjects and methods
2.1. Subjects The subjects of this study were type 2 diabetic patients who visited the Institute for Diabetes Care and Research, Asahi Life Foundation, from 1985 to 1990. We studied patients with no DR at the first visit and whose age at the first visit was less than 70 years. They were treated at our clinic for at least 3 years (range, 3.0 – 9.5 years; mean, 6.7 years). The diagnosis of diabetes mellitus was made according to the WHO criteria of 1985 [3]. The total number of patients was 787, and their baseline clinical characteristics are shown in Table 1. The mean age of the patients was 54 years, and the mean duration of diabetes at the first visit to our clinic was 8 years. The mean HbA1c and the mean body mass index (BMI) were 8.6% and 22.6 kg/m2, respectively, at the first visit. The methods of existing treatment at the first visit were diet alone for 472 patients (60.0%), oral agents for 269 patients (34.2%), and insulin treatment for 46
patients (5.8%). The patients visited our clinic every month or every other month during the follow-up period.
2.2. Methods DR was diagnosed by the ocular fundus test, performed by any three ophthalmologists at least once every year. Direct and indirect ophthalmoscopy were performed after full dilatation of the pupils. The development of DR was defined as a finding of background retinopathy (such as at least two dot hemorrhages with microaneurysms and/or a hard exudate in at least one eye) and more severe findings for the retina. The patients were excluded from this study if they could not be evaluated because of severe cataracts, or if their lesion could not be positively identified as DR, as in the case of bleeding alone. The endpoint was defined as the development of DR. The longest follow-up period was 9 years and 5 months until September 1994, when the method for measurement of HbA1c was changed. The numbers of patients who were followed for 3, 5, 7 and 9 years were 787, 697, 485 and 319. HbA1c was measured by an HPLC method (HLC723GHb I until May of 1988, and HLC723GHb II thereafter). The coefficient of variation (CV) of each intra-assay was 1.7 and 2.0%, respectively, while the CV of inter-assay was 0.6 and 1.4%, respectively. Both HPLC meth-
Table 1 Characteristics of the patients at the first visit n (M/F)
787 (597/190)
Method of therapy (%)
Diet alone 472 (60)
OHA 269 (34)
Insulin 46 (6)
Mean 9S.D.
Median
Range
53.6 98.1 8.0 96.8 8.6 91.9 130 9 19 79 9 12 22.6 93.0 26.0 9 3.3 205 9 41
54.0 6.0 8.2 130 78 22.4 25.8 201
18–69 0–38 5.4–16.7 86–218 42–123 14.6–42.3 16.6–45.1 101–446
Age (years) Duration of diabetes at the first visit (years) HbA1c (%)a Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) BMI (kg/m2) Maximal BMI (kg/m2) Total cholesterol (mg/dl) a
HbA1c includes unstable fraction.
Y. Yoshida et al. / Diabetes Research and Clinical Practice 51 (2001) 195–203
ods included detection of the unstable type HbA1c. The mean9S.D. of HbA1c in normal subjects in our clinic is 5.890.5%. Serum total cholesterol was measured by an enzyme method.
2.3. Statistical methods 2-Analysis was performed to test for univariate associations between risk factors and the development of DR. Logistic regression analysis was used to evaluate the relative influence of HbA1c on the development of DR. Cox’ proportional hazards model was used to examine the significance of individual variables in predicting the development of DR.
3. Results
3.1. Patient characteristics The mean treatment period at our outpatient clinic was 6.79 2.3 years. The distribution of the methods of therapy at the endpoint or at the last visit was as follows, diet alone in 233 patients (29.6%); oral agents in 415 patients (52.7%); and insulin therapy in 139 patients (17.7%), which had been 60.0, 34.2 and 5.8%, respectively, at the time of the first visit to our clinic. The numbers of patients on oral agents and insulin therapy were significantly increased, while those on diet therapy decreased (PB 0.01). Development of DR was recognized in 132 patients (16.8%) out of the total of 787. Two cases showed rapid development from no DR at the first visit to preproliferative retinopathy within 1 year from the first visit. The mean observation period and the estimated duration of diabetes until the time of development of DR were 4.39 2.5 and 12.39 9.2 years, respectively.
3.2. Correlations between HbA1c, blood pressure and BMI and the de6elopment of diabetic retinopathy First, we investigated for correlations between the HbA1c, BMI, systolic blood pressure and diastolic blood pressure at the first visit and the
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development of DR during follow-up. All patients were stratified into quartiles on the basis of these factors at the first visit. The frequency of development of DR during the follow-up period was investigated in each subgroup. The results showed that the frequency of development of DR was significantly higher in the groups with higher HbA1c values. On the other hand, there were no significant differences among the four groups when the BMI, systolic blood pressure and diastolic blood pressure at the first visit were compared (Fig. 1). We next analyzed the same factors during follow-up for correlations with the development of DR. The patients were monitored for 3, 5 or 7 years, and the value of HbA1c was determined every 6 months and the mean value during the observation period was calculated for each patient. Next, the patients were monitored for 3 more years for the development of DR. Within each of the patient groups, the patients were stratified into quartiles on the basis of the mean HbA1c level. The frequency of development of DR in each HbA1c quartile was compared. Similar stratification was performed using the mean BMI, mean systolic blood pressure and mean diastolic blood pressure. The results showed that, in the cases of the 3-, 5- and 7-year follow-up periods, the mean HbA1c contributed significantly to the development of DR (Fig. 2A). Concerning the BMI, the obese group (BMI of more than 23.7 kg/m2) showed a higher incidence of DR (PB 0.05) in the subjects with 7-year follow-up compared with the other groups (Fig. 2B). The systolic blood pressure revealed a weak association with the development of DR (P B0.05) only in the 3-year follow-up group (Fig. 2C), while it showed no significant contribution in the 5- and 7-year follow-up groups. The diastolic blood pressure showed no evidence of a relationship with the development of DR in any the follow-up groups (Fig. 2D).
