Interpretation of cardiovascular outcome trials in type 2 diabetes needs a multiaxial approach

In cardiovascular (CV) diabetology a "one-size fits-all" approach needs caution as vasculopathy and CV manifestations in patients with type 2 diabetes (T2D) with short disease duration are different as compared to those with longer duration. This is of relevance when interpreting results of CV outcome trials as responses to any intervention aimed to reduce CV risk might be different in patients with established vasculopathy as compared to those without, where also the duration of the intervention may play a role. Additionally, the mode-of-action of the intervention and its assumed time to peak CV risk modulation need to be taken into account: an intervention with possibly immediate effects, like on blood pressure or other direct functional dynamic parameters such as endothelial function or renal hemodynamics, could likely provide a meaningful impact on CV outcomes over a shorter time span than interventions that primarily target pathways that work on atherosclerotic processes, organ-remodelling, or vessel integrity. We are now faced with CV outcome results to interpret from a plethora of outcomes trials in T2D, some of which are testing the CV risk modulation predominantly beyond glucose lowering, e.g., as is the case for several trials testing the newer therapy classes di-peptidyl peptidase-4 inhibitors, glucagon-like protein-1 receptor analogues and sodium glucose co-transporter-2 inhibitors, and this paper reviews the data that support a call for a multiaxial approach to interpret these results.