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Better glycaemic control and risk reduction of diabetic complications in Type 2 diabetes: comparison with the DCCT
Diabetes Research and Clinical Practice 42 (1998) 77 – 83
Better glycaemic control and risk reduction of diabetic complications in Type 2 diabetes: comparison with the DCCT L.M. Molyneaux *, M.I. Constantino, M. McGill, R. Zilkens, D.K. Yue Diabetes Center of Royal Prince Alfred Hospital and Department of Medicine of The Uni6ersity of Sydney, 2nd Floor, QE11 Building, 59 Missenden Road, Camperdown, NSW 2050, Australia Received 24 May 1998; received in revised form 4 August 1998; accepted 24 August 1998
Abstract Objective: To construct dose response curves relating the development of diabetic complications (retinopathy and microalbuminuria) to mean glycaemic exposure in a cohort of Type 2 patients followed over a period of several years. This allows a comparison with similar data on Type 1 subjects reported by the Diabetes Control and Complications Trial (DCCT) and provides a rational basis for deciding what levels of glycaemic control should be aimed for in advising individual patients and in setting guidelines for conducting health services. Research design and methods: This was an analysis of data prospectively collected in our computerized data base for Type 2 patients who attended and were followed up at the Complications Assessment Service of our Diabetes Center. The initial development of retinopathy and microalbuminuria was analyzed with respect to the mean HbA1c during the follow up period. Statistical procedures identical to those employed in the DCCT were used to construct the dose response curve. Results: A smooth relationship between the development of retinopathy with increasing hyperglycaemia was found. For every 10% decrease in HbA1c, there was a 24% (confidence interval (CI): 16–32) reduction in relative risk, about 2/3 of that reported for insulin-dependent diabetes mellitus (IDDM) patients. The relationship between microalbuminuria and HbA1c was more linear and less steep with a relative risk reduction of 9% (CI: − 2 – 19%) for any 10% fall in HbA1c, about 1/3 of that reported for IDDM subjects. No threshold of HbA1c can be found for the relative risk of developing complications. However, more cases of complications are prevented by the same degree of improvement in glycaemic control at higher levels of HbA1c. Conclusions: The development of diabetic retinopathy in Type 2 subjects is also related to the magnitude of hyperglycaemia although the degree of dependence is less than that in Type 1. Glycaemic control has less influence on microalbuminuria in Type 2. In terms of relative risk, no threshold of ‘safe HbA1c’ can be found but in absolute terms more cases of diabetic complications can be prevented by improving the glycaemic control of the very hyperglycaemic patients. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Risk reduction; DCCT; Retinopathy; Microalbuminuria; Type 2 diabetes
* Corresponding author. Tel.: +61 2 95159715; fax: + 61 2 95159780; e-mail: [email protected] 0168-8227/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII: S0168-8227(98)00095-3
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L.M. Molyneaux et al. / Diabetes Research and Clinical Practice 42 (1998) 77–83
1. Introduction The benefits of achieving near-normoglycaemia for Type 1 subjects have been established unequivocally by the findings of the Diabetes Control and Complications Trial (DCCT) [1,2]. What has been debated in the literature is whether there is a threshold below which further improvement in glycaemic control does not result in a substantial reduction in diabetic complications [3,4]. This is an important question because near-normoglycaemia in Type 1 diabetes can only be achieved at a cost of increased hypoglycaemia. Therefore, taking into consideration the risk/benefit ratio, it is important not only in advising an individual patient whether he/she should undergo intensive insulin treatment, but also in deciding how much of the health care resources should be spent on supporting this philosophy of treatment. In this context, information about the shape and the slope of the dose-response curve relating development of diabetic complications to glycaemic control is crucial. Whilst the DCCT has provided excellent data in this regard, a similar approach to analysis for Type 2 diabetes is far more scanty, although we acknowledge that there is also overwhelming evidence that hyperglycaemia is associated with more complications [5 – 9]. Therefore we have studied data from our computerized database to examine the relationship between initial development of diabetic complications and glycaemic control over time for Type 2 patients who have attended our Complications Assessment Service on more than one occasion. By employing identical statistical procedures as those used by the DCCT [1–3], our aim was to compare our data with that of the DCCT to evaluate if improvement in glycaemic control in Type 2 patients will result in the same degree of risk reduction in diabetic complications [10].
