Diabetes Ther (2019) 10:375–392 https://doi.org/10.1007/s13300-019-0563-0 REVIEW Epidemiology, Quality of Life, and Costs Associated with Hypoglycemia in Patients with Diabetes in Spain: A Systematic Literature Review Mercedes Núñez . Silvia Dı́az . Tatiana Dilla . Jesús Reviriego . Antonio Pérez Received: November 6, 2018 / Published online: January 19, 2019  The Author(s) 2019 ABSTRACT extensively between studies, making it difficult to draw a conclusion. Total costs per SH event Objective: To assess the burden of hypo- ranged from €409.97 in patients with T1DM to glycemia in patients with diabetes mellitus €713.10 in patients with DM. Work absence was (DM) in Spain, including epidemiological data reported in 11.80–18% of the working patients. and information relating to healthcare resource Further, patients who experienced hypo- utilization (HRU) and costs, and patients’ qual- glycemic events expressed a higher fear and had ity of life (QoL). a poorer QoL than those who did not report Methods: A systematic literature review (SLR) these events. was conducted to identify studies that included Conclusion: Although the data included in the original information on epidemiology, HRU SLR were difficult to synthesize due to hetero- and costs, and/or QoL associated with hypo- geneity of the study designs and patient char- glycemia in patients with DM in Spain, pub- acteristics in the 14 studies, our search lished in either Spanish or English, between identified a high burden associated with hypo- January 2007 and April 2017. glycemic events in terms of HRU and costs, and Results: Fifteen articles, involving 14 studies, patients’ QoL. Further research is recommended were identified in the SLR and included in the to reach a consensus on hypoglycemia defini- analysis. The estimated rate of severe hypo- tion and study design to provide robust evi- glycemia (SH) events per patient per year ranged dence on the burden of hypoglycemia and to from 0.90 to 1.50 in patients with type 1 DM accurately weigh the impact of this acute com- (T1DM) and from 0.30 to 0.63 in patients with plication in Spain. type 2 DM (T2DM). The data on HRU differed Funding: Eli Lilly and Company. Enhanced Digital Features To view enhanced digital Keywords: Diabetes mellitus; Hypoglycemia; features for this article go to https://doi.org/10.6084/ Observational studies; Spain; Systematic m9.figshare.7547183. literature review M. Núñez (&)  S. Dı́az  T. Dilla  J. Reviriego Eli Lilly and Company, Madrid, Spain e-mail: nunez_mercedes@lilly.com INTRODUCTION A. Pérez Diabetes mellitus (DM) is a group of metabolic Department of Endocrinology and Nutrition, disorders characterized by chronic hyper- Hospital de la Santa Creu I Sant Pau, Barcelona, Spain glycemia that develops because of insufficient 376 Diabetes Ther (2019) 10:375–392 insulin secretion, reduced responsiveness to coma, and ultimately death. Recent post hoc insulin, or both [1]. The eighth edition of the analyses of the ACCORD, ADVANCE and International Diabetes Federation (IDF) 2017 DEVOTE 3 trials, all of which examined the Diabetes Atlas, a global reference report, esti- outcomes of intensive glycemic control, mates that 424.90 million (8.80%) adults were revealed a high association between SH and affected by DM in 2017 globally. This number is significantly higher rates of death [13–15]. For estimated to increase to 628.60 million (9.90%) all of these reasons, these SH episodes are asso- by 2045 [2]. A survey was conducted in ciated with considerable costs, both to the 2009–2010 with the aim to quantify the preva- individual and to the healthcare system [16], lence of DM in Spain [3]; at that time it was and they also contribute to significant reduc- estimated that DM affected 13.80% of the pop- tions in QoL in patients with DM and to a fear ulation and that these numbers would likely of hypoglycemia [17]. increase given estimated global figures [4]. In Despite the importance of being aware of addition, global expenditure attributable to the this information for the correct management of care of DM patients has become an enormous hypoglycemia, none of the studies to date in the economic burden on healthcare services, Spanish landscape have collected integrated reaching US $727 billion in 2017 [2]. Projec- data related to the burden of hypoglycemia. The tions in Spain reveal a comparable growth in aim of this systematic literature review (SLR) upcoming years in the expenditure of the was to review available data in order to assess Spanish healthcare system for the care of DM the burden of hypoglycemia in terms of its patients [5–7]. Moreover, these predictions may epidemiology, healthcare resource utilization worsen since the available estimations are usu- (HRU), costs, and QoL in patients with DM in ally described for patients who have been diag- Spain. nosed with diabetes and do take into account the significant number of undiagnosed diabetic cases [8]. The most distressing consequence of METHODS DM appears to be its late complications. How- ever, hypoglycemia, one of the acute compli- This