De la mémoire du glucose au droit à l'oubli : quantifier les années d'hyperglycémie

Type 2 diabetes remains a leading cause of cardiovascular disease (CVD). Glycemic level and risk of major adverse cardiovascular events (MACE) were consistently associated in observational studies. However, evidence from intervention studies supporting the reduction of cardiovascular burden of diabetes by intensive glucose control was limited. The concept of cumulative glycemic exposure may be helpful for explaining the protection against CVD in diabetes. We propose to move from a binary approach in trials to a more quantitative approach, based on differences in cumulative glycemic exposure. In this purpose, we plotted the association between differential glycemic exposure between the study arms and Hazard Ratio for MACE, in randomized controls trials comparing intensive vs. conventional glycemic control. There was a striking correlation between differential exposure and cardiovascular risk reduction. Similar results were obtained with trials comparing glucose-lowering agents vs. placebo. They suggest that a minimal study duration and a minimal gain in HbA1c reduction are necessary to drive a relevant risk reduction in CVD risk, and we provide a quantificative perspective in that respect. According to this approach, we also found that the cardioprotective effect observed in recent studies evaluating empagliflozin, liraglutide, and semaglutide, did not significantly exceed what could be expected from the cumulated reduction of glycemic exposure. This analysis underlines that the duration of the intensification, and the amplitude of the resulting reduction in HbA1c, are important notions for clinical decision making, and for future trial design.