care physicians specifically for assessment of diabetic complications [11]. This includes recording of visual acuity, examination of retina by direct fundoscopy through dilated pupils, collection of a morning spot urine sample for measurement of microalbuminuria [12] together with examination of sensation, reflexes and pulses of the lower limbs. Blood was collected for HbA1c, routine biochemistry and lipid determinations. The examination of fundi was conducted by one physician. The validity of the retinal findings of the physician has been verified against an ophthalmologist. The results showed a sensitivity of 100%, specificity of 80% and a positive predictive value of 93%, for the detection of any degree of retinopathy. Agreement between the two was also measured and there was excellent agreement (k= 0.85; PB 0.0001). All other procedures were carried out according to a standardized protocol which did not vary substantially during the period that this study covered and results of each visit were entered into a purpose designed computer data base [13]. Patients are re-referred by their primary care physicians for another complication assessment according to a Shared Care Protocol at intervals which vary between 1 and 4 years depending on the severity and duration of diabetes [13]. For the purpose of statistical calculation, retinopathy in our patients was defined as the development of any diabetic retinopathy on fundal examination. This is comparable to the DCCT classification ‘sustained onset of retinopathy’ in their primary cohort [3]. Microalbuminuria in our patients was defined as urinary albumin concentration greater than 30 mg/l, similar to the DCCT category of greater than 40 mg/day. HbA1c was measured by HbA1c (BIO-RAD, CA, USA; CVB 2%) and the mean of serial HbA1c measurements was used to estimate cumulative glycaemic exposure. Albumin was measured using a commercially available radio immunoassay kit by Diagnostic Product (UK).
2. Materials and methods
2.2. Patients 2.1. Complications assessment In the system of diabetes care provided by our Diabetes Center, patients are referred by primary
Nine hundred and sixty-three Type 2 subjects (defined by WHO criteria) [14] who had no retinopathy at the initial visit and who had made
L.M. Molyneaux et al. / Diabetes Research and Clinical Practice 42 (1998) 77–83
subsequent visits for Complications Assessment formed the cohort for this analysis. At the initial visit their median age was 57.5 years (interquartile range (IQ) 50.0–64.6) and their median duration of diabetes 3.8 years (IQ range 0.8 – 8.8). The percentage on diet, oral agent and insulin treatment was 27%, 63% and 10%, respectively, and their median HbA1c was 7.8% (IQ range 6.7 – 9.5, normal 4.0–6.0%). They had made a median of 3.5 visits (range 2– 6) over a median follow-up period of 28 months (IQ range 16.4 – 45.1). A subset of 399 patients who had normal urine albumin concentration at the first visit was analyzed for the development of microalbuminuria. At our Diabetes Center, 60% of patients resumed for a follow up Complication Assessment within the studied period of 4 years. Comparison of the patients who returned against those who did not return revealed no significant difference in clinical and complication status except that the former had a higher proportion on oral hypoglycaemic agent treatment at the initial visit (63% vs. 55%).
2.3. Statistical methods The relationship between glucose exposure over time and new retinopathy or microalbuminuria was assessed using the mean of serial HbA1c. To allow us to compare the data with insulin-dependent diabetes mellitus (IDDM) patients, we used the statistical procedures employed by the DCCT [3]. The risk gradients for retinopathy and microalbuminuria in our non-insulin-dependent diabetes mellitus (NIDDM) subjects were estimated from a Poisson regression model using the natural log (ln) of mean serial HbA1c. A linear relationship between ln (HbA1c) versus retinopathy and ln (HbA1c) versus microalbuminuria allowed us to calculate the risk reduction of complications for any 10% reduction of HbA1c. This reduction remained constant over the full range of HbA1c, ([(0.9b − 1)*100], where b is the coefficient for ln (HbA1c)). The relationship between ln (HbA1c) and the absolute risk per 100 patient years for developing retinopathy or microalbuminuria was calculated from the Poisson regression model. The absolute risk of an event per 100 patient
79
years was presented in the original units [exp(ln100) + a + (b lnHbA1c)]; where, a= intercept, and b= coefficient of ln(HbA1c). Confidence intervals were calculated for the Poisson regression models, (although not shown, as it makes Figs. 1 and 2 too complex to present graphically). The DCCT used an offset of ln (0.5) years, as their patients were assessed every 6 months. Our Type 2 cohort was assessed at different time periods, therefore our offset for each subject is the ln time difference in years from the first visit. The DCCT [3] found no significant threshold for the risk gradients of HbA1c 5 8.0% and greater than 8.0% for retinopathy and microalbuminuria. We also analyzed our data using less than or equal to 8.0% and greater than 8.0% as the cut off to enable comparison with DCCT. The Poisson model was fitted with a threshold variable [ 5ln 8.0%= 0 and if \ ln 8.0%= (ln mean HbA1c − log 8.0%)]. The threshold (5 8.0% and \8.0%) was tested using a Wald test. Statistical analysis was performed using SAS and NCSS (Number Crunching Statistical System) software. Continuous data was analyzed using Mann–Whitney U-test and expressed as median and IQ. Categorical data was analyzed using the x 2-test and expressed as a proportion with 95% CI. Statistical significance was accepted at less than 0.05 level.
