Association of long-term visit-to-visit variability of HbA1c and fasting glycemia with hypoglycemia in type 2 diabetes mellitus

BACKGROUND: Self-management of blood glucose levels to avoid hypoglycemia is vital for patients with type 2 diabetes mellitus (T2DM). The association between specific metrics of glycemic variability (glycosylated hemoglobin A1c [HbA1c] and fasting plasma glucose [FPG]) and severe hypoglycemia has not been fully studied in patients with T2DM. METHODS: In this post hoc analysis, patients with established T2DM with a high risk of cardiovascular disease were included in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study. The Cox proportional hazards model was used to investigate the relationship between glycemic variability and hypoglycemia requiring medical assistance (HMA) and hypoglycemia requiring any third-party assistance (HAA). The prognostic value of HbA1c/FPG variability for our predefined outcomes was compared using Harrell’s C method. RESULTS: After adjusting for confounders, each increase in HbA1c variability of 1 standard deviation (SD) indicated a higher risk of HAA (hazard ratio [HR]: 1.10; 95% confidence interval [CI]: 1.03–1.16; P < 0.01) and HMA events (HR: 1.11; 95% CI: 1.03–1.20; P < 0.01). Meanwhile, each increase in FPG variability of 1 SD increased the risk of HAA (HR: 1.40; 95% CI: 1.31–1.49; P < 0.01) and HMA events (HR: 1.46; 95% CI: 1.35–1.57; P < 0.01). Meanwhile, models, including FPG variability, had better prognostic value for our predefined outcomes than HbA1c variability (P < 0.01). CONCLUSIONS: Increased visit-to-visit variability in HbA1c and fasting glycemia is associated with a greater risk of severe hypoglycemic events in T2DM patients. FPG variability is a more sensitive indicator than HbA1c variability. TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00000620.