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

OBJECTIVE: Glycemic variability is emerging as a measure of glycemic control, which may be a reliable predictor of complications. This systematic review and meta-analysis evaluates the association between HbA1c variability and micro- and macrovascular complications and mortality in type 1 and type 2 diabetes. RESEARCH DESIGN AND METHODS: Medline and Embase were searched (2004-2015) for studies describing associations between HbA1c variability and adverse outcomes in patients with type 1 and type 2 diabetes. Data extraction was performed independently by two reviewers. Random-effects meta-analysis was performed with stratification according to the measure of HbA1c variability, method of analysis, and diabetes type. RESULTS: Seven studies evaluated HbA1c variability among patients with type 1 diabetes and showed an association of HbA1c variability with renal disease (risk ratio 1.56 95% CI 1.08-2.25, two studies), cardiovascular events (1.98 1.39-2.82), and retinopathy (2.11 1.54-2.89). Thirteen studies evaluated HbA1c variability among patients with type 2 diabetes. Higher HbA1c variability was associated with higher risk of renal disease (1.34 1.15-1.57, two studies), macrovascular events (1.21 1.06-1.38), ulceration/gangrene (1.50 1.06-2.12), cardiovascular disease (1.27 1.15-1.40), and mortality (1.34 1.18-1.53). Most studies were retrospective with lack of adjustment for potential confounders, and inconsistency existed in the definition of HbA1c variability. CONCLUSIONS: HbA1c variability was positively associated with micro- and macrovascular complications and mortality independently of the HbA1c level and might play a future role in clinical risk assessment.