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BRIEF COMMUNICATION
Year : 2012  |  Volume : 16  |  Issue : 1  |  Page : 102-104

Does hypoglycemia cause cardiovascular events?


Department of Cardiology, Christian Medical College and Hospital, Ludhiana, Punjab, India

Date of Web Publication26-Dec-2011

Correspondence Address:
Sandeep Chopra
Department of Cardiology, Christian Medical College and Hospital, Ludhiana, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2230-8210.91203

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   Abstract 

Hypoglycemia is a very common side effect of insulin therapy and, to a lesser extent, of treatment with oral hypoglycemic agents. Severe hypoglycemia can precipitate adverse cardiovascular outcomes such as myocardial ischemia and cardiac arrhythmia. These are mainly secondary to autonomic activation which results in hemodynamic changes, vasoconstriction and rise in intravascular coagulability and viscosity.

Keywords: Cardiac arrhythmia, hypoglycemia, myocardial ischemia


How to cite this article:
Chopra S, Kewal A. Does hypoglycemia cause cardiovascular events?. Indian J Endocr Metab 2012;16:102-4

How to cite this URL:
Chopra S, Kewal A. Does hypoglycemia cause cardiovascular events?. Indian J Endocr Metab [serial online] 2012 [cited 2019 Dec 12];16:102-4. Available from: http://www.ijem.in/text.asp?2012/16/1/102/91203


   Introduction Top


Diabetes is a major risk factor for cardiovascular disease. [1] Patients with coronary artery disease (CAD) and diabetes have higher mortality and morbidity than patients without diabetes. Data from studies such as the UK Prospective Diabetes Study suggest that very good glycemic control is associated with fewer cardiovascular events. [2] However, tight glycemic control may increase the risk of hypoglycemia.

Hypoglycemia is a very common side effect of insulin therapy and, to a lesser extent, of treatment with sulfonylureas. Risk factors for severe hypoglycemia include age, duration of diabetes, strict glycemic control, sleep, impaired awareness of hypoglycemia, renal impairment, C-peptide negativity and previous history of severe hypoglycemia. [3],[4]

Acute hypoglycemia provokes pronounced physiological responses, the important consequences of which are to maintain the supply of glucose to brain and promote hepatic production of glucose. Blood flow is increased to the myocardium, splanchnic circulation and the brain. Hypoglycemia and the rapid changes in blood glucose have been shown to increase counter-regulatory hormones such as epinephrine and nor-epinephrine, which may induce vasoconstriction and platelet aggregation, thereby precipitating myocardial ischemia. [5],[6] Autonomic activation, principally of the sympatho-adrenal system, results in end-organ stimulation and the profuse release of epinephrine which precipitates hemodynamic changes like tachycardia, increased peripheral systolic blood pressure, decreased central blood pressure and increased myocardial contractility with an increased ejection fraction. [7],[8] The increased activity of sympathetic nervous system and secretion of other hormones and peptides such as the potent vasoconstrictor endothelin have pronounced effects on intravascular coagulability and viscosity. [9] Increased plasma viscosity occurs during hypoglycemia because of an increase in erythrocyte concentration, while coagulation is promoted by platelet activation and an increment in factor VIII and von-Willebrand factor. Endothelial functions may be compromised during hypoglycemia because of an increase in C-reactive protein, mobilization and activation of neutrophils and platelet activation.

The catecholamine-induced increased myocardial contractility may induce ischemia in the myocardium in patients with CAD. The greater oxygen demand is not met because of not only the rigid vessels, but also endothelial dysfunction with failure to vasodilate.