SLR was planned, conducted, and reported cations of DM [9], also significantly impacts according to the Preferred Reporting Items for disease management, patients’ quality of life Systematic Reviews and Meta-Analyses (QoL), and costs [8, 10]. (PRISMA) guidelines. Two independent review- Insulin and a number of other glucose-low- ers screened each retrieved record to identify ering drugs may cause hypoglycemia. According potentially relevant articles for the full-publi- to the recommendations of the International cation review. A third senior researcher arbi- Hypoglycemia Study Group [11], a hypo- trated in case of any doubt on eligibility or glycemia alert value of B 70 mg/dL (3.90 mmol/ disagreement between the two primary L) is often related to symptomatic hypo- reviewers. glycemia and can be an considered important The SLR included observational studies con- value for therapeutic dose adjustment of glu- ducted in Spain published between January cose-lowering drugs for patients in clinical care. 2007 and April 2017 that involved patients with Further, a blood glucose level of \ 54 mg/dL any type of diabetes and which present original (3.00 mmol/L) is considered sufficiently low to information on epidemiology, costs, HRU and/ indicate clinically significant hypoglycemia. or QoL of patients with hypoglycemia. Both Severe hypoglycemia (SH) is defined as severe English and Spanish language publications were cognitive impairment requiring assistance from included in the search. Articles not presenting another person for recovery [11]. original data (such as SLR, reviews, letters to the Symptoms attributed to hypoglycemia are editor, etc.), clinical trials, cost-effectiveness categorized as neurogenic (autonomic) or neu- models, and abstracts or congress communica- roglycopenic [12]. Depending on its severity or tions, and those studies that present duration, hypoglycemia can lead to seizure or Diabetes Ther (2019) 10:375–392 377 hypoglycemia data associated with a specific huelva OR almeria OR cadiz OR jaen drug or intervention were not included in our OR malaga OR [cORdoba not argentin*] SLR. OR extremadura OR caceres OR badajoz Articles that reported costs were actualized to OR madrid OR castilla OR salamanca OR the corresponding value in euros in 2016 using zamORa OR valladolid OR segovia OR the CCEMG-EPPI-Centre Cost Converter tool in sORia OR palencia OR avila OR burgos order to enable meaningful comparisons OR [leon not {france OR clermont OR between costs [18]. rennes OR lyon OR USA OR mexic*}] OR A comprehensive search strategy was devel- galicia OR gallego OR compostela OR oped for the databases: Ovid (Embase ? vigo OR cORuna OR ferrol OR ORense MEDLINE) and MEDES (Spanish bibliographic OR ourense OR pontevedra OR oviedo database). The corresponding search strategies OR gijon OR asturia* OR cantabr* OR used are presented as follows: santander OR vasco OR euskadi OR • MEDES (https://www.medes.com/Public/ basque OR bilbao OR bilbo OR donosti* Home.aspx): (((hipoglucem*[tı́tulo] OR OR san sebastian OR vizcaya OR biscaia hipoglucem*[resumen] OR hipoglucem*[- OR guipuzcoa OR gipuzkoa OR alava OR palabras_clave]) AND ((epidemiologia[tı́tulo] araba OR vitORia OR gazteiz OR navarr* OR epidemiologia[resumen] OR epidemiolo- OR nafarrona OR pamplona OR iruna OR gia[palabras_clave]) OR (incidencia[tı́tulo] irunea OR aragon* OR zaragoza OR OR incidencia[resumen] OR incidencia[pal- teruel OR huesca OR mancha OR ciudad abras_clave]) OR (prevalencia[tı́tulo] OR real OR albacete OR cuenca OR [toledo prevalencia[resumen] OR prevalencia[pal- not {ohio OR us OR usa OR OH}] OR abras_clave]) OR (calidad[tı́tulo] OR cali- (guadalajara not mexic*) OR balear* OR dad[resumen] OR calidad[palabras_clave]) mallORca OR menORca OR ibiza OR OR (vida[tı́tulo] OR vida[resumen] OR eivissa OR palmas OR lanzarote OR vida[palabras_clave]) OR (carga[tı́tulo] OR canari* OR tenerife).mp. (223,672) carga[resumen] OR carga[palabras_clave]) 4. Items 2 and 3 (140) OR (coste*[tı́tulo] OR coste*[resumen] OR 5. Limit 4 to year = ‘‘2007–2017’’ (103) coste*[palabras_clave]) OR (econom*[tı́tulo] 6. 5 not clinical trial/(93) OR econom*[resumen] OR econom*[pal- 7. Limit 6 to (conference abstract or con- abras_clave])))) AND (2007[año_publi- ference paper or conference proceeding cación]: 2017[año_publicación]) or ‘‘conference review’’ or editorial) • Ovid (http://link.am.lilly.com/sites/link/ [Limit not valid in Ovid MEDLINE(R); DataSources/Pages/EMBASE.aspx): Database: records were retained] (18) Embase \1974–2017 April 17[ ; Ovid 8. 