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Biological Variation in HbA_1c Predicts Risk of Retinopathy and Nephropathy in Type 1 Diabetes

¹ Biostatistics and Informatics Unit, Children’s Research Institute, The Children’s National Medical Center, Washington, DC
² Department of Pediatrics, George Washington University School of Medicine, Washington, DC
³ Department of Epidemiology and Biostatistics, George Washington University School of Medicine, Washington, DC
⁴ Department of Pediatrics, Louisiana State University Heath Sciences Center, New Orleans, Louisiana
⁵ Research Institute for Children, Children’s Hospital of New Orleans, Louisiana

Address correspondence and reprint requests to Dr. Stuart Chalew, Endocrinology/Diabetes, Children’s Hospital of New Orleans, 200 Henry Clay Ave., New Orleans, LA 70118. E-mail: schale{at}lsuhsc.edu

OBJECTIVE—We hypothesized that biological variation in HbA_1c, distinct from variation attributable to mean blood glucose (MBG), would predict risk for microvascular complications in the Diabetes Control and Complications Trial (DCCT).

RESEARCH DESIGN AND METHODS—A longitudinal multiple regression model was developed from MBG and HbA_1c measured in the 1,441 DCCT participants at quarterly visits. A hemoglobin glycation index (HGI = observed HbA_1c - predicted HbA_1c) was calculated for each visit to assess biological variation based on the directional deviation of observed HbA_1c from that predicted by MBG in the model. The population was subdivided by thirds into high-, moderate-, and low-HGI groups based on mean participant HGI during the study. Cox proportional hazard analysis compared risk for development or progression of retinopathy and nephropathy between HGI groups controlled for MBG, age, treatment group, strata, and duration of diabetes.

RESULTS—Likelihood ratio and t tests on HGI rejected the assumption that HbA_1c levels were determined by MBG alone. At 7 years’ follow-up, patients in the high-HGI group (higher-than-predicted HbA_1c) had three times greater risk of retinopathy (30 vs. 9%, P < 0.001) and six times greater risk of nephropathy (6 vs. 1%, P < 0.001) compared with the low-HGI group.

CONCLUSIONS—Between-individual biological variation in HbA_1c, which is distinct from that attributable to MBG, was evident among type 1 diabetic patients in the DCCT and was a strong predictor of risk for diabetes complications. Identification of the processes responsible for biological variation in HbA_1c could lead to novel therapies to augment treatments directed at lowering blood glucose levels and preventing diabetes complications.

Abbreviations: DCCT, Diabetes Control and Complications Trial • HGI, hemoglobin glycation index • MBG, mean blood glucose • UAER, urinary albumin excretion rate

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