Risk of Cardiac Arrhythmias During Hypoglycemia in Patients With Type 2 Diabetes and Cardiovascular Risk

Recent trials of intensive glycemic control suggest a possible link between hypoglycemia and excess cardiovascular mortality in patients with type 2 diabetes. Hypoglycemia might cause arrhythmias through effects on cardiac repolarization and changes in cardiac autonomic activity. Our aim was to study the risk of arrhythmias during spontaneous hypoglycemia in type 2 diabetic patients with cardiovascular risk. Twenty-five insulin-treated patients with type 2 diabetes and a history of cardiovascular disease or two or more risk factors underwent simultaneous continuous interstitial glucose and ambulatory electrocardiogram monitoring. Frequency of arrhythmias, heart rate variability, and markers of cardiac repolarization were compared between hypoglycemia and euglycemia and between hyperglycemia and euglycemia matched for time of day. There were 134 h of recording at hypoglycemia, 65 h at hyperglycemia, and 1,258 h at euglycemia. Bradycardia and atrial and ventricular ectopic counts were significantly higher during nocturnal hypoglycemia compared with euglycemia. Arrhythmias were more frequent during nocturnal versus daytime hypoglycemia. Excessive compensatory vagal activation after the counterregulatory phase may account for bradycardia and associated arrhythmias. QT intervals, corrected for heart rate, >500 ms and abnormal T-wave morphology were observed during hypoglycemia in some participants. Hypoglycemia, frequently asymptomatic and prolonged, may increase the risk of arrhythmias in patients with type 2 diabetes and high cardiovascular risk. This is a plausible mechanism that could contribute to increased cardiovascular mortality during intensive glycemic therapy.

[1]  M. Özkaya,et al.  Action to Control Cardiovascular Risk in Diabetes , 2013 .

[2]  C. Napolitano,et al.  Torsade de Pointes , 2012, Drugs.

[3]  A. Vaag,et al.  Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials , 2011, BMJ : British Medical Journal.

[4]  C. Emery,et al.  Relationship between interstitial and blood glucose during hypoglycemia in subjects with type 2 diabetes. , 2011, Diabetes technology & therapeutics.

[5]  R. Freeman,et al.  Methods of investigation for cardiac autonomic dysfunction in human research studies , 2011, Diabetes/metabolism research and reviews.

[6]  R. Bolognesi,et al.  Marked sinus bradycardia and QT prolongation in a diabetic patient with severe hypoglycemia. , 2011, Journal of diabetes and its complications.

[7]  Michael E. Miller,et al.  Long-Term Effects of Intensive Glucose Lowering on Cardiovascular Outcomes , 2011 .

[8]  S. Aydoǧdu,et al.  A peculiar medical cardioversion of atrial fibrillation with glucose infusion--a rare cause of atrial fibrillation: hypoglycemia. , 2011, The American journal of emergency medicine.

[9]  J. Randløv,et al.  QT Measurement and Heart Rate Correction during Hypoglycemia: Is There a Bias? , 2010, Cardiology research and practice.

[10]  Mark Woodward,et al.  Severe hypoglycemia and risks of vascular events and death. , 2010, The New England journal of medicine.

[11]  Rayaz A. Malik,et al.  Diabetic Neuropathies: Update on Definitions, Diagnostic Criteria, Estimation of Severity, and Treatments , 2010, Diabetes Care.

[12]  C. Nordin The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence , 2010, Diabetologia.

[13]  Grant D. Huang,et al.  Glucose control and vascular complications in veterans with type 2 diabetes. , 2009, The New England journal of medicine.

[14]  S. Schinner Intensive Blood Glucose Control and Vascular Outcomes in Patients with Type 2 Diabetes , 2009 .

[15]  S. Schinner,et al.  Effects of Intensive Glucose Lowering in Type 2 Diabetes , 2009 .

[16]  J. Dempster,et al.  Importance of vagally mediated bradycardia for the induction of torsade de pointes in an in vivo model , 2008, British journal of pharmacology.

[17]  G. Gill,et al.  Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes—the ‘dead in bed’ syndrome revisited , 2008, Diabetologia.

[18]  D. Kerr,et al.  Moderators, Monitoring and Management of Hypoglycaemia , 2007 .

[19]  R. Brazg,et al.  Accuracy of the 5-Day FreeStyle Navigator Continuous Glucose Monitoring System , 2007, Diabetes Care.

[20]  UK Prospective Diabetes Study Group Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration , 2007, Diabetologia.