6 not 7 (75) MEDLINE(R) \1946 to April Week 1 2017[. The reviewers collected the following informa- 1. exp *nocturnal hypoglycemia/or exp tion from each article selected in the SLR. *hypoglycemia/or exp *insulin hypo- 1. Variables which described the main glycemia/(41,684) methodological characteristics, including 2. Item 1 or hypoglyc*.ti. (51,796) the study design, information on follow- 3. (spain OR espagne OR espana OR spain up and data collection, sample inclusion OR espagne OR espana OR osasunbide* criteria, type of DM, number of patients in OR osakidetza OR insalud OR sergas OR the study, mean age of the patients, mean catalunya OR catalonia OR catalogne OR duration of the DM, time frame to record cataluna OR catala OR barcelon* OR hypoglycemia, severity of the hypoglycemic tarragona OR lleida OR lerida OR girona event reported, and healthcare system OR gerona OR sabadell OR hospitalet OR setting. l’hospitalet OR valencia* OR castello* OR 2. Epidemiology variables, comprising fre- alacant OR alicant* OR murcia* OR quency of SH and non-severe hypoglycemia andalu* OR sevill* OR granad* OR (NSH), hypoglycemic events per year for SH 378 Diabetes Ther (2019) 10:375–392 Fig. 1 PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram and NSH, and frequency of nocturnal in the analysis after the systematic review pro- hypoglycemia. cess (Fig. 1). 3. HRU and costs’ variables, involving HRU per hypoglycemic event, costs related to Description of the Selected Studies hypoglycemia (direct and indirect costs), in the SLR total costs, and information on impact at work. Of the 15 publications (14 studies) included in 4. QoL variables, including questionnaires the SLR, six studies focused exclusively on data used and main results, i.e., the scores for from patients with type 2 DM (T2DM) [19–24] the hypoglycemic population versus the and five studies reported combined data from defined control population in each article patients with either type 1 DM (T1DM) or and statistical significance of the T2DM [25–30]. Only two studies highlighted comparison. data exclusively for patients with T1DM Ethical approval was not required since this [31, 32], and one study reported neonatal article is based on previously conducted studies hypoglycemia [33]. All of the studies collected and did not involve experiments with animals data retrospectively employing a cross-sectional or humans performed by any of the authors. study design, with the exception of one study that used a longitudinal study design [22]. The RESULTS majority of the studies reported the manage- ment of hypoglycemia events at either hospitals The search strategy identified 206 references (75 or a primary care setting; the exceptions were from Ovid and 131 from MEDES), of which 15 two studies that presented data from specialized publications involving 14 studies were included care and emergency service settings [24, 29] and Diabetes Ther (2019) 10:375–392 379 two studies that did not report the study set- Type 2 Diabetes Mellitus tings [26–28]. The frequency of hypoglycemic events was The number of patients in the studies ranged described in eight studies. An incidence of 1.82 widely, from 100 in a study determining the episodes per 10,000 patients per year for SH was costs of SH in patients with T1DM [31] to reported by Lindner et al. [25]. Orozco-Beltrán 5,447,725 clinical records from the basic mini- et al. reported an annual frequency of 0.30–0.40 mum data set (BMDS) registry of the Spanish events per year for SH, and 18.30–42.10 events National Health System that includes general per year for NSH [26]. Three studies described information on patients with DM [30]. The the incidence of SH as the percentage of mean age of patients with T1DM ranged from patients who experienced an episode in 1 year, 33.20 to 33.90 years, while studies reporting namely, 6.80% [20], 1.90% [21] and 0.56% [23], data for patients with T2DM included patient with the setting of the first two studies being populations with a mean age ranging from 64 to primary care and that of the third study being 79.70 years. However, a wide-ranging mean age the hospital. was observed in studies presenting data of In the study of Pérez et al., 93.20% of patients with either T1DM or T2DM, from 39.90 patients reported NSH or no hypoglycemia in a to 70.20 years. The mean duration of the disease 1-year period [20], while Depablos-Velasco et al. in patients with T1DM and T2DM ranged from reported that 9.60% of patients had NSH in the 16.50 to 18.50 and from 8.40 to 20 years, previous month [21]. A small number of studies respectively. One of the studies included in the did not differentiate between SH and NSH in SLR focused exclusively on neonatal hypo- these patients. Durán-Alonso et al. reported that glycemia; the aim of this study was to deter- 15.70% of patients in nursing homes experi- mine whether an association exists between enced symptomatic hypoglycemia [19]. In a maternal pre-pregnancy body mass index cate- 2-year study by Sicras-Mainar et al., 37.70% of gory and the occurrence of neonatal hypo- patients reported at least an episode of hypo- glycemia among infants born to women with glycemia [22], and Jódar-Gimeno et al. reported gestational DM [33]. that 45% of patients experienced hypoglycemia in the previous 6 months [24]. Epidemiology of Hypoglycemia Nocturnal Hypoglycemia Table 1 presents the epidemiology data on The epidemiologic data for nocturnal hypo- hypoglycemia detailed in the studies selected glycemia were analyzed from three studies. for inclusion in this SLR (15 publications). Barranco et al. employed