Effect of Glycemic Exposure on the Risk of Microvascular Complications in the Diabetes Control and Complications Trial—Revisited
- John M. Lachin1,
- Saul Genuth2,
- David M. Nathan3,
- Bernard Zinman4,
- Brandy N. Rutledge1 and
- for the DCCT/EDIC Research Group*
- 1The Biostatistics Center, The George Washington University, Rockville, Maryland
- 2Case Western Reserve University, Cleveland, Ohio
- 3Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
- 4Samuel Lunenfeld Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
- Address correspondence and reprint requests to John M. Lachin, The Biostatistics Center, 6110 Executive Blvd., Rockville, MD 20852. E-mail:
OBJECTIVE— The Diabetes Control and Complications Trial (Diabetes 44:968–983, 1995) presented statistical models suggesting that subjects with similar A1C levels 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 A1C level.
RESEARCH DESIGN AND METHODS— We performed statistical evaluations of these models and additional analyses to 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 used. 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 A1C levels, similarly for other outcomes. Furthermore, subjects within the intensive and conventional treatment groups with similar A1C levels over time have similar risks of retinopathy progression, especially after adjusting for factors in which they differ.
CONCLUSIONS— A1C explains virtually all of the difference in risk of complications between the intensive and conventional groups, and a given A1C level 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.
- AER, albumin excretion rate
- DCCT, Diabetes Control and Complications Trial
- MBG, mean blood glucose
- PH, proportional hazards
- Received November 16, 2007.
- Accepted January 2, 2008.