The Role of Hypoglycemia

Hypoglycemia is a well-recognized side effect of glucoselowering therapies in patients with diabetes mellitus. The incidence of mild self-reported hypoglycemic episodes in patients with type 1 diabetes mellitus is approximately 30 episodes per patient per year, whereas the incidence of severe hypoglycemic episodes (ie, those that require third-party assistance) may be as high as 3.2 episodes per patient per year.1–3 Hypoglycemic episodes occur much less frequently in patients with type 2 diabetes mellitus, in whom the incidence of mild and severe hypoglycemic episodes is 2 to 10 per patient per year and 0.1 to 0.7 per patient per year, respectively.2 When patients are alerted to the occurrence of a hypoglycemic episode by symptoms such as tremor, diaphoresis, tachycardia, malaise, hunger, and anxiety, they can abort these episodes by consuming carbohydrates. However, if hypoglycemic episodes occur rapidly or are unrecognized and untreated, the resulting neuroglycopenia may cause confusion, seizures, accidents, angina, and, rarely, death or permanent cognitive impairment.3,4 Patients who experience frequent episodes of hypoglycemia are especially at risk of having unrecognized hypoglycemic episodes (and their sequelae), because their counterregulatory response to hypoglycemia becomes blunted. Indeed, the rare occurrence of sudden death during sleep in young patients with type 1 diabetes mellitus (the so-called dead-in-bed syndrome) has been attributed to hypoglycemia, although this cause is seldom proven.5–7 It is well known that hypoglycemic episodes are associated with a surge of sympathetic activity and a release of catecholamines.8–10 These observations have supported the suggestion that the tachycardia and the rise in blood pressure observed during a hypoglycemic episode might destabilize an atherosclerotic plaque.11 These hemodynamic changes, the increased myocardial work, and hypoglycemia-induced increases in platelet aggregation, platelet activity,12–14 and hematocrit15,16 may precipitate cardiac and cerebral ischemic events in patients at high risk of cardiovascular disease.17 Support for this possibility comes from a number of small studies and case reports. For example, continuous glucose and ECG monitoring in 19 patients with coronary artery disease and type 2 diabetes mellitus18 revealed a higher frequency of ischemic ECG changes when glucose levels fell below 3.9 mmol/L (70 mg/dL). A similar study in 24 patients with type 1 diabetes mellitus19 revealed a nocturnal increase in the corrected QT interval and some minor rhythm disturbances when nocturnal glucose levels fell below 3.5 mmol/L (63 mg/dL) that were not observed when nocturnal glucose levels were 5 mmol/L (90 mg/dL). Experimentally induced hypoglycemia prolonged the corrected QT interval and reduced potassium levels in healthy adults10 and in people with type 1 and type 2 diabetes mellitus.20,21 Finally, case reports have shown a relationship between ischemic cerebral changes and concurrent severe hypoglycemia in patients presenting with neurological deficits22,23 and between arrhythmias and concurrent low blood glucose levels that responded to glucose administration.24,25 These considerations clearly provide the basis for concerns that hypoglycemic episodes may promote cardiovascular events (myocardial infarction [MI], stroke, and cardiovascular death) and death. These concerns are magnified by the fact that hospitalized and ambulatory individuals with diabetes may have concomitant renal disease, liver disease, weight loss, or other conditions that increase the likelihood of having a hypoglycemic episode and that are themselves risk factors for serious health outcomes. If hypoglycemic episodes precipitate (rather than are simply associated with) cardiovascular events and death, then epidemiological studies would identify hypoglycemia as an independent risk factor for serious cardiovascular outcomes, and interventions that increase the risk of hypoglycemia might increase the risk of these outcomes. The recent publication of several large randomized trials and epidemiological studies that were restricted to people with diabetes and that collected and reported data regarding both hypoglycemia and serious outcomes provides an opportunity to examine this possibility. These studies are reviewed and summarized below so as to address the following questions: