Even Silent Hypoglycemia Induces Cardiac Arrhythmias

While many studies have shown that intensive glycemic control can prevent the microvascular complications of diabetes, the benefits of intensive glycemic control in preventing macrovascular complications, including heart attacks, strokes, and overall mortality, have been less clear. Intensive glycemic control almost always increases the frequency and severity of hypoglycemic episodes. What remains unclear is whether hypoglycemia directly contributes to, or is merely associated with, the increased mortality noted in recent large trials (e.g., Normoglycaemia in Intensive Care Evaluation and Survival Using Glucose Algorithm Regulation [NICE-SUGAR], Control of Hyperglycaemia in Paediatric intensive care [CHiP], Action to Control Cardiovascular Risk in Diabetes [ACCORD]) (1–3). In the intensive care setting, noniatrogenic hypoglycemia serves as a harbinger of mortality, but it is unlikely to be a direct cause of mortality (4). By contrast, in the outpatient setting, insulin-induced hypoglycemia can be lethal. Among people with diabetes, the mortality rate due to hypoglycemia has been reported to be as high as 10% (5). Indeed, insulin-induced hypoglycemia has been considered responsible for nocturnal deaths in diabetic patients (6), and has been documented to be associated with the “dead-in-bed” syndrome (7). Therefore in the outpatient setting, the microvascular benefits of intensive glycemic control in people with diabetes have to be weighed against the apparent increased mortality associated with iatrogenic hypoglycemia. The mechanism(s) by which hypoglycemia may increase mortality remains unknown. In patients with cardiac disease, hypoglycemia has been associated with ischemic chest pain (8). Hypoglycemia also increases markers of thrombosis and inflammation, potentially increasing the risk of acute thrombotic events or accelerating development of atherosclerosis (9). Although hypoglycemia-associated fatal cardiac arrhythmias are understandably difficult to document, arrhythmic deaths were reported as a direct cause of mortality in the NICE-SUGAR trial (4). Furthermore, severe hypoglycemia was noted to increase the risk of arrhythmic death by 77% in the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial (9). Whether contributing to the development of coronary artery disease or acutely inducing an ischemic or arrhythmic event, the nature and magnitude of the contribution of hypoglycemia to mortality in diabetes is unknown and almost certainly underestimated. Iatrogenic hypoglycemia changes cardiac repolarization and induces arrhythmias in people with type 1 and type 2 diabetes (10–15). Recently, animal studies have highlighted examination of cardiac events during very severe hypoglycemia (10–15 mg/dL). Supporting the available clinical data, these animal studies demonstrated that if hypoglycemia is severe enough, cardiac arrhythmias (induced by the counterregulatory sympathoadrenal response) can be lethal (16). Unfortunately, there are few data examining hypoglycemia-induced arrhythmias among patients in the outpatient setting, making these findings difficult to translate to real-world situations. In this issue, Chow et al. (17) address the question of hypoglycemia-induced arrhythmias in an observational study of patients with type 2 diabetes by simultaneously equipping subjects with outpatient Holter monitors and continuous interstitial glucose monitors (CGM). All patients had insulin-treated type 2 diabetes and a history of either cardiovascular disease or two cardiovascular risk factors. The CGM recordings showed that hypoglycemia (#63 mg/dL) was common, occurring 6% of the time. The authors also observed that hypoglycemia was associated with possible ischemic changes (T-wave flattening), repolarization defects (increased QT intervals corrected for heart rate), and various cardiac arrhythmias, suggesting that these events could be interconnected. Like another CGM study (18), the vast majority of hypoglycemic episodes were asymptomatic and occurred at night. The authors’ most striking data were the eightfold increase in bradycardia and fourfold increase in atrial ectopy during