Incidence and cost of hypoglycemic events requiring medical assistance in a hospital setting in Denmark

The term hypoglycemia is generally used to describe a situation of abnormally low plasma glucose that could expose the individual to potential harm and is a particular risk for those treated with a sulphonylurea or insulin [1]. Hypoglycemic episodes (HEs) are classed as either severe or nonsevere (mild); nonsevere HEs can be managed without third party intervention, whereas severe HEs are defined as requiring the assistance of another person to either administer carbohydrates, or glucagon, or take other corrective actions [1]. The annual frequency of severe HEs in Type 1 diabetes has recently been estimated to be 0.7 episodes per patient per year, depending on duration of the disease [2]. In insulin-treated Type 2 diabetes, the annual frequency is reported to be between 0.1 and 0.2 episodes, again depending on disease duration [2]. Edridge et al. report an incidence of severe HE of 0.8 per patient-year [3].

Hypoglycemia can be a significant cause of morbidity and even mortality, in both Type 1 and 2 diabetes [1], with a significant impact on health-related quality of life [4]. Severe hypoglycemia may lead to neuroglycopenia when glucose levels drop below the threshold for sufficient cerebral supply (usually ≤3.0 mmol/l) resulting in seizures or unconsciousness, among other symptoms [5]. As a result, some physicians and patients may be reluctant to initiate or intensify insulin therapy due to the fear and perceived risks of hypoglycemia, leading to suboptimal glycemic control [6–9]. In an attempt to address this challenge, updated Danish guidelines for Type 2 diabetes recommend that glucose lowering agent regimens be individually tailored to achieve HbA_1c targets that balance the personal benefits, safety (including the risk of hypoglycemia) and tolerability of the treatment [10].

The economic burden associated with hypoglycemia is also substantial, with acute use of healthcare resources through HE-related emergency room (ER) visits, hospital admittance and in the longer term, indirectly as a result of the increased risk of complications such as cardiovascular diseases, which carries a heavy cost burden [5,11]. The increased risk of cardiovascular disease may stem from a number of factors, such as weight gain and/or due to the release of catecholamines locally in the heart during HEs [5].

Data on the incidence of HEs and the related medical costs, particularly for severe events are important for estimating the economic burden of hypoglycemia. In the UK, the annual cost of hospitalizations and the use of ambulances associated with severe HEs was recently estimated to be GB£15 million (€21 million), consistent with an earlier estimate based on the incidence and cost burden of severe HEs treated by emergency medical services in Scotland [12,13]. In Sweden, the estimated total of direct and indirect costs of HEs in Type 2 diabetes was €4.25 million per year, with severe HEs accounting for €0.87 million of these costs [14]. Each severe HE leading to hospitalization incurs an average cost of €2806.8 [14]. In a US setting, Foos et al. estimate the direct cost of an HE requiring assistance from a healthcare practitioner of US$1161 (€1088) per episode [15]; and Samuel et al. estimate the yearly cost of mild HE to approximately US$900 million roughly equal to that of severe HE [16].

In Denmark, there are limited published data on the national incidence of hypoglycemia and the use of healthcare resources associated with the treatment of severe hypoglycemia. Healthcare provision in Denmark is publicly funded and all interactions with the primary and secondary healthcare sector are exhaustively recorded by the National Patient Registry (‘Landspatientregisteret’ [LPR]) [17]. The LPR was established in Denmark in 1977 as a central governmental nationwide registry to record all hospital discharges and outpatient treatments by personal identification, dates, diagnosis-related group (DRG) tariffs and International Classification of Diseases (ICD) codes for diagnosis. In addition to this, all Danish citizens diagnosed with diabetes are registered in the National Diabetes Registry [18]. Set up in 1990, this registry holds information on gender, age and date of inclusion in the registry.

The objective of the current study was to utilize data from LPR and the National Diabetes Registry to estimate incidence of HEs necessitating hospitalization or ER visits and the direct costs associated with these events in a Danish setting.

This retrospective, population-based analysis covered LPR data from 1 January 2008 to 31 December 2011, to ensure that hospitalizations due to hypoglycemia were analyzed within the context of recent clinical practice. Data extracted from the LPR included information about gender, age, type of hospital contact, specialty of contact, DRG tariffs, diagnoses and procedure codes. Prevalence data from the National Diabetes Registry were used to calculate the incidence of hypoglycemia hospital contacts (HHC) per 1000 of the diabetes population [18].

Danish legislation permits access to national databases for research purposes and the study was approved by the Danish Data Protection Agency. Ethics committee approval and written informed consent are not required for retrospective studies using national registry data in Denmark.