3.3. Relationship of de6elopment of DR to hyperglycemia We studied the effect of the mean HbA1c on the development of DR in relation to the duration of
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Fig. 1. Three-year frequency of development of DR as function of HbA1c, BMI, systolic blood pressure and diastolic blood pressure at the first visit. Only HbA1c at the first visit was significantly associated with the development of DR. The P values are given for the 2-test.
follow-up. Patients were monitored as above, and the probability of development of DR during the next 3 years was estimated by logistic regression analysis (Fig. 3). The odds ratio for the development of DR was 2.45 after 3-year follow-up, 2.75 after 5-year follow-up, and 5.17 after 7-year follow-up. That is, as the follow-up period became longer, the correlation between HbA1c and the development of DR became stronger. In other words, the probability of development of DR increased, as the duration of poor glycemic control became longer. It was thus inferred that the development of DR could be prevented if good glycemic control was maintained longer. By statistical analysis, we estimated that the probability of development of DR during 3 years of observation after 5-year follow-up was 50% when the mean HbA1c during the 5-year follow-up was 10.9%, while the probability was only 10% when the mean HbA1c was 8.7%. When the mean HbA1c was maintained under 8% for more than 5 years, the probability of development of DR during the next 3 years was estimated to be less than 5% (Table 2).
It was also found that the probability of development of DR was lower when the HbA1c value at the first visit was lower, even if the blood glucose control was similar during the follow-up period. Patients were monitored for 1, 3, 5 or 7 years, and the mean HbA1c level was calculated as above. Then, within each of the patient groups, the patients were stratified on the basis of the median baseline HbA1c level (8.2%). The probability of DR during the next 3 years was estimated by logistic regression analysis. This analysis revealed that patients whose HbA1c at the first visit was higher than the median value of 8.2% showed a higher probability of development of DR during the next 3 years, even when the same blood glucose control was maintained during the followup (Fig. 4).
3.4. Multi6ariate analysis between risk factors and the de6elopment of diabetic retinopathy Lastly, multivariate analysis was performed for various factors possibly related to the develop-
Y. Yoshida et al. / Diabetes Research and Clinical Practice 51 (2001) 195–203
ment of DR, which were determined at the first visit and during the follow-up period. Among the factors detected at the first visit, significant correlations with the development of DR were observed for HbA1c (P B 0.0001), the method of therapy (PB0.005), the duration of diabetes at the first visit (PB 0.005) and the past maximal BMI (P B0.01). No significant correlation was found with the blood pressure, age, gender, total
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cholesterol or BMI (Table 3). Among the followup variables, HbA1c (PB0.0001) and the duration of diabetes (PB 0.001) were significantly associated with the development of DR (Table 4), whereas the systolic and diastolic blood pressures, BMI and age were not significantly associated. Among the associated factors, the most influential factor was HbA1c during the follow-up period, and the second was the duration of diabetes.
Fig. 2. Three-year frequency of development of DR as function of mean HbA1c level (A), mean BMI (B), mean systolic blood pressure (C) and mean diastolic blood pressure (D) during previous 3-, 5- and 7-year periods. HbA1c includes the unstable fraction. The mean HbA1c contributed significantly to the development of DR (A). On the other hand, the obese group (BMI more than 23.7 kg/m2) showed a significantly higher incidence of DR in the subjects with 7-year follow-up compared with the other groups (B). The systolic blood pressure was significantly associated with the development of DR only in the 3-year follow-up group (C). The diastolic blood pressure showed no evidence of a relationship with the development of DR in any the follow-up groups (D). The P values are given for the 2-test.
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Fig. 3. Relationship between the mean HbA1c during 3-, 5and 7-year follow-up periods and the probability of development of DR during the next 3 years. The probability of DR during the next 3 years was estimated by logistic regression analysis. HbA1c includes the unstable fraction.
Based on these results, we found that a 1% decrease in HbA1c during the follow-up led to a 35% reduction in the risk of development of retinopathy.
4. Discussion The UKPDS [2] found that strict control of blood glucose was essential for the prevention of DR. HbA1c was 7% in the intensive group compared with 7.9% in the conventional group. Compared with the conventional group, the risk of DR in the intensive group was 21% lower. Molyneaux et al. [4] reported that a 10% decrease in HbA1c Table 2 Relationship between the mean HbA1c during 5-year follow-up and the probability of development of DR during the next 3 yearsa Probability of DR Mean HbA1c during 5-year follow-up (%) (%) 50 10 5 a
10.9 8.7 7.9 n= 622, HbA1c includes unstable fraction.
Fig. 4. Relationship between the mean HbA1c during 1-, 3-, 5and 7-year follow-up and the probability of development of DR during the next 3 years. All cases stratified on the basis of a median baseline HbA1c of 8.2%. The incidence of DR was lower when the HbA1c value at the first visit was lower ( B median value, 8.2%) even under similar blood glucose control during the follow-up period.
resulted in a 24% reduction in the relative risk for development of DR. Because the method of our study was different from the methods of the above two studies, direct comparison of the results of the three studies might not be valid. However, our study also demonstrated a significant risk reduction for DR by keeping HbA1c low. The risk reduction of retinopathy was approximately 35% for a 1% reduction in the mean HbA1c in our study. As shown in Fig. 3, the three plots of the probability of development of retinopathy, which correspond to the 3-, 5- and 7-year follow-up periods, intersected at a mean HbA1c of about 9%. This suggests that the probability of development of DR will decrease when HbA1c is maintained below 9% for as long as possible during follow-up; conversely, the longer the follow-up period with HbA1c higher than 9% is, the higher
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Table 3 Relationships between various baseline factors and the development of DRa Variable
P value
Risk ratio
(95% CI)
HbA1c at first visit Method of therapy Duration of diabetes at the first visit Maximal BMI Gender Diastolic blood pressure Age at first visit BMI at first visit Total cholesterol Systolic blood pressure
0.0001 0.0018 0.0021 0.0090 0.1519 0.3125 0.5672 0.5857 0.6347 0.7001
1.47 1.53 1.04 1.10 1.33 1.01 1.01 0.98 1.00 1.00
(1.35–1.61) (1.17-2.01) (1.02–1.07) (1.098–1.104) (0.90–1.96) (0.99–1.03) (0.98–1.03) (0.90–1.06) (0.99–1.01) (0.99–1.02)
a
n= 776.
