Hypoglycemic episodes in hospitalized people with diabetes in Portugal: the HIPOS-WARD study

Associated Data

Data Availability Statement
Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA’s data sharing policy, including restrictions, is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to dataaccess@merck.com.

Abstract

Introduction

Diabetes mellitus (DM) is a chronic disease, characterized by hyperglycemia due to insulin deficiency, insulin resistance, or both [1, 2]. In Portugal the estimated prevalence of DM among adults (20–79 years) is 13.3% [3]. The relationship between the burden of hypoglycemia and hyperglycemia has been shifting and evolving [4, 5]. Achieving HbA1c targets < 7% (53 mmol/mol) has been shown to reduce microvascular complications of both type 1 and type 2 diabetes when instituted early in the course of disease [6]. International guidelines recommend lowering HbA1c to < 7.0% in most patients and to keep glycemic control well balanced and managed [7, 8]. However caution is needed in treating diabetes aggressively to near normal HbA1c goals in people with advanced age/frailty, with longstanding type 2 diabetes with or at significant risk of cardiovascular disease. Hypoglycemia is a limiting factor in achieving glycemic control and often related to poor clinical outcomes in patients with DM, making it difficult to manage [9–11]. Sometimes requiring assistance/hospitalization, hypoglycemia has a significant impact in patients’ lives. Typically, hyperglycemia related admissions (diabetes ketoacidosis (DKA), hyperglycemic hyperosmolar non-ketotic syndrome (HHNS)) are the major cause of DM related admissions in non-surgical wards. In the last decade there has been an increasing drive to improve glycemic target achievement with mean HbA1c at the primary care level dropping from 7.8% in 2010 to 6.8% in 2015 [3, 12]. While lowering HbA1c might be associated with an increase in the risk of hypoglycemia, Portugal has had a high uptake of innovative anti-hyperglycemic agents associated with lower risk of hypoglycemia (DPP4 inhibitors, SGLT2 inhibitors and GLP1 analogues) and a decrease in the use of sulphonylurea (SU) [3]. It is unclear if this trend impacted diabetes admissions.

Data from HIPOS-ER (HIPOS-Emergency Room) [13, 14] showed that 44.1% of patients with type 2 diabetes (T2DM) admitted to the emergency room with hypoglycemic episodes due to anti-hyperglycemic therapy were admitted to internal medicine/endocrinology wards, and discharged after 5 days on average. Results confirmed that hypoglycemia places a significant burden both to patient and society, accounting for adverse clinical and financial outcomes. In Portugal there is still a gap in the understanding of hypoglycemia admissions, hypoglycemia risk factors, and how they have evolved since the data from HIPOS-ER increased awareness of the magnitude of the problem.

This observational study aimed to evaluate the ratio of DM patients admitted in the ward due to hypoglycemia episodes vs. hyperglycemic emergencies, to calculate the prevalence of previously described hypoglycemia risk factors and diabetic complications in this population and to characterize patients by treatment group and type of diabetes.

Materials and methods

The observational, cross-sectional, multicentered HIPOS-WARD (Hypoglycemia In Portugal Observational Study – WARD) study primarily assessed the proportion of hypoglycemic and hyperglycemia emergency episodes in DM treated adult patients that accounted for the admission to an endocrinology/internal medicine ward due to hypoglycemia. The proportion of hypoglycemia/hyperglycemia emergency episodes was also evaluated for T2DM patients.

Patients with diabetes and a hypoglycemic episode were characterized demographically and clinically (type and duration of diabetes, treatment group, diabetes complications, comorbidities, history of hypoglycemia, HbA1c, glycemia, repeated episodes during hospitalization). The prevalence of previously described hypoglycemia risk factors and diabetic complications were also calculated as well as hypoglycemia literacy of patients. Exploratory analyses by treatment group and type of diabetes were performed.