[21]  P. Maison-Blanche,et al.  QT interval analysis on ambulatory electrocardiogram recordings: a selective beat averaging approach , 2006, Medical & Biological Engineering & Computing.

[22]  Boris Kovatchev,et al.  Evaluating the clinical accuracy of two continuous glucose sensors using continuous glucose-error grid analysis. , 2005, Diabetes care.

[23]  Heikki V Huikuri,et al.  Effects of sustained insulin-induced hypoglycemia on cardiovascular autonomic regulation in type 1 diabetes. , 2005, Diabetes.

[24]  Frank H Wilhelm,et al.  Increased high-frequency heart rate variability during insulin-induced hypoglycaemia in healthy humans. , 2004, Clinical science.

[25]  N. Harris,et al.  Influence of autonomic neuropathy on QTc interval lengthening during hypoglycemia in type 1 diabetes. , 2004, Diabetes.

[26]  N. Harris,et al.  Changes in cardiac repolarization during clinical episodes of nocturnal hypoglycaemia in adults with Type 1 diabetes , 2004, Diabetologia.

[27]  P. Cryer,et al.  Sleep-related hypoglycemia-associated autonomic failure in type 1 diabetes: reduced awakening from sleep during hypoglycemia. , 2003, Diabetes.

[28]  Baofeng Yang,et al.  Impairment of Human Ether-à-Go-Go-related Gene (HERG) K+ Channel Function by Hypoglycemia and Hyperglycemia , 2003, The Journal of Biological Chemistry.

[29]  Benjamin Cheong,et al.  Association of hypoglycemia and cardiac ischemia: a study based on continuous monitoring. , 2002, Diabetes care.

[30]  Anahit Mehrabyan,et al.  Diagnosis and management of diabetic autonomic neuropathy , 2003, Comprehensive therapy.

[31]  A. Moran,et al.  Spurious reporting of nocturnal hypoglycemia by CGMS in patients with tightly controlled type 1 diabetes. , 2002, Diabetes care.

[32]  Abnormalities of the electrocardiogram during hypoglycaemia: the cause of the dead in bed syndrome? , 2002, International journal of clinical practice. Supplement.

[33]  P. Cryer,et al.  Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. , 2002, Diabetes.

[34]  Cardiac responses to insulin-induced hypoglycemia in nondiabetic and intensively treated type 1 diabetic patients. , 2001, American journal of physiology. Endocrinology and metabolism.

[35]  U. Adamson,et al.  Increased QT dispersion during hypoglycaemia in patients with type 2 diabetes mellitus , 1999, Journal of internal medicine.

[36]  Jefferson Luiz Brum Marques,et al.  Altered ventricular repolarization during hypoglycaemia in patients with diabetes , 1997, Diabetic medicine : a journal of the British Diabetic Association.

[37]  A. Malliani,et al.  Heart rate variability. Standards of measurement, physiological interpretation, and clinical use , 1996 .

[38]  G. Breithardt,et al.  Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. , 1996 .

[39]  J A Hobson,et al.  Sleep, dreams, and sudden death: the case for sleep as an autonomic stress test for the heart. , 1996, Cardiovascular research.

[40]  A. Porta,et al.  Power spectrum analysis of heart rate variability to assess the changes in sympathovagal balance during graded orthostatic tilt. , 1994, Circulation.

[41]  L. Jorfeldt,et al.  Hypoglycaemia and Cardiac Arrhythmias in Patients with Type 2 Diabetes Mellitus , 1992, Diabetic medicine : a journal of the British Diabetic Association.

[42]  J. Jalife,et al.  Cardiac Electrophysiology: From Cell to Bedside , 1990 .

[43]  B. Frier,et al.  Cardiac responses to acute insulin-induced hypoglycemia in humans. , 1990, The American journal of physiology.

[44]  D Tzivoni,et al.  Torsade de pointes. , 1989, American heart journal.

[45]  I. O'Brien,et al.  Heart rate variability in healthy subjects: effect of age and the derivation of normal ranges for tests of autonomic function. , 1986, British heart journal.

[46]  A. Spiers,et al.  HAEMORRHAGIC CYSTITIS AFTER LOW-DOSE CYCLOSPHOSPHAMIDE , 1983, The Lancet.

[47]  S. Oram,et al.  MODIFICATION BY PROPRANOLOL OF CARDIOVASCULAR EFFECTS OF INDUCED HYPOGLYCÆMIA , 1975, The Lancet.

[48]  B. Surawicz,et al.  The Measurement of the Q‐T Interval of the Electrocardiogram , 1952, Circulation.