the probability of development of DR will become. A recent report from the American Diabetes Association (ADA) discussed the goal of diabetic control [5]. It stated that the goal for HbA1c should be less than 7%, and the treatment method should be changed when HbA1c exceeds 8%. Because the HbA1c data compiled in this study included the unstable fractions, they are about 1% higher than the stable HbA1c data generally measured in Japan at present. Considering this difference in the methods of HbA1c measurement, the 9% HbA1c value determined in this study is almost the same as the 8% level at which the ADA recommended changing the method of treatment. Our study demonstrated that the metabolic state before starting treatment in our clinic clearly affected the deterioration of eye complications even after 7 years of follow-up. The effect of glycemic control at the first visit on the development of DR during the next several years was also demonstrated in the DCCT and WESDR studies [6,7]. Recently, the Epidemiology of Diabetes Interventions and Complications study reported that the reduction in the risk of progressive DR resulting from intensive therapy in patients with type 1 diabetes lasted for at least 4 years [8]. Considering that the onset of type 2 diabetes is suggested to occur 4 – 7 years before the diagnosis of diabetes [9], our study results support the importance of early diagnosis of diabetes and quick commencement of metabolic control.
In light of the finding that the method of therapy affected the incidence of DR, it was inferred that the methods of therapy in our patients had been changed because glycemic control had deteriorated. In some reports, the positive association of insulin therapy with the incidence of DR may suggest that diabetic subjects who take insulin therapy experience more severe metabolic deterioration [10 –12]. However, the Kumamoto Study [13] and Tovi et al. [14] reported that the frequency of development of DR was lower when glycemic control was improved by using insulin, even among type 2 diabetic patients. UKPDS demonstrated that good glycemic control for a long period strongly inhibited the development of DR, regardless of the method of treatment [2]. Table 4 Relationships between various factors during follow-up and the development of DRa Variable
P value
Risk ratio
(95% CI)
Mean HbA1c during follow-up Duration of diabetes Mean diastolic blood pressure Mean BMI Age Mean systolic blood pressure
0.0001
1.77
(1.56–2.01)
0.0006
1.06
(1.02–1.09)
0.2226
1.02
(0.99–1.05)
0.3525 0.5408 0.5713
1.04 1.01 1.01
(0.96–1.13) (0.98–1.04) (0.99–1.02)
a Cox’ proportional hazards model; mean follow-up for all cases, 6.7 years; n =787.
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Fig. 5. The mean change in BMI in total patients and in the patients followed for 9 years. No significant increase in the body weight was demonstrated in this study. Data are given as the mean 9 S.E. The numbers of total patients at each time are shown in the graph.
A special characteristic of these studies is that the number of obese patients was small among Japanese type 2 patients compared with that in Europe and the US. The mean BMI of the subjects of our study was low, i.e. about 26.0 kg/m2 as the maximum in the past and 22.6 kg/m2 at the first visit. The mean BMI of the subjects in the Kumamoto Study was similar [13]. Furthermore, no significant increase in the body weight occurred in our study (Fig. 5), whereas the body weight gradually increased during the follow-up period in UKPDS [2]. The obese group (BMI of more than 23.7 kg/m2) showed a higher incidence of DR (PB 0.05) in the subjects with 7year follow-up compared with the other groups (Fig. 2B). This is an interesting finding, and it is assumed that there is some influence from insulin resistance [15]. This will require further evaluation. It is unknown why the period during which various individual risk factors were associated with the development of DR varies. We also found no significant association, in general, between the blood pressure and the development of DR under the condition that the blood pressure was controlled in a majority of the subjects (Fig. 2C). This was in significant contrast to the UKPDS results, which found a
clear association between the blood pressure and the development and progression of DR. This striking contrast between UKPDS and this study may be due to the good control of the body weight of the Japanese subjects during the follow-up. Several studies found hypertension to be a risk factor for the development of DR or progression of preproliferative DR [1,16 –18], while other studies reported no significant correlation [19 –22]. It is controversial whether there is a racial difference in the effect of hypertension on the development of DR [10,23]. Two Asian prospective studies found no significant relationship between blood pressure and the development of DR [19,20]. To our knowledge, there have been no published prospective studies which examined the difference in development of DR between Asians and Caucasians. There are still various unclear points, such as which of the systolic blood pressure and diastolic blood pressure is more important [16,24,25], whether there is any difference in the effect of the blood pressure between the development of DR and the progression to preproliferative retinopathy [16,22], and the effects of the blood pressure in type 1 and type 2 diabetes [22].
5. Conclusion The primary factor that affected the incidence of retinopathy was glycemic control. Good glycemic control for a long period decreased the incidence of retinopathy. It was clarified that the state of glycemic control influenced the incidence of retinopathy for several years afterwards. There was no significant association between the blood pressure and the incidence of retinopathy.
Acknowledgements We acknowledge the help rendered by T. Nakamura and M. Goromaru in the analysis of the data. We also thank M. Okayasu for her skilled secretarial assistance.