The study population included adult (≥18 years old) patients with diabetes treated with a known anti-hyperglycemic agent, hospitalized in the ward for a hypoglycemia event or as a result of a hypoglycemia episode in the non-hospitalized setting, in one of the 16 participating medical units (18 departments).

Hypoglycemia was defined according to the American Diabetes Association (ADA) [15, 16] definition of a modified Whipple’s triad (signs and symptoms suggestive of hypoglycemia that resolve with the administration of carbohydrates or glucagon and a glycemia < 70 mg/dL). Diagnosis was made by the attending ER physician, and ward admission was considered if: patients were admitted from the ER due to hypoglycemia; and/or patients that had an episode of hypoglycemia while at the hospital (outpatient clinic/other non-hospitalized setting) were admitted as a direct result of that hypoglycemia. Hospitalization was considered for patients admitted for at least 24 h for diagnosis/treatment.

Hospitalized hyperglycemic emergencies included DKA, HHNS and significant hyperglycemia. DKA and HHNS were defined according to ADA’s criteria [17]. Significant hyperglycemia was defined as glycemia ≥600 mg/dL or clinical symptoms (polyuria, polydipsia). Hyperglycemic emergencies were used to calculate the ratio hypoglycemia/hyperglycemia and not further assessed in this study.

Hypoglycemia literacy was evaluated by a non-validated questionnaire created and performed by the investigator to the patient/caregiver (if the patient was unable). Questions focused on the knowledge of the signs and symptoms of hypoglycemia and knowledge of strategies to prevent hypoglycemia.

Treatment subgroups were classified according to the anti-hyperglycemic agent therapy regimen: i) insulin-based therapy (included patients on insulin monotherapy/on insulin with or without other non-secretagogue drugs); ii) secretagogue-based regimen (included patients on secretagogue monotherapy (sulphonylurea and/or meglitinides), with/without other non-secretagogue drugs); iii) non-secretagogue-based therapy (included patients on drugs that do not include a secretagogue type drug (i.e. metformin, acarbose, glitazones, DPP4 inhibitors, GLP1 receptor agonists, SGLT2 inhibitors)); iv) combination of insulin and secretagogue (included patients that were treated with at least one insulin and one secretagogue type drug (other drugs may have been present)).

The total study duration was 21 months (November2016–August2018).

All study procedures were performed under standard clinical approach. Observational study data was collected by physicians from hospitalization admission to discharge or death. Data collected included sociodemographic, anthropometrics; diabetes characterization, risk factors; characterization of hypoglycemia episode; hypoglycemia literacy evaluation; laboratory and diagnostic exams; and discharge information.

The study was approved by the Hospital’s or local Ethics Committees and by the National Committee for Data Protection. Written informed consent was obtained from all participants.

Results

Discussion

In the HIPOS-WARD study we evaluated patients with diabetes and a hypoglycemic episode that caused a hospitalization, focusing on the clinical characterization.

The hypoglycemia/hyperglycemia ratio was 0.27 for all DM patients and 0.38 in T2DM patients. For each hypoglycemia episode, there were approximately 4 hyperglycemic emergencies for all DM patients, and 3 for T2DM patients. These results were not as expected, and might be explained due to the safer and more effective state of hypoglycemia drugs, which lead to its decreasing occurrence. Additionally, the burden of hypoglycemia in inpatients in Portugal appears to be relevant but lower than the burden of hyperglycemia both in T1DM and T2DM. As no longitudinal data is available it is unknow how the situation has evolved over recent years. Lipska et al. [5] described between 1999 and 2011 in the USA a steady increase of admissions due to hypoglycemia, eventually overtaking admissions due to hyperglycemia in the first decade of this century. However, this was before therapies with a lower potential of hypoglycemia (DPP4i, SGLT2i and GLP1 analogues) were introduced or widely used [18, 19]. It is unknown if wider use of these agents, as well as decreasing use of SU type drugs and growing awareness of the risk of hypoglycemia reversed the trend once more. More recent insulin formulations are also associated with lower rates of hypoglycemia in T1DM and in some settings for T2DM [20–22]. In Portugal the use of anti-hyperglycemic agents with a low risk of hypoglycemia—DPP4i in particular—has increased substantially since early in the twenty-first century representing 25% of all oral drugs in 2015, while SU’s dropped from 54% in 2000 to 20% in 2015 [3]. Furthermore, increased awareness of hypoglycemia conveyed by national and international guidelines [21, 23] as well as the national studies HIPOS-ER [13], on severe hypoglycemia and HIPOS-PHARMA [24], a pharmacy level evaluation of mild/moderate hypoglycemia, might have contributed to a blunting in the rates of hypoglycemia. Also, glycemic target achievement in the National Health System (NHS) primary care has improved between 2010 and 2015 [3, 12]. This, overall, might suggest the importance of anti-hyperglycemic agent with a lower risk of hypoglycemia in containing the risk of severe hypoglycemia.

