Hypoglycemia: An overview of fear of hypoglycemia, quality-of-life, and impact on costs

Abstract

Background:

The clinical goal in the treatment of diabetes is to achieve good glycemic control. Tight glycemic control achieved with intensive glucose lowering treatment reduces the risk of long-term micro- and macro-vascular complications of diabetes, resulting in an improvement in quality-of-life for the patient and decreased healthcare costs. The positive impact of good glycemic control is, however, counterbalanced by the negative impact of an increased incidence of hypoglycemia.

Methods:

A search of PubMed was conducted to identify published literature on the impact of hypoglycemia, both on patient quality-of-life and associated costs to the healthcare system and society.

Results:

In people with type 1 or type 2 diabetes, hypoglycemia is associated with a reduction in quality-of-life, increased fear and anxiety, reduced productivity, and increased healthcare costs. Fear of hypoglycemia may promote compensatory behaviors in order to avoid hypoglycemia, such as decreased insulin doses, resulting in poor glycemic control and an increased risk of serious health consequences. Every non-severe event may be associated with a utility loss in the range of 0.0033–0.0052 over 1 year, further contributing to the negative impact.

Limitations:

This review is intended to provide an overview of hypoglycemia in diabetes and its impact on patients and society, and consequently it is not a comprehensive evaluation of all studies reporting hypoglycemic episodes.

Conclusion:

To provide the best possible care for patients and a cost-effective treatment strategy for healthcare decision-makers, a treatment that provides good glycemic control with a limited risk of hypoglycemia would be a welcome addition to diabetes management options.

Key words::

• Diabetes
• Glycemic control
• Hypoglycemia
• Fear of hypoglycemia
• Quality-of-life
• Utility
• Healthcare costs

Introduction

Diabetes is a major cause of morbidity and premature mortality. Long-term complications of the disease, which are a consequence of prolonged hyperglycemia, include retinopathy, nephropathy, neuropathy, and cardiovascular disease. These complications have a considerable impact on health, a negative impact on patient quality-of-life1,2, and represent a significant proportion of the economic burden of diabetes. The clinical goal in the treatment of diabetes is to achieve good glycemic control. Tight glycemic control with intensive diabetes therapy prevents or delays microvascular complications, and reduces cardiovascular and all-cause mortality, thus improving health-related quality-of-life. Intensive diabetes therapy to achieve optimal glycemic control is also a cost-effective treatment in that the increased treatment costs are offset by the reduced cost of treating diabetes-related complications and the improvement in quality-of-life3,4.

However, a frequent complication of intensive diabetes therapy is hypoglycemia. The Diabetes Complications and Controls Trial (DCCT) found that intensive therapy in subjects with type 1 diabetes caused a 3-fold increase in the number of hypoglycemic events, compared with those treated less aggressively5. Similarly, the maintenance of tight glycemic control in individuals with insulin-treated type 2 diabetes led to a significant increase in the incidence of hypoglycemia in the UK Prospective Diabetes Study (UKPDS)6. Hypoglycemia is consequently a major limiting factor in the management of type 1 and type 2 diabetes, indeed were it not for the problem of hypoglycemia, glycemia targets would be much easier to achieve.

Here we review the effects of hypoglycemia on patient well-being and the associated costs to the healthcare system and society; and how together these impact on the overall management of patients with diabetes, see Figure 1.

Figure 1.  Impact of hypoglycemia on patients and the healthcare system.

Methods

A search of PubMed was conducted to identify published literature on hypoglycemia in diabetes. The search was originally conducted on 15 October 2009, with no restrictions placed on search date (i.e., search dates were 1966 to 15th October 2009 inclusive), and subsequently updated in March 2011. Search terms included: diabetes; fear and hypoglyc*; (QoL or quality-of-life) and hypoglyc*; hypoglyc* and utilit*; hypoglyc* and cost; hypoglyc* and a search string including euroqol, SF36, EQ-5D, and QALY. Identified publications were screened and relevant studies selected for inclusion in this review. There were no pre-defined inclusion or exclusion criteria, studies were deemed relevant if the reported outcomes were specific to the effects of hypoglycemia (focus on fear of hypoglycemia, HRQoL, and costs), rather than diabetes in general.

