Modification of the Association Between Severe Hypoglycemia and Ischemic Heart Disease by Surrogates of Vascular Damage Severity in Type 1 Diabetes During ∼30 Years of Follow-up in the DCCT/EDIC Study

Literature suggests that severe hypoglycemia (SH) may be linked to cardiovascular events only in older individuals with high cardiovascular risk score (CV-score). Whether a potential relationship between any-SH and cardiovascular disease exists and whether it is conditional on vascular damage severity in a young cohort with type 1 diabetes (T1D) without apparent macrovascular and no or mild-to-moderate microvascular complications at baseline is unknown. We evaluated data of 1,441 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study volunteers (diabetes duration 1-15 years) followed for ∼30 years. Time-dependent associations between any-SH and ischemic heart disease (IHD: death, silent/nonfatal myocardial infarct, revascularization, or confirmed angina) and associations between interactions of any-SH with surrogates of baseline micro-/macrovascular damage severity and IHD were analyzed. Diabetes duration, steps on DCCT Early Treatment Diabetic Retinopathy Study severity scale (DCCT-ETDRS), Diabetes Complications Severity Index (DCSI), and CV-scores were considered as surrogates of baseline micro-/macrovascular damage severity. Without interactions, in the minimally adjusted model controlling for confounding bias by age and HbA , SH was a significant IHD factor ( = 0.003). SH remained a significant factor for IHD in fully adjusted models ( < 0.05). In models with interactions, interactions between SH and surrogates of microvascular complications severity, but not between SH and CV-score, were significant. Hazard ratios for IHD based on SH increased 1.19-fold, 1.32-fold, and 2.21-fold for each additional year of diabetes duration, DCCT-ETDRS unit, and DCSI unit, respectively. At time of IHD event, ∼15% of 110 participants with SH had high CV-scores. In a young cohort with T1D with no baseline macrovascular complications, surrogates of baseline microvascular damage severity impact the effect of SH on IHD. Older age with high CV-score per se is not mandatory for an association of SH with IHD. However, the association is multifactorial.