Biological variation in HbA1c predicts risk of retinopathy and nephropathy in type 1 diabetes.
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).


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.
McCarter
Robert J
RJ
Endocrinology/Diabetes, Children's Hospital of New Orleans, 200 Henry Clay Avenue, New Orleans, LA 70118, USA.
Hempe
James M
JM
Gomez
Ricardo
R
Chalew
Stuart A
SA
D015415:Biomarkers / Q000097:blood*; D003922:Diabetes Mellitus, Type 1 / Q000097:blood* / Q000150:complications; D003928:Diabetic Nephropathies / Q000453:epidemiology*; D003930:Diabetic Retinopathy / Q000453:epidemiology*; D005500:Follow-Up Studies; D006442:Glycated Hemoglobin / Q000378:metabolism*; D006801:Humans; D016013:Likelihood Functions; D008137:Longitudinal Studies; D012044:Regression Analysis; D018570:Risk Assessment; D013997:Time Factors
D015415:Biomarkers; D006442:Glycated Hemoglobin