Hypoglycemia

Hypoglycemia (low blood glucose) can occur suddenly and with varying severity. Common causes of hypoglycemia include; over-medication with insulin, delays in mealtimes or insufficient carbohydrate intake to match insulin dose, unplanned physical activity, or insufficient carbohydrate intake during physical activity. Symptoms of hypoglycemia include, but are not limited to, pounding heart, trembling, hunger, and sweating. Symptoms often include difficulty concentrating and/or frank confusion7, but can, in severe cases, include seizure, coma, and even death8. Hypoglycemic episodes can be categorized as either severe, events that require the assistance of another person to actively administer a remedy, or non-severe, events which do not require assistance from another person. These non-severe hypoglycemic events may be symptomatic events documented as typical symptoms of hypoglycemia and confirmed by a measured low blood glucose level. They may also be asymptomatic and not accompanied by typical symptoms, but confirmed by a low blood glucose reading, or, more commonly, having typical symptoms, but not confirmed by a blood glucose reading9.

It has been estimated that patients with insulin-treated type 1 and type 2 diabetes experience an average of 43 and 16 non-severe symptomatic hypoglycemic episodes per year, respectively10. For severe hypoglycemia, up to two episodes are experienced annually by patients with type 1 diabetes and approximately one episode in 5 years by patients with type 2 diabetes. Severe hypoglycemia is more common in those with a history of hypoglycemia and with increasing duration of insulin treatment10,11. However, it is difficult to accurately determine the frequency of hypoglycemic episodes due to the lack of consistency in definition and differences in data collection. Patient recall is frequently used, and can be inaccurate12. Also, patient databases can under-estimate the number of episodes, particularly non-severe episodes, as patients infrequently report them to their physician13.

Nocturnal hypoglycemia which occurs during sleep is common, affecting up to 50% of adults and 78% of children, but is often asymptomatic and undetected14. Undetected nocturnal hypoglycemia may contribute to hypoglycemic unawareness, anxiety, and loss of vitality14,15. Severe nocturnal hypoglycemia is suspected to contribute to the ‘dead-in-bed syndrome’ which is responsible for an estimated 6% of all deaths in patients with diabetes below 40 years of age16.

Summary

• Symptoms of hypoglycemia include, but are not limited to, pounding heart, trembling, hunger, and sweating. Symptoms also often include difficulty concentrating and/or confusion.

• Hypoglycemic episodes can be categorized as either severe, events that require the assistance of another person, or non-severe, events which do not require assistance from another person.

• Nocturnal hypoglycemia which occurs during sleep is common, but is often asymptomatic and undetected.

Fear of hypoglycemia

The negative consequences and unpleasant symptoms associated with hypoglycemia may lead to significant anxiety or fear of hypoglycemia in patients with diabetes17. There may also be other psychological manifestations associated with the constant threat of hypoglycemia, such as chronic anxiety which can affect normal sleep and normal domestic and social life. Nocturnal hypoglycemia is particularly feared, as in this state the usual warning symptoms are not felt.

The Hypoglycemic Fear Survey (HFS) was developed to measure the degree of diabetes-related fear experienced by patients and their relatives18. The HFS is divided into sections on worry and behavior; the behavior sub-scale includes items relating to diabetes self-management, and the worry sub-scale is concerned with items relating to anxiety provoking aspects of hypoglycemia17.

Unsurprisingly, the development of fear of hypoglycemia is associated with a history of hypoglycemia. In a study of patients with type 1 diabetes, Irvine et al.19 found that high scores on the HFS behavior scale were significantly associated with an increased frequency of past hypoglycemia episodes. They also reported that higher levels of fear, according to the HFS worry scale, were reported by patients with a lower mean daily blood glucose level and higher mean blood glucose level variability, i.e., those patients at a higher risk of hypoglycemia. HFS worry scores were also found to be positively associated with a history of hypoglycemia in patients with type 1 diabetes by Polonsky et al.20. In another study, patients with type 1 diabetes reported an increased fear of hypoglycemia with increased frequency of severe hypoglycemic episodes, and patients with type 2 diabetes reported increased fear as both the number of mild/moderate and severe episodes increased21. These studies suggest that fear of hypoglycemia is linked with both the severity and frequency of previous hypoglycemic episodes.

Fear of hypoglycemia has also been connected to state and trait anxiety. Polonsky et al.20 observed that in patients with both type 1 and type 2 diabetes there was a correlation between higher scores on the worry scale of the HFS and higher levels of trait anxiety and general fearfulness. In patients with type 1 diabetes, higher scores on the worry scale were also associated with difficulty in discriminating between anxiety and initial hypoglycemia symptoms20. A diminished ability to discriminate between anxiety and hypoglycemia could delay or prevent the patient from responding appropriately to hypoglycemia, and thus a more severe hypoglycemic episode may occur.

In addition to psychological distress, fear of hypoglycemia can have a behavioral impact on diabetes management and metabolic control. In order to avoid hypoglycemia, patients may reduce or omit an insulin dose, which may result in sub-optimal glucose control and increase the risk of long-term complications17. For some patients immediate consequences, such as hypoglycemia, are more tangible than the possibility of future health problems. The impact of hypoglycemia and fear of future hypoglycemic episodes was assessed via a self-administered survey in 202 patients with type 1 and 133 patients with type 2 diabetes13. Following a mild or moderate hypoglycemic episode, 37.8% of type 1 and 29.9% of type 2 diabetes patients reported increased fear of future episodes; and 74.1% and 43.3%, respectively, reported modifying their insulin dose. Following a severe hypoglycemic episode the majority of patients; 63.6% type 1 and 84.2% type 2, reported increased fear of future episodes; and 78.2% and 57.9%, respectively, reported modifying their insulin dose13. A recent survey of 1404 employed individuals with diabetes across the US, UK, Germany, and France found that, of the 1024 individuals taking insulin, 25% decreased their insulin dose following a non-severe hypoglycemic episode22.

Fear of hypoglycemia is also common among the parents of children with diabetes23. Scores on the behavior scale of the HFS, particularly of mothers, suggest that they may maintain slightly higher than optimal glucose levels in their children in order to avoid hypoglycemia24,25.

Fear of hypoglycemia is a major contributor to health-related quality-of-life (HRQoL) in patients with diabetes. Patients with hypoglycemia symptoms report more fear and worry of hypoglycemia and are more affected by their diabetes compared with those without hypoglycemia symptoms26.

Summary

• Fear of hypoglycemia is widespread and impacts patient lifestyle.

• Fear of hypoglycemia is associated with the frequency and severity of previous hypoglycemic episodes.

• Glycemic control can be compromised as fear of future hypoglycemic episodes may result in patients modifying their insulin dose.

Quality-of-life (utility)

Hypoglycemia has a major impact on patient lives in terms of physical, mental, and social functioning; all aspects of life can be affected including employment, driving, travel, and leisure activities27. Hypoglycemia can have both short- and long-term effects on HRQoL28. Short-term effects relate to the symptoms associated with the actual episode and risks of dangerous situations. Long-term effects relate to the negative psychological sequelae, including behavioral changes and fear of future episodes. Patients suffering hypoglycemic episodes are more likely to develop anxiety and panic attacks17,29. Across the studies summarized in Table 1

Table 1.  Studies reporting utility of hypoglycemia.

