Fear of hypoglycemia—An underestimated problem

Abstract Introduction Fear of hypoglycemia (FOH) is a phenomenon that affects people with diabetes experiencing hypoglycemia. On the one hand, FOH is an adaptive mechanism that helps to protect patients from hypoglycemia and its consequences. On the other hand, the non‐normative level of FOH causes anxiety and tension, disturbs normal functioning, and makes normoglycemia maintenance difficult. Objective The main objective of this review was to describe factors influencing FOH and methods of measurement of FOH levels. Moreover, we highlighted the impact of the new technologies used in diabetes therapy on FOH and different therapeutic possibilities helping patients cope with excessive levels of FOH. We also presented clinical cases of patients with high FOH levels met in clinical practice and discussed methods to better diagnose and assist people with this kind of problem. Methods We searched for studies and articles via PubMed using the keywords fear of hypoglycemia, diabetes, and hypoglycemia. From screened documents identified from literature search, 67 articles were included in our review. Results We divided results from literature screening into five parts: fear of hypoglycemia and hypoglycemia definition, risk factors for the FOH, methods of measuring levels of FOH, therapies for the FOH, and modern technologies. We also described clinical examples of abnormal fear of hypoglycemia in patients. Conclusion The review highlights the importance of taking into consideration fear of hypoglycemia phenomenon in diabetic patients in everyday clinical practice.

TA B L E 1 Categories of hypoglycemia according to the American Diabetes Association (2021)

Level of hypoglycemia Criteria/description
Level 1 Blood glucose value between 3.0 mmol/L (54 mg/dl) and 3.9 mmol/L (70 mg/dl) Level 2 Blood glucose level lower than 3.0 mmol/L (54 mg/dl) Level 3 Severe hypoglycemic events characterized by altered mental and/or physical status that require assistance for resolution (e.g., cognitive impairment or behavioral disturbances) (Kępiński, 2020;Szadkowska, 2012). For this reason, anxiety might mask the symptoms of hypoglycemia (Boyle et al., 2004).
Recurrent hypoglycemia may result in the fear of hypoglycemia (FOH) (Wredling et al., 1992). It is a state of unpleasant tension, anxiety, and discomfort, manifested by, among other things, palpitations, shortness of breath, or hand tremors, which are present in many diabetic patients who experience hypoglycemia or are at risk of developing it (Krawczyk et al., 2020). A high level of FOH in patients might lead to behaviors inappropriate to the actual risk of hypoglycemia, suboptimal metabolic control of diabetes, and a significant reduction in the patient's quality of life (Böhme et al., 2013). This problem is often underestimated in everyday clinical practice.

Definition
Hypoglycemia is diagnosed when the blood glucose level drops below 3.9 mmol/L (70 mg/dl) regardless of clinical symptoms (Araszkiewicz et al., 2021). Symptoms of hypoglycemia also may occur with higher blood glucose levels, especially if a rapid decrease in blood glucose has occurred (Szadkowska, 2012). Clinically significant hypoglycemia is diagnosed when the blood glucose level is lower than 3.0 mmol/L (54 mg/dl). Severe hypoglycemia is an episode requiring the help of another person, regardless of blood glucose level (Araszkiewicz et al., 2021). Table 1 presents the categories of hypoglycemia according to the American Diabetes Association (2021).
Hypoglycemia is the most common acute complication of diabetes treatment (Szadkowska, 2012). It is a consequence of the pursuit of optimal blood glucose control to reduce the risk of long-term complications in diabetes (Duckworth et al., 2009;Inzucchi et al., 2012;Nathan et al., 1993;Patel et al., 2008 (Szadkowska, 2012).
The risk of hypoglycemia depends on the type of antihyperglycemic therapy. The risk is higher in patients treated with insulin as well as sulfonylureas and glinides that stimulate the secretion of endogenous insulin (Balijepalli et al., 2017). The main reasons for the occurrence of hypoglycemia are the failure to adjust the insulin dose to food intake or physical activity (Cryer, 2013). Liver insufficiency, renal failure, hypopituitarism, hypothyroidism, or adrenal cortex insufficiency coexisting with diabetes also contribute to an excessive reduction in blood glucose levels (Kalra et al., 2013). Complications of hypoglycemia include traumas, cardiovascular events, and progressive dementia (Amiel, 2021).
Recurrent hypoglycemic episodes may lead to hypoglycemia unawareness, when the patient does not experience symptoms of hypoglycemia despite low blood glucose levels. Therefore, patients have more frequent and longer episodes of hypoglycemia, which they are unaware of (Vignesh & Mohan, 2004). Recurrent episodes of hypoglycemia also influence the occurrence and intensification of FOH (Wredling et al., 1992).