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References [1] UK Prospective Diabetes Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38, Br. Med. J. 317 (1998) 703– 713. [2] UK Prospective Diabetes Study Group, Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837– 853. [3] World Health Organization, Diabetes mellitus, report of a WHO Study Group. Tech. Rep. Ser. No. 727, Geneva, 1985, pp. 9 – 17. [4] L.M. Molyneaux, M.I. Constantino, M. McGill, R. Zilkens, D.K. Yue, Better glycaemic control and risk reduction of diabetic complications in type 2 diabetes: comparison with the DCCT, Diabetes Res. Clin. Pract. 42 (1998) 77 – 83. [5] American Diabetes Association, Standards of medical care for patients with diabetes mellitus, Diabetes Care 21 (Suppl. 1) (1998) S23–S31. [6] The Diabetes Control and Complications Trial Research Group, The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial, Diabetes 44 (1995) 968– 983. [7] R. Klein, B.E.K. Klein, S.E. Moss, K.J. Cruickshanks, Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy, Arch. Intern. Med. 154 (1994) 2169–2178. [8] The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Retinopathy and nephropathy in patients with type 1 diabetes 4 years after a trial of intensive therapy, New Engl. J. Med. 342 (2000) 381–389. [9] M.I. Harris, R. Klein, T.A. Welborn, M.W. Knuiman, Onset of NIDDM occurs at least 4–7 years before clinical diagnosis, Diabetes Care 15 (1992) 815–819. [10] S.M. Tudor, D.W. Johnson, R.F. Hamman, S.M. Shetterly, A. Baron, Incidence and progression of diabetic retinopathy in Hispanics and non-Hispanic Whites with type 2 diabetes, Diabetes Care 21 (1998) 53–61. [11] S.M. Haffner, D. Fong, M.P. Stern, et al., Diabetic retinopathy in Mexican Americans and non-Hispanic Whites, Diabetes 37 (1988) 878–884. [12] E.T. Lee, V.S. Lee, M. Lu, D. Russell, Development of proliferative retinopathy in NIDDM. A follow-up study of American Indians in Oklahoma, Diabetes 41 (1992) 359– 367.
.
203
[13] Y. Ohkubo, H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, M. Shichiri, Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective study, Diabetes Res. Clin. Pract. 28 (1995) 103– 117. [14] J. Tovi, S.O. Ingemansson, P. Engfeldt, Insulin treatment of elderly type 2 diabetic patients: effects on retinopathy, Diabetes Metabol. 24 (1998) 442– 447. [15] R.O. Estacio, E.E. Wolfel, J.G. Regensteiner, B. Jeffers, E.P. Havranek, S. Savage, R.W. Schrier, Effect of risk factors on exercise capacity in NIDDM, Diabetes 45 (1996) 79 – 85. [16] A. Teuscher, H. Schnell, P.W.F. Wilson, Incidence of diabetic retinopathy and relationship to baseline plasma glucose and blood pressure, Diabetes Care 11 (1988) 246– 251. [17] W.C. Knowler, P.H. Bennett, E.J. Ballantine, Increased incidence of retinopathy in diabetics with elevated blood pressure, New Engl. J. Med. 302 (1980) 645– 650. [18] R.G. Nelson, J.A. Wolfe, M.B. Horton, D.J. Pettitt, P.H. Bennett, W.C. Knowler, Proliferative retinopathy in NIDDM: incidence and risk factors in Pima Indians, Diabetes 39 (1989) 435– 440. [19] A. Sasaki, N. Horiuchi, K. Hasegawa, M. Uehara, Development of diabetic retinopathy and its associated risk factors in type 2 diabetic patients in Osaka district, Japan: a long-term prospective study, Diabetes Res. Clin. Pract. 10 (1990) 257– 263. [20] H.K. Kim, S.K. Hong, C.-H. Kim, et al., Development and progression of diabetic retinopathy in Koreans with NIDDM, Diabetes Care 21 (1998) 134– 138. [21] L. Yanko, U. Goldbourt, I.C. Michaelson, A. Shapiro, S. Yaari, Prevalence and 15-year incidence of retinopathy and associated characteristics in middle-aged and elderly diabetic men, Br. J. Ophthalmol. 67 (1983) 759– 765. [22] B.E.K. Klein, R. Klein, S.E. Moss, M. Palta, A cohort study of the relationship of diabetic retinopathy to blood pressure, Arch. Ophthalmol. 113 (1995) 601– 606. [23] E.L. Harris, S.H. Sherman, A. Georgopoulos, Black– white differences in risk of developing retinopathy among individuals with type 2 diabetes, Diabetes Care 22 (1999) 779– 783. [24] G.K. Dowse, A.R.G. Humphrey, V.R. Collins, et al., Prevalence and risk factors for diabetic retinopathy in the multiethnic population of Mauritius, Am. J. Epidemiol. 147 (1998) 448– 457. [25] R. Klein, B.E.K. Klein, S.E. Moss, K.J. Cruickshanks, The Wisconsin epidemiologic study of diabetic retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes, Ophthalmology 105 (1998) 1801– 1815.
Risk factors for the development of diabetic retinopathy in Japanese type 2 diabetic patients Y. Yoshida *, R. Hagura, Y. Hara, G. Sugasawa, Y. Akanuma The Institute for Diabetes Care and Research, Asahi Life Foundation, 1 -6 -1 Marunouchi, Chiyoda-ku, Tokyo 100 -0005, Japan Received 28 April 2000; received in revised form 13 July 2000; accepted 22 August 2000
Abstract This study investigated the risk factors for development of diabetic retinopathy (DR) in 787 type 2 diabetic patients with no retinopathy at the first visit. The subjects were followed up for at least 3 years (mean, 6.7 years). Among the baseline factors, significant correlations were observed between the development of DR and HbA1c (P B0.0001), the method of therapy (P B 0.005), the duration of diabetes at the first visit (PB 0.005) and the past maximal body mass index (BMI) (PB 0.01). No significant correlation was found with the blood pressure, age, gender, TC or BMI. Among the follow-up variables, the mean HbA1c (PB 0.0001) and duration of diabetes (PB 0.001) correlated significantly with DR development, whereas the blood pressure and age did not. We found that a 1% decrease in HbA1c led to a 35% reduction in the risk of development of DR during the follow-up. The patients whose HbA1c at the first visit was higher than the median value of 8.2% showed a higher probability of development of DR during the next 3 years even when the same blood glucose control was maintained during the follow-up. In conclusion, our study demonstrated that the most important risk factor influencing the development of DR was the blood glucose control. Moreover, we found that the glycemic level at the first visit also influenced the development of DR. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Retinopathy; Blood glucose control; Type 2 diabetes
1. Introduction In contemporary Japan, the increase in microangiopathy is one of the most important problems in the clinical field of diabetes mellitus. The primary cause of acquired blindness is diabetes mellitus, and diabetic nephropathy has recently become the main reason for the introduction of
* Corresponding author. Tel.: +81-3-32016781; fax: + 813-32016881; e-mail address: [email protected]
hemodialysis, surpassing chronic nephritis. The recent UK Prospective Diabetes Study (UKPDS) disclosed that strict control of the blood pressure as well as blood glucose is essential for the prevention of diabetic microangiopathy [1]. While steady increases in blood glucose and body weight were reported by UKPDS [2], our clinical experience seemed somewhat different, i.e. no significant increase in body weight or blood glucose was noted in diabetic patients at our institute. Therefore, we decided to study, using
0168-8227/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 8 - 8 2 2 7 ( 0 0 ) 0 0 2 1 2 - 6
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our follow-up data, the correlations between the development of diabetic retinopathy (DR) and various baseline clinical parameters, such as the body weight, blood glucose control and blood pressure, of patients at their first visit to our institute and also during the follow-up period.