Study	Patient population	Type of hypoglycemia	Utility reported	Strengths and weaknesses
Levy et al.28	Type 1 and type 2 diabetes	• Symptomatic non-severe	• Quarterly hypoglycemia: 0.91 • Monthly hypoglycemia: 0.87 • Weekly hypoglycemia: 0.75 • Per non-severe event: −0.0033 (for 1 year)	• Interview-based TTO method with specific health states • Patient population in both UK and Canada • Subjects with and without diabetes included • Reports utility score by single non-severe episodes
Matza et al.31	Type 2 diabetes	Fear of hypoglycemia: • Sometimes worry about hypoglycemia • Rarely worry about hypoglycemia	• No complications: 0.89. • Rarely worry: −0.01 • Sometimes worry: −0.03	• EQ-5D • Small patient population • Reports utility scores for 12 hypothetical health states • Reports utility for ‘fear of hypoglycemia’ • Do not report by severity or frequency
Currie et al.35	Type 1 and type 2 diabetes	• None • Mild • Moderate • Severe	• None (type 1/type 2): 0.644/0.711 • Mild (type 1/type 2): 0.758/0.656 • Moderate (type 1/type 2): 0.68/0.49 • Severe (type 1/type 2): 0.522/0.467 • Per non-severe event: −0.0142 for 3 months (corresponding to −0.0036 per year) • Per severe event: −0.047 for 3 months (corresponding to 0.0118 per year)	• EQ-5D • Large patient population (pooled analysis of two surveys) • Reports utility score by episodes and severity • Reports utility for type 1 and 2 diabetes separately
Lundkvist et al.26	Type 2 diabetes	• Symptomatic (mix of severe and non-severe)	• Patients without hypoglycemia: 0.77 • Patients with hypoglycemia symptoms: 0.70	• EQ-5D • Small patient population • Does not report utility by episode and/or severity
Marrett et al.30	Type 2 diabetes treated with OADs	• Severe and non-severe	• No symptom: 0.86 • Any symptoms: 0.78 • Mild: 0.83 • Moderate: 0.77 • Severe: 0.67	• EQ-5D • Large patient population (survey) • Reports utility score by severity • Does not report utility by single episode
Vexiau et al.49	Type 2 diabetes treated with sulfonylurea and metformin	• Severe and non-severe	Mean utility decreased as severity of hypoglycemia increased: • None: 0.801 • Mild: 0.733 • Moderate: 0.698 • Severe/very severe: 0.544	• EQ-5D • Small number of patients in severe hypoglycemia group • Reports utility score by severity • Does not report utility by episode
Alvarez-Guisasola et al.33	Type 2 diabetes treated with OADs	• Severe and non-severe	• None: 0.73 • Mild: 0.71 • Moderate: 0.66 • Severe: 0.54	• EQ-5D survey in seven European countries • Only EQ-5D VAS analysed • Large patient population • Reports utility score by severity • Does not report utility by single episode
Solli et al.34	Type 1 and type 2 diabetes	• Severe and non-severe	• Per index score: 0.023 (type 1 diabetes) • Per index score: 0.004 (type 2 diabetes)	• EQ-5D survey in Norway • Large patient population • Reports utility score by hypoglycemia index. • Normative hypoglycemia index score (unclear why severity and frequency were combined)
Davis et al.32	Type 1 and type 2 diabetes	• Severe and non-severe	Mean utility decreased as severity of hypoglycemia increased: • Nocturnal: 0.77 • Mild/moderate: 0.65 • Severe: 0.53	• EQ-5D • Large patient population • Reports utility score for severe, mild/moderate combined and nocturnal hypoglycemia • Does not report utility by episode

OAD, oral anti-diabetic drug; TTO, time trade off; VAS, visual analog scale.

, results consistently demonstrate a lower health-related utility associated with hypoglycemia (‘utility’ is a measure of quality-of-life, on a scale between 0 (death) and 1 (perfect health), and is used in health economic modeling). However, there is a lack of consistency in terms of hypoglycemic event classification and only two studies report utility per event, while most address one or more events simultaneously or pool different event types.

In a study of 309 Swedish patients with type 2 diabetes, 37% (n = 115) reported hypoglycemic symptoms in the past month (very few patients reported severe events, n = 7). Health-related utility, as measured via the EQ-5D, was significantly lower in patients with hypoglycemia symptoms (0.70) than those without (0.77), (p = 0.006)26. In another study of subjects with type 2 diabetes (n = 1984), 62.9% reported symptoms of hypoglycemia in the past 6 months30. Compared with subjects suffering no hypoglycemic episodes, subjects with hypoglycemic episodes of any severity reported lower HRQoL, as measured by EQ-5D (0.78 vs 0.86; p < 0.0001) and greater fear and worry of hypoglycemia, as measured by the HFS (17.5 vs 6.2; p < 0.001). There was a negative association between symptom severity and HRQoL (p < 0.0001), and a positive association between symptom severity and fear of hypoglycemia (p < 0.0001)30.

