Severe Hypoglycemia and Cardiovascular Disease in Type 2 Diabetes

Corresponding author: Hyeong Kyu Park Department of Internal Medicine, Soonchunhyang University Hospital, Soonchunhyang University College of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea E-mail: [email protected] Cardiovascular disease (CVD) is the main cause of morbidity and mortality in subjects with diabetes mellitus (DM). Strict glycemic control has been shown to reduce the risk of microvascular complications of DM, but its effects on the risk of CVD appear less conclusive. Recent large randomized trials have demonstrated that intensive glycemic control failed to show significant benefits on the macrovascular outcomes. In particular, the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study has shown that participants in intensive therapy had 22% higher mortality with 3-fold higher incidence of severe hypoglycemia than those in standard therapy, suggesting a possible association between hypoglycemia and increased mortality [1]. However, the post hoc analysis of ACCORD study suggested that the high mortality in the intensive treatment group was not directly explained by higher rate of hypoglycemia [2]. In contrast, a retrospective analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) study has shown that severe hypoglycemia is strongly associated with an increased risk of macrovascular events, presenting hypoglycemia as a possible cause for adverse cardiovascular events and deaths [3]. Furthermore, several epidemiologic studies have demonstrated that symptomatic or severe hypoglycemia is associated with an increased risk of cardiovascular events and mortality in patients with type 2 diabetes mellitus (T2DM) [4,5]. Hypoglycemia occurs commonly during the treatment of DM and is also a major hurdle to attaining better glycemic control. Experience of hypoglycemic episodes can discourage subjects with DM from achieving their glycemic goals, breaking patient’s will to keep optimal glycemic control. Among the categories of hypoglycemia, severe hypoglycemia is generally defined as an event that requires the assistance of another person to overcome hypoglycemia, posing a serious health problem in subjects with DM [6]. As discussed earlier, hypoglycemia appears to be associated with adverse cardiovascular events and deaths in large clinical trials and several epidemiologic studies, even though no direct evidence of causal relationship between hypoglycemia and increased cardiovascular mortality has been found in patients with DM until now. There are potential mechanisms by which acute hypoglycemia may increase cardiovascular events and deaths. Acute hypoglycemia induces sympathoadrenal activation, endothelial dysfunction, vasoconstriction, prolongation of QT interval, enhanced inflammation, and increased thrombogenesis [7-9]. All of these physiological changes may trigger myocardial ischemia and cardiac arrhythmia in patients with DM, which could cause adverse cardiovascular events and deaths (Fig. 1). The major causes of hypoglycemic episodes in patients with T2DM are changes related to diet, exercise, or glucose-lowering medications. In addition, clinical factors that predispose to hypoglycemia include advanced age, polypharmacy, low education level, poor cognitive function, intensive glycemic control, longer duration of DM, and longer duration of insulin therapy. Peripheral or autonomic neuropathy is also associated with hypoglycemia [10]. In particular, hypoglycemia unawareness or a Editorial Complications