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

Abstract

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 (HR_SD).

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 (HR_SD 1.09 [95% CI 1.03-1.15]) and all-cause mortality (HR_SD 1.13 [95% CI 1.07-1.20]), whereas there were no associations with type 2 diabetes (HR_SD 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.