Hypoglycemia is a common metabolic emergency representing an imbalance in the energy demands of the brain and the available glucose supply despite normal arterial oxygen tension.¹,² This imbalance results in autonomic symptoms (e.g., anxiety, sweating, and tremulousness) and neurologic symptoms (e.g., weakness, fatigue, and mental confusion).¹,³ Approximately 7% of patients presenting to the emergency department (ED) with complaints of altered mental status have hypoglycemia, and 20% of patients with diabetes mellitus (DM) treated with insulin or anti-diabetic agents (ADAs) will have symptoms related to hypoglycemia requiring ED evaluation and treatment.⁴ Severe hypoglycemia, if unrecognized and untreated, can result in neural damage, impaired cognitive function, coma, seizures, or death.^4-7 Single and recurrent episodes of hypoglycemia may cause physical and psychological morbidity and increase the risk of death, but may also prevent euglycemia.⁸ Risk factors placing diabetic patients at greater risk for developing hypoglycemia include male gender, adolescence or age > 55, increased amounts of exercise or activity, decreased carbohydrate intake, alcohol consumption, impaired renal or liver function, intensive glucose control, changes in insulin or ADA regimen, infection, significant comorbidities, and polypharmacy.²,⁹,¹⁰

Patients with severe hypoglycemia and who are at risk for recurrent hypoglycemia should be admitted, while those with a rapidly normalized glucose level and not at risk may not require admission. The purpose of this study is to identify risk factors for recurrent hypoglycemia in diabetic patients hospitalized for severe hypoglycemia.

We identified 504 patients presenting to the ED with severe hypoglycemia during the study period. Of these, 244 patients were hospitalized (Fig. 1). The remaining 260 patients' medical records were also examined and none of those patients were readmitted to the ED for hypoglycemia. Eleven patients did not have type 2 DM or incomplete information and were excluded from analysis. Of the remaining 233 study patients (92 males and 141 females; mean age, 74.1 ? 9.8 years), 74 (31.8%) were categorized as recurrent hypoglycemia and 159 (68.2%) were categorized as non-recurrent hypoglycemia. All patients studied were diagnosed as type 2 DM.

Table 1 presents the comparison of the basic characteristics and laboratory results for the two study groups. There were significant differences of loss of a recent meal, duration of diabetes, duration of hospital stay, initial serum glucose level, WBC, hemoglobin, estimated GFR, serum creatinine, BUN, and albumin among the two groups (p < 0.05). The recurrent hypoglycemia group had a higher percentage of patients (59.5%) with loss of a recent meal (p < 0.001). Patients in the recurrent hypoglycemia group had a significantly longer duration of diabetes and hospital stays than the non-recurrent group. WBC, serum creatinine, and BUN were significantly higher in the recurrent hypoglycemia group as compared to the non-recurrent group. Initial serum glucose level, estimated GFR, and albumin were significantly lower in the recurrent hypoglycemia group as compared to the non-recurrent group.

Table 2 presents the medications and comorbidities data. The recurrent hypoglycemia group had significantly higher percentages of patients taking benzodiazepines, alpha-blocker agents, beta-blocker agents, diuretics, and polypharmacy as compared to the non-recurrent group; however, the recurrent hypoglycemia group had a significantly lower percentage of CCBs compared to the non-recurrent group (21.6% vs. 36.1%, p = 0.033). When examining comorbidities, the recurrent hypoglycemia group was found to have a significantly higher prevalence of CAD (60.8%) and infection (47.3%) as compared to the non-recurrent group. There was no statistical significance regarding the different types of oral anti-diabetic medications between the two groups.

Univariate logistic regression analysis for possible risk factors associated with recurrent hypoglycemia for the 233 subjects are presented in Table 3. Significant risk factors for the development of recurrent hypoglycemia were loss of a recent meal, duration of diabetes, initial serum glucose level, WBC count, hemoglobin, estimated GFR, serum creatinine, BUN, albumin, the use of benzodiazepines, alpha-blocker agents, beta-blocker agents, and diuretics, polypharmacy, and the presence of CAD and infection. The use of CCBs showed a protective effect.

After controlling for age and gender, as shown in Table 4, multivariate logistic regression analysis found that patients with loss of a recent meal (OR = 3.93; 95% CI, 1.82-8.50; p < 0.001), who had CAD (OR = 2.30; 95% CI, 1.04-5.10; p = 0.041) or infection (OR = 2.97; 95% CI, 1.08-6.30; p = 0.032), or who had a renal insufficiency (lower estimated GFR) (OR = 0.97; 95% CI, 0.95-0.98; p < 0.001) were at risk for recurrent hypoglycemia. The use of CCBs (OR = 0.19; 95% CI, 0.08-0.46; p < 0.001) was a protective factor the development of recurrent hypoglycemia.

The purpose of this study is to identify risk factors for recurrent hypoglycemia in diabetic patients hospitalized for severe hypoglycemia. Our study suggests that there is a subset of patients, presenting to the ED with severe hypoglycemia and certain risk factors, who should be admitted due to a greater risk of recurrent hypoglycemia.

