Correspondence

Glycosylated Hemoglobin and the Risk of Retinopathy in Insulin-Dependent Diabetes Mellitus

N Engl J Med 1995; 332:1305-1306May 11, 1995

Article

To the Editor:

Since we found evidence of a threshold for the effect of hyperglycemia on the risk of microalbuminuria in patients with insulin-dependent diabetes mellitus (IDDM),1 we used published data to examine whether there was a similar pattern for diabetic retinopathy. In the Diabetes Control and Complications Trial (DCCT),2 the incidence of the development or progression of retinopathy in the group assigned to intensive treatment fluctuated around 2.0 per 100 person-years in the nine deciles of the hemoglobin A_1c distribution below 8.5 percent and rose to 7.0 per 100 person-years in the highest decile, consistent with a threshold value for hemoglobin A_1c of about 8.5 percent.

Other evidence supporting a rapidly increasing risk of the progression of retinopathy in patients with hemoglobin A_1c values above 8.5 percent comes from two prospective studies in which three quarters of the patients had values in that range.3,4 The risk of the development or progression of retinopathy, assessed by fundus photography as in the DCCT and presented according to quartiles of the hemoglobin A_1c distribution at base line, rose steeply — most strikingly for proliferative retinopathy (Table 1Table 1Risk of Progression of Retinopathy in Diabetic Patients, According to Quartiles of Hemoglobin A1c (HgbA1c) Values at Base Line in Two Four-Year Prospective Studies.). Although the broad range of the lowest quartile in these studies allows uncertainty about the risk gradient across low values of hemoglobin A_1c, the results of the DCCT demonstrate that a steep gradient cannot be extrapolated into the range below 8.5 percent, and the risk did not disappear for patients in the DCCT with hemoglobin A_1c values within the normal range.

Finally, in a recent study of the risk of the development or progression of retinopathy as assessed by fluorescein angiography, a more accurate measure than fundus photography, the authors estimated the hemoglobin A_1c threshold to be 9.0 percent.5 These combined empirical data suggest that there is a threshold value for hemoglobin A_1c in patients with IDDM above which the risk of retinopathy increases greatly. The precise value cannot be stated, but it appears to be near the value described for microalbuminuria, 8.1 percent.1 The nonlinear increase in the risk of retinopathy suggests that hyperglycemia damages retinal vessels through at least two mechanisms (e.g., the polyol pathway, nonenzymatic glycation, or the nitric oxide synthase pathway) that have different thresholds.

What are the implications of this analysis? At a hemoglobin A_1c value of 6.0 percent, a value recorded in very few patients in the DCCT, the incidence of the development or progression of retinopathy was 1.2 per 100 person-years (an incidence that would result in a cumulative risk of 31 percent after 30 years). The increase in risk for patients with hemoglobin A_1c values that range from 6.0 to 8.0 percent is very small. Therefore, almost all the reduction in the risk of retinopathy achievable by improving glycemic control will be realized when patients with IDDM have hemoglobin A_1c values below 8.1 percent, and the side effects that would occur if the goal were a lower value would be avoided.

James H. Warram, M.D., Sc.D.
Joslin Diabetes Center, Boston, MA 02215

JoAnn E. Manson, M.D., Dr.P.H.
Brigham and Women's Hospital, Boston, MA 02115

Andrzej S. Krolewski, M.D., Ph.D.
Joslin Diabetes Center, Boston, MA 02215

5 References

1. 1

   Krolewski AS, Laffel LMB, Krolewski M, Quinn M, Warram JH. Glycated hemoglobin and risk of microalbuminuria in patients with insulin-dependent diabetes mellitus. N Engl J Med 1995;332:1251-1255
   Full Text | Web of Science | Medline

2. 2

   The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329:977-986
   Full Text | Web of Science | Medline

3. 3

   Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. Glycosylated hemoglobin predicts the incidence and progression of diabetic retinopathy. JAMA 1988;260:2864-2871
   CrossRef | Web of Science | Medline

4. 4

   Janka HU, Warram JH, Rand LI, Krolewski AS. Risk factors for progression of background retinopathy in long-standing IDDM. Diabetes 1989;38:460-464
   CrossRef | Web of Science | Medline

5. 5

   Danne T, Weber B, Hartmann R, Enders I, Burger W, Hovener G. Long-term glycemic control as a nonlinear association to the frequency of background retinopathy in adolescents with diabetes. Diabetes Care 1994;17:1390-1396
   CrossRef | Web of Science | Medline

Citing Articles (17)

Citing Articles

1. 1

   Ezra Israel, Abdallah Geara, Omar Maarouf, Isabelle Ayoub, Jacques Abi Rached, Sanaa Rizk, Norbert Staynberg, Majed Samarneh, Suzanne El-Sayegh. (2010) Correlation between glycated hemoglobin and mean plasma glucose in hemodialysis patients. International Urology and Nephrology
   CrossRef