HIPOS-WARD only focused on the most severe hypoglycemia occurrences that lead to hospitalization and identified its clinical and economic burden [25] but does not cover the entire scope of the hypoglycemia problem.

Unfortunately, the lack of longitudinal data in Portugal cannot exclude the possibility–although unlikely–that the rate of hypoglycemia is still increasing. Irrespective of the causes our data reinforces the importance of anti-hyperglycemic agent with a low risk of hypoglycemia either as a contributing factor to curb it’s putative increase or to limit a future increase.

HIPOS-WARD reinforces the relevance of these therapies: the occurrence of hypoglycemic episodes was higher in patients on an insulin-based therapy followed by those on a secretagogue-based therapy, which are indeed associated to additional side effects and an increased risk of hypoglycemia [26–28]. Insulin+secretagogue therapy accounted for 10.2% of the sample and 9.7% were on non-secretagogue regimen. Therapeutic regimens based on or including secretagogues were more common in elderly patients and those followed in primary healthcare, which might be associated to treatment cost restrictions or related to clinical inertia. Drug prescription is indifferently managed by specialists/GPs and new antidiabetic drugs can be freely prescribed by all physicians. Although these patients are mostly seen at a primary care setting they are usually evaluated by in-hospital consultation when they fail to achieve control and need to add injectable therapy—like insulin—to their care or when they show complications from the disease. Our findings have shown that the insulin+secretagogue based therapy group was statistically associated with risk factors including disease duration and age, having higher proportion of patients with coronary heart disease, peripheral artery disease and osteoporosis. Also, a large group of patients reported nephropathy, a conventional risk factor for hypoglycemia in people with diabetes, due to multiple factors as the decrease of insulin clearance and it’s degradation in peripheral tissues, reduction in glycogen stores, reduced renal gluconeogenesis [29–31]. Also, commonly used antidiabetic drugs are renally excreted and have a prolonged half-life in patients with CKD, predisposing them to episodes of hypoglycemia. The confluence of these factors may contribute to a greater risk for hypoglycemia among patients with CKD and may be an unintended consequence of therapy to treat hyperglycemia in these patients [32]. Patients on secretagogue-based therapy had a higher proportion of cerebrovascular disease and heart failure. Again, this denotes the frailty of patients at higher risk of hypoglycemia and the importance of adopting strategies and therapies that minimize its risk [33, 34]. The actual increasing number of new AHAs with an intrinsic low risk of hypoglycemia are an important therapeutic option, however, patients and caregivers education are also crucial [35, 36].

