The glycemic triumvirate and diabetic complications: is the whole greater than the sum of its component parts?

The dysglycemia of diabetes mellitus can be depicted as the glycemic triumvirate with its 3 main components: the sustained chronic (ambient) hyperglycemia, glucose variability and hypoglycemic episodes. The respective contributions of these glycemic disorders to the overall risk for diabetic complications remain a subject of debate. At present, there is cogent evidence for the direct deleterious effect of ambient hyperglycemia while the roles exerted by glucose variability and hypoglycemia remain less documented and only based on observational and pathophysiological studies. In addition, these 3 glycemic disorders could be regarded as components of either an additive or an initiator/accelerator model according to whether each disorder exerts an independent or inter-dependent effect on the development and progression of diabetes-related complications, respectively. In the present review, pros and cons arguments for each model are debated. However it is highly likely that these 3 glycemic disorders have both direct (spoke in a wheel) and indirect (link in a chain) causal effects on clinical cardiovascular outcomes. As a consequence, the relationship between the so-called glycemic triumvirate and diabetic complications might be summarized by the famous Aristotle's aphorism: "the whole is greater than the sum of its parts".