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 .
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 .
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 .
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 .
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 .
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 . 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 ( qtc ) in subjects with and without diabetes .
these changes are likely seen because of increased catecholamine release during hypoglycemia , and qtc prolongation , in particular , could lead to a high risk of ventricular tachycardia and sudden death .
hyperinsulinemia and increased secretion of catecholamines may lead to hypokalemia during hypoglycemia , thus potentiating cardiac repolarizing abnormalities .
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 .
however , other studies did not find any associations between heart rate variability , hypoglycemia and increased catecholamine release .
episodes of hypoglycemia have been found to be associated with rise in inflammatory cytokines including interleukin ( il)-6 , il-8 , tumor necrosis factor ( tnf)- , c - reactive protein and endothelin-1 .
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 .
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 .
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 . in the smaller study of veterans with type-2 diabetes , veterans affairs diabetes trial ( vadt ) ,
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 .
sudden death during sleep has been described in patients with type-1 diabetes , the mechanism being a significant cardiac arrhythmia induced by nocturnal hypoglycemia .
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 .
 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 . 