Biological Variation in HbA1c Predicts Risk of Retinopathy and Nephropathy in Type 1 Diabetes

Abstract

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 ϭ 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 (higherthan-predicted HbA 1c ) had three times greater risk of retinopathy (30 vs. 9%, P Ͻ 0.001) and six times greater risk of nephropathy (6 vs. 1%, P Ͻ 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.

The ratio of glycated albumin to hemoglobin A1c measured in IFCC units accurately represents the glycation gap

“…Some previous authors have argued that a high GA/A1C ratio is associated with postprandial glucose excursion, early progression to insulin therapy in type 2 diabetes, or other events [35,36]. A high G-gap, corresponding to a low GA/ A1C ratio in the present study, has been reported to be a predictive indicator of diabetic complications, especially diabetic nephropathy [3][4][5]7]. These differences of high and low GA/A1C ratios in various clinical aspects may reflect the difference between pathological glycation of albumin and hemoglobin in the circulation and within the cell, respectively.…”

“…Deviations between mean blood glucose and A1C values with continuous glucose monitoring (CGM) have been shown to be consistent in each individual [39][40][41]. These deviations in mean blood glucose and the A1C value are called the glycohemoglobin index (GHI), and the biological variation of A1C has been examined [3,4,42,43]. The G-gap is also reported to be an indicator with biological variation [5,31], and Nayak et al [6] reported that the G-gap has consistent biological variability in individuals.…”

Can A1C Replace Oral Glucose Tolerance Test in the Evaluation of Patients with Impaired Fasting Glucose?

“…Elevated HbA1c level has also been linked to a higher risk of diabetic retinopathy [48], nephropathy [49], cardiovascular diseases [50,51] and premature death [52,53]. Other studies must be done to establish the best cut point of A1C that correlates with specific diabetic microvascular complications, especially when the diagnostic tests are discordant.…”

The proposed terminology ‘A1c-derived average glucose’ is inherently imprecise and should not be adopted. Reply to Bloomgarden ZT, Inzucchi SE, Karnieli E, et al. [letter]

“…Essentially, the authors stressed that the agreement between the measurement of mean plasma glucose and A 1c in the DCCT was only approximately 50% according to a subsequent analysis [2], although the original data reported an agreement of 67% [3]. They presented well-known evidence that different treatment modalities for diabetes may have an impact on the agreement between mean plasma glucose and A 1c .…”