The rising prevalence of type 2 diabetes mellitus (T2DM) has increased the global burden of diabetic complications, morbidity, mortality, and healthcare costs. Achieving optimal glycemic control with glucose-lowering agents and lifestyle modification are the only effective means to prevent or minimize diabetes-related complications in patients with T2DM [1]. However, patients may find it difficult to maintain a healthy lifestyle and adhere to pharmacological treatment over a lifetime. Moreover, T2DM is a chronic metabolic disease with progressive deterioration of the beta-cell reserve, and many patients eventually require insulin treatment [2]. Furthermore, as the proportion of older people with multiple morbidities and polypharmacy increases, intensive glycemic control with insulin in those with long-standing, advanced T2DM (i.e., absolute endogenous insulin deficiency) increases the risk of hypoglycemia [2–4].

Hypoglycemia is a major barrier to achieving optimal glycemic control in patients with T2DM. Treatment-induced hypoglycemia is associated with an increased risk of cardiovascular (CV) events and all-cause mortality in patients with type 1 diabetes mellitus (T1DM) and T2DM [5]. Moreover, hypoglycemia has a negative impact on emotional well-being, cognitive function, and quality of life, particularly in patients with severe hypoglycemia (SH), which negates the benefits of strict glycemic control. Hypoglycemic events incur substantial economic and psychosocial costs for patients, their family members, and society [6].

Prevention is recognized as the most effective strategy for the management of hypoglycemia in patients with T2DM. Therefore, an understanding of adverse CV outcomes related to SH and screening for patients with T2DM at high risk for SH are of particular importance.

The American Diabetes Association and Endocrine Society (ADA/ES) workgroup on hypoglycemia defined hypoglycemia in diabetes as all episodes of abnormally low plasma glucose concentrations that expose the individual to potential harm [7]. Hypoglycemia may be a frequent outcome of glucose-lowering treatments, particularly insulin and insulin secretagogues. In contrast to the diagnosis of clinical hypoglycemia, which is based on Whipple’s triad (symptoms consistent with hypoglycemia, a low plasma glucose concentration, and the resolution of symptoms after the plasma glucose concentration is raised to normal), the presence of relevant symptoms and signs is not a prerequisite for the diagnosis of diabetic hypoglycemia because episodes may be asymptomatic, in which individuals are unaware of low blood glucose levels. The ADA/ES workgroup recommended that a plasma glucose concentration ≤ 70 mg/dL serve as an alert for the possibility of a hypoglycemic event in patients at risk of hypoglycemia. This value is data driven and approximates the glycemic threshold for activation of physiological glucose counterregulatory systems in nondiabetic individuals. The ADA/ES adapted the three-level iatrogenic hypoglycemia in diabetes clinical classification proposed by the International Hypoglycemia Study Group (Table 1) [8]. Although the overall incidence of hypoglycemia is higher in patients with T1DM than in those with T2DM, given that the prevalence of T2DM is approximately 20-fold greater than that of T1DM and many patients with long-standing T2DM ultimately require insulin treatment, most episodes of iatrogenic hypoglycemia occur in patients with T2DM [9–12].

Because the symptoms and signs of hypoglycemia can be nonspecific, patients may not be aware of a hypoglycemic event, or mild episodes that are self-treated may not be remembered or reported. In contrast, although SH represents a small fraction of the total hypoglycemic burden, estimates of the frequency of SH are more reliable because they are dramatic events that are difficult to ignore and are more likely to be reported.

SH not only affects quality of life and healthcare costs it also directly contributes to mortality Although profound neuroglycopenia can cause fatal brain injury, the condition is rare; thus, more attention has been focused on the causal association between hypoglycemia and cardiac dysfunction. SH is a strong predictor of major CV events and mortality in patients with T2DM [13–16], although it is unclear whether this is due to a direct pathophysiological association or whether SH acts as a marker of vulnerability to CV events. Accumulating observational evidence indicates that several CV events occur during SH either as a result of hypoglycemia itself or via activation of the sympathoadrenal response. Several underlying pathophysiological processes have been proposed including (1) hemodynamic changes that increase cardiac workload and attenuate myocardial perfusion; (2) arrhythmogenic electrophysiological changes; (3) the induction of a prothrombotic state; and (4) the release of inflammatory cytokines [17]. Ultimately, it is likely that multiple factors contribute to CV events, which can be triggered by SH in high-risk patients.