Fear of hypoglycemia
Depending on its intensity, the FOH might be normal or abnormal. Normal fear, otherwise known as adaptive, allows the patient to respond adequately to the risk of hypoglycemia. It is an evolutionarily developed defense mechanism against anticipated danger. On the other hand, abnormal fear is persistent, recurrent, or objectively inappropriate to the risk of hypoglycemia, and its intensity might be too low or too high (Óhman, 2005). Low levels of fear cause the disregard of risk, underestimation of symptoms, and creation opportunities for subsequent episodes of hypoglycemia, which increases the risk of potentially life-threatening hypoglycemia or its complications. On the other hand, excessively high fear causes constant anxiety, emotional stress, discomfort, and insecurity, which in turn leads to a significant reduction in the self-assessed quality of life in patients with diabetes and may trigger or intensify depressive disorders. Because of these features, abnormal FOH can be classified as a cluster of anxiety disorders (Krawczyk et al., 2020). Moreover, patients with high levels of fear tend to maintain higher glucose levels to prevent hypoglycemia, which may lead to suboptimal metabolic control of diabetes and increase the risk of long-term complications (Krawczyk et al., 2020). The FOH is manifested as the fear of the negative impact of hypoglycemia on health and life, fear of an emergency, fear of losing self-control, and the onset of behavioral or cognitive disorders, which may result in behaviors that are generally socially unacceptable (Böhme et al., 2013;Gjerløw et al., 2014). All of this determines the daily functioning of patients. The FOH concerns not only diabetic patients but also their parents, caregivers, partners, and other people from their close environment (Monaghan et al., 2009).  Gjerløw et al., 2014;Irvine et al., 1992;Kępiński, 2020).

Risk factors for the FOH
There is also a negative correlation between the intensity of FOH and education level (Gonder-Frederick et al., 2011). Not only the severity but also the frequency of previous hypoglycemic episodes is related to the intensity of the FOH (Irvine et al., 1992;Polonsky et al., 1992).
The experience of an episode of severe hypoglycemia in the last 12 months, as well as the unawareness of hypoglycemia associated with a higher risk of future hypoglycemia, significantly increases the level of fear (Anderbro et al., 2010;Böhme et al., 2013). Moreover, the level of fear increases with the number of symptoms experienced during mild hypoglycemic episodes (Anderbro et al., 2010(Anderbro et al., , 2015. The occurrence of hypoglycemia and fear is higher at night, which deteriorates sleep quality and, for this reason, has a negative effect on the patient's quality of life (Gjerløw et al., 2014;Martyn-Nemeth, Quinn, Phillips, et al., 2014).
The FOH may determine the behavior of patients and influence their insulin dosing, physical activity, and food intake (Brazeau et al., 2008;McCoy et al., 2013;Zander et al., 2014). When there is an anticipated risk of low blood glucose levels, patients consume additional meals, especially those rich in simple carbohydrates, and tend to snack at night (Desjardins et al., 2014;Richmond, 1996). This behavior is particularly common in women with type 1 diabetes (Martyn-Nemeth, Quinn, Hacker, et al., 2014). In one study on patients with type 1 diabetes, the mean number of hypoglycemic episodes was 5.7 ± 3.8 per week, which was associated with the intake of an additional 600 kcal per week (Molęda et al., 2017). A high level of FOH is associated with greater differences in blood glucose levels and increased caloric intake and prevents patients from taking up physical activity since they exercise less frequently and less intensively (Brazeau et al., 2008;Martyn-Nemeth et al., 2017). Another study revealed the highest level of FOH in patients with low mean glucose levels and high glycemic variability (Irvine et al., 1992). There was no clear correlation between  (Cox et al., 1987). Currently, it is widely used in a modified version (HFS-II), which is a 33-item questionnaire organized into two subscales. The first subscale concerns behaviors aimed at preventing hypoglycemia, while the second subscale concerns worries associated with hypoglycemia and its consequences. The validity of each item in the questionnaire is scored by the patient from 0 (never) to 4 (always) depending on their personal experience from the last 4 weeks. Then, the scores obtained in both subscales are summed. The maximum score is 60 points for the first subscale and 72 points for the second subscale. The higher the total score obtained for the whole questionnaire is, the higher the level of fear in the patient. Both subscales of the survey also can be analyzed separately. The HFS was originally developed for adult patients with type 1 diabetes, but over time, it found its application in patients with type 2 diabetes, pregnant women, and children. HFS-II also has been translated into and adapted for many languages (Haugstvedt et al., 2010;Jeddou et al., 2017).