2. Subjects and methods
2.1. Subjects The subjects of this study were type 2 diabetic patients who visited the Institute for Diabetes Care and Research, Asahi Life Foundation, from 1985 to 1990. We studied patients with no DR at the first visit and whose age at the first visit was less than 70 years. They were treated at our clinic for at least 3 years (range, 3.0 – 9.5 years; mean, 6.7 years). The diagnosis of diabetes mellitus was made according to the WHO criteria of 1985 [3]. The total number of patients was 787, and their baseline clinical characteristics are shown in Table 1. The mean age of the patients was 54 years, and the mean duration of diabetes at the first visit to our clinic was 8 years. The mean HbA1c and the mean body mass index (BMI) were 8.6% and 22.6 kg/m2, respectively, at the first visit. The methods of existing treatment at the first visit were diet alone for 472 patients (60.0%), oral agents for 269 patients (34.2%), and insulin treatment for 46
patients (5.8%). The patients visited our clinic every month or every other month during the follow-up period.
2.2. Methods DR was diagnosed by the ocular fundus test, performed by any three ophthalmologists at least once every year. Direct and indirect ophthalmoscopy were performed after full dilatation of the pupils. The development of DR was defined as a finding of background retinopathy (such as at least two dot hemorrhages with microaneurysms and/or a hard exudate in at least one eye) and more severe findings for the retina. The patients were excluded from this study if they could not be evaluated because of severe cataracts, or if their lesion could not be positively identified as DR, as in the case of bleeding alone. The endpoint was defined as the development of DR. The longest follow-up period was 9 years and 5 months until September 1994, when the method for measurement of HbA1c was changed. The numbers of patients who were followed for 3, 5, 7 and 9 years were 787, 697, 485 and 319. HbA1c was measured by an HPLC method (HLC723GHb I until May of 1988, and HLC723GHb II thereafter). The coefficient of variation (CV) of each intra-assay was 1.7 and 2.0%, respectively, while the CV of inter-assay was 0.6 and 1.4%, respectively. Both HPLC meth-
Table 1 Characteristics of the patients at the first visit n (M/F)
787 (597/190)
Method of therapy (%)
Diet alone 472 (60)
OHA 269 (34)
Insulin 46 (6)
Mean 9S.D.
Median
Range
53.6 98.1 8.0 96.8 8.6 91.9 130 9 19 79 9 12 22.6 93.0 26.0 9 3.3 205 9 41
54.0 6.0 8.2 130 78 22.4 25.8 201
18–69 0–38 5.4–16.7 86–218 42–123 14.6–42.3 16.6–45.1 101–446
Age (years) Duration of diabetes at the first visit (years) HbA1c (%)a Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) BMI (kg/m2) Maximal BMI (kg/m2) Total cholesterol (mg/dl) a
HbA1c includes unstable fraction.
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ods included detection of the unstable type HbA1c. The mean9S.D. of HbA1c in normal subjects in our clinic is 5.890.5%. Serum total cholesterol was measured by an enzyme method.
2.3. Statistical methods 2-Analysis was performed to test for univariate associations between risk factors and the development of DR. Logistic regression analysis was used to evaluate the relative influence of HbA1c on the development of DR. Cox’ proportional hazards model was used to examine the significance of individual variables in predicting the development of DR.
3. Results
3.1. Patient characteristics The mean treatment period at our outpatient clinic was 6.79 2.3 years. The distribution of the methods of therapy at the endpoint or at the last visit was as follows, diet alone in 233 patients (29.6%); oral agents in 415 patients (52.7%); and insulin therapy in 139 patients (17.7%), which had been 60.0, 34.2 and 5.8%, respectively, at the time of the first visit to our clinic. The numbers of patients on oral agents and insulin therapy were significantly increased, while those on diet therapy decreased (PB 0.01). Development of DR was recognized in 132 patients (16.8%) out of the total of 787. Two cases showed rapid development from no DR at the first visit to preproliferative retinopathy within 1 year from the first visit. The mean observation period and the estimated duration of diabetes until the time of development of DR were 4.39 2.5 and 12.39 9.2 years, respectively.
