Is HbA1c a valid surrogate for macrovascular and microvascular complications in type 2 diabetes?

Recent recommendations regarding type 2 diabetes (T2D) patients' treatments have focused on personalizing glycosylated haemoglobin (HbA1c) targets. Because the relationship between HbA1c and diabetes prognosis has been established from large prospective cohorts, it is valid to question the extrapolation from population-based risk reduction estimations to individual predictions. Our study aimed to investigate the relationship between HbA1c reductions and clinical outcomes in randomized controlled trials (RCTs), using a meta-regression approach. Included were RCTs comparing intensive vs. standard glucose-lowering regimens for cardiovascular events and microvascular complications in T2D patients. Eight studies (33,396 patients) providing data for HbA1c reductions were found. In our meta-regression, HbA1c decreases were not significantly associated with reductions in our main study outcomes: total and cardiovascular mortality. They were also not associated with any of the secondary endpoints, including myocardial infarction, stroke and severe hypoglycaemia. Sensitivity analysis showed a significant correlation only between HbA1c-lowering and severe hypoglycaemia (P = 0.014). Meta-regression analysis could find no significant association between HbA1c-lowering and a decrease in clinical outcomes, thereby questioning the use of HbA1c as a surrogate outcome for T2D-related complications. Thus, RCTs vs. placebo are urgently required to evaluate the risk-benefit ratios of therapeutic strategies beyond HbA1c control in T2D patients.