The effect of fear of hypoglycemia was explored in a standard gamble study. In this study, participants were asked to rate a basic type 2 diabetes health state describing a patient with good glycemic control. They were then asked to rate the same health state, but with an additional attribute such as fear of hypoglycemia, in this way the disutility of the attribute could be determined. Fear of hypoglycemia was associated with a significant disutility (p < 0.001). Rarely worrying about hypoglycemia was associated with a utility change of −0.01 and sometimes worrying was associated with a utility change of −0.0331, suggesting that increasing fear is associated with decreasing utility.

Other studies have demonstrated that HRQoL decreases with increasing severity and also with increasing frequency of hypoglycemic episodes. A survey of 861 patients with type 1 and type 2 diabetes found that mean health-related utility decreased as the severity of hypoglycemia increased; the mean EQ-5D score as a function of one or more episodes in the past 3 months was 0.53 for severe, 0.65 for mild/moderate, and 0.77 for nocturnal hypoglycemia32. Likewise, a large survey in patients with type 2 diabetes conducted across seven European countries reported scores of 0.54 for severe, 0.66 for moderate, and 0.71 for mild hypoglycemia, compared with 0.73 for no hypoglycemia33. A survey which combined severity and frequency into an index score demonstrated a significant impact of the index score on EQ-5D scores34.

A loss of utility with increasing frequency of non-severe hypoglycemic episodes was observed in a time-trade-off study conducted in Canada and the UK. The estimated utility loss was –0.0033 per event for 1 year28. A UK-based study examined the effect of both frequency and severity of hypoglycemia on health-related utility (EQ-5D) in patients with type 1 and type 2 diabetes35. Data were derived from two previous postal surveys. The study demonstrated that the most predictive estimate of health-related utility was fear of hypoglycemia. Each symptomatic hypoglycemic episode corresponded to a −0.0142 decrement in utility over a 3-month period (corresponding to a utility reduction of −0.0036 per event for 1 year), and each severe event had a utility reduction of −0.047 (corresponding to −0.0118 per severe event for 1 year)35. In an appraisal by the National Institute for Clinical Excellence (NICE) of long-acting insulin a utility reduction of −0.0052 per non-severe event was used36.

Hypoglycemia and quality-of-life

• Hypoglycemia has a large impact on patient lives in terms of physical, mental, and social functioning; all aspects of life can be affected including employment, driving, travel, and leisure activities.

• Quality-of-life decreases with increasing frequency and severity of hypoglycemic events.

• Studies suggest that each non-severe hypoglycemic event reduces utility in the range of −0.0033 to −0.0052.

Impact on costs

Hypoglycemia is not only associated with considerable cost to the individual in terms of their wellbeing, it also represents a substantial cost burden to healthcare systems and society. Costs are incurred when healthcare resources are used to treat a hypoglycemic event (direct costs) and also when absence from work results in lost productivity (indirect costs).

The cost of an episode of hypoglycemia is dependent on the severity of the episode, and ranges from minimal for a mild episode, to very high for a severe episode requiring hospitalization. However, even for episodes defined as the same severity there is wide variation in published cost per episode (Table 2

Table 2.  Studies reporting costs of hypoglycemia.