This study also included T1DM patients, representing the first Portuguese national dataset on this population. Patients with T1DM, due to intensive insulin therapy, are usually associated with a higher risk of hypoglycemia [10] and in our study 85.7% of T1DM vs only 40.4% of T2DM had a hypoglycemic episode in previous 12 months. However, during the study period only 10.2% of the total hypoglycemia admissions were in T1DM and so hypoglycemia in T2DM represented the biggest burden of hypoglycemia events requiring hospitalization, highlighting that hypoglycemia is a very relevant issue in T2DM. It is well known that hypoglycemia triggered by secretagogues can be long-lasting, more severe and recurrent. Although expected, this data also shows that T1DM have a higher burden of microvascular complications whereas T2DM more atherosclerotic complications. This data alert to the importance of a patient centered approach to choosing appropriate pharmacologic treatment of blood glucose, including important comorbidities such as atherosclerotic cardiovascular disease. The rates of microvascular complications in T2DM ranged between 20.9–46.2% underscoring the importance of glycemic control on both groups in order to prevent these complications with great impact in quality of life [37–39].

Elderly, functionally dependent individuals (frail/non-frail) are exposed [40] and identified to have higher risk of hypoglycemia [10, 16, 33, 41–44]. Therefore, these patients should be cared for in a different way to mitigate the risk of this and other adverse events. Our results are consistent with a ward admitted patient population having T2DM, predominantly elderly, frail, with multiple comorbidities and moderately dependent, mainly treated with insulin and secretagogues. These hospitalizations were frequently preceded by similar and recent episodes, which reinforces the idea that these patients usually present recurrent hypoglycemia episodes, increasing the risk to develop complications at each occurrence. Moreover, more than half of patients need help (total/partial) to manage their diabetes treatment, denoting the frailty of these individuals at high risk of inadequate use of drugs and consequently at risk of having more severe episodes related to uncontrolled glycemia. The main risk factors for a hypoglycemia event were polypharmacy (> 5 distinct drugs, for one or more conditions) [45, 46] and age > 75 years, and heart failure was the most frequent risk factor for complications after an event.

Results are consistent with HIPOS-ER study [13], which triggered HIPOS-WARD by showing that, in a setting of ER, more than 40% of T2DM patients with severe hypoglycemia had been hospitalized as consequence of the event.

Overall, our data suggests that while hyperglycemia is still the major cause of hospital admissions for both types of diabetes, over 60% of all hypoglycemia admissions happened in patients with functional impairment and, in T2DM, elderly patients. This underscores that there is still work to be done in terms of avoiding clinical inertia and recurrence of hypoglycemic events in this patient group, questioning the use of secretagogue-based therapy and some combinations like SU + insulin, reinforcing the importance to increase the number of anti-hyperglycemic agents with low risk of hypoglycemia as a therapeutic option [35, 36] and developing educational and/or support programs for patients/caregivers, especially designed for populations at higher risk, in order to minimize the risk for complications.

Overall, the most likely causes of hypoglycemia were due to carbohydrate deficit, by a cause secondary to acute illness or related to insulin therapy. These potential causative factors should be addressed by systematically discussing it with all patients who are at increased risk of hypoglycemia as well as with their caregivers. For three quarters of patients hypoglycemia was the main driver for ward admission and the most frequent complications as result of the hypoglycemia episode that triggered the admission were neurologic and infection. This might indicate the Portuguese NHS approach by both specialists and primary care providers might have curbed the rates of hypoglycemia despite improving in diabetes target achievement. The growing use of new antihyperglycemic drug classes which have an intrinsic lower risk of hypoglycemia might be contributing to a decrease in the prevalence of severe hypoglycemia.

This study was not randomized or controlled, therefore results are primarily descriptive. Its observational nature may be considered a limitation and since no individual drug level information has been collected (only anti-hyperglycemic agent therapy group as pre-determined), it was not possible to determine specific causal associations. In order to minimize selection bias, patients were enrolled in a consecutive manner, in different centers throughout the country, which gives a wider overview of the information collected [41, 42]. However, there was clearly a higher number of T2DM patients and a low number of patients on non-secretagogue and insulin+secretagogue therapies in this study.