3.2. Correlations between HbA1c, blood pressure and BMI and the de6elopment of diabetic retinopathy First, we investigated for correlations between the HbA1c, BMI, systolic blood pressure and diastolic blood pressure at the first visit and the
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development of DR during follow-up. All patients were stratified into quartiles on the basis of these factors at the first visit. The frequency of development of DR during the follow-up period was investigated in each subgroup. The results showed that the frequency of development of DR was significantly higher in the groups with higher HbA1c values. On the other hand, there were no significant differences among the four groups when the BMI, systolic blood pressure and diastolic blood pressure at the first visit were compared (Fig. 1). We next analyzed the same factors during follow-up for correlations with the development of DR. The patients were monitored for 3, 5 or 7 years, and the value of HbA1c was determined every 6 months and the mean value during the observation period was calculated for each patient. Next, the patients were monitored for 3 more years for the development of DR. Within each of the patient groups, the patients were stratified into quartiles on the basis of the mean HbA1c level. The frequency of development of DR in each HbA1c quartile was compared. Similar stratification was performed using the mean BMI, mean systolic blood pressure and mean diastolic blood pressure. The results showed that, in the cases of the 3-, 5- and 7-year follow-up periods, the mean HbA1c contributed significantly to the development of DR (Fig. 2A). Concerning the BMI, the obese group (BMI of more than 23.7 kg/m2) showed a higher incidence of DR (PB 0.05) in the subjects with 7-year follow-up compared with the other groups (Fig. 2B). The systolic blood pressure revealed a weak association with the development of DR (P B0.05) only in the 3-year follow-up group (Fig. 2C), while it showed no significant contribution in the 5- and 7-year follow-up groups. The diastolic blood pressure showed no evidence of a relationship with the development of DR in any the follow-up groups (Fig. 2D).
3.3. Relationship of de6elopment of DR to hyperglycemia We studied the effect of the mean HbA1c on the development of DR in relation to the duration of
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Fig. 1. Three-year frequency of development of DR as function of HbA1c, BMI, systolic blood pressure and diastolic blood pressure at the first visit. Only HbA1c at the first visit was significantly associated with the development of DR. The P values are given for the 2-test.
follow-up. Patients were monitored as above, and the probability of development of DR during the next 3 years was estimated by logistic regression analysis (Fig. 3). The odds ratio for the development of DR was 2.45 after 3-year follow-up, 2.75 after 5-year follow-up, and 5.17 after 7-year follow-up. That is, as the follow-up period became longer, the correlation between HbA1c and the development of DR became stronger. In other words, the probability of development of DR increased, as the duration of poor glycemic control became longer. It was thus inferred that the development of DR could be prevented if good glycemic control was maintained longer. By statistical analysis, we estimated that the probability of development of DR during 3 years of observation after 5-year follow-up was 50% when the mean HbA1c during the 5-year follow-up was 10.9%, while the probability was only 10% when the mean HbA1c was 8.7%. When the mean HbA1c was maintained under 8% for more than 5 years, the probability of development of DR during the next 3 years was estimated to be less than 5% (Table 2).
It was also found that the probability of development of DR was lower when the HbA1c value at the first visit was lower, even if the blood glucose control was similar during the follow-up period. Patients were monitored for 1, 3, 5 or 7 years, and the mean HbA1c level was calculated as above. Then, within each of the patient groups, the patients were stratified on the basis of the median baseline HbA1c level (8.2%). The probability of DR during the next 3 years was estimated by logistic regression analysis. This analysis revealed that patients whose HbA1c at the first visit was higher than the median value of 8.2% showed a higher probability of development of DR during the next 3 years, even when the same blood glucose control was maintained during the followup (Fig. 4).
3.4. Multi6ariate analysis between risk factors and the de6elopment of diabetic retinopathy Lastly, multivariate analysis was performed for various factors possibly related to the develop-
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ment of DR, which were determined at the first visit and during the follow-up period. Among the factors detected at the first visit, significant correlations with the development of DR were observed for HbA1c (P B 0.0001), the method of therapy (PB0.005), the duration of diabetes at the first visit (PB 0.005) and the past maximal BMI (P B0.01). No significant correlation was found with the blood pressure, age, gender, total
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cholesterol or BMI (Table 3). Among the followup variables, HbA1c (PB0.0001) and the duration of diabetes (PB 0.001) were significantly associated with the development of DR (Table 4), whereas the systolic and diastolic blood pressures, BMI and age were not significantly associated. Among the associated factors, the most influential factor was HbA1c during the follow-up period, and the second was the duration of diabetes.
Fig. 2. Three-year frequency of development of DR as function of mean HbA1c level (A), mean BMI (B), mean systolic blood pressure (C) and mean diastolic blood pressure (D) during previous 3-, 5- and 7-year periods. HbA1c includes the unstable fraction. The mean HbA1c contributed significantly to the development of DR (A). On the other hand, the obese group (BMI more than 23.7 kg/m2) showed a significantly higher incidence of DR in the subjects with 7-year follow-up compared with the other groups (B). The systolic blood pressure was significantly associated with the development of DR only in the 3-year follow-up group (C). The diastolic blood pressure showed no evidence of a relationship with the development of DR in any the follow-up groups (D). The P values are given for the 2-test.
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Fig. 3. Relationship between the mean HbA1c during 3-, 5and 7-year follow-up periods and the probability of development of DR during the next 3 years. The probability of DR during the next 3 years was estimated by logistic regression analysis. HbA1c includes the unstable fraction.
Based on these results, we found that a 1% decrease in HbA1c during the follow-up led to a 35% reduction in the risk of development of retinopathy.
4. Discussion The UKPDS [2] found that strict control of blood glucose was essential for the prevention of DR. HbA1c was 7% in the intensive group compared with 7.9% in the conventional group. Compared with the conventional group, the risk of DR in the intensive group was 21% lower. Molyneaux et al. [4] reported that a 10% decrease in HbA1c Table 2 Relationship between the mean HbA1c during 5-year follow-up and the probability of development of DR during the next 3 yearsa Probability of DR Mean HbA1c during 5-year follow-up (%) (%) 50 10 5 a
10.9 8.7 7.9 n= 622, HbA1c includes unstable fraction.
