Research Article For reprint orders, please contact: [email protected]

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

Aims: The purpose of this study was to estimate the incidence and hospital costs associated with hypoglycemic episodes (HEs) requiring hospital admission or emergency room (ER) visits in Denmark. Materials & methods: This study analyzed data from the National Patient Registry. Data on HE-related hospital admissions or ER visits occurring between 2008 and 2011 were collected and analyzed. Results: There were 1906 hospital admissions and 803 ER visits in 2008 compared with 1646 hospital admissions and 547 ER visits in 2011, corresponding to a decrease in incidence from 10.6 to 7.1. The estimated annual total hospital costs ranged from €3.0 million in 2008 to €2.3 million in 2011. Conclusion: HEs represent a major burden for the Danish healthcare system.

Pavika J Lyngsie*,1, Sandra Lopes1 & Jens Olsen2 Novo Nordisk Scandinavia AB, Arne Jacobsens Allé 17, DK-2300 KØbenhavn S, Denmark 2 Incentive, Holte Stationsvej 14, DK-2840 Holte, Denmark *Author for correspondence: pvja@ novonordisk.com 1

First draft submitted: 19 October 2015; Accepted for publication: 2 December 2015; Published online: 19 April 2016 Keywords:  burden of disease • diabetes • hospital costs • incidence • severe hypoglycemia

Background 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

10.2217/cer.15.68 © Pavika Jain Lyngsie

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 HbA1c 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 HErelated 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

J. Comp. Eff. Res. (2016) 5(3), 239–247

part of

ISSN 2042-6305

239

Research Article  Lyngsie, Lopes & Olsen 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. Materials & methods 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,

240

J. Comp. Eff. Res. (2016) 5(3)

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. Incidence

The study population was defined as people with diabetes who had at least one secondary care interaction due to hypoglycemia as a primary or secondary diagnosis between January 2008 and December 2011. This included hospital admissions and ER visits, identified by specific ICD10 diagnostic codes as outlined in Box 1. Scheduled outpatient visits with hypoglycemia as the primary diagnosis were excluded as they were considered not related to an acute event. The incidence of HHCs was based on the number of admissions and ER visits with hypoglycemia as the primary or secondary diagnosis per 1000 of the population (people with diabetes in Denmark). Costs

DRG tariffs are typically based on the average cost estimates for admissions within the group of diagnoses but there is usually a range of costs within the group [19] . The DRG that includes hypoglycemia diagnostic codes also includes codes for other diabetes-related complications such as ketoacidosis, renal complications and hyperosmolar coma. The length of stay (LoS) for the average admission within this DRG was longer than the average LoS for the subgroup of admissions where hypoglycemia was the primary diagnosis, suggesting that the DRG tariff may not accurately reflect the true cost of hospital admissions resulting from hypoglycemia. To adjust for potential bias, bed-day charges (i.e., a tariff per admission day) taken from price list data for a Danish University Hospital were applied as the unit costs for these admissions  [Aarhus Universitets Hospital, Pers. Comm.] . The unit costs for ER visits where hypoglycemia was the primary or secondary diagnosis were taken from the Danish Ambulatory Grouping System tariffs [19] . The applied unit costs were €640 per bed-day and €139 per ER visit; all costs were adjusted to a 2014 price level applying price indices for the healthcare sector provided by Danish Regions. As a sensitivity analysis, the annual costs using bed-day charges were compared with the annual costs generated using the average DRG tariff for the years 2008–2011 (€3489 per admission).

future science group

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

A hospital sector (healthcare provider) perspective was applied, including only direct costs associated with HEs, which required hospital admission or an ER visit. When analyzing these direct costs, only hospital admissions, where hypoglycemia was the primary diagnosis, were considered, since the primary diagnosis determines the DRG that the admission will map to, therefore being the main cost driver. However, direct costs associated with ER visits were included in the analysis whether hypoglycemia was registered as primary or secondary diagnosis. The tariff for ER visits does not change with diagnosis, and hypoglycemia in the ER setting was assumed to have the same resource use implications, regardless of whether it was coded as a primary or secondary diagnosis. Subgroup analyses

Within each year, subgroup analyses were conducted based on three age groups (60 years old) and also based on the five geographical regions within the Danish healthcare system (Capital, Zealand, south, central Denmark and north) [20] . Results at the regional level are reported in Supplementary Tables 1 & 2. Student’s t-tests, at the 0.05 significance level, were performed to investigate any regional differences in LoS, any differences between LoS for the admissions included versus the relevant DRG group as a whole, and for any differences between average and median LoS. Similar tests were also performed to investigate any differences in LoS, cost per admission and age, between patients experiencing one versus multiple admissions. Costs are reported in Euros (€); €1 = DKK7.5. Results 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),

future science group

Research Article

Box 1. ICD10-codes defining hypoglycemia. ICD10-code & description • DE100E insulin-dependent diabetes mellitus with hypoglycemic coma • DE110B noninsulin-dependent diabetes mellitus with hypoglycemic coma • DE120B malnutrition-related diabetes mellitus with hypoglycemic coma • DE140D unspecified diabetes mellitus with hypoglycemic coma • DE159 hypoglycemic coma not otherwise specified • DE159B hyperinsulinism with hypoglycemic coma • DE160 drug-induced hypoglycemia without coma • DE161B posthypoglycemic coma encephalopathy • DE162 hypoglycemia, unspecified

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 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 threetimes, 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