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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 A1c (HbA1c) 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 HbA1c measurements within normal range (<6.5% [48 mmol/mol]). For each individual, we measured the HbA1c variability as the SD of the residuals obtained from a linear regression on the three HbA1c measurements. From the linear regression, we also obtained the estimated index HbA1c (intercept) and the trend over time (slope). Follow-up began at the date of the third measurement. Associations between HbA1c 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 HbA1c 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 HbA1c variability–defined subgroups. CONCLUSIONS In a primary care population free of diabetes and cardiovascular disease, high HbA1c variability was associated with increased risks of MACE and all-cause mortality.