3. Results The annual incidence of retinopathy and microalbuminuria in the Type 2 cohort was 5.7% (CI: 4.0–7.2) and 8.3% (CI: 5.7–10.9), respectively. There was a linear relationship found between ln (HbA1c) versus retinopathy and ln (HbA1c) versus microalbuminuria, which was similar to the DCCT. The percentage reduction in the risk of retinopathy and microalbuminuria for a 10% reduction in HbA1c is shown in Table 1. Corresponding values for the DCCT [3] are also shown for comparison. There was a significant reduction in the risk of retinopathy for a 10% reduction in HbA1c (x 2 = 25.6; PB0.0001), however the corresponding risk reduction found for microalbuminuria in our NIDDM population just
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Fig. 1. Absolute risk of retinopathy for Type 2 and Type 1 subjects. —— Type 2 data*; – – – Type 1 data (DCCT)†. *Poisson regression model: a = − 8.63, b= 2.62 (coefficient of ln HbA1c). †Poisson regression model: a = −11.68, b =4.13 (coefficient of ln HbA1c), b1 = 0.5*0.15 (coefficient for treatment group).
failed to reach statistical significance (x 2 =2.6; P= 0.1). The relationship between the absolute risk (risk per 100 patient years) of developing diabetic retinopathy or microalbuminuria and the mean HbA1c are shown in Figs. 1 and 2, respectively. Similar data published by the DCCT on Type 1 patients are again included for comparison. As can be seen in Fig. 1, the results from our Type 2 patients show a smooth curve relating to the development of diabetic retinopathy with increasing hyperglycaemia. Fig. 1 also shows that for every 10% decrease in HbA1c (e.g. from 11.0% to 9.9%), there was a 24% (CI: 16 – 32) relative risk reduction in the development of retinopathy, this can be compared to the DCCT (Sustained onset of retinopathy) which was 35% (CI: 29 – 41). In absolute terms, in these Type 2 subjects, a reduction in HbA1c from 11.0% to 9.9% reduced the risk by three cases per 100 patient years, whereas at the same 10% reduction, DCCT found a decrease of 6.5
cases per 100 patient years. Decreasing HbA1c from 8.0% to 7.2% reduced risk in Type 2 patients by one case per 100 patient years and in the DCCT, 0.8 case per 100 patient years. The absolute risk reduction for retinopathy is greater the higher the HbA1c and the relative risk reduction is about 2/3 of that reported for Type 1 patients. Fig. 2 shows that the relationship between microalbuminuria and HbA1c for Type 2 patients was more linear and less steep with a relative risk reduction of 9% (CI: (2–19) for any 10% fall in HbA1c, whereas the DCCT found a 25% risk reduction (CI: 19–32). Stated in absolute terms, in these Type 2 subjects, a reduction in HbA1c from 11.0% to 9.9% reduced the risk of developing microalbuminuria by 0.8 cases per 100 patient years, whereas for the equal 10% reduction, the DCCT found a reduction of 2.1 cases per 100 patient years. Decreasing HbA1c from 8.0% to 7.2% reduced the risk by 0.6 case per 100 patient years and in the case of the
L.M. Molyneaux et al. / Diabetes Research and Clinical Practice 42 (1998) 77–83
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Fig. 2. Absolute risk of microalbuminuria for Type 2 and Type 1 subjects. —— Type 2 data*; – – – Type 1 data (DCCT)†. *Poisson regression model: a= −4.68, b= 0.92 (coefficient of ln HbA1c). †Poisson regression model: a = −9.18, b =2.79 (coefficient of ln HbA1c), b1= 0.5*0.15 (coefficient for treatment group).
DCCT 0.9 case per 100 patient years. In our Type 2 patients there was no significant difference in the risk gradients for HbA1c of less than or equal to 8.0% and greater than 8.0% in retinopathy (x 2 =0.6; P=0.4) or microalbuminuria (x 2 =0.5; P= 0.5). Similar findings were found by the DCCT. Table 1 Relative risk reductions for retinopathy and microalbuminuria associated with a 10% lower mean HbA1c in Type 2 and the DCCT patients Complication status
% Risk reduction
95% CI
Retinopathy (NIDDM) Retinopathy (DCCT)a Microalbuminuria (NIDDM) Microalbuminuria (DCCT)a
24 35 9
(16–32)* (29–41)* (−2–19)
25
(19–32)*
Poisson regression model *PB0.0001. a Model adjusted for intensive versus conventional treatment.
