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Expert commentary

by Sridharan Raghavan, MD, PhD

Hypoglycemia is a serious and preventable adverse effect of diabetes treatment associated with older age, chronic kidney disease, and use of insulin and sulfonylureas.1 Several studies have described associations of hypoglycemia with cardiovascular events,2-4 and others have described effects of hypoglycemia on different aspects of cardiac conduction, implicating hypoglycemia as arrhythmogenic.2,5-8 Similarly, measures of glycemic variability have been associated with cardiovascular risk and excess mortality though the mechanism of this effect remains unclear.9,10

In the study titled “Hypoglycemia, Glycemic Variability, and Risk of Cardiac Arrhythmias in Insulin-Treated Patients with Type 2 Diabetes,” Andersen and colleagues used continuous glucose monitoring (CGM) and implanted loop recorders to investigate the relationship of hypoglycemia, glycemic variability, and cardiac arrhythmias in type 2 diabetes (T2D). They studied 21 adults with insulin-treated T2D, reasonably well-controlled glycemia, and a history of diabetes complications. Individuals with known cardiac arrhythmia, with devices that may affect cardiac conduction, or with medical conditions that could affect cardiac conduction were excluded. Participants were followed for 12 months with intermittent CGM and year-long loop recorder to capture suspected arrhythmia events. Arrhythmias of interest included atrial fibrillation, pauses, high-grade atrioventricular block and bradycardia, and ventricular tachycardia. On average, participants were 67 years old, with over 10 years’ diabetes duration, and only 2 of 21 had pre-existing cardiovascular disease.

The investigators identified day/night variation in frequency, severity, and duration of hypoglycemic episodes – with daytime episodes being of shorter duration, but with steeper downslope in glucose. The investigators did not observe an association of hypoglycemia, time in hypoglycemia per hour, mean plasma glucose per hour, or change in plasma glucose over 2 hours with cardiac arrhythmias. However, they did observe associations of standard deviation in plasma glucose and coefficient of variation in plasma glucose during the night-time, with increased incidence rate of cardiac arrhythmias. Strengths of the study include the longitudinal data and excellent temporal resolution in arrhythmia occurrence due to the use of implanted loop recorder for an entire year. Limitations include the small sample size, the absence of measurement of other circulating molecules that could contribute to a mechanistic understanding of the described associations, and inclusion of only insulin-treated individuals precluding insight into hypoglycemia related to sulfonylurea use. Despite the limitations, this clear and well-designed study provides provocative data implicating glycemic variability – rather than hypoglycemia or other glucose measures – as a risk factor for cardiac arrhythmias in T2D patients.

 

References

  1. Karter AJ, Warton EM, Lipska KJ, et al. Development and Validation of a Tool to Identify Patients With Type 2 Diabetes at High Risk of Hypoglycemia-Related Emergency Department or Hospital Use. JAMA Intern Med 2017;177(10):1461–70.
  2. International Hypoglycaemia Study Group. Hypoglycaemia, cardiovascular disease, and mortality in diabetes: epidemiology, pathogenesis, and management. Lancet Diabetes Endocrinol 2019;7(5):385–96.
  3. Lee AK, Warren B, Lee CJ, et al. The Association of Severe Hypoglycemia With Incident Cardiovascular Events and Mortality in Adults With Type 2 Diabetes. Diabetes Care 2018;41(1):104–11.
  4. Standl E, Stevens SR, Lokhnygina Y, et al. Confirming the Bidirectional Nature of the Association Between Severe Hypoglycemic and Cardiovascular Events in Type 2 Diabetes: Insights From EXSCEL. Diabetes Care 2020;43(3):643–52.
  5. Chow E, Bernjak A, Williams S, et al. Risk of cardiac arrhythmias during hypoglycemia in patients with type 2 diabetes and cardiovascular risk. Diabetes 2014;63(5):1738–47.
  6. Lindstrom T, Jorfeldt L, Tegler L, Arnqvist HJ. Hypoglycaemia and cardiac arrhythmias in patients with type 2 diabetes mellitus. Diabet Med 1992;9(6):536–41.
  7. Nordin C. The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence. Diabetologia 2010;53(8):1552–61.
  8. Novodvorsky P, Bernjak A, Chow E, et al. Diurnal Differences in Risk of Cardiac Arrhythmias During Spontaneous Hypoglycemia in Young People With Type 1 Diabetes. Diabetes Care 2017;40(5):655–62.
  9. Hirakawa Y, Arima H, Zoungas S, et al. Impact of visit-to-visit glycemic variability on the risks of macrovascular and microvascular events and all-cause mortality in type 2 diabetes: the ADVANCE trial. Diabetes Care 2014;37(8):2359–65.
  10. Zhou JJ, Koska J, Bahn G, Reaven P. Fasting Glucose Variation Predicts Microvascular Risk in ACCORD and VADT. J Endocrinol Metab 2021;106(4):1150–62.
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