Public Company for Health Emergencies Service (EPES; Andalusian emergency service) data and noted that there Type 1 Diabetes Mellitus were 2297 nocturnal SH episodes in a 1-year, The average number of hypoglycemia episodes which translated into 0.34 episodes per hour per patient was reported in three studies. that required the assistance of emergency ser- Reviriego et al. recorded a mean of 2.99 SH vices [29]. Brod et al. explored the impact of events per patient per 2-year period, with a nocturnal NSH events in similar patients who higher number of overall hypoglycemic epi- experienced an event in the past month and sodes (54.40 events/patient/2 years) [31]. reported a mean of 21.60 nocturnal NSH events Orozco-Beltrán et al. reported an annual fre- in 1 year [27]. In terms of nocturnal hypo- quency of 0.90 events for SH and 1.70 NSH glycemia according to the type of diabetes, the events per week, or an annual frequency of 88 proportion of NSH events occurring at night NSH events [26]. Carral et al. reported a mean of was 26% in T1DM patients and 30–32% in 7.40 events (SH or NSH) per patient in 1 month T2DM patients recorded in the previous week [32]. [26]. 380 Table 1 Summary of the epidemiology data reported in the studies included in the systematic literature review Studies/references Study design Period to register Study entry criteria (cases) Healthcare system Number of patients Mean age hypoglycemia setting (years)a According to According to data follow-up collection T1DM Reviriego et al. Retrospective Cross-sectional 2 years Patients who experienced at Hospital 100 33.22 ± 12.17 [31] least one SH Carral et al. [32] Retrospective Cross-sectional 1 month 16 to 60 year-old patients with Hospital 130 33.90 ± 11.50 T1DM (at least 12 months) (endocrinologist) T2DM Durán Alonso Retrospective Cross-sectional NA Elderly patients with T2DM PC (nursing 312 79.70 et al. [19] homes) Pérez et al. [20] Retrospective Cross-sectional 1 year C 18 year-old patients with PC 5382 66.70 ± 10.80 T2DM (at least 12 months) Depablos-Velasco Retrospective Cross-sectional 1 year C 40 year-old patients with PC 751 67.70 ± 9.90 et al. [21] T2DM (at least 12 months) Sicras-Mainar Retrospective Longitudinal 2 year C 40 year-old patients with PC and hospital 3760 67.80 ± 11.30 et al. [22] T2DM (at least 12 months) Alonso-Morán Retrospective Cross-sectional 1 year Patients with T2DM or Hospital 134,413 – et al. [23] unspecified Jódar-Gimeno Retrospective Cross-sectional 6 months C 18 year-old patients with PC and specialized 3812 64 ± 11 et al. [24] DM (at least 12 months), care receiving treatment T1DM and T2DM Lindner et al. [25] Retrospective Cross-sectional 1 year Hospitalizations due to SHE Hospital 3,254,464 – obtained from BMDS Orozco-Beltrán Retrospective Cross-sectional 7 previous days (NSHE) and [ 15 year-old patients with – 630 T1DM: et al. [26] 1 year (SHE) DM, receiving insulin 39.90 ± 12.80 T2DM: 63.50 ± 15.10 DM Brod et al. [27] Retrospective Cross-sectional 1 month C 18 year-old patients, with – 242 42.20 ± 11.90 DM, who presented at least one episode of NSNHE the last month Brod et al. [28] Retrospective Cross-sectional 1 month C 18 year-old patients, with – 242 42.20 ± 11.90 DM, who presented at least one episode of NSNHE the last month Diabetes Ther (2019) 10:375–392 Table 1 continued Studies/references Study design Period to register Study entry criteria (cases) Healthcare system Number of patients Mean age hypoglycemia setting (years)a According to According to data follow-up collection Barranco et al. Retrospective Cross-sectional 1 year All registered emergency calls in Emergency service 8683 emergency calls for 66 ± 20.20 [29] Andalusia hypoglycemic event Gómez-Huelgas Retrospective Cross-sectional 14 years Discharges with diabetes Hospital 5,447,725 70.20 ± 13.90 et al. [30] obtained from BMDS Neonatal Diabetes Ther (2019) 10:375–392 Garcı́a-Patterson Retrospective Cross-sectional 20 years Pregnancies with GDM with a Hospital 2029 newborns Maternal 33 et al. [33] gestational age [ 22 weeks (17–46) Studies/ Mean duration of Hypoglycemia frequency Total number of Nocturnal references diabetes (years)a hypoglycemic events/year hypoglycemia SHE NSHE SHE NSHE T1DM Reviriego 16.90 ± 10.90 Mean: 2.99 events/patient/2 years (1.50 – – et al. [31] events/patient/yearb) Median: 2/patient/2 years (1/patient/yearb) Mean: 54.40 events/patient/2 years – (27.20 events/patient/yearb) Median: 24/patient/2 years (12/patient/yearb) Carral et al. 16.50 ± 9.50 7.40 events/patient ± 5.80 in the last month – – [32] T2DM Durán 66.90% C 10 years 15.70% (symptomatic) – – Alonso et al. 25.40% C 5 years [19] 6.10% B 5 years 1.60% B 1 year Pérez et al. 8.80 ± 6.30 6.80% 93.20% (NSHE or not hypo) – – [20] Depablos- 8.40 ± 6.50 1.90% (C 1/ 9.60% ([ 1/month) – – – Velasco et al. year) [21] Sicras-Mainar 8.50 ± 3.50 37.70% (need medical attention) – – et al. [22] 381 Table 1 continued 382 Studies/ Mean duration of Hypoglycemia frequency Total number of Nocturnal references diabetes (years)a hypoglycemic events/year hypoglycemia SHE NSHE SHE NSHE