title: Effect of glycemic exposure on the risk of microvascular complications in the diabetes control and complications trial--revisited.
abstract: 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.
  
  
  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.
authors.affiliation: The Biostatistics Center, The George Washington University, Rockville, MD 20852, USA. jml@biostat.bsc.gwu.edu
authors.forename: John M
authors.initials: JM
authors.lastname: Lachin
authors.forename: Saul
authors.initials: S
authors.lastname: Genuth
authors.forename: David M
authors.initials: DM
authors.lastname: Nathan
authors.forename: Bernard
authors.initials: B
authors.lastname: Zinman
authors.forename: Brandy N
authors.initials: BN
authors.lastname: Rutledge
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000097:blood; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000453:epidemiology / Q000503:physiopathology*; D018450:Disease Progression; D005260:Female; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D015233:Models, Statistical; D018579:Patient Selection; D044469:Racial Groups; D015203:Reproducibility of Results
chemical_list: D015415:Biomarkers; D006442:Glycated Hemoglobin; D007328:Insulin