4. Conclusion These data show that the development of retinopathy in Type 2 subjects is related to the magnitude of hyperglycaemia, although the degree of dependence is less than that in Type 1 [1–3,15–17]. In the case of microalbuminuria, the relationship is less strong, presumably reflecting that many other factors can influence albumin excretion in Type 2 subjects [18,19]. The relationship of complications in Type 2 diabetic patients with hyperglycaemia and other risk factors has also been studied by others [20,21]. As our aim was to compare our Type 2 data with Type 1 subjects in the DCCT, we have not presented results adjusting for the confounding variables such as blood pressure and lipid levels. For both complications examined, in terms of relative risk, no threshold of ‘safe’ HbA1c can be found. In absolute terms, however, similar degree of improvement in glycaemic control would prevent more cases of retinopathy in subjects who are very
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hyperglycaemic. Klein et al. [5] and Ohkubo et al. [6] also had extensive data on the development of retinopathy and microalbuminuria in Type 2 subjects. The data of Klein et al. [5] were based on observation of a large cohort of patients. The data of Okubo et al. [6] were prospective, interventional and provided a great deal of much needed information in this area. However, by using the same statistical procedures and presentations as the DCCT, our results provide the clinicians and health care planners with a more direct comparison of Type 1 and Type 2 subjects to help them in advising individual patients and in allocating health resources [10]. As we did not take retinal photographs to allow grading, we limited our analysis to new development of retinopathy, but not its deterioration, such as the three steps sustained progression included in the DCCT. Our data are only observational in nature whereas those of the DCCT were derived from a randomized interventional trial. However, our data provide information on the order of magnitude of the relationship between diabetic complications and glycaemic control in a group of patients reasonably representative of the ‘average’ Type 2 patient [13]. Knowledge in this regard is important. In Type 2 diabetic patients, especially those with obesity and severe insulin resistance, attainment of better diabetic control is often achieved by higher dosage of pharmacological agents with resultant excessive weight gain. To make rational decisions clinicians and patients need to know how much there is to gain in terms of complication reduction. We were impressed that even over a relatively short follow up period, poorer metabolic control can be shown to be definitely associated with worse retinopathy outcomes. This indicates the need for controling hyperglycaemia in Type 2 patients without undue delay.
Acknowledgements We wish to thank Dr Judy Simpson, Associate Professor from the Department of Public Health and Community Services, Sydney University for her help and guidance in statistical methods. We
also wish to thank Dr John Lachin, Professor of Statistics and Director of the DCCT Coordinating Center for his help with the statistical methods used in the DCCT and for providing copies of the DCCT analysis documentation of ‘Sustained onset of retinopathy’. References [1] The Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus, New Engl. J. Med. 329 (1993) 977 – 986. [2] The Diabetes Control and Complications Trial Research Group, The relationship of glycaemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial, Diabetes 44 (1995) 968 – 983. [3] The Diabetes Control and Complications Trial Research Group, The absence of a glycaemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial, Diabetes 45 (1996) 1289 – 1298. [4] A.S. Krolewski, L.M.D. Laffel, M. Krolewski, M. Quinn, J.H. Warram, Glycosylated hemoglobin and the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus, New Engl. J. Med. 332 (1995) 1251 – 1255. [5] R. Klein, B.E.K. Klein, S.E. Moss, M.D. Davis, D.L. DeMets, Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy, J. Am. Med. Assoc. 260 (1988) 2864 – 2871. [6] 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, Diab. Res. Clin. Pract. 28 (1995) 103 – 117. [7] P.J. Guillausseau, P. Massin, M.A. Charles, H. Allaguy, Z. Guvenli, M. Virally, D. Tielmans, M. Assayag, A. Warnet, J. Lubetzki, Glycaemic control and development of retinopathy in type 2 diabetes mellitus: a longitudinal study, Diabetic Med. 15 (1998) 151 – 155. [8] N. Emanuele, R. Klein, C. Abraira, J. Colwell, J. Comstock, W.G. Henderson, S. Levin, F. Nuttall, C. Sawin, C. Silbert, H.S. Lee, N. Johnson-Nagel, Evaluation of retinopathy in the VA Cooperative Study on glycaemic control and complications in type 11 diabetes (VA CSDM). A feasibility study, Diab. Care 19 (1996) 1375 – 1381. [9] UK Prospective Diabetes Study Group, Perspective in diabetes. UK Prospective Diabetes Study 16: overview of 6 years’ therapy of type 2 diabetes: a progressive disease, Diabetes 44 (1995) 1249 – 1258.