Alonso- – 0.56% – 0.63 episodes/patient Morán et al. [23] – – Jódar- 10 ± 7 45% – Gimeno et al. [24] T1DM and T2DM Lindner et al. – – – 0.82% – – [25] T2DM: 1.82 per 10,000 Orozco-Beltrán T1DM: 18.50 ± 11 – T1DM: 1.70 events/week T1DM: 0.90 T1DM: 88 T1DM NSHE: et al. [26] T2DM: 20 ± 16.40 T2DM: 0.40-0.80 events/week events/year events/year 26% T2DM: 0.30- T2DM: 18.30- T2DM NSHE: 0.40 events/ 42.10 events/ 30–32% year year DM Brod et al. 10.20 ± 8.50 – 100% – 100% [27] Brod et al. 10.20 ± 8.50 – 100% – 100% (21.60 [28] events/year) Barranco – – – General – No. of patients: et al. [29] population: 2297 10.34 Nocturnal SHEs: episodes 0.34 episodes per per 10,000 hour of all person/year urgencies DM patients: registered 80 (78-83) episodes per 10,000 person/year Gómez- – 1.70% hypoglycemia – – Huelgas discharges 2.80% with secondary et al. [30] with primary hypoglycemia – Diabetes Ther (2019) 10:375–392 Diabetes Ther (2019) 10:375–392 383 Resource Utilization and Costs BMDS Basic minimum data set, DM diabetes mellitus, GDM gestational diabetes mellitus, NSHE non-severe hypoglycemic event, NSNHE non-severe nocturnal hypoglycemic event, PC primary care, SHE Table 2 summarizes information on HRU and costs associated with hypoglycemia obtained in hypoglycemia the SLR (11 articles involving 10 studies) Nocturnal [20, 22–31]. – Severe Hypoglycemia Sicras-Mainar et al. reported that 0.50% of patients with T2DM needed to be hospitalized, among whom 1.00% had to be treated in the specialized care departments, and 34.10% NSHE attended medical visits in primary care settings hypoglycemic events/year over a period of 2 years [22]. Lindler et al. reported that 6.34% and 5.01% of the patients with T1DM and T2DM, respectively, required Total number of hospitalization [25]. Orozco-Beltrán et al. reported that among the respondents with either T1DM or T2DM, 30% required emergency SHE hospital visits and 19% were admitted to hos- – pital because of their hypoglycemia [26]. In terms of costs associated with patients with T1DM, Reviriego et al. reported an overall mean cost per episode of €409.97, of which 65.40% were direct costs and 34.60% were indirect costs [31]. These authors found that the highest costs were due to hospitalization (€204.98 per episode), representing 50% of the NSHE total costs [31]. Alonso-Morán et al. provided data on patients with T2DM [23]. These authors Hypoglycemia frequency observed that the average overall cost per patient with T2DM was higher in a patient who had experienced one or more hypoglycemic severe hypoglycemic event, T1DM Type 1 DM, T2DM Type 2 DM episodes than in a patient who did not experi- ence any such episode. The results presented by SHE 3% these authors were differentiated by gender and were specifically related to primary care, pre- scriptions, specialized care, emergencies and hospitalizations [23]. Barranco et al. recorded an Mean duration of diabetes (years)a estimated mean direct cost of €713.10 per epi- sode in patients with either T1DM or T2DM. These costs increased if the hypoglycemia was nocturnal or if it required emergency hospital – care or caused loss of consciousness [29]. Table 1 continued Standard deviation Severe and Non-Severe Hypoglycemia In the study by Pérez et al., a total of 6.80% of Calculated et al. [33] Patterson references Neonatal patients with T2DM required medical attention Garcı́a- Studies/ in the preceding year, of whom 0.50 and 4.60% b a Table 2 Summary of the healthcare resource utilization and costs related to hypoglycemia events reported in the studies included in the systematic literature review 384 Studies/ Type of Follow-up period Number of Healthcare resources Costs related to hypoglycemia Work impact references hypoglycemia patients/cases utilization/ hypoglycemia Direct costs Indirect Total costs costs T1DM Reviriego SHE 2 years 100 Cost per SHE: Cost per Cost per SHE: €409.97 et al. [31] SHE: Hospitalization: €142.26 €204.98 Diagnosis: €12.32 Medication: €5.60 Other: €45.93 T2DM Pérez et al. SHE/NSHE 1 year 5382 Medical attention: 6.80% [20] Hospitalization: 0.50% Outpatient care: 4.60% Unspecified: 1.70% Sicras- SHE 2 years 3760 PC: 34.10% Mainar Hospitalization: 0.50% et al. [22] ED: 1% Alonso- SHE 1 year 134,413 Annual cost per Total healthcare annual cost per patient Morán patient who who suffered C 1 HE, by sex: et al. [23] suffered C 1 M: €11,257.50 HE: W: €10,759.52 PC: On average an SHE accounted for M: €1049.83 additional €2549.88 in annual healthcare W: €1160.61 costs Prescriptions: M: €1419.76 W: €1570.18 Specialized care: M: €1268.34 W: €1513.26 ED: M: €432.94 W: €439.04 Hospitalization: M: €7085.61 W: €6076.43 Diabetes Ther (2019) 10:375–392 Table 2 continued Studies/ Type of Follow-up period Number of Healthcare resources Costs related to hypoglycemia Work impact references hypoglycemia patients/cases utilization/ hypoglycemia Direct costs Indirect Total costs costs Jódar- SHE/NSHE 6 months 3812 Hospitalization: 11% Work absences: 14% of patients Gimeno (mean: 1.63 visits) et al. [24] ED: 26% (mean: 1.86 visits) T1DM and T2DM Diabetes