Characterizing Associations of QTc Interval with Nocturnal Glycemic Control in Children with Type 1 Diabetes

An association between QT prolongation (Bazett's corrected QT interval, QTcB) of 7 milliseconds and nocturnal hypoglycemia, compared with euglycemia, has been observed in children with type 1 diabetes (T1D). The objective of this pharmacometric analysis was to understand this association and other sources of QTc variability quantitatively. Data originate from a prospective observational study (25 cardiac healthy children with T1D, aged 8.1-17.6 years) with continuous subcutaneous glucose and electrocardiogram measurements for 5 consecutive nights. Mixed-effect modeling was used to compare QTcB with individual heart-rate correction (QTcI). Covariate models accounting for circadian variation, age, and sex were evaluated, followed by an investigation of glucose-QTc relationships (with univariable and combined adjusted analysis). Factors potentially modifying sensitivity to QTc lengthening were explored. Random inter-individual variability was reduced in the QTcI versus QTcB model (±12.6 vs 14.1 milliseconds), and was further reduced in the adjusted covariate model (±9.7 milliseconds), accounting for the significantly (P < .01) shortened QTc in adolescent boys (-14.6 milliseconds), circadian variation (amplitude, 19.2 milliseconds; shift, 2.9 hours), and linear glucose-QTc relationship (delay rate, 0.56^-h ; slope, 0.76 milliseconds [95%CI 0.67- 0.85 milliseconds] per 1 mmol/L decrease in glucose). Differing sensitivity was suggested to depend upon hemoglobin A1c (HbA1c), T1D duration, and time spent in nocturnal hypoglycemia. In conclusion, a clinically mild association of QTc prolongation with nocturnal hypoglycemia was confirmed and quantified in this pharmacometric analysis, and the longest QTc interval was around 03:00 a.m. The characterized delayed association with glucose highlights the relevance of both the extent and the duration of hypoglycemia. Further clinical studies are warranted to investigate whether these factors contribute to increased risk of hypoglycemia-associated cardiac arrhythmia in children with T1D.