The total number of HEs resulting in hospital admission or ER visit (HHCs) and the prevalence of diabetes in Denmark are reported in Table 1 [18]. Over the 4-year study period (2008–2011), there were 7310 hospital admissions and 2750 ER visits with hypoglycemia as the primary or secondary diagnosis, giving a total of 10,060 HHCs. National prevalence data show that over the study period the number of people with diabetes in Denmark increased by approximately 20%, from 256,377 in 2008 to 307,016 in 2011. This is in contrast to the decrease in the number of HHCs over the same time period (2709 vs 2193; Table 1). The incidence of HHCs per 1000 of the total population with diabetes in Denmark decreased from 10.6 in 2008 to 7.1 in 2011, indicating a 34% reduction.

For admissions where hypoglycemia was registered as secondary diagnosis, the most frequent primary diagnoses were insulin-dependent diabetes mellitus (with or without unspecified complications), noninsulin-dependent diabetes mellitus (with or without unspecified complications), pneumonia, urinary tract infection and dehydration.

The number of HHCs adjusted for diabetes prevalence and stratified by age is presented in Table 1. Across the study period, 47.4% (range: 44.1–49.9) of the total HHCs occurred within the >60 years of age population. However, adjusting for overall diabetes prevalence revealed more HHCs per 1000 annually in the age group of <30 years (mean: 61.7; range: 47.8–75.2) compared with annual HHCs per 1000 in the age group of >60 years (mean: 6.6; range: 5.4–7.8). Regional differences were also observed, with the highest number of HHCs per 1000 of the population, occurring in the north region (Supplementary Table 1).

In total during the 4-year period, there were 5958 hospital admissions with hypoglycemia as the primary diagnosis (Table 1). Of these, 4259 were one-off admissions. A total of 634 people were admitted two- to three-times, with 66 people having 4–16 admissions each.

For hospital admissions where hypoglycemia was the primary diagnosis, the mean LoS was 2.7 days (range: 2.6–2.9 days), significantly longer than the median LoS (1.0 days; p < 0.0001) (Table 2). However, this was shorter than the average LoS for the DRG group as a whole (range: 5.0–5.3 days) [19]. Within the subgroup analyses, patients >60 years old had highest average LoS (Table 2), while patients in the north region had the highest average annual LoS (Supplementary Table 2). In 2010, this difference was significant versus other regions (3.8 days vs 2.4–2.3 days; p = 0.001) (Supplementary Table 2). The average LoS was significantly lower for people experiencing multiple admissions compared with those with only one admission during the study period (2.5 days vs 2.8 days; p = 0.0312). People with only one admission were also significantly older than those with multiple admissions (average age 62 years vs 58 years; p < 0.0001).

There were 46 deaths (0.8%) among the hospital admissions for hypoglycemia as the primary diagnosis and two among those visiting the ER (0.07%).

In line with the reduction in HHCs during the study time frame, the estimated annual direct hospital costs associated with HHCs decreased by 24% from €3.0 million in 2008 to €2.3 million in 2011 (Table 2). Furthermore, the average cost per hospital admission with hypoglycemia as the primary diagnosis decreased during the years 2008–2011 by 12% (Table 2). The average cost per admission was highest in 2008 at €1883, falling to around €1680 in 2009–2011. Hospital admission costs constituted the majority of the costs (96%), whereas ER costs only constituted 4%.

There was some variation in costs between different age groups and regions (Table 2). Although the number of HHCs per 1000 people with diabetes was lowest in the >60 years age group (Table 2), the costs associated with this age group were not the lowest found in our analysis. The cost per 1000 people with diabetes was lowest in the 30–60 years age group (approximately €6267 per 1000); 42% lower than the >60 years age group.

Results of the sensitivity analysis suggest that applying the DRG tariff approximately doubles the estimated costs when compared with applying a bed-day charge (Supplementary Table 3).

This study reports on the incidence and the estimated direct hospital costs of HHCs between 2008 and 2011 in Denmark. These data will be important for relevant decision makers and for those involved in evaluating the cost–effectiveness of current and future treatments for diabetes.

The results highlight a 34% decrease in the incidence of HHCs despite an increase in diabetes prevalence of 20% during the same time frame. This may be a result of increased use of treatments associated with a lower risk of hypoglycemia (e.g., modern basal analogs, dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists), which obtained improved reimbursement status in December 2007 in Denmark [21,22]. Statistics from the Danish Medicines Agency show that the number of patients on sulphonylureas decreased whereas the number of patients treated with dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptors increased markedly (80–450% increase) from 2008 to 2011 [23]. Reduced incidence of HHCs may also stem from an increased focus on, and awareness of, the causes and consequences of hypoglycemia among both people with diabetes and healthcare professionals, resulting in better overall management. This is further reflected in the increased emphasis placed on hypoglycemia in the current Danish guidelines for Type 2 diabetes [10]. Changes in the healthcare infrastructure could also contribute to the incidence of HHCs, with an increased number of people with diabetes potentially being treated in a prehospital setting (e.g., in an ambulance) [24]. Instances where HHCs are successfully treated in prehospital settings would not be recorded in the current national dataset. It is, therefore, not known whether the decreasing incidence of HHCs is counterbalanced by an increase in HEs requiring medical assistance in a prehospital setting. This is indirectly supported by a study by Hatting et al., in which it is concluded that treatment of HE in a prehospital setting is safe and in 50% of the registered HE episodes, the patients were released at home following treatment [25].

