Diabetes is at epidemic proportions in the U.S. Patients with diabetes are at increased risk for micro- and macrovascular complications. The benefit of glycemic control in decreasing the risk for microvascular disease is well established. However, the role of glycemic control in decreasing macrovascular complications has been controversial. Several large clinical trials looking at this issue have either shown no benefit or even potential harm. The possibility of hypoglycemia as a risk factor for cardiovascular events is a topic of much debate. In this review article, we discuss the evidence for and against this hypothesis and the possible mechanisms that might be involved. Patients with diabetes have an increased risk of cardiovascular disease. The link between glycemic control and microvascular complications has been firmly established (1,2). However, the association between glycemic control and macrovascular disease is mainly obtained from epidemiological studies, and intensive glucose control has often failed to reduce macrovascular events. Intensive glucose control invariably increases the risk of hypoglycemia and sometimes the severity of hypoglycemia (2) Several epidemiological studies and smaller prospective studies have linked hypoglycemia to increased cardiovascular risk (3⇓–5). Recent large randomized trials looking at intensive glycemic control have either shown no benefit (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation [ADVANCE] and Veterans Affairs Diabetes Trial [VADT]) or increased all cause mortality (Action to Control Cardiovascular Risk in Diabetes [ACCORD]) (6). While the reason for the increased mortality is unclear and hypoglycemia has not been implicated as a cause of death, these studies have increased the debate about the degree of glycemic control required to decrease diabetes complications and the role of hypoglycemia in cardiovascular morbidity and mortality. The modern definition of hypoglycemia is plasma glucose <70 mg/dl (7⇓–9). At plasma glucose …