About two-thirds of patients with diabetes who were admitted to the hospital due to a hypoglycemic coma did not develope recurrent hypoglycemia. Previous studies have focused on patients treated in the ED who then return for recurrent hypoglycemia. In these studies, the accumulated recurrent hypoglycemia rates has been described as 6.1% by Socransky, et al.,⁶ 9% by Mechem, et al.,¹⁴ and 10.14% by Carter, et al.¹⁵ We focused on the hospital course of patients admitted due to severe hypoglycemia. As a result, we estimate a rate of recurrent hypoglycemia of 14.7% derived from the number of patients presenting to the ED with hypoglycemia and 31.8% admitted that subsequently developed recurrent hypoglycemia, suggesting a higher rate of recurrent hypoglycemia than previously appreciated.

Once further analyzed with a multiple logic regression analysis, we found that loss of a recent meal was a significant risk factor for recurrent hypoglycemia. Restricted carbohydrate intake had previously been noted as a predisposing factor for drug-induced hypoglycemia.² Reduced carbohydrate intake can lead to a low energy reservoir, potentiating the development of severe hypoglycemia.² Renal insufficiency may lead to reduced renal gluconeogenesis and energy intake, as well as a longer half-life of medications that primarily require kidney elimination.¹⁶,¹⁷ Moreover, CAD and infection were additional risk factors identified. CAD may be a marker for dyslipidemia, which is associated with insulin resistance and metabolic abnormalities. ¹⁸ Infection has long been recognized as a risk factor for hyper- and hypoglycemia in diabetic patients.²,⁹,¹⁹ Inflammatory stress from endotoxins,²⁰ fever, and increased metabolism all increase energy consumption. In a prolonged infection, basal glucose production may increase and insulin resistance may develop with or without the presence of hyperglycemia.²¹,²²

The only identifiable protective factor for the recurrence of hypoglycemia was the use of CCBs. It is well known that CCBs are less likely to have metabolic effects. Tsukuda, et al.²³ found nifedipine could improve diabetes-associated cognitive impairment. CCBs may also be used in the treatment of hyperinsulinemia hypoglycemia in children.²⁴ However, CCBs as a protective factor for recurrent hypoglycemia has not been reported before, and currently we are unable to explain this unique finding. Further studies are needed to validate this observation.

We have also found that patients who had a longer duration of diabetes, leukocytosis, hypoalbuminemia, the use of certain medications (benzodiazepines, alpha-blockers, beta-blockers, and diuretics), as well polypharmacy, tended to have recurring hypoglycemia during hospitalization. A longer duration of diabetes may be associated with a defect in, or blunting of, the counter-regulatory response to hypoglycemia.⁹ In addition to poor nutrition, albumin levels are impacted by other factors including inflammation, infection, and trauma. Providing adequate nutrition in the setting of inflammation, infection, or trauma does not improve albumin levels alone; however, inadequate nutrition negatively impacts albumin synthesis. Mediators of inflammatory responses alter hepatic protein synthesis and albumin metabolism leading to a net protein loss followed by anorexia and decreased nutritional intake.⁹,²⁵ Hypoalbuminemia in the recurrent hypoglycemia group may be a marker for undiagnosed inflammation or infection and for increased morbidity and mortality.⁹,²⁵ Patients with recurrent hypoglycemia were also at greater risk for longer hospital stays, and hypoalbuminemia has also been associated with longer hospital stays.²⁶ Benzodiazepines, such as alprazolam, have been demonstrated to reduce the neuroendocrine response to insulin-induced hypoglycemia in humans²⁷ and reduce the plasma catecholamine response to exercise stress.²⁸ The long-term use of benzodiazepines may blunt the response to repeated low levels of serum glucose. Several anti-hypertensive agents, such as RASBs, beta-blockers, and diuretics are associated with recurrent hypoglycemia.^29-31 Although beta-blockers showed no significant effect after multiple logistic regression in our study, non-selective beta-blockers have been reported to cause severe hypoglycemia in diabetic and non-diabetic patients.³² Beta-blockers may decrease the awareness of hypoglycemia and blunt counter-regulation.³⁰ Using selective beta-blockers may lessen the risk of inducing hypoglycemia.³³,³⁴

RASB use in our study population was high (56.7%), and diuretics have been associated with glucose intolerance and insulin resistance in diabetic patients.³⁵,³⁶ Although there are some ADAs with a duration of action as long as 72 hours, we did not find use of these drugs in our study population. We found that polypharmacy was a significant risk factor for recurrent hypoglycemia, consistent with other studies. This is a particular problem for the elderly. Ben-Ami, et al.², in their study of 102 diabetic patients on ADAs, found that 15% of the 93 patients at risk for a drug-induced hypoglycemic coma were medicated with additional drugs known to potentiate hypoglycemia such as beta-blockers, cimetidine, and aspirin. Shorr, et al.⁹ in their retrospective cohort study of 586 persons with a first episode of serious hypoglycemia found that the use of 5 or more medications was a risk factor in the development of serious hypoglycemia. No patient was treated with glucagon in this study, since we do not routinely administer glucagon to treat hypoglycemia at our institution, and the emergency medicine technicians are not allowed to use glucagon in Taiwan.

The authors have no financial conflicts of interest.