Fig. 4. Relationship between the mean HbA1c during 1-, 3-, 5and 7-year follow-up and the probability of development of DR during the next 3 years. All cases stratified on the basis of a median baseline HbA1c of 8.2%. The incidence of DR was lower when the HbA1c value at the first visit was lower ( B median value, 8.2%) even under similar blood glucose control during the follow-up period.
resulted in a 24% reduction in the relative risk for development of DR. Because the method of our study was different from the methods of the above two studies, direct comparison of the results of the three studies might not be valid. However, our study also demonstrated a significant risk reduction for DR by keeping HbA1c low. The risk reduction of retinopathy was approximately 35% for a 1% reduction in the mean HbA1c in our study. As shown in Fig. 3, the three plots of the probability of development of retinopathy, which correspond to the 3-, 5- and 7-year follow-up periods, intersected at a mean HbA1c of about 9%. This suggests that the probability of development of DR will decrease when HbA1c is maintained below 9% for as long as possible during follow-up; conversely, the longer the follow-up period with HbA1c higher than 9% is, the higher
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Table 3 Relationships between various baseline factors and the development of DRa Variable
P value
Risk ratio
(95% CI)
HbA1c at first visit Method of therapy Duration of diabetes at the first visit Maximal BMI Gender Diastolic blood pressure Age at first visit BMI at first visit Total cholesterol Systolic blood pressure
0.0001 0.0018 0.0021 0.0090 0.1519 0.3125 0.5672 0.5857 0.6347 0.7001
1.47 1.53 1.04 1.10 1.33 1.01 1.01 0.98 1.00 1.00
(1.35–1.61) (1.17-2.01) (1.02–1.07) (1.098–1.104) (0.90–1.96) (0.99–1.03) (0.98–1.03) (0.90–1.06) (0.99–1.01) (0.99–1.02)
a
n= 776.
the probability of development of DR will become. A recent report from the American Diabetes Association (ADA) discussed the goal of diabetic control [5]. It stated that the goal for HbA1c should be less than 7%, and the treatment method should be changed when HbA1c exceeds 8%. Because the HbA1c data compiled in this study included the unstable fractions, they are about 1% higher than the stable HbA1c data generally measured in Japan at present. Considering this difference in the methods of HbA1c measurement, the 9% HbA1c value determined in this study is almost the same as the 8% level at which the ADA recommended changing the method of treatment. Our study demonstrated that the metabolic state before starting treatment in our clinic clearly affected the deterioration of eye complications even after 7 years of follow-up. The effect of glycemic control at the first visit on the development of DR during the next several years was also demonstrated in the DCCT and WESDR studies [6,7]. Recently, the Epidemiology of Diabetes Interventions and Complications study reported that the reduction in the risk of progressive DR resulting from intensive therapy in patients with type 1 diabetes lasted for at least 4 years [8]. Considering that the onset of type 2 diabetes is suggested to occur 4 – 7 years before the diagnosis of diabetes [9], our study results support the importance of early diagnosis of diabetes and quick commencement of metabolic control.
In light of the finding that the method of therapy affected the incidence of DR, it was inferred that the methods of therapy in our patients had been changed because glycemic control had deteriorated. In some reports, the positive association of insulin therapy with the incidence of DR may suggest that diabetic subjects who take insulin therapy experience more severe metabolic deterioration [10 –12]. However, the Kumamoto Study [13] and Tovi et al. [14] reported that the frequency of development of DR was lower when glycemic control was improved by using insulin, even among type 2 diabetic patients. UKPDS demonstrated that good glycemic control for a long period strongly inhibited the development of DR, regardless of the method of treatment [2]. Table 4 Relationships between various factors during follow-up and the development of DRa Variable
P value
Risk ratio
(95% CI)
Mean HbA1c during follow-up Duration of diabetes Mean diastolic blood pressure Mean BMI Age Mean systolic blood pressure
0.0001
1.77
(1.56–2.01)
0.0006
1.06
(1.02–1.09)
0.2226
1.02
(0.99–1.05)
0.3525 0.5408 0.5713
1.04 1.01 1.01
(0.96–1.13) (0.98–1.04) (0.99–1.02)
a Cox’ proportional hazards model; mean follow-up for all cases, 6.7 years; n =787.
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Fig. 5. The mean change in BMI in total patients and in the patients followed for 9 years. No significant increase in the body weight was demonstrated in this study. Data are given as the mean 9 S.E. The numbers of total patients at each time are shown in the graph.
A special characteristic of these studies is that the number of obese patients was small among Japanese type 2 patients compared with that in Europe and the US. The mean BMI of the subjects of our study was low, i.e. about 26.0 kg/m2 as the maximum in the past and 22.6 kg/m2 at the first visit. The mean BMI of the subjects in the Kumamoto Study was similar [13]. Furthermore, no significant increase in the body weight occurred in our study (Fig. 5), whereas the body weight gradually increased during the follow-up period in UKPDS [2]. The obese group (BMI of more than 23.7 kg/m2) showed a higher incidence of DR (PB 0.05) in the subjects with 7year follow-up compared with the other groups (Fig. 2B). This is an interesting finding, and it is assumed that there is some influence from insulin resistance [15]. This will require further evaluation. It is unknown why the period during which various individual risk factors were associated with the development of DR varies. We also found no significant association, in general, between the blood pressure and the development of DR under the condition that the blood pressure was controlled in a majority of the subjects (Fig. 2C). This was in significant contrast to the UKPDS results, which found a
clear association between the blood pressure and the development and progression of DR. This striking contrast between UKPDS and this study may be due to the good control of the body weight of the Japanese subjects during the follow-up. Several studies found hypertension to be a risk factor for the development of DR or progression of preproliferative DR [1,16 –18], while other studies reported no significant correlation [19 –22]. It is controversial whether there is a racial difference in the effect of hypertension on the development of DR [10,23]. Two Asian prospective studies found no significant relationship between blood pressure and the development of DR [19,20]. To our knowledge, there have been no published prospective studies which examined the difference in development of DR between Asians and Caucasians. There are still various unclear points, such as which of the systolic blood pressure and diastolic blood pressure is more important [16,24,25], whether there is any difference in the effect of the blood pressure between the development of DR and the progression to preproliferative retinopathy [16,22], and the effects of the blood pressure in type 1 and type 2 diabetes [22].
