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A1C variability and the risk of microvascular complications in type 1 diabetes: Data from the diabetes control and complications trial

Kilpatrick, Eric S.; Rigby, Alan S.; Atkin, Stephen L.


Eric S. Kilpatrick

Alan S. Rigby

Stephen L. Atkin


OBJECTIVE—Debate remains as to whether short- or long-term glycemic instability confers a risk of microvascular complications in addition to that predicted by mean glycemia alone. In this study, we analyzed data from the Diabetes Control and Complications Trial (DCCT) to assess the effect of A1C variability on the risk of retinopathy and nephropathy in patients with type 1 diabetes.

RESEARCH DESIGN AND METHODS—A1C was collected quarterly during the DCCT in 1,441 individuals. The mean A1C and the SD of A1C variability after stabilization of glycemia (from 6 months onwards) were compared with the risk of retinopathy and nephropathy with adjustments for age, sex, disease duration, treatment group, and baseline A1C.

RESULTS—Multivariate Cox regression showed that the variability in A1C added to mean A1C in predicting the risk of development or progression of both retinopathy (hazard ratio 2.26 for every 1% increase in A1C SD [95% CI 1.63–3.14], P < 0.0001) and nephropathy (1.80 [1.37–2.42], P < 0.0001), with the relationship a feature in conventionally treated patients in particular.

CONCLUSIONS—This study has shown that variability in A1C adds to the mean value in predicting microvascular complications in type 1 diabetes. Thus, in contrast to analyses of DCCT data investigating the effect of short-term glucose instability on complication risk, longer-term fluctuations in glycemia seem to contribute to the development of retinopathy and nephropathy in type 1 diabetes.

The effect that glycemic variability may have on the risk of development of microvascular complications of diabetes remains controversial (1). Studies such as the Diabetes Control and Complications Trial (DCCT) in type 1 diabetes and the UK Prospective Diabetes Study (UKPDS) in type 2 diabetes have left little doubt that the risk of microvascular complications rises exponentially as mean blood glucose (assessed using A1C) increases (2–5). However, with regard to glycemic variability, the clinical evidence has not been consistent. For example, in the DCCT the rate of complications at a given value of A1C was apparently higher in the conventionally treated patients than in those treated intensively (3), leading to the suggestion that this result may be a consequence of larger glycemic excursions in the former group of patients as they received fewer injections of insulin per day (6). Nonetheless, further analyses of the DCCT dataset has shown that within-day glucose variability, using seven-point laboratory measured glucose profiles, had no additional influence on the risk of micro- or macrovascular complication risk beyond that predicted by the mean glucose value alone (7–9). A more recent reanalysis of the A1C data by the DCCT group has shown that the original differences between treatment groups was probably an artifact of model assumptions originally used and that no discrepancies in microvascular risk at the same A1C actually existed (10). Indeed, it has subsequently been suggested that the increased complication risk in conventionally treated patients was simply because their blood glucose values were higher compared with those of intensively treated patients at the same A1C (11).

It is also currently unknown whether short-term (within-day) variability may have a different influence on complications compared with longer-term (day-to-day or week-to-week) glucose fluctuations. Certainly, data from the Pittsburgh Epidemiology Study showed that A1C variability seemed to be an additional risk factor for the development of macrovascular complications (12).

It is fundamental to managing diabetes for a clinician to know whether a patient with glucose instability has a higher risk of microvascular complications than one without, especially because many of the recent pharmacological advances have focused on reducing glucose variability (as well as mean glucose) largely by targeting postprandial hyperglycemia. Therefore, in this current study we have analyzed the publicly available DCCT dataset to investigate the potential for A1C variability to have an influence on microvascular complications.


Kilpatrick, E. S., Rigby, A. S., & Atkin, S. L. (2008). A1C variability and the risk of microvascular complications in type 1 diabetes: Data from the diabetes control and complications trial. Diabetes Care, 31(11), 2198-2202. doi:10.2337/dc08-0864

Journal Article Type Article
Acceptance Date Mar 1, 2008
Online Publication Date Jul 23, 2008
Publication Date 2008-10
Deposit Date Nov 13, 2014
Publicly Available Date Nov 13, 2014
Journal Diabetes care
Print ISSN 0149-5992
Electronic ISSN 1935-5548
Publisher American Diabetes Association
Peer Reviewed Peer Reviewed
Volume 31
Issue 11
Pages 2198-2202
Keywords Internal Medicine; Endocrinology, Diabetes and Metabolism; Advanced and Specialised Nursing
Public URL
Publisher URL
Additional Information Authors' accepted manuscript of article published in: Diabetes care, 2008, v.31, issue 11