Associations Between Mean HbA1c, HbA1c Variability, and Both Mortality and Macrovascular Complications in Patients with Diabetes Mellitus: A Registry-Based Cohort Study

Background: We investigate the association between mean HbA1c, HbA1c variability, and all-cause mortality and diabetes-related macrovascular complications in patients with diabetes.Methods: We performed a retrospective cohort study using patients present in the Singapore Health Services diabetes registry (SDR) during 2013 to 2014. We assessed mean HbA1c using three models: a baseline mean HbA1c for 2013-14, the mean across the whole follow-up period, and a time-varying yearly updated mean. We assessed HbA1c variability at baseline using the patient's HbA1c variability score (HVS) for 2013-14. The association between mean HbA1c, HVS, and 6 outcomes were assessed using Cox proportional hazard models.Results: We included 43,837-53,934 individuals in the analysis; 99.3% had type 2 diabetes mellitus. The data showed a J-shaped distribution in adjusted hazard ratios (HRs) for all-cause mortality, ischemic heart disease, acute myocardial infarction, peripheral arterial disease, and ischemic stroke, with an increased risk of developing these outcomes at HbA1c <6% (42 mmol/mol) and >= 8% (64 mmol/mol). With the addition of HVS, the J-shaped distribution was maintained for the above outcomes, but HRs were greater at HbA1c <6.0% (42 mmol/mol) and reduced at HbA1c >= 8.0% (64 mmol/mol) when compared to models without HVS. The risk for all outcomes increased substantially with increasing glycaemic variability.Conclusion: Both low (<6.0% [42 mmol/mol]) and high (>= 8.0% [64 mmol/mol]) levels of glycaemic control are associated with increased all-cause mortality and diabetes-related macrovascular complications. Glycaemic variability is independently associated with increased risk for these outcomes. Therefore, patients with stable glycaemic level of 6-8% (42-64mmol/mol) are at lowest risk of all -cause mortality and diabetes-related macrovascular complications.