Study	Patient population	Definition of hypoglycemia	Costs reported	Strengths and weaknesses
Harris et al.38	Type 1 and type 2 diabetes	• Mild, moderate, and severe	Out-of-pocket expenses Type 1 diabetes annual cost/person • Mild-to-moderate hypoglycemia $122.08 • Severe hypoglycemia $129.37 Type 2 diabetes annual cost/person • Mild-to-moderate hypoglycemia $70.96 • Severe hypoglycemia $77.87	• Reports out-of-pocket costs, therefore cost of doctors’ visits, hospitalization, etc. is not included • Doesn’t report number of patients experiencing hypoglycemia • Reports mild/moderate and severe hypoglycemia for type 1 and type 2 diabetes separately • Hypoglycemia was patient reported
Jönsson et al.37	Type 2 diabetes	• Severe hypoglycemia – requiring no medical attention (#1) • Severe hypoglycemia – requiring help of medical personnel, but no hospital admission (#2) • Severe hypoglycemia – requiring inpatient care (#3)	Total cost (direct + indirect) per episode • #1: €63 (€26 + €37) • #2: €380 (€335 + €45) • #3: €3917 (€2807 + €1110)	• Incidence of hypoglycemia based on several published studies • Reports direct and indirect costs per episode for different types of severe hypoglycemia • Definitions of hypoglycemia severity are different to those conventionally used
Heaton et al.50	Type 1 and type 2 diabetes	• Severe hypoglycemia – with physician visit • Severe hypoglycemia – with emergency room visit or inpatient care	Payer perspective • $1186/episode	• Large patient population and large number of hypoglycemic episodes reported • Segregates costs according to treatment site
Leiter et al.13	Type 1 and type 2 diabetes	• Mild/moderate hypoglycemia • Severe hypoglycemia	• Two extra test strips within 24 hours after mild/moderate event, 7–10% leaving work early and 2–9% staying home the next day • Three extra test strips within 24 hours after event, 26–32% leaving work and 20–26% staying home the next day	• Mild/moderate and severe events examined in large sample • Focus on patient’s behavior after event • Survey based
Leese et al.51	Type 1 and type 2 diabetes	• Severe hypoglycemia – blood glucose < 3.5 mmol/l associated with treatment with glucagon or IV dextrose to effect recovery	• Annual direct cost for severe hypoglycemia in Tayside (244 episodes in 160 patients) £92,078, equivalent to £377 per severe episode	• Reports costs of severe hypoglycemia requiring emergency assistance only • Segregates costs according to treatment site
Curkendall et al.52	All diabetes	• Laboratory evidence, blood glucose < 70 mg/dL	• Hypoglycemia that develops during an inpatient stay incurs 39% increase in total cost	• Large inpatient population • Doesn’t distinguish mild, moderate, or severe hypoglycemia • Compares patient populations and doesn’t report cost per episode
Lundkvist et al.26	Type 2 diabetes	• Symptomatic hypoglycemia – blood glucose < 3.3 mmol/l • Severe hypoglycemia – required assistance from another person	Direct costs • Severe hypoglycemia $82.90/episode	• Reports severe hypoglycemia only • Small number of patients experiencing severe hypoglycemia
Reviriego et al.41	Type 1 diabetes	• Severe hypoglycemia – any episode that required external assistance, resulted in loss of consciousness, or required treatment with glucagon or IV glucose	Direct and indirect costs • Severe hypoglycemia €239/episode direct costs and €127/episode indirect costs	• Small patient population, but includes only those who experienced severe hypoglycemia • Reports severe hypoglycemia only • Segregates costs into those for hospitalization, diagnostic analyses, medications, other
Bullano et al.47	All diabetes	• Severe hypoglycemia with appropriate ICD-9^† code	Payer perspective • Mean cost per hypoglycemic event $1807	• Large patient population, but small population experiencing hypoglycemia • Doesn’t distinguish mild, moderate, or severe hypoglycemia
Hammer et al.53	Type 1 and type 2 diabetes	• Severe hypoglycemia	• Treatment costs were higher for patients with type 2 diabetes (Germany, €533; Spain, €691; UK, €537) than type 1 diabetes patients (Germany, €441; Spain, €577; UK, €236)	• Includes all direct costs related to event (drugs, GP visits, hospitalization) • Indirect costs included • Similar results across three EU countries • Based on survey
Rhoads et al.54	Diabetes patients using insulin	• Severe hypoglycemia with appropriate ICD-9^† code	• Annual excess medical expenditures directly associated with hypoglycemic episodes $3241/patient	• Large patient population • Doesn’t distinguish mild, moderate, or severe hypoglycemia • Compares patient populations; those with and those without experience of hypoglycemia • Does not report cost/episode
Brod et al.22	Type 1 and type 2 diabetes	• Non-severe hypoglycemic episode – any episode that did not require assistance from another person	Indirect cost – lost productivity per non-severe hypoglycemic episode • $15.26–$93.47 across the US, UK, Germany, and France	• Large patient population across four countries • Reports indirect costs only