Ther (2019) 10:375–392 Lindner SHE 1 year 3,254,464 Hospitalization: et al. [25] hospitalizations T1DM: 6.34% due to SHE T2DM: 5.01% Orozco- SHE/NSHE 7 previous days 630 SHE: Test strips by T1DM NSHE: Beltrán (NSHE) and 1 year event: €1.32 Hospitalization: 19% 18% lost work time (mean: et al. [26] (SHE) 1.50 h/event) ED: 30% T2DM NSHE: NSHE: 15% lost work time (mean: 1 h/ PC: 8% daytime and 12% event) nocturnal (T1DM) PC: 20% (T2DM) DM Brod et al. NSNHE 1 month 242 HCP: 24% – [27] Brod et al. NSNHE 1 month 242 HCP: 24% Yearly cost for Cost per Annual economic burden of the sample: 11.80% patients missed a mean [28] fall: €686.83 NSHE: €32810.65 of 10.40 h of working time €357.45 385 Table 2 continued 386 Studies/ Type of Follow- Number of patients/cases Healthcare resources utilization/ Costs related to hypoglycemia Work references hypoglycemia up hypoglycemia impact period Direct costs Indirect Total costs costs Barranco et al. SHE 1 year 8683 emergency calls for HE After emergency call: Cost per SHE: Cost per SHE, by type: [29] 13.83% events solved over the Emergency care in SHE: phone place or residence: €713.10 ± 573.94 €471.34 ± 277.32 85% required domiciliary assistance Nocturnal: by emergency team Transfer to hospital: €678.57 ± 11.17 €30.47 ± 74.15 After receiving domiciliary Requiring emergency assistance: Emergency hospital care: care (\ 24 h): €1703.53 ± 308.81 21% of patients required hospital €211.29 ± 414.45 referral (24.10% M and 19.40% Loss of consciousness: W) Cost per nocturnal €1028.01 ± 610.51 SHE: Emergency care in place or residence: €481.50 ± 255.99 Transfer to hospital: €24.38 ± 69.08 Emergency hospital care (\ 24 h): €172.69 ± 383.98 Cost per SHE requiring emergency hospital care: Emergency care in place or residence: €532.29 ± 315.92 Transfer to hospital: €145.26 ± 99.55 Emergency hospital care (\ 24 h): €1025.98 ± 0 Cost per SHE causing loss of consciousness: Emergency care in place or residence: €656.22 ± 268.18 Transfer to hospital: €38.60 ± 76.19 Emergency hospital care (\ 24 h): €333.19 ± 480.48 Diabetes Ther (2019) 10:375–392 Diabetes Ther (2019) 10:375–392 387 impact Work required hospitalization and outpatient care, respectively [20]. Jódar-Gimeno et al. reported that 11 and 26% of patients with T2DM required a mean of 1.63 ± 1.34 (± standard deviation) hospitalizations and 1.86 ± 1.32 Total costs emergency department visits in the preceding 6 months [24]. Impact at Work Indirect Costs related to hypoglycemia costs Analysis of the data on amount of working time lost revealed that among employed respondents with T1DM, 18% of NSH events led to lost work time of approximately 1.50 h per event. In Direct costs T2DM patients, 15% of NSH events led to lost work time of approximately 1 h per event [26]. Brod et al. showed that 11.80% of patients with Primary hypoglycemia: 9.01 (11.72) Healthcare resources utilization/ DM experienced nocturnal NSH events that led Secondary hypoglycemia: 12.04 to a mean of 10.40 h of lost work time per Mean of stay in hospital: month [28]. Quality of Life (13.40) days hypoglycemia days The QoL and fear of hypoglycemia data obtained in two studies [21, 24] through the use 5,447,725 discharges with a diagnosis of diabetes obtained from BMDS (1.70% primary hypoglycemia and 2.80% secondary hypoglycemia) of validated questionnaires are shown in Table 3. The authors of these studies assessed data only from patients with T2DM who expe- rienced both SH and NSH. In a study by Depablos-Velasco et al., patients with at least one SH or more than one NSH per month in the past year had a poorer QoL than did patients with no such events, as concluded from the results obtained from the ED Emergency department, HCP healthcare professional, M men, W women Audit of Diabetes-Dependent QoL (ADDQoL) Number of patients/cases Where applicable, data are reported as the mean ± standard deviation questionnaire [21]. No statistical significance was reached in the treatment satisfaction results obtained from the Diabetes Treatment Satisfac- tion Questionnaire (DTSQ). However, a signifi- cantly greater fear of hypoglycemia was observed for both groups of patients, those with 14 years Follow- at least one SH and those with one or more than period one NSH per month in the past year, than for up patients with no such events (results from the hypoglycemia SHE/NSHE Hypoglycemia Fear Survey [HFS-II]) [21]. Jódar- Table 2 continued Type of Gimeno et al. showed that patients with hypo- glycemia expressed a higher fear for hypo- glycemia than those who did not experience et al. [30] Huelgas references hypoglycemia; the difference was statistically Gómez- Studies/ significant (results from HFS-II), and the overall 388 Diabetes Ther (2019) 10:375–392 impact on their QoL was more negative in this ADDQoL: The Audit Diabetes Dependent Quality of Life questionnaire. Mean score obtained from the 19 items, indicating the mean impact of diabetes on the patients’ health-related QoL. Scores range \ 0.001 p value 0.003 0.001 population (p \ 0.001 [results from the ADDQoL]) [24]. hypoglycemia:31.32 [ 1 NSHE/month: Hypo population 16.90 (14.50) DISCUSSION 24.10 (22.10) Patients with C 1 SHE: (15.71) This SLR provides an overview of the burden of hypoglycemia in patients with DM in Spain based on data published in the literature in the NSHE/month: hypoglycemia: Patients without last 10 years by reporting information on the 10.90 (14.40) 10.60 (14.50) 18.85 (16.03) population rate of hypoglycemia and on its impact on HRU \ 1 SHE: HFS-IIc Control and costs, and patients’ QoL. The search strat- B1 egy was robust and focused on collecting extensive and elaborate data. However, due to p value 0.157 0.238 the observational nature and heterogeneity of Table 3 Summary of the quality of life data reported in the studies included in the systematic literature review – the included studies, further high-quality NSHE/month: prospective studies are necessary to accurately establish the burden of hypoglycemia in 26.90 (7.10) 28.50 (5.30) population C 1 SHE: patients with DM in Spain. Hypo The quality of the studies was not evaluated [1 DTSQ: Diabetes Treatment Satisfaction Questionnaire. Scores range from 0 (very dissatisfied) to 36 (very satisfied) – because the majority of articles selected in the search were observational studies, with different NSHE/month: 29.40 (6.10) designs and objectives, making it difficult to use 29.30 (6.00) population any assessment tool. This difficulty is due to the \ 1 SHE: Control DTSQb fact that most questionnaires available in the B1 literature have been designed for assessing the – quality of observational studies, having been \ 0.001 p value 0.049 0.405 developed mainly for comparative research between specific types of design or different NSHE/month: intervention arms, which was not the objective hypoglycemia: Health-related QoL questionnaires - 2.80 (2.10) - 2.00 (1.80) - 2.48 (1.61) HFS-II: Hypoglycemia Fear Survey-II. Higher scores indicate increased fear of this study [34–36]. Patients with population C 1 SHE: The data collected in the search showed a from - 9 (maximum negative impact) to 3 (maximum positive impact) Hypo wide heterogeneity, possibly due to the large [1 QoL Quality of Life, SHE severe hypoglycemia event (in past year) variety in study design, participants’ inclusion NSHE/month: criteria, study period and strategy used to reg- hypoglycemia: Patients without - 1.80 (1.90) - 1.80 (1.90) - 1.64 (1.36) ister hypoglycemia (such as percentage of the population ADDQoLa \ 1 SHE: sample in a specific timeframe, rates of events Control per unit of time, etc.), in addition to a lack of B1 consensus in the definition of hypoglycemia. This led to a large variation in the results that of patients Number detailed the estimated burden and costs of 3812 751 hypoglycemia. The data observed in our analysis seem to be diabetes Type of T2DM T2DM comparable to the results of a recent structured literature review by Elliott et al. [37]. These authors identified hypoglycemic event rates in Jódar-Gimeno et al. [21] et al. [24] patients with T1DM and T2DM and categorized references Velasco Depablos- Studies/ them according to the insulin regimen. In patients with T1DM, SH rates ranged from 0.70 b a c Diabetes Ther (2019) 10:375–392 389 to 1.59 episodes per patient per year, and NSH the higher the associated costs and HRU and the rates ranged from 91.00 to 136.80 episodes per worse the QoL. A recent study in Italy collected patient per year. In patients with T2DM, SH data on cases with an established diagnosis of rates ranged from 0 to 0.20 episodes per year; hypoglycemia in emergency departments. The further, NSH ranged from 0.22 to 38.90 episodes results demonstrated that SH in patients with per year depending on the insulin regimen [37]. DM contributes substantially to the economic Although these data cannot be directly com- burden on national healthcare systems [43]. pared with the results of our analysis, we did Another study assessed the total annual, direct, observe some degree of similarity in the num- and indirect cost of SH events in nine European bers extracted in our search and global fig- countries, including Spain. This study, con- ures reported by Elliott et al. [37]. We postulate ducted in 2016, reported an annual total cost that standardizing the definition of hypo- for single SH event of €1076.05, €209.28 and glycemic measures could help in the systematic €0.46 for hospital-treated, medical professional- collection of information, thereby enabling treated and family-treated SH events in Spain, comparison of burden of this complication which in terms of the whole population affected across countries [38]. translates into €32,339,530.58, €19,513,354.64 Additionally, hypoglycemia has been con- and €94,856.70, respectively [44]. Taking these sidered to cause significant consequences that figures into consideration, the prevention of depend on the severity and duration of the hypoglycemia is essential in DM management episodes. Hypoglycemia has been shown to programs given its impact on patients and on result in cardiovascular [39] and cognitive healthcare systems. Failure to