Is A1c Variability a Useful Measure in Diabetes?

Gregory A. Nichols, PhD


March 21, 2016

Association of the Average Rate of Change in HbA1c With Severe Adverse Events: A Longitudinal Evaluation of Audit Data From the Bavarian Disease Management Program for Patients With Type 2 Diabetes Mellitus

Bonke FC, Donnachie E, Schneider A, Mehring M
Diabetologia. 2016;59:286-293

This observational study evaluated the association between glycated hemoglobin (A1c) variability and cardiovascular events, emergency admissions, and episodes of severe hypoglycemia among 13,777 patients with type 2 diabetes and newly initiated insulin therapy. The investigators calculated variability using differences between A1c measurements scaled according to length of time between measurements, thereby producing a standardized rate of change.

The outcomes of interest were new occurrence of myocardial infarction (MI), stroke, hypoglycemia that required medical attention, and unplanned hospitalizations related to complications of diabetes. Increase in risk for each of these four outcomes was assessed with Cox models that controlled for age, sex, smoking status, baseline A1c, diabetes duration longer than 8 years (median), the presence of cardiovascular disease (CVD), peripheral artery disease, diabetic complications (retinopathy, neuropathy, or nephropathy), and previous MI, stroke, or diabetes-related emergency admission.

Low (But Not No) Variability May Be Optimal

Most patients (56%) had low A1c variability (0%-0.49% per quarter), and about one third had moderate variability (0.5%-1%). The lowest risk for the outcomes of MI, stroke, and severe hypoglycemia was seen with a variability of approximately 0.5% per quarter, with greater risk for patients with both lower and higher variability.

Emergency admissions produced a more linear relationship, with the lowest risk occurring among those with no variability. Estimated 5-year incidences of all outcomes increased dramatically with greater A1c variability.


Long-term Glycemic Variability and Risk of Adverse Outcomes: A Systematic Review and Meta-analysis

Gorst C, Kwok CS, Aslam S, et al
Diabetes Care. 2015;38:2354-2369

Gorst and colleagues conducted a systematic review and meta-analysis to evaluate the association between A1c variability and micro- and macrovascular complications and mortality among patients with type 1 and type 2 diabetes. In addition to examining studies separately by diabetes type, the investigators also considered whether variability was measured by standard deviation (SD; how much values differ from the group mean) or by coefficient of variation (CV; ratio of SD to the mean). They further considered whether studies compared the highest vs lowest variability group (eg, quartiles) or evaluated continuous (incremental) increase in variability.

Variability Matters

Seven studies of patients with type 1 diabetes showed an association of A1c variability with renal disease, cardiovascular events, and retinopathy. Thirteen studies evaluated A1c variability among patients with type 2 diabetes. Higher A1c variability was associated with higher risk for renal disease, macrovascular events, ulceration/gangrene, CVD, and mortality.

Results were similar regardless of the measure used (SD vs CV) or how the measure was evaluated (highest vs lowest or incremental variability). Moreover, eight studies (three in type 1 diabetes and five in type 2 diabetes) indicated that A1c variability was statistically significantly associated with risk for diabetes-related complications after controlling for mean A1c.



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