Abstract
Research indicates a U-shaped association between mortality and glycated hemoglobin (HbA1c) levels in patients receiving sulfonylurea or insulin. However, the relationship between glucose levels and cardiovascular events in patients on novel agents with a lower hypoglycemic potential remains unknown. This study was aimed to examine the association between cardiovascular events and HbA1c in patients with type 2 diabetes receiving drugs with different hypoglycemic potentials. This is an observational cohort study using a multicenter electronic medical record database. This study included patients who received a diagnosis of type 2 diabetes between 2009 and 2020 and received non-insulin antidiabetic drugs. These drugs were divided into drugs with a high-hypoglycemic-risk (sulfonylurea and meglitinides) and drugs with a low-hypoglycemic-risk (incretin mimetics, sodium-glucose cotransporter-2 inhibitors, thiazolidinediones, and acarbose). The events of interest were mortality and major adverse cardiovascular events (MACEs). A total of 6,789 patients were included, with 3,191 patients in low-hypoglycemic-risk drugs cohort and 3,598 patients in high-hypoglycemic-risk drugs cohort. Both cohorts exhibited a U-shaped association between HbA1c levels and the risk of mortality and MACEs. Among patients receiving low-hypoglycemic-risk drugs, HbA1c levels of 6.7% and 6.8% were associated with the lowest risk of mortality and MACEs, respectively. Similarly, in patients receiving high-hypoglycemic-risk drugs, the lowest risk of mortality and MACEs was observed at HbA1c levels of 6.8% and 7.2%, respectively. Both low and high HbA1c levels were associated with an increased risk of mortality and cardiovascular events, whereas intermediate levels were linked to the lowest risk. These findings support a U-shaped association between glycemic control and adverse outcomes in patients with type 2 diabetes receiving non-insulin-based therapies.