2. 2

   Khurram Nasir, Raul D. Santos, Kashif Tufail, Juan Rivera, Jose A.M. Carvalho, Romeu Meneghello, Thomas D. Brady, Roger S. Blumenthal. (2007) High-normal fasting blood glucose in non-diabetic range is associated with increased coronary artery calcium burden in asymptomatic men. Atherosclerosis 195:2, e155-e160
   CrossRef

3. 3

   José Antonio Gimeno Orna, Francisco J. Castro Alonso, Raquel Sánchez Vañó, Beatriz Latre Rebled, Luis M. Lou Arnal, Edmundo Molinero Herguedas. (2006) Relación entre la presencia de retinopatía diabética y la mortalidad en pacientes con diabetes tipo 2. Medicina Clínica 126:18, 686-689
   CrossRef

4. 4

   Margaret Grey, Maryanne Davidson, Elizabeth A Boland, William V Tamborlane. (2001) Clinical and psychosocial factors associated with achievement of treatment goals in adolescents with diabetes mellitus. Journal of Adolescent Health 28:5, 377-385
   CrossRef

5. 5

   Stuart J. Brink. (2001) Complications of pediatric and adolescent type 1 diabetes mellitus. Current Diabetes Reports 1:1, 47-55
   CrossRef

6. 6

   P. T. Sawicki, R. Bender, M. Berger, I. Muhlhauser. (2000) Non-linear effects of blood pressure and glycosylated haemoglobin on progression of diabetic nephropathy. Journal of Internal Medicine 247:1, 131-138
   CrossRef

7. 7

   Margaret Grey, Elizabeth A. Boland, Maryanne Davidson, Chang Yu, William V. Tamborlane. (1999) Coping skills training for youths with diabetes on intensive therapy. Applied Nursing Research 12:1, 3-12
   CrossRef

8. 8

   L.M Molyneaux, M.I Constantino, M McGill, R Zilkens, D.K Yue. (1998) Better glycaemic control and risk reduction of diabetic complications in Type 2 diabetes: comparison with the DCCT. Diabetes Research and Clinical Practice 42:2, 77-83
   CrossRef

9. 9

   Ronald Klein, Barbara E.K Klein, Scot E Moss, Karen J Cruickshanks. (1998) The Wisconsin epidemiologic study of diabetic retinopathy: XVII. Ophthalmology 105:10, 1801-1815
   CrossRef

10. 10

    Chihiro Nishimura, Yoshihiro Hotta, Tong Gui, Ayumi Seko, Takuro Fujimaki, Takashi Ishikawa, Mutuko Hayakawa, Atsushi Kanai, Tomohiro Saito. (1997) The level of erythrocyte aldose reductase is associated with the severity of diabetic retinopathy. Diabetes Research and Clinical Practice 37:3, 173-177
    CrossRef

11. 11

    Sheila H. Roman, Maureen I. Harris. (1997) MANAGEMENT OF DIABETES MELLITUS FROM A PUBLIC HEALTH PERSPECTIVE. Endocrinology & Metabolism Clinics of North America 26:3, 443-474
    CrossRef

12. 12

    Marianne Henricsson, Leif Groop, Anders Heijl. (1996) Progression of retinopathy is related to glycaemic control even in patients with mild diabetes mellitus. Acta Ophthalmologica Scandinavica 74:6, 528-532
    CrossRef

13. 13

    Marianne Henricsson, Maria Tyrberg, Anders Heijl, Lars Janzon. (1996) Incidence of blindness and visual impairment in diabetic patients participating in an ophthalmological control and screening programme. Acta Ophthalmologica Scandinavica 74:6, 533-538
    CrossRef

14. 14

    Andrzej S. Krolewski, James H. Warram, Maria Beatriz S. Freire. (1996) EPIDEMIOLOGY OF LATE DIABETIC COMPLICATIONS. Endocrinology & Metabolism Clinics of North America 25:2, 217-242
    CrossRef

15. 15

    (1995) Glycosylated Hemoglobin and the Risk of Microalbuminuria in Insulin-Dependent Diabetes Mellitus. New England Journal of Medicine 333:14, 940-941
    Full Text

16. 16

    Krolewski, Andrzej S., Laffel, Lori M.B., Krolewski, Martin, Quinn, Maryanne, Warram, James H., . (1995) Glycosylated Hemoglobin and the Risk of Microalbuminuria in Patients with Insulin-Dependent Diabetes Mellitus. New England Journal of Medicine 332:19, 1251-1255
    Full Text

17. 17

    Viberti, GianCarlo, . (1995) A Glycemic Threshold for Diabetic Complications?. New England Journal of Medicine 332:19, 1293-1294
    Full Text