Despite an overall decrease in the incidence of HHCs from 2008 to 2011, a substantial number of people with diabetes (7718 unique person HHCs; 3% of all people with diabetes in Denmark) still required hospital contact for acute hypoglycemia, highlighting the relative frequency of these severe events. A proportion of 3% is approximately at the same level as reported by Chevalier et al. [26] and Khunti et al. [24] but higher than the rates reported by Geller et al. [27].

We find a death rate on 0.8% for admissions and 0.07% for ER visits. Compared with other studies (e.g., Marchesini et al. [28], Chevalier et al. [26] and Cryer [29]) these death rates are low.

Our results showed that the frequency of HHCs varied with age. The adjusted incidence of HHCs was higher among those <30 years of age. These individuals are more likely to have Type 1 versus 2 diabetes and, therefore, are most likely treated with insulin, which is associated with an increased risk of hypoglycemia compared with other therapies. The frequency of HHCs is however, greatest among patients aged >60 years (and likely stems from the higher prevalence of Type 2 diabetes in this age group). Since the National Diabetes Registry does not include information on the subtype of diabetes, it was not possible to stratify patients by Type 1 or 2 diabetes in this study [18]. In comparison, Geller et al. report that 80+ years old insulin-treated patients had the highest risk to visit the ER due to HE [27].

The annual direct hospital costs of HHCs were estimated at €3.0 million in 2008 and €2.3 million in 2011, and reflect a decrease in the number of HHCs, as well as a lower cost per event. It should be noted that since the current analysis only included hospital sector costs, any potential shifting of costs to the primary care sector were not taken into account in this analysis. It is also important to note that this study only takes into account the economic aspect of the burden of severe hypoglycemic events. However, the burden on health-related quality of life for the patient and relatives should not be overlooked. These events are associated with great distress, anxiety and physical discomfort, and over 50% of people with diabetes worry about the risk of hypoglycemia [30].

The main purpose of this study was to estimate the hospital sector costs of HEs requiring hospital care, implying that we only included direct hospital costs in the analysis and excluded prescription medicine costs and indirect costs. Therefore, costs for the patient (and relatives) and potential productivity costs are not considered. The latter (i.e., productivity costs associated with a severe HE) are likely to be considerable and may involve absenteeism from work for one or more days [14].

We have only analyzed the costs of HHCs and have not included any costs associated with nonsevere HEs. Östenson et al. showed that the frequency of nonsevere HEs is higher than that of severe HEs; however, due to lack of reporting to healthcare professionals, the true burden (incidence and cost) of hypoglycemia may be underestimated [2].

In this study, we estimated an average LoS of 2.7 days for hospital admissions relating to HEs, which is lower than the LoS for diabetes-related admissions reported in other studies (4.19–17.0) [31–35]. While cross-country comparison of healthcare sector costs should be made with caution, the cost estimates for HEs leading to hospitalization, as reviewed by Frier et al., are similar to our average cost per admission estimates [36].

This study has some limitations; first, costs associated with hospital admissions, where HE was not the primary diagnosis, were also excluded from this analysis. This approach thus underestimates the true cost of hypoglycemia since it does not account for the cost of events that occur while patients are being treated in hospitals, that is, during admissions unrelated to hypoglycemia. Furthermore, our data do not include severe HEs that may be managed in a primary care setting or episodes of prehospital ambulance care and assistance, which are not recorded systematically in Denmark, therefore, associated costs are not reflected in these findings. Finally, as with all retrospective database studies, there is a risk of data misclassification in the National Patient Registry. HHCs may be incorrectly recorded and therefore not captured in the current study, leading to an underestimation of costs. It is also possible that some HEs, such as those reported using diagnosis codes DE160, DE161B and DE162 (Box 1) may include some cases of hypoglycemia in nondiabetic patients, although such cases are rare.

The results of this study showed a decrease in the incidence of HHCs in Denmark between 2008 and 2011, with a corresponding decrease in the associated direct costs. Despite these reductions, HHCs are still experienced by 3% of those with diabetes in Denmark and the economic burden to the healthcare system is significant. Our analysis also revealed that there are subgroups of patients who require more intensive resource use to treat hypoglycemia in a hospital setting, including patients who experience multiple admissions as well as older patients, highlighting the continuing challenges posed by hypoglycemia for the management of diabetes.

Editorial support was provided by Adelphi Values.

This study was funded by Novo Nordisk. PJ Lyngsie and S Lopes are employees of Novo Nordisk. Incentive has received consulting fees. J Olsen is an employee of Incentive. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

This work is licensed under the Attribution-NonCommercial-NoDerivatives 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/