Evidence suggests that SH can cause myocardial ischemia. The autonomic nervous system is activated as part of the counterregulatory response to a hypoglycemic episode. Sympathoadrenal activation, which stimulates plasma catecholamine secretion, has profound CV effects including decreased parasympathetic activity. A hypoglycemic clamp study (plasma glucose 54 mg/dL) in nondiabetic subjects found that a surge in plasma epinephrine was associated with increased heart rate and stroke volume and decreased peripheral vascular resistance, resulting in an increase in cardiac output and a fall in central arterial pressure [18–20]. Such hemodynamic responses to SH may be detrimental to patients with long-duration diabetes and underlying heart disease [21,22].

Of further clinical significance is the finding that hypoglycemia can induce cardiac arrhythmias, which may cause sudden death [23–25]. The arrhythmogenic effect of hypoglycemia may act through several mechanisms: a low blood glucose concentration has a direct effect on ion channels, and catecholamines induce hypokalemia and action potential/QT prolongation, which increases the risk of ventricular arrhythmias and sudden death [26–28]. A previous study of lethal hypoglycemia in rats revealed disturbances of cardiac electrical stability. SH initially induced sinus tachycardia, QT prolongation, and atrial fibrillation (AF) followed by ventricular tachycardia, atrioventricular blockade, and eventual bradycardia and cardiorespiratory arrest [29].

The prothrombotic and proinflammatory effects of hypoglycemia may be associated with CV events. Hormones, including catecholamines, released during hypoglycemia increase blood viscosity and promote platelet aggregation and activation [22,30–32]. Furthermore, insulin-induced hypoglycemia has been shown to increase coagulation factors and promote the release of inflammatory cytokines, which may remain elevated for several days after hypoglycemia is corrected [31–35]. These proinflammatory and procoagulant effects together with endothelial dysfunction can directly affect vascular flow for some time after a hypoglycemic episode and may contribute to the development of CV events.

Despite the suggestion of a causal relationship between SH and CV events reported by mechanistic studies, evidence from large prospective studies is limited. A causal relationship between SH and CV events is supported by the findings of the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE), the Action to Control Cardiovascular Risk in Diabetes (ACCORD), and the Outcome Reduction With Initial Glargine Intervention (ORIGIN) studies, all of which found higher rates of hypoglycemia-related mortality in the intensive treatment arm than in the standard treatment arm [15,16,36]. However, the association between SH and CV events is strongest in patients at high CV risk Currently available evidence suggests that SH can trigger CV events in vulnerable patients with high CV risk; therefore, hypoglycemia should be avoided in patients with known cardiovascular disease (CVD) [37].

Healthcare professionals who treat patients with T2DM in the clinical setting should be aware of the potential detrimental effects of hypoglycemia on prognosis, major CV events, and mortality. Based on accurate assessment of SH risk, immediate intervention should be considered for patients deemed high risk, including setting a less stringent glycated hemoglobin target, modifying antidiabetic management, increasing self-monitoring of plasma glucose levels, adopting lifestyle modification practices and regular mealtimes, and SH education. Of these interventions, we believe that intensive individualized education is the most fundamental and effective way to prevent SH. Therefore, it is reasonable to devote considerable attention and medical resources to education for patients with T2DM at high risk of SH. Moreover, with technological advances, the availability of continuous glucose monitoring systems (CGMS) has increased. Wider use of CGMS will improve understanding of blood glucose patterns and glucose management; moreover, CGMS provide a more precise measurement of blood glucose levels than self-monitoring. Therefore, accurate CGMS data will allow the development of more individualized and tailored SH prevention education programs.