^†ICD-9, International classification of diseases, ninth revision – the severity of hypoglycemia necessary to receive an ICD-9 code assignment is most consistent with the glucose threshold for severe hypoglycemia.

). Cost differences between studies reflect variables such as; the country of the study, the type of costs included, data collection methodologies used, and there is disparity in the definition of hypoglycemia severity across studies. In addition, some studies report the cost per hypoglycemic episode and others report the annual cost per patient, making comparisons difficult. Amongst the studies summarized in Table 2, the lowest reported cost per episode of severe hypoglycemia is $82.90 (direct cost only)26. In this study a severe hypoglycemic event was defined as needing assistance from another person – there were no hospitalizations as a result of hypoglycemia, thus reflecting the lower cost. In contrast, in the study reporting the highest cost per episode of severe hypoglycemia (total cost €3917, direct cost €2807), the definition of severe hypoglycemia was that it required inpatient care37, thus reflecting the much higher cost.

There are more studies that have evaluated the cost of severe hypoglycemia, most likely as the costs associated with such episodes are more defined; hospitalization, emergency services, healthcare professionals, diagnostic tests, treatments administered, etc. Also, because the cost of a severe hypoglycemic episode is higher than that of a mild episode, one may assume it has a bigger impact on the economy. However, the annual costs of non-severe episodes of hypoglycemia should not be overlooked. Due to the greater event frequency non-severe hypoglycemia may incur similar annual costs to severe hypoglycemia. Annual out-of-pocket costs per person attributable to the treatment of hypoglycemia were similar for mild/moderate events and severe events in the study by Harris et al.38. An important cost component related to hypoglycemic events is the increased frequency of blood glucose testing after an event (extra lancets, test strips, alcohol swaps). Studies have demonstrated that, following a hypoglycemic episode, patients monitor their blood glucose more frequently and, consequently, the use of blood glucose tests is increased22,39,40. Leiter et al.13 reported an average of two extra tests within 24 hours of a mild event and three extra tests 24 hours after a severe event. Brod et al.22 reported an average of 5.9 extra tests in the week following a non-severe event.

The contribution of lost productivity to the cost of hypoglycemia is considerable. Lost productivity following a severe hypoglycemic episode is not surprising considering the effects of such events. In the study by Reviriego et al.41, Table 2, lost productivity was estimated to account for ∼35% of the cost of a severe hypoglycemic episode. Leiter et al.13 demonstrated that after a severe event 25–32% individuals went home from work/school and 20–26% stayed home the following day.

However, the impact of non-severe hypoglycemic episodes on productivity is not inconsequential. In the study by Leiter et al.13, following a mild event, 7–10% of individuals went home from work/school and 2–9% stayed home the next day. Similarly, in the survey by Brod et al.22, of 1404 employed individuals with diabetes across the US, UK, Germany, and France, a substantial proportion of respondents across all countries reported missing work as a result of a non-severe hypoglycemic episode. Of respondents who reported having a non-severe hypoglycemic episode at work, 18.3% reported missing work. Episodes experienced outside working hours also had an impact on lost productivity (14.3% reporting missed work) and 22.7% of respondents experiencing a nocturnal non-severe hypoglycemic episode were either late for work or missed a whole day. The estimated lost productivity cost per non-severe hypoglycemic episode ranged from $15–$93 across the four countries, costs were highest for nocturnal episodes22.