5. Conclusion The primary factor that affected the incidence of retinopathy was glycemic control. Good glycemic control for a long period decreased the incidence of retinopathy. It was clarified that the state of glycemic control influenced the incidence of retinopathy for several years afterwards. There was no significant association between the blood pressure and the incidence of retinopathy.
Acknowledgements We acknowledge the help rendered by T. Nakamura and M. Goromaru in the analysis of the data. We also thank M. Okayasu for her skilled secretarial assistance.
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References [1] UK Prospective Diabetes Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38, Br. Med. J. 317 (1998) 703– 713. [2] UK Prospective Diabetes Study Group, Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837– 853. [3] World Health Organization, Diabetes mellitus, report of a WHO Study Group. Tech. Rep. Ser. No. 727, Geneva, 1985, pp. 9 – 17. [4] L.M. Molyneaux, M.I. Constantino, M. McGill, R. Zilkens, D.K. Yue, Better glycaemic control and risk reduction of diabetic complications in type 2 diabetes: comparison with the DCCT, Diabetes Res. Clin. Pract. 42 (1998) 77 – 83. [5] American Diabetes Association, Standards of medical care for patients with diabetes mellitus, Diabetes Care 21 (Suppl. 1) (1998) S23–S31. [6] The Diabetes Control and Complications Trial Research Group, The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial, Diabetes 44 (1995) 968– 983. [7] R. Klein, B.E.K. Klein, S.E. Moss, K.J. Cruickshanks, Relationship of hyperglycemia to the long-term incidence and progression of diabetic retinopathy, Arch. Intern. Med. 154 (1994) 2169–2178. [8] The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group, Retinopathy and nephropathy in patients with type 1 diabetes 4 years after a trial of intensive therapy, New Engl. J. Med. 342 (2000) 381–389. [9] M.I. Harris, R. Klein, T.A. Welborn, M.W. Knuiman, Onset of NIDDM occurs at least 4–7 years before clinical diagnosis, Diabetes Care 15 (1992) 815–819. [10] S.M. Tudor, D.W. Johnson, R.F. Hamman, S.M. Shetterly, A. Baron, Incidence and progression of diabetic retinopathy in Hispanics and non-Hispanic Whites with type 2 diabetes, Diabetes Care 21 (1998) 53–61. [11] S.M. Haffner, D. Fong, M.P. Stern, et al., Diabetic retinopathy in Mexican Americans and non-Hispanic Whites, Diabetes 37 (1988) 878–884. [12] E.T. Lee, V.S. Lee, M. Lu, D. Russell, Development of proliferative retinopathy in NIDDM. A follow-up study of American Indians in Oklahoma, Diabetes 41 (1992) 359– 367.
.
203
[13] Y. Ohkubo, H. Kishikawa, E. Araki, T. Miyata, S. Isami, S. Motoyoshi, Y. Kojima, N. Furuyoshi, M. Shichiri, Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective study, Diabetes Res. Clin. Pract. 28 (1995) 103– 117. [14] J. Tovi, S.O. Ingemansson, P. Engfeldt, Insulin treatment of elderly type 2 diabetic patients: effects on retinopathy, Diabetes Metabol. 24 (1998) 442– 447. [15] R.O. Estacio, E.E. Wolfel, J.G. Regensteiner, B. Jeffers, E.P. Havranek, S. Savage, R.W. Schrier, Effect of risk factors on exercise capacity in NIDDM, Diabetes 45 (1996) 79 – 85. [16] A. Teuscher, H. Schnell, P.W.F. Wilson, Incidence of diabetic retinopathy and relationship to baseline plasma glucose and blood pressure, Diabetes Care 11 (1988) 246– 251. [17] W.C. Knowler, P.H. Bennett, E.J. Ballantine, Increased incidence of retinopathy in diabetics with elevated blood pressure, New Engl. J. Med. 302 (1980) 645– 650. [18] R.G. Nelson, J.A. Wolfe, M.B. Horton, D.J. Pettitt, P.H. Bennett, W.C. Knowler, Proliferative retinopathy in NIDDM: incidence and risk factors in Pima Indians, Diabetes 39 (1989) 435– 440. [19] A. Sasaki, N. Horiuchi, K. Hasegawa, M. Uehara, Development of diabetic retinopathy and its associated risk factors in type 2 diabetic patients in Osaka district, Japan: a long-term prospective study, Diabetes Res. Clin. Pract. 10 (1990) 257– 263. [20] H.K. Kim, S.K. Hong, C.-H. Kim, et al., Development and progression of diabetic retinopathy in Koreans with NIDDM, Diabetes Care 21 (1998) 134– 138. [21] L. Yanko, U. Goldbourt, I.C. Michaelson, A. Shapiro, S. Yaari, Prevalence and 15-year incidence of retinopathy and associated characteristics in middle-aged and elderly diabetic men, Br. J. Ophthalmol. 67 (1983) 759– 765. [22] B.E.K. Klein, R. Klein, S.E. Moss, M. Palta, A cohort study of the relationship of diabetic retinopathy to blood pressure, Arch. Ophthalmol. 113 (1995) 601– 606. [23] E.L. Harris, S.H. Sherman, A. Georgopoulos, Black– white differences in risk of developing retinopathy among individuals with type 2 diabetes, Diabetes Care 22 (1999) 779– 783. [24] G.K. Dowse, A.R.G. Humphrey, V.R. Collins, et al., Prevalence and risk factors for diabetic retinopathy in the multiethnic population of Mauritius, Am. J. Epidemiol. 147 (1998) 448– 457. [25] R. Klein, B.E.K. Klein, S.E. Moss, K.J. Cruickshanks, The Wisconsin epidemiologic study of diabetic retinopathy: XVII. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes, Ophthalmology 105 (1998) 1801– 1815.