Association of HbA1c levels with vascular complications and death in patients with type 2 diabetes: evidence of glycaemic thresholds

Abstract

Aims/hypothesis There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA_1c and the risks of vascular complications and death in such patients. Methods Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA_1c measurements during follow-up and prior to the first event. Adjusted risks for each HbA_1c decile were estimated using Cox models. Possible differences in the association between HbA_1c and risks at different levels of HbA_1c were explored using linear spline models. Results There was a non-linear relationship between mean HbA_1c during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA_1c studied (5.5–10.5%), there was evidence of ‘thresholds’, such that below HbA_1c levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p > 0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA_1c level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p < 0.0001). Conclusions/interpretation In patients with type 2 diabetes, HbA_1c levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm. Trial Registration: ClinicalTrial.gov NCT00145925 Funding: Servier and the National Health and Medical Research Council of Australia (project grant ID 211086 and programme grant IDs 358395 and 571281)