account for these impairment, as well as falls, fall-related frac- costs may underestimate management strate- tures, among other events, in certain popula- gies that minimize hypoglycemia. tions, such as pediatric and elderly populations With reference to the QoL information [40, 41]. Further, the cognitive impairment in obtained from our literature search, none of the these populations could worsen the develop- studies reported data on patients with T1DM. ment of functional cognition. On the other Further, only two articles assessed the health- hand, cardiovascular impairment may worsen related QoL and treatment satisfaction in the morbidity associated with hypoglycemia patients with T2DM. We infer that the reason and lead to increased mortality due to sudden for this lack of data may not be a lack of interest death syndrome [30, 40]. Further, the impor- to measure this outcome in patients with T1DM tance of appropriately managing nocturnal but, rather, because we excluded studies from hypoglycemia is well-known as poor manage- our SLR that presented hypoglycemia data ment leads to increased costs and resources, associated with a specific drug or intervention fear, anxiety, poor QoL, and a number of [45]. Patients with T2DM who experienced potential clinical consequences, including con- hypoglycemia had a poorer QoL versus patients vulsions and coma and even death [42]. It has with no such events. Further, patients with been well documented that hypoglycemia may hypoglycemia expressed a higher fear of hypo- lead to emergencies and hospitalization, result- glycemia, and the overall impact on their QoL ing in an increased economic burden on was more negative as previously reported [38]. patients with DM. Differences in study designs, In summary, our analysis of studies included timeframe, health system setting, etc. have in our SLR reinforces the high burden of hypo- hampered the comparability of results between glycemia on patients with DM. However, we studies. We were unable to draw any meaning- consider that existing data are too heteroge- ful comparisons in terms of hospitalization rate, neous to provide any consistent understanding direct and indirect costs in patients experienc- of hypoglycemia episodes. Further, all included ing SH versus NSH due to the heterogeneity of studies had retrospective data, implying that the studies. However, these data are comparable the development of the evidence are faster and with the results in the literature highlighting generally less expensive than in prospective that the more severe the hypoglycemic events, studies. Nonetheless, these data can lead to an 390 Diabetes Ther (2019) 10:375–392 erroneous estimate of the real rate of hypo- Disclosures. Mercedes Núñez is an employee glycemic events due to a lack of systematic of Eli Lilly and company and has no other collection of events in medical records, with conflicts of interest. Silvia Dı́az is an employee these events being more difficult to follow if of Eli Lilly and company and has no other they are NSH episodes. Another aspect to take conflicts of interest. Tatiana Dilla is an into account is the definition of hypoglycemia employee of Eli Lilly and company and has no in these articles, which varies across studies. The other conflicts of interest. Jesús Reviriego is an International Hypoglycemic Study Group has employee of Eli Lilly and company and has no recently worked on the definition and classifi- other conflicts of interest. Antonio Pérez has cation of hypoglycemia and on the ways to participated as a consultant for or has received attribute severity to an event. Such guidelines lecture fees or travel reimbursement from may help researchers to design future studies Sanofi-Aventis, Esteve, GSK, Almirall, Novo better [11]. Nordisk, Eli Lilly, MSD, Boehringer Ingelheim, To conclude, this study delineates hypo- Novartis, Menarini, Janssen and AstraZeneca. glycemia as a frequent acute complication of DM that presents a high clinical, personal and Compliance with Ethics Guidelines. Ethical socioeconomic impact, and it provides infor- approval was not required since this article is mation that could be useful to improve diabetes based on previously conducted studies and did care in Spain. However, considering the not involve experiments with animals or heterogeneity of the methods used in the humans performed by any of the authors. reviewed studies, we believe that in future studies and analyses there is a need to compre- Data Availability. Data sharing is not hend the evolution of hypoglycemia and to applicable to this article as no datasets were determine the factors that may influence and generated or analyzed during the current study. help focus the data obtained in this SLR in terms of epidemiology, HRU and patients’ well- Open Access. This article is distributed being in Spain. under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/ by-nc/4.0/), which permits any non- ACKNOWLEDGEMENTS commercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, Funding. 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