Visit-to-Visit Variability of Hemoglobin A1c in People Without Diabetes and Risk of Major Adverse Cardiovascular Events and All-Cause Mortality

OBJECTIVE We aimed to study whether visit-to-visit variability of glycated hemoglobin A(1c) (HbA(1c)) is associated with incident major adverse cardiovascular events (MACE), all-cause mortality, and type 2 diabetes in people without diabetes. RESEARCH DESIGN AND METHODS We included primary care patients with no history of diabetes or cardiovascular disease and with three annual HbA(1c) measurements within normal range (< 6.5% [48 mmol/mol]). For each individual, we measured the HbA(1c) variability as the SD of the residuals obtained from a linear regression on the three HbA(1c) measurements. From the linear regression, we also obtained the estimated index HbA(1c) (intercept) and the trend over time (slope). Follow-up began at the date of the third measurement. Associations between HbA(1c) variability and outcome were analyzed using Cox regression, adjusted for traditional risk factors, intercept, and trend and reported as hazard ratio per SD increase in variability (HRSD). RESULTS In total, 6,756 individuals were included. During a median follow-up time of 6.3 years, 996 developed MACE, 856 died, and 1,267 developed type 2 diabetes. We found a significant association between increasing HbA(1c) variability and incident MACE (HRSD 1.09 [95% CI 1.03-1.15]) and all-cause mortality (HRSD 1.13 [95% CI 1.07-1.20]), whereas there were no associations with type 2 diabetes (HRSD 1.00 [95% CI 0.95-1.05]). We calculated 5-year absolute risks of MACE and all-cause mortality and found clinically relevant differences across several age, sex, comorbidity, and HbA(1c) variability-defined subgroups. CONCLUSIONS In a primary care population free of diabetes and cardiovascular disease, high HbA(1c) variability was associated with increased risks of MACE and all-cause mortality.