Despite the variability in published figures, it is evident that hypoglycemia represents a substantial cost burden to healthcare systems and society. It should also be noted that the cost of hypoglycemia is likely to be considerably more if the negative impact on glycemic control is added into the equation (Figure 1), in that, as patients maintain higher than optimal glucose levels in order to avoid hypoglycemia, the risk of costly long-term complications is increased. There is clearly a paucity of data in this area and more economic studies are needed to accurately define the direct and indirect costs associated with both hypoglycemia and any consequent effects on glycemic control.

Costs of hypoglycemia

• Severe hypoglycemia represents a substantial cost burden to healthcare systems

• The average published cost of treating a hypoglycemic episode is variable

• Due to event frequency the cost of mild/moderate hypoglycemic events is significant with both extra direct costs (for extra lancets and test strips) and indirect costs (absence from work) and

• A paucity of cost data for hypoglycemia identifies an area of future research.

Discussion

This review highlights the considerable negative effects of hypoglycemia on patient quality-of-life and the substantial costs to the healthcare system and society, and how together these factors can impact the overall management of people with diabetes. To provide the best possible care for patients, decision-making based on both clinical and economic evidence is essential. In today’s economic climate, interventions must be shown to be good value for money, with Health Technology Assessment bodies such as the National Institute for Health and Clinical Excellence (NICE) in the UK, the Dental and Pharmaceutical Benefits Agency (TLV) in Sweden, and the Pharmaceutical Benefits Advisory Committee (PBAC) in Australia, utilizing cost-effectiveness thresholds to determine which treatments should be funded through national healthcare systems. The determination of cost-effectiveness takes into consideration the costs and HRQoL associated with a treatment over currently used therapies.

This review focused on studies that reported outcomes specifically related to the effects of hypoglycemia, and it is acknowledged that it may not be fully comprehensive due to the focus on fear of hypoglycemia, HRQoL, and costs. Other clinical outcomes such as increased risk of dementia42 or increased risk of cardiovascular events43 were not in scope for this review. Nevertheless, it gives a clear overview of the impact that hypoglycemia has on the patient, the healthcare system, and society. Studies evaluating interventions to avoid or reduce the incidence of hypoglycemic episodes were not included, as this was not an objective of the review. However, it is evident that such interventions should be a key factor in diabetes management. Studies have demonstrated that improved education on hypoglycemia symptom awareness can reduce the incidence of severe hypoglycemia44,45. Similarly, a study that assigned a ‘care ambassador’ to youths with diabetes to monitor and encourage routine diabetes care visits demonstrated a reduced rate of hypoglycemia in these individuals46. By reducing the rate of hypoglycemia, cost savings have been observed with these education-based programs45,46. Basal human insulin preparations, such as NPH insulin, have a pharmacodynamic profile that falls short of that of endogenous insulin; they have a sub-optimal duration of action, a marked peak effect and high within-patient variability, which can predispose patients to hypoglycemia. However, the newer basal insulin analogs, such as glargine and detemir, have no significant peak activity, longer duration of action, less variability, and are consequently less prone to triggering hypoglycemia. These newer agents consequently fulfil some of the unmet needs for patients with diabetes. Furthermore, they have been shown to be cost-effective compared with NPH insulin, largely due to the cost savings associated with reduced hypoglycemic events47,48.

Conclusions

For diabetes treatment the ultimate goal is good glycemic control, achieved without debilitating hypoglycemic episodes which compromise patient quality-of-life and adherence to their medication – and ultimately increase healthcare costs. Interventions that reduce the frequency and severity of hypoglycemia, whilst maintaining glycemic control are likely to improve patient quality-of-life and reduce healthcare costs, i.e., represent a cost-effective treatment strategy for healthcare decision-makers.

Declaration of interest

TC is an employee of Novo Nordisk who sponsored this project. CF and SG are employees of Abacus International a private health economic consultancy company who were paid by Novo Nordisk to conduct the review. All authors contributed to the design of the review and drafting of the manuscript. All authors read and approved the final manuscript.

Transparency

Declaration of funding

This review was funded by Novo Nordisk A/S.