L.M. Molyneaux et al. / Diabetes Research and Clinical Practice 42 (1998) 77–83 [10] D.M. Nathan, Inferences and implications. Do results from the Diabetes Control and Complications Trial Apply in NIDDM?, Diab. Care 18 (1995) 251–257. [11] M. McGill, L.M. Molyneaux, D.K. Yue, J.R. Turtle, A single visit diabetes complication assessment service: a complement to diabetes management at the primary care level, Diabetic Med. 10 (1993) 366–370. [12] T. Zelmanovitz, J.L. Gross, J.R. Oliveira, A. Paggi, M. Tatsch, M.J. Azevedo, The receiver operating characteristics curve in the evaluation of a random urine specimen as a screening test for diabetic nephropathy, Diab. Care 20 (1997) 516 – 519. [13] J. Overland, M. McGill, D.K. Yue, Ambulatory diabetes care: a diabetic centre based model, Pract. Diab. 14 (1997) 111 – 115. [14] World Health Organisation, Diabetes mellitus, report of a WHO Study Group. Tech. Rep. Ser. no. 727. World Health Org. Geneva, 1985, pp. 9–17. [15] T. Danne, B. Weber, R. Hartmann, I. Enders, W. Burger, G. Hovener, Long-term glycemic control has a nonlinear association to the frequency of background retinopathy in adolescents with diabetes, Diab. Care 17 (1994) 1390– 1396.
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[16] J.H. Warram, J.E. Manson, A.S. Krolewski, Glycosylated hemoglobin and the risk of retinopathy in insulin-dependent diabetes mellitus, New Engl. J. Med. 332 (1995) 1305 – 1306. [17] H.U. Janka, J.H. Warram, L.I. Rand, A.S. Krolewski, Risk factors for the progression of background in longstanding IDDM, Diabetes 38 (1989) 460 – 464. [18] Y.M. Smulders, M. Rakic, C.D.A. Stehouwer, R.N.M. Weijers, E.H. Slaats, J. Silverbusch, Determinants of progression of microalbuminuria in patients with NIDDM, Diab. Care 20 (1997) 999 – 1005. [19] G.C. Viberti, S. Marshall, R. Beech, V. Brown, P. Derben, N. Higson, P. Home, H. Keen, M. Plant, J. Walls, Report on Renal Disease, Diabetes 13 (1996) S6 – S12. [20] B. Gaster, I.B. Hirsch, The effects of improved glycemic control on complications in type 2 diabetes, Arch. Intern. Med. 158 (1998) 134 – 140. [21] M. Ravid, D. Brosh, D. Ravid-Safran, Z. Levy, R. Rachmani, Main risk factors for nephropathy in type 2 diabetes mellitus are plasma cholesterol levels, mean blood pressure, and hyperglycemia, Arch. Intern. Med. 158 (1998) 998 – 1004.
Better glycaemic control and risk reduction of diabetic complications in Type 2 diabetes: comparison with the DCCT L.M. Molyneaux *, M.I. Constantino, M. McGill, R. Zilkens, D.K. Yue Diabetes Center of Royal Prince Alfred Hospital and Department of Medicine of The Uni6ersity of Sydney, 2nd Floor, QE11 Building, 59 Missenden Road, Camperdown, NSW 2050, Australia Received 24 May 1998; received in revised form 4 August 1998; accepted 24 August 1998
Abstract Objective: To construct dose response curves relating the development of diabetic complications (retinopathy and microalbuminuria) to mean glycaemic exposure in a cohort of Type 2 patients followed over a period of several years. This allows a comparison with similar data on Type 1 subjects reported by the Diabetes Control and Complications Trial (DCCT) and provides a rational basis for deciding what levels of glycaemic control should be aimed for in advising individual patients and in setting guidelines for conducting health services. Research design and methods: This was an analysis of data prospectively collected in our computerized data base for Type 2 patients who attended and were followed up at the Complications Assessment Service of our Diabetes Center. The initial development of retinopathy and microalbuminuria was analyzed with respect to the mean HbA1c during the follow up period. Statistical procedures identical to those employed in the DCCT were used to construct the dose response curve. Results: A smooth relationship between the development of retinopathy with increasing hyperglycaemia was found. For every 10% decrease in HbA1c, there was a 24% (confidence interval (CI): 16–32) reduction in relative risk, about 2/3 of that reported for insulin-dependent diabetes mellitus (IDDM) patients. The relationship between microalbuminuria and HbA1c was more linear and less steep with a relative risk reduction of 9% (CI: − 2 – 19%) for any 10% fall in HbA1c, about 1/3 of that reported for IDDM subjects. No threshold of HbA1c can be found for the relative risk of developing complications. However, more cases of complications are prevented by the same degree of improvement in glycaemic control at higher levels of HbA1c. Conclusions: The development of diabetic retinopathy in Type 2 subjects is also related to the magnitude of hyperglycaemia although the degree of dependence is less than that in Type 1. Glycaemic control has less influence on microalbuminuria in Type 2. In terms of relative risk, no threshold of ‘safe HbA1c’ can be found but in absolute terms more cases of diabetic complications can be prevented by improving the glycaemic control of the very hyperglycaemic patients. © 1998 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Risk reduction; DCCT; Retinopathy; Microalbuminuria; Type 2 diabetes
* Corresponding author. Tel.: +61 2 95159715; fax: + 61 2 95159780; e-mail: [email protected] 0168-8227/98/$ - see front matter © 1998 Elsevier Science Ireland Ltd. All rights reserved. PII: S0168-8227(98)00095-3
