BACKGROUND: Severe hypoglycemic events (SHEs) in type 2 diabetes (T2D) are associated with an increased risk of subsequent cardiovascular (CV) events. A reverse relationship, however, in which nonfatal CV events are associated with a subsequent increased SHE risk has been demonstrated in TECOS. We sought to validate this novel bidirectional relationship using EXSCEL data.
METHODS: Time-dependent associations were examined between SHEs and subsequent CV events or all-cause mortality (ACM) in a post hoc analysis of 14,752 EXSCEL participants with T2D, and between nonfatal CV events and subsequent SHEs, in both partial and fully adjusted models.
RESULTS: Participants with (versus without) SHEs were on average older, with longer diabetes duration and lower estimated glomerular filtration rate, and were more frequently non-White, insulin treated, and had prior CV or heart failure events. SHEs were not associated with once-weekly exenatide therapy, compared with placebo (hazard ratio 1.13, 95% CI 0.94-1.36, P=0.18). In fully adjusted models, SHEs increased the risk of ACM, CV death and hospitalization for heart failure (hHF), whilst non-fatal MI, non-fatal stroke and hHF all increased subsequent risk of SHEs (Table).
CONCLUSIONS: A robust bidirectional association between SHEs and subsequent risk of CV events, and between nonfatal CV events and subsequent risk of SHEs, was confirmed, suggesting a “frail” T2D sub-phenotype with increased susceptibility to both SHEs and CV events.