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The Effect of Glycemic Exposure on the Risk of Microvascular Complications in the Diabetes Control and Complications Trial -- Revisited

¹The Biostatistics Center, The George Washington University (J.M. Lachin, B.N. Rutledge), Rockville, MD
²Case Western Reserve University (S.M. Genuth), Cleveland, OH
³Massachusetts General Hospital and Harvard Medical School (D.M. Nathan), Boston MA
⁴Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto (B Zinman)

Objective: The Diabetes Control and Complications Trial (Diabetes 44: 968-983, 1995) presented statistical models suggesting that subjects with similar levels of HbA1c had a higher risk of retinopathy progression in the conventional treatment group than in the intensive treatment group. That analysis has been cited to support the hypothesis that specific patterns of glucose variation, in particular postprandial hyperglycemia, contribute uniquely to an increased risk of microvascular complications above and beyond that explained by the level of HbA1c.

Research Design and Methods: Statistical evaluations of these models and additional analyses assess whether the original analyses were flawed.

Results: Statistically, we show that the original results are an artifact of the assumptions of the statistical model employed. Additional analyses show that virtually all (96%) of the beneficial effect of intensive versus conventional therapy on progression of retinopathy is explained by the reductions in the mean levels of HbA1c, similarly for other outcomes. Further, subjects within the intensive and conventional treatment groups with similar levels of HbA1c over time have similar risks of retinopathy progression, especially after adjusting for factors on which they differ.

Discussion: HbA1c explains virtually all of the difference in risk of complications between the intensive and conventional groups, and a given level of HbA1c has similar effects within the two treatment groups. While other components of hyperglycemia, such as glucose variation, may contribute to the risk of complications, such factors can only explain a small part of the differences in risk between intensive and conventional therapy over time.

Key Words: Diabetes mellitus • glycohemoglobin • HbA1c • microvascular complications • retinopathy • nephropathy • DCCT

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