Intensive insulin therapy in the intensive care unit, hypoglycemia, and cardiovascular mortality

Several studies have shown that elevated glucose concentrations in patients with acute coronary syndrome and other acute severe illnesses are associated with increased short- and long-term all-cause and cardiovascular mortality (CVM). This has subsequently led to the use of intensive insulin therapy (IIT) to control hyperglycemia. Earlier studies have shown that the prevention of hyperglycemia in acute illness through the use of IIT reduces mortality. More recent studies have failed to confirm this benefit, and in some cases IIT was associated with increased all-cause mortality. The reason for these discrepant results is not clear, although accumulating evidence suggests that the higher prevalence of insulin-induced hypoglycemia associated with IIT may be responsible. This has led to the development of guidelines from the American Heart Association and American Diabetes Association, which recommend IIT for in-patient control of hyperglycemia but also add the caveat that "care should be taken to avoid hypoglycemia." Despite this advice, however, the rates of hypoglycemia in patients receiving IIT continue to be as high as 19%. Although the physiological basis for this "paradox" is unclear, hypoglycemia is considered to be a putative cause. A strong association between hypoglycemia and adverse cardiovascular events has been observed in several studies. This article will encompass the various studies that have used IIT to treat patients during acute illnesses. Furthermore, it will aim to provide a mechanistic basis for the observed association between hypoglycemia and CVM.