Several studies have shown that the hypoglycemia is associated with a significant lengthening of the corrected QT interval (QT C ) in subjects with and without diabetes. [10],[11] These changes are likely seen because of increased catecholamine release during hypoglycemia, and QT C prolongation, in particular, could lead to a high risk of ventricular tachycardia and sudden death. [12] Hyperinsulinemia and increased secretion of catecholamines may lead to hypokalemia during hypoglycemia, thus potentiating cardiac repolarizing abnormalities. These effects can be reversed by β-blockade and potassium replacements.[12]

Cardiovascular autonomic neuropathy or impairment is associated with increased mortality. Effects of antecedent hypoglycemia on cardiac autonomic regulation may contribute to the occurrence of adverse cardiac events. Abnormalities in high-frequency and low-frequency heart rate variability have been associated with hypoglycemia and increased catecholamine release. [13] However, other studies did not find any associations between heart rate variability, hypoglycemia and increased catecholamine release. [10]

Inflammation has been associated with cardiovascular disease and diabetes. Episodes of hypoglycemia have been found to be associated with rise in inflammatory cytokines including interleukin (IL)-6, IL-8, tumor necrosis factor (TNF)-α, C-reactive protein and endothelin-1.[14] These inflammatory cytokines result in endothelial injury and abnormalities in coagulation, resulting in rise of cardiovascular events. Inflammatory cytokines like IL-1 have also been shown to increase the severity of hypoglycemia, thus perpetuating a positive feedback cycle. [15] Studies have suggested that endothelial function may be compromised during acute hypoglycemia. Vessel wall stiffness was found to be increased during hypoglycemia in patients with type-1 diabetes of longer duration than those with shorter duration of diabetes. [16] Thus, hypoglycemia may increase the risk of cardiovascular events, especially in subsets of patients with longer duration of diabetes. Inflammation and endothelial dysfunction could potentially be the aggravating factors that contribute to increased cardiovascular risk with severe hypoglycemia, especially in the subset of patients with pre-existing cardiovascular disease, diabetes, and severe autonomic neuropathy.

A direct relationship between hypoglycemia and fatal cardiovascular event is difficult to demonstrate as blood glucose and cardiac monitoring are seldom performed simultaneously. In the ACCORD study, excess of deaths was noted in the intensive treatment arm, which led to discontinuation of study. [17] In the smaller study of veterans with type-2 diabetes, Veterans Affairs Diabetes Trial (VADT), [18] severe hypoglycemia was found to increase the risk of adverse events and deaths. There have been multiple case reports associating angina with hypoglycemia. [19] ECG changes, including ectopic activity, flattening of T-wave, ST depression, ventricular tachycardia, and atrial fibrillation, have been reported in cases of low plasma glucose. [20]

Sudden death during sleep has been described in patients with type-1 diabetes, the mechanism being a significant cardiac arrhythmia induced by nocturnal hypoglycemia. [21] Many of these patients have no evidence of severe hypoglycemia-induced neuronal damage at autopsy, implying that a cardiac arrhythmia had been triggered by hypoglycemia, resulting in sudden death. Despite the high frequency of nocturnal hypoglycemia in young patients with type-1 diabetes, sudden nocturnal death ("dead in bed" syndrome) is rare.

Evidence is accumulating that severe hypoglycemia can provoke adverse cardiovascular outcomes such as myocardial ischemia or cardiac arrhythmia. Episodes of severe hypoglycemia are common during intensive therapy in type-1 and type-2 diabetes in the out-patient as well as in-patient setting. Larger clinical trials are required to look specifically at the association between hypoglycemia and cardiovascular events and to determine the mechanism further. The challenge to the physicians is to lower blood glucose to normal values to decrease the risk for long-term complications and at the same time minimize hypoglycemia and hypoglycemia-associated morbidity and mortality.

 
   References Top

1.Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Diabetologia 2001;44 Suppl 2:S14-21.  Back to cited text no. 1
    
2.United Kingdom Prospective Diabetes Study Group. United Kingdom Diabetes Study 24: A 6-year, randomized,controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Intern Med 1998;128:165-75.  Back to cited text no. 2
    
3.Mühlhauser I, Overmann H, Bender R, Bott U, Berger M. Risk factors of severe hypoglycaemia in adult patients with type 1 diabetes: A prospective population based study. Diabetologia 1998;41:1274-82.  Back to cited text no. 3
    
4.Strachan MW. Frequency, causes and risk factors for hypoglycaemia in type 1 diabetes. In: Frier BM, Fisher M, editors. Hypoglycaemia in Clinical Diabetes. 2 nd ed. Chichester: John Wiley and Sons; 2007. p. 49-81.  Back to cited text no. 4
    