As a strength of the study we point out the specific tools (study questionnaire and literacy questionnaire) designed to adequately capture the information in accordance with its cross-sectional nature [44, 47]. Also, this study was part of an integrated series designed to evaluate adult patients with diabetes in pharmacies–HIPOS-PHARMA [24], in the emergency room–HIPOS-ER [13, 14], and hospitalized–HIPOS-WARD, contributing to a full country perspective.

In conclusion, in this study hyperglycemic emergencies were more frequent while the lack of longitudinal data doesn’t allow for trend projection. Elderly T2DM patients with functional impairment represent the bulk of admissions for hypoglycemia, highlighting there is still the need to optimize therapy in terms of the potential for hypoglycemia in this patient group, balancing glycemic target achievement with hypoglycemia avoidance. The study confirms higher rates of hypoglycemia in T1DM, highlighting the critical problem this complication represents, the overwhelming contribution of T2DM to the total burden, and the importance of this complication for both patients and the National Health System. Future efforts should also be taken to better characterize and prevent hyperglycemic occurrences especially in T2DM patients.

Acknowledgments

Authors’ contributions

Sílvia Alão contributed to conceptualization, methodology, project administration, validation, and review of final version. João Conceição contributed to conceptualization, methodology, project administration, investigation, validation, original draft and review/editing of final version. Jorge Dores contributed to conceptualization, methodology, data curation, validation, original draft and review/editing of final version. Lèlita Santos contributed to conceptualization, methodology, data curation, validation, original draft and review/editing of final version. Francisco Araújo contributed to conceptualization, methodology, data curation, validation, original draft and review/editing of final version. Estevão Pape contributed to data curation and review of final version. Mónica Reis contributed to data curation and review of final version. Árcia Chipepo contributed to data curation and review of final version. Edite Nascimento contributed to data curation and review of final version. Ana Baptista contributed to data curation and review of final version. Vanessa Pires contributed to data curation and review of final version. Carlos Marques contributed to data curation and review of final version. Adriana De Sousa Lages contributed to data curation and review of final version. João Pelicano-Romano contributed to investigation, validation, original draft and review/editing of final version. Paula M de Jesus contributed to project administration. The author(s) read and approved the final manuscript.

Funding

This work was supported by Merck Sharp & Dohme (MSD) Portugal [MK0431–854]. The study was scientifically promoted by the Portuguese Society of Diabetology (Sociedade Portuguesa de Diabetologia), Portuguese Society of Endocrinology, Diabetes and Metabolism (Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo) and Portuguese Society of Internal Medicine (Sociedade Portuguesa de Medicina Interna).

Availability of data and materials

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA’s data sharing policy, including restrictions, is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the EngageZone site or via email to dataaccess@merck.com.

Ethics approval and consent to participate

The study was approved by the Hospital’s or local Ethics Committees and by the National Committee for Data Protection.

Consent for publication

Not applicable.

Competing interests

Sílvia Alão is an employee of MSD Portugal.

Lèlita Santos has served as a paid lecturer and/or a consultant to Merck Sharp & Dohme, Lda, Portugal, and Astra-Zeneca Portugal.

Jorge Dores has served as a paid lecturer and/or a consultant to Merck Sharp & Dohme, Lda, Portugal, Abbott Diagnostics, Portugal, Astra-Zeneca Portugal, Boehringer-Ingelheim, Portugal, Lilly Produtos Farmacêuticos, Portugal, Novartis Farma, Novo-Nordisk Portugal and Sanofi, Portugal.

Francisco Araújo has served as a paid lecturer and/or research grant to Merck Sharp & Dohme, Lda, Portugal, Astra-Zeneca Portugal, Medinfar Portugal.

João Conceição is an employee of MSD International GmbH (Singapore Branch).

João Pelicano-Romano is an employee of MSD Portugal.

Paula M de Jesus is an employee of MSD Portugal.

Estevão Pape, Mónica Reis, Árcia Chipepo, Edite Nascimento, Ana Baptista, Vanessa Pires, Carlos Marques, Adriana De Sousa Lages have no conflict of interests.

Footnotes

References