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L.M. Molyneaux et al. / Diabetes Research and Clinical Practice 42 (1998) 77–83
1. Introduction The benefits of achieving near-normoglycaemia for Type 1 subjects have been established unequivocally by the findings of the Diabetes Control and Complications Trial (DCCT) [1,2]. What has been debated in the literature is whether there is a threshold below which further improvement in glycaemic control does not result in a substantial reduction in diabetic complications [3,4]. This is an important question because near-normoglycaemia in Type 1 diabetes can only be achieved at a cost of increased hypoglycaemia. Therefore, taking into consideration the risk/benefit ratio, it is important not only in advising an individual patient whether he/she should undergo intensive insulin treatment, but also in deciding how much of the health care resources should be spent on supporting this philosophy of treatment. In this context, information about the shape and the slope of the dose-response curve relating development of diabetic complications to glycaemic control is crucial. Whilst the DCCT has provided excellent data in this regard, a similar approach to analysis for Type 2 diabetes is far more scanty, although we acknowledge that there is also overwhelming evidence that hyperglycaemia is associated with more complications [5 – 9]. Therefore we have studied data from our computerized database to examine the relationship between initial development of diabetic complications and glycaemic control over time for Type 2 patients who have attended our Complications Assessment Service on more than one occasion. By employing identical statistical procedures as those used by the DCCT [1–3], our aim was to compare our data with that of the DCCT to evaluate if improvement in glycaemic control in Type 2 patients will result in the same degree of risk reduction in diabetic complications [10].
care physicians specifically for assessment of diabetic complications [11]. This includes recording of visual acuity, examination of retina by direct fundoscopy through dilated pupils, collection of a morning spot urine sample for measurement of microalbuminuria [12] together with examination of sensation, reflexes and pulses of the lower limbs. Blood was collected for HbA1c, routine biochemistry and lipid determinations. The examination of fundi was conducted by one physician. The validity of the retinal findings of the physician has been verified against an ophthalmologist. The results showed a sensitivity of 100%, specificity of 80% and a positive predictive value of 93%, for the detection of any degree of retinopathy. Agreement between the two was also measured and there was excellent agreement (k= 0.85; PB 0.0001). All other procedures were carried out according to a standardized protocol which did not vary substantially during the period that this study covered and results of each visit were entered into a purpose designed computer data base [13]. Patients are re-referred by their primary care physicians for another complication assessment according to a Shared Care Protocol at intervals which vary between 1 and 4 years depending on the severity and duration of diabetes [13]. For the purpose of statistical calculation, retinopathy in our patients was defined as the development of any diabetic retinopathy on fundal examination. This is comparable to the DCCT classification ‘sustained onset of retinopathy’ in their primary cohort [3]. Microalbuminuria in our patients was defined as urinary albumin concentration greater than 30 mg/l, similar to the DCCT category of greater than 40 mg/day. HbA1c was measured by HbA1c (BIO-RAD, CA, USA; CVB 2%) and the mean of serial HbA1c measurements was used to estimate cumulative glycaemic exposure. Albumin was measured using a commercially available radio immunoassay kit by Diagnostic Product (UK).
2. Materials and methods
2.2. Patients 2.1. Complications assessment In the system of diabetes care provided by our Diabetes Center, patients are referred by primary
Nine hundred and sixty-three Type 2 subjects (defined by WHO criteria) [14] who had no retinopathy at the initial visit and who had made
L.M. Molyneaux et al. / Diabetes Research and Clinical Practice 42 (1998) 77–83
subsequent visits for Complications Assessment formed the cohort for this analysis. At the initial visit their median age was 57.5 years (interquartile range (IQ) 50.0–64.6) and their median duration of diabetes 3.8 years (IQ range 0.8 – 8.8). The percentage on diet, oral agent and insulin treatment was 27%, 63% and 10%, respectively, and their median HbA1c was 7.8% (IQ range 6.7 – 9.5, normal 4.0–6.0%). They had made a median of 3.5 visits (range 2– 6) over a median follow-up period of 28 months (IQ range 16.4 – 45.1). A subset of 399 patients who had normal urine albumin concentration at the first visit was analyzed for the development of microalbuminuria. At our Diabetes Center, 60% of patients resumed for a follow up Complication Assessment within the studied period of 4 years. Comparison of the patients who returned against those who did not return revealed no significant difference in clinical and complication status except that the former had a higher proportion on oral hypoglycaemic agent treatment at the initial visit (63% vs. 55%).
