Intensive glycemic control may increase cardiovascular (CV) risk and mortality due to hypoglycemia. The pathophysiology of glucose counter-regulation in patients with type 1 or type 2 diabetes for over 15 years is characterized by impairment of the defense mechanisms against hypoglycemia. Hypoglycemia causes pronounced physiological and pathophysiological effects on the CV system as consequences of autonomic system activation and counter regulatory hormones release. These effects provoke a series of hemodynamic changes that include an increase in heart rate and peripheral systolic blood pressure, a decrease in central blood pressure, reduced peripheral arterial resistance, and increased myocardial contractility and cardiac output. Cardiac electrophysiological changes including flattening or inversion of T waves, QT prolongation, and ST segment depression were observed in both insulin-induced and spontaneous hypoglycemia. Sympathoadrenal activation is the main cause of these changes through mechanisms that involve, but are not limited to, catecholamine-mediated hypokalemia. Hypoglycemia is also involved in platelet activation. There is growing concern about the long-term effects of hypoglycemia, especially as related to inflammation and atherogenesis.