AbstractBackgroundThe relationship between glucose fluctuation and the risk of cardiovascular disease (CVD) in patients with diabetes remains elusive. Glycated hemoglobin (HbA1c) variability is a key parameter of glucose fluctuation.MethodsPubMed, Cochrane Library, Web of Science, and Embase were searched up to 1 July 2022. Studies reporting associations of HbA1c variability (HbA1c‐SD), coefficient of variation of HbA1c (HbA1c‐CV), and HbA1c variability score [HVS] with the risk of CVD among patients with diabetes were included. We used three different insights (a high‐low value meta‐analysis, a study‐specific meta‐analysis, and a non‐linear dose–response meta‐analysis) to explore the relationship between HbA1c variability and CVD risk. A subgroup analysis was also performed to screen the potential confounding factors.ResultsA total of 14 studies with 254 017 patients with diabetes were eligible. The highest HbA1c variability was significantly associated with increased risks of CVD (HbA1c‐SD, risk ratio [RR] 1.45; HbA1c‐CV, RR 1.74; HVS, RR 2.46; allp< .001) compared to the lowest HbA1c variability. The RRs of CVD for per HbA1c variability were significantly >1 (allp< .001). The subgroup analysis for per HbA1c‐SD found a significant exposure‐covariate interaction in the types of diabetes (p= .003 for interaction). The dose–response analysis showed a positive association between HbA1c‐CV and CVD risk (Pfor nonlinearity <.001).ConclusionsOur study suggests that the higher glucose fluctuation is significantly associated with the higher CVD risk in diabetes patients based on HbA1c variability. The CVD risk associated with per HbA1c‐SD might be higher among patients type 1 diabetes than patients with type 2 diabetes.