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Hypoglycemia in Type 1 Diabetes Associated with Proarrhythmogenic Effects

Arrhythmia incidents differ in nocturnal and diurnal hypoglycemic patients.

In young adults with type 1 diabetes (T1D), severe hypoglycemia may increase the risk of all-cause mortality and cardiovascular diseases. According to Peter Novodvorsky, from the University of Sheffield in the United Kingdom, and his colleagues, there are differences in arrhythmic risk and cardiac repolarization during nocturnal versus daytime hypoglycemia. Hypoglycemia may exert proarrhythmogenic effects on the heart by sympathoadrenal stimulation and hypokalemia. The dysrhythmias induced by hypoglycemia have been associated with the “dead-in-bed syndrome,” a devastating condition that is rarely heard of. In this study, the effects of nocturnal and daytime clinical hypoglycemia are examined through electrocardiogram (ECG) in young people with T1D.

In an observational study, 37 participants were recruited from Sheffield Teaching Hospitals outpatient clinics with a median age of 34 years with T1D for at least four years. The purpose of this study was to examine the effect of clinical hypoglycemia in T1D patients age 50 or less and compare it with matched euglycemia on the frequency of cardiac arrhythmias, HRV, and cardiac repolarization. Mann-Whitney U test compared the median duration and nadir values of nighttime and daytime hypoglycemic episodes. P values indicated comparison of nocturnal and daytime hypoglycemic data via paired t test.

Baseline assessment measured urea, electolytes, glycated hemoglobin A1c at the onset of the monitoring period. Participants were told to avoid vigorous exercise, caffeine, and smoking 12 h prior to monitoring. Hypoglycemia awareness was assessed using a visual analog Likert-type scale of 1 to 7. All subjects underwent 96 h of simultaneous 12-lead Holter ECG and blinded continuous interstitial glucose monitoring (CGM) while continuing daily activities and symptomatic hypoglycemia were recorded. Frequency of arrhythmias, heart rate variability (HRV), and cardiac repolarization were measured during hypoglycemia and compared with time-matched euglycemia during night and day.

The researchers obtained 2,395 hours of simultaneous ECG and CGM recordings with 159 and 1,355 hours designated hypoglycemia and euglycemia respectively. The median duration of hypoglycemia was longer during the night (60 min) than daytime (44 min) [P =0.020]. Overall, there were 24.1% of nocturnal and 51% of daytime symptomatic episodes respectively. Bradycardia was more frequent during nocturnal hypoglycemia in comparison to matched euglycemia with an incidence rate ratio [IRR] 6.44 [95% CI, 6.26-6.66; P <0.001]. During daytime hypoglycemia, bradycardia was less frequent with an IRR 0.023 [95% CI, 0.002-0.26; P =0.002], while atrial ectopic was more frequent (IRR: 2.29; 95% CI, 1.19-4.39; P =.013). Moreover, during nocturnal and daytime hypoglycemia there was decreased T-wave symmetry, but prolonged QTc and T-peak to T-end interval duration.

Some limitations included only counting hypoglycemic episodes that lasted at least 20 min, which underestimates the amount of hypoglycemia and 70% return rate of questionnaires to identify symptomatic responses. Also, changes in arrhythmias in the subgroups were unmeasured. The majority of cardiac arrhythmias occurred during euglycemia as it was more frequent and long-lasting compared with hypoglycemia. The study detected a mean QTc prolongation of 5ms and 12mg during nocturnal and daytime hypoglycemia respectively in comparison to euglycemia. Although the changes in QTc duration show smaller differences, that is probably due to both lower insulin levels and sympathoadrenal responses during spontaneous compared with experimental episodes. However, the difference compared with mean QTc duration during matched euglycemia was statistically significant [P: 0.001].

The study directly compared the diurnal differences in young people with T1D by examining the effect of spontaneous hypoglycemia. It confirmed that asymptomatic hypoglycemia commonly occurs in T1D. An increased risk of bradycardia during nocturnal versus daytime hypoglycemia was observed, but the bradycardia was significantly lower and the atrial ectopic frequency was significantly higher in comparison with euglycemia. Also, significant prolongation of QTc and TpTend intervals, symmetric shape of T wave during night and day confirmed proarrhythmogenic effect of hypoglycemia. Factors that may have affected the frequency of cardiac arrhythmias, HRV, and cardiac repolarization include diurnal variability in autonomic tone, different sympathoadrenal responses to hypoglycemia when awake or asleep, and the effect of body position.

Practice Pearls:

  • Hypoglycemia is proarrhythmogenic.
  • The study confirmed that there is high frequency of hypoglycemia, particularly of nocturnal asymptomatic episodes among young people with type 1 diabetes.
  • Hypoglycemia-induced mechanism is independent of the type of diabetes, age, or cardiovascular risk profile.

References:

  1. American Diabetes Association. 5. Glycemic targets. Diabetes Care. 2016;39 (Suppl. 1):S39–S46
  2. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia. 2010;53:1552–1561
  3. Novodvorsky P, bernjak A, Chow E, Iqbal A, Sellors L, Williams S, et al. Diurnal differences in risk of cardiac arrhythmias during spontaneous hypoglycemia in young people with type 1 diabetes. Diabetes Care. 2017, Feb 17.