Hypoglycemia and the Risk of Cardiovascular Events: Causality or (Just) an Epidemiological Association?!

Since the early termination of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial in 2008 due to higher mortality in the intensive glucose arm, the relationship between hypoglycemia, mainly severe hypoglycemic episodes (SHE), and negative outcomes (with focus on cardiovascular [CV] events and mortality, and all-cause mortality) started to be more carefully scrutinized by scientific researchers and avoidance of hypoglycemia has been included in all diabetes guidelines among the targets set for the management of hyperglycemia. Numerous randomized clinical trials and epidemiological studies found a robust association between SHE and incident major CV events and mortality, as well as all-cause deaths but this association was not found for non-severe hypoglycemia. Two recent reports suggest that a “frail” T2D phenotype, characterized by older age, longer diabetes duration, lower glomerular filtration rate, who were more frequently non-White, insulin treated, and had prior CV or heart failure events, increased susceptibility to both SHEs and CV events and that SHEs do not cause deleterious CV outcomes. Nevertheless, other researchers claim that the causality exists between SHEs and increased risk for subsequent CV events and mortality. Avoidance of hypoglycemia remains a target of antihyperglycemic strategies while efforts to attain and maintain individualized glucose targets should be done from the time of diagnosis and throughout all diabetes duration.