5.DeFronzo RA, Hendler R, Christensen N. Stimulation of counterregulatory hormonal responses in diabetic man by a fall in glucose concentration. Diabetes 1980;29:125-31.  Back to cited text no. 5
    
6.Galassetti P, Davis SN. Effects of insulin per se on neuroendocrine and metabolic counter-regulatory responses to hypoglycaemia. Clin Sci (Lond) 2000;99:351-62.  Back to cited text no. 6
    
7.Hilsted J, Bonde-Petersen F, Norgaard MB, Grreniman M, Christsen NJ, Parving HH, et al. Haemodynamic changes in insulin-induced hypoglycaemia in normal man. Diabetologia 1984;26:328-32.  Back to cited text no. 7
    
8.Fisher BM, Gillen G, Hepburn DA, Dargie HJ, Frier BM. Cardiac responses to acute insulin-induced hypoglycemia in humans. Am J Physiol Heart Circ Physiol 1990;258:1775-9.  Back to cited text no. 8
    
9.Wright RJ, Frier BM. Vascular disease and diabetes: Is hypoglycaemia an aggravating factor? Diabetes Metab Res Rev 2008;24:353-63.  Back to cited text no. 9
    
10.Laitinen T, Lyyra-Laitinen T, Huopio H, Vauhkonen I, Halonen T, Hartikainen J, et al. Electrocardiographic alterations during hyperinsulinemic hypoglycemia in healthy subjects. Ann Noninvasive Electrocardiol 2008;13:97-105.  Back to cited text no. 10
    
11.Gill GV, Woodward A, Casson IF, Weston PJ. Cardiac arrhythmia and nocturnal hypoglycaemia in type 1 diabetes: The 'dead in bed' syndrome revisited. Diabetologia 2009;52:42-5.  Back to cited text no. 11
    
12.Robinson RT, Harris ND, Ireland RH, Lee S, Newman C, Heller SR. Mechanisms of abnormal cardiac repolarization during insulin-induced hypoglycemia. Diabetes 2003;52:1469-74.  Back to cited text no. 12
    
13.Vlcek M, Radikova Z, Penesova A, Kvetnansky R, Imrich R. Heart rate variability and catecholamines during hypoglycemia and orthostasis. Auton Neurosci 2008;143:53-7.  Back to cited text no. 13
    
14.Galloway PJ, Thomson GA, Fisher BM, Semple CG. Insulin-inducedhypoglycemia induces a rise in C-reactive protein. Diabetes Care 2000;23:861-2.  Back to cited text no. 14
    
15.Fisher BM, Hepburn DA, Smith JG, Frier BM. Responses of peripheral blood cells to acute insulin-induced hypoglycaemia in humans: Effect of alpha-adrenergic blockade. Horm Metab Res Suppl 1992;26:109-10.   Back to cited text no. 15
    
16.Sommerfield AJ, Wilkinson IB, Webb DJ, Frier BM. Vessel wall stiffness in type 1 diabetes and the central hemodynamic effects of acute hypoglycemia. Am J Physiol Endocrinol Metab 2007;293:E1274-9.  Back to cited text no. 16
    
17.ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.  Back to cited text no. 17
    
18.Duckworth W, Abraira C, Moritz T, Redad D, Emmanuele M, Reaven PD, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360:129-39.  Back to cited text no. 18
    
19.Kamijo Y, Soma K, Aoyama N, Fukuda N, Ohwada T. Myocardial infarction with acute insulin poisoning: A case report. Angiology 2000;51:689-93.  Back to cited text no. 19
    
20.Galizia AC, Fava S, Foale R. Nesidioblastosis-associated hypoglycaemia presenting with prominent cardiac manifestations. Postgrad Med J 1996;72:231-2.  Back to cited text no. 20
    
21.Tattersall RB, Gill GV. Unexplained deaths of type 1 diabetic patients. Diabet Med 1991;8:49-58.  Back to cited text no. 21
    



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