HbA1c for diagnosis of type 2 diabetes. Is there an optimal cut point to assess high risk of diabetes complications, and how well does the 6.5% cutoff perform?

Glycated hemoglobin (HbA1c) has recently been recommended for the diagnosis of type 2 diabetes mellitus (T2DM) by leading diabetes organizations and by the World Health Organization. The most important reason to define T2DM is to identify subjects with high risk of diabetes complications who may benefit from treatment. This review addresses two questions: 1) to assess from existing studies whether there is an optimal HbA1c threshold to predict diabetes complications and 2) to assess how well the recommended 6.5% cutoff of HbA1c predicts diabetes complications. HbA1c cutoffs derived from predominantly cross-sectional studies on retinopathy differ widely from 5.2%-7.8%, and among other reasons, this is due to the heterogeneity of statistical methods and differences in the definition of retinopathy. From the few studies on other microvascular complications, HbA1c thresholds could not be identified. HbA1c cutoffs make less sense for the prediction of cardiovascular events (CVEs) because CVE risks depend on various strong risk factors (eg, hypertension, smoking); subjects with low HbA1c levels but high values of CVE risk factors were shown to be at higher CVE risk than subjects with high HbA1c levels and low values of CVE risk factors. However, the recommended 6.5% threshold distinguishes well between subjects with and subjects without retinopathy, and this distinction is particularly strong in severe retinopathy. Thus, in existing studies, the prevalence of any retinopathy was 2.5 to 4.5 times as high in persons with HbA1c-defined T2DM as in subjects with HbA1c <6.5%. To conclude, from existing studies, a consistent optimal HbA1c threshold for diabetes complications cannot be derived, and the recommended 6.5% threshold has mainly been brought about by convention rather than by having a consistent empirical basis. Nevertheless, the 6.5% threshold is suitable to detect subjects with prevalent retinopathy, which is the most diabetes specific complication. However, most of the studies on associations between HbA1c and microvascular diabetes complications are cross-sectional, and there is a need for longitudinal studies.