2.3. Statistical methods The relationship between glucose exposure over time and new retinopathy or microalbuminuria was assessed using the mean of serial HbA1c. To allow us to compare the data with insulin-dependent diabetes mellitus (IDDM) patients, we used the statistical procedures employed by the DCCT [3]. The risk gradients for retinopathy and microalbuminuria in our non-insulin-dependent diabetes mellitus (NIDDM) subjects were estimated from a Poisson regression model using the natural log (ln) of mean serial HbA1c. A linear relationship between ln (HbA1c) versus retinopathy and ln (HbA1c) versus microalbuminuria allowed us to calculate the risk reduction of complications for any 10% reduction of HbA1c. This reduction remained constant over the full range of HbA1c, ([(0.9b − 1)*100], where b is the coefficient for ln (HbA1c)). The relationship between ln (HbA1c) and the absolute risk per 100 patient years for developing retinopathy or microalbuminuria was calculated from the Poisson regression model. The absolute risk of an event per 100 patient
79
years was presented in the original units [exp(ln100) + a + (b lnHbA1c)]; where, a= intercept, and b= coefficient of ln(HbA1c). Confidence intervals were calculated for the Poisson regression models, (although not shown, as it makes Figs. 1 and 2 too complex to present graphically). The DCCT used an offset of ln (0.5) years, as their patients were assessed every 6 months. Our Type 2 cohort was assessed at different time periods, therefore our offset for each subject is the ln time difference in years from the first visit. The DCCT [3] found no significant threshold for the risk gradients of HbA1c 5 8.0% and greater than 8.0% for retinopathy and microalbuminuria. We also analyzed our data using less than or equal to 8.0% and greater than 8.0% as the cut off to enable comparison with DCCT. The Poisson model was fitted with a threshold variable [ 5ln 8.0%= 0 and if \ ln 8.0%= (ln mean HbA1c − log 8.0%)]. The threshold (5 8.0% and \8.0%) was tested using a Wald test. Statistical analysis was performed using SAS and NCSS (Number Crunching Statistical System) software. Continuous data was analyzed using Mann–Whitney U-test and expressed as median and IQ. Categorical data was analyzed using the x 2-test and expressed as a proportion with 95% CI. Statistical significance was accepted at less than 0.05 level.
3. Results The annual incidence of retinopathy and microalbuminuria in the Type 2 cohort was 5.7% (CI: 4.0–7.2) and 8.3% (CI: 5.7–10.9), respectively. There was a linear relationship found between ln (HbA1c) versus retinopathy and ln (HbA1c) versus microalbuminuria, which was similar to the DCCT. The percentage reduction in the risk of retinopathy and microalbuminuria for a 10% reduction in HbA1c is shown in Table 1. Corresponding values for the DCCT [3] are also shown for comparison. There was a significant reduction in the risk of retinopathy for a 10% reduction in HbA1c (x 2 = 25.6; PB0.0001), however the corresponding risk reduction found for microalbuminuria in our NIDDM population just
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Fig. 1. Absolute risk of retinopathy for Type 2 and Type 1 subjects. —— Type 2 data*; – – – Type 1 data (DCCT)†. *Poisson regression model: a = − 8.63, b= 2.62 (coefficient of ln HbA1c). †Poisson regression model: a = −11.68, b =4.13 (coefficient of ln HbA1c), b1 = 0.5*0.15 (coefficient for treatment group).
failed to reach statistical significance (x 2 =2.6; P= 0.1). The relationship between the absolute risk (risk per 100 patient years) of developing diabetic retinopathy or microalbuminuria and the mean HbA1c are shown in Figs. 1 and 2, respectively. Similar data published by the DCCT on Type 1 patients are again included for comparison. As can be seen in Fig. 1, the results from our Type 2 patients show a smooth curve relating to the development of diabetic retinopathy with increasing hyperglycaemia. Fig. 1 also shows that for every 10% decrease in HbA1c (e.g. from 11.0% to 9.9%), there was a 24% (CI: 16 – 32) relative risk reduction in the development of retinopathy, this can be compared to the DCCT (Sustained onset of retinopathy) which was 35% (CI: 29 – 41). In absolute terms, in these Type 2 subjects, a reduction in HbA1c from 11.0% to 9.9% reduced the risk by three cases per 100 patient years, whereas at the same 10% reduction, DCCT found a decrease of 6.5
cases per 100 patient years. Decreasing HbA1c from 8.0% to 7.2% reduced risk in Type 2 patients by one case per 100 patient years and in the DCCT, 0.8 case per 100 patient years. The absolute risk reduction for retinopathy is greater the higher the HbA1c and the relative risk reduction is about 2/3 of that reported for Type 1 patients. Fig. 2 shows that the relationship between microalbuminuria and HbA1c for Type 2 patients was more linear and less steep with a relative risk reduction of 9% (CI: (2–19) for any 10% fall in HbA1c, whereas the DCCT found a 25% risk reduction (CI: 19–32). Stated in absolute terms, in these Type 2 subjects, a reduction in HbA1c from 11.0% to 9.9% reduced the risk of developing microalbuminuria by 0.8 cases per 100 patient years, whereas for the equal 10% reduction, the DCCT found a reduction of 2.1 cases per 100 patient years. Decreasing HbA1c from 8.0% to 7.2% reduced the risk by 0.6 case per 100 patient years and in the case of the
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Fig. 2. Absolute risk of microalbuminuria for Type 2 and Type 1 subjects. —— Type 2 data*; – – – Type 1 data (DCCT)†. *Poisson regression model: a= −4.68, b= 0.92 (coefficient of ln HbA1c). †Poisson regression model: a = −9.18, b =2.79 (coefficient of ln HbA1c), b1= 0.5*0.15 (coefficient for treatment group).
DCCT 0.9 case per 100 patient years. In our Type 2 patients there was no significant difference in the risk gradients for HbA1c of less than or equal to 8.0% and greater than 8.0% in retinopathy (x 2 =0.6; P=0.4) or microalbuminuria (x 2 =0.5; P= 0.5). Similar findings were found by the DCCT. Table 1 Relative risk reductions for retinopathy and microalbuminuria associated with a 10% lower mean HbA1c in Type 2 and the DCCT patients Complication status
% Risk reduction
95% CI
Retinopathy (NIDDM) Retinopathy (DCCT)a Microalbuminuria (NIDDM) Microalbuminuria (DCCT)a
24 35 9
(16–32)* (29–41)* (−2–19)
25
(19–32)*
Poisson regression model *PB0.0001. a Model adjusted for intensive versus conventional treatment.
4. Conclusion These data show that the development of retinopathy in Type 2 subjects is related to the magnitude of hyperglycaemia, although the degree of dependence is less than that in Type 1 [1–3,15–17]. In the case of microalbuminuria, the relationship is less strong, presumably reflecting that many other factors can influence albumin excretion in Type 2 subjects [18,19]. The relationship of complications in Type 2 diabetic patients with hyperglycaemia and other risk factors has also been studied by others [20,21]. As our aim was to compare our Type 2 data with Type 1 subjects in the DCCT, we have not presented results adjusting for the confounding variables such as blood pressure and lipid levels. For both complications examined, in terms of relative risk, no threshold of ‘safe’ HbA1c can be found. In absolute terms, however, similar degree of improvement in glycaemic control would prevent more cases of retinopathy in subjects who are very
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hyperglycaemic. Klein et al. [5] and Ohkubo et al. [6] also had extensive data on the development of retinopathy and microalbuminuria in Type 2 subjects. The data of Klein et al. [5] were based on observation of a large cohort of patients. The data of Okubo et al. [6] were prospective, interventional and provided a great deal of much needed information in this area. However, by using the same statistical procedures and presentations as the DCCT, our results provide the clinicians and health care planners with a more direct comparison of Type 1 and Type 2 subjects to help them in advising individual patients and in allocating health resources [10]. As we did not take retinal photographs to allow grading, we limited our analysis to new development of retinopathy, but not its deterioration, such as the three steps sustained progression included in the DCCT. Our data are only observational in nature whereas those of the DCCT were derived from a randomized interventional trial. However, our data provide information on the order of magnitude of the relationship between diabetic complications and glycaemic control in a group of patients reasonably representative of the ‘average’ Type 2 patient [13]. Knowledge in this regard is important. In Type 2 diabetic patients, especially those with obesity and severe insulin resistance, attainment of better diabetic control is often achieved by higher dosage of pharmacological agents with resultant excessive weight gain. To make rational decisions clinicians and patients need to know how much there is to gain in terms of complication reduction. We were impressed that even over a relatively short follow up period, poorer metabolic control can be shown to be definitely associated with worse retinopathy outcomes. This indicates the need for controling hyperglycaemia in Type 2 patients without undue delay.
Acknowledgements We wish to thank Dr Judy Simpson, Associate Professor from the Department of Public Health and Community Services, Sydney University for her help and guidance in statistical methods. We
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