Other scales examples
Other shown that participants in these programs responded earlier and more appropriately to low glucose levels, which reduced the number of hypoglycemic episodes (Cox et al., 2004(Cox et al., , 2001Hermanns et al., 2007). Moreover, BGAT-2 training contributed to a reduction of glycemic variability, a reduction of the intensity of FOH and depressive symptoms, and an improved quality of life for the participating patients with type 1 diabetes (Cox et al., 2001). On the other hand, HypoCOMPaSS, aimed at patients with hypoglycemia unawareness, emphasizes the prevention of hypoglycemia, strict control of blood glucose levels and identification of circumstances that could lead to a drop in glucose levels. Patients treated with intensive insulin therapy used an application to calculate their insulin dose (bolus calculator) while simultaneously using the continuous glucose monitoring system or taking self-measurements of blood glucose with a glucose meter. In all patients, a significant reduction in the frequency of hypoglycemia, intensity of FOH, and improved awareness of hypoglycemia and glucose variability were observed, and 24 weeks after the end of the training, the patients still controlled their glucose levels more effectively than before the study (Little et al., 2014).
Psychoeducational programs are aimed not only at patients but also people from their close environment. Reducing Emotional Distress for Childhood Hypoglycemia in Parents (REDCHiP) is a program that includes seven group sessions and three individual sessions conducted using telemedicine techniques. Participating parents of children with type 1 diabetes were re-educated about the disease affecting their children and learned about methods of cognitive and behavioral therapy.
Studies using REDCHiP have shown a significant reduction in the levels of FOH and stress in parents Patton et al., 2020).

Modern technologies and FOH
New devices used by diabetic patients allow for more accurate glycemic monitoring and better metabolic control of diabetes (Wunna et al., 2021).

Flash glucose monitoring systems
The flash glucose monitoring system (FGMS) consists of a sensor that continuously measures interstitial glucose level and a reader device.
After swiping the reader device over the sensor, a patient obtains his/her current interstitial glucose level and 8-h trend graph. FGMS allows to demonstrate prolonged higher glucose levels after meals and night hypoglycemia episodes that a patient is often unaware of. The 18-month study trial by Rouhard et al. indicates that using FGMS in patients with type 1 diabetes may not only improve glycemic control but also reduce FOH in the behavioral subscale of the HFS-II questionnaire (Rouhard et al., 2020).

Bolus calculator
The bolus calculator is a function of an insulin pump, glucose meter, or a mobile application designed to precisely calculate the insulin dose required in a given situation, appropriate to the amount of carbohydrates taken in a meal and adjusted to the current glucose level and the amount of active insulin still circulating in the body. Studies on patients with type 1 diabetes treated with multiple insulin injections showed that the use of an automatic bolus calculator was associated with reduced FOH (Barnard et al., 2012;Vallejo Mora et al., 2017).

Personal insulin pump
The use of a personal insulin pump in the treatment of diabetes reduces the number of hypoglycemic episodes, especially severe episodes (Quirós et al., 2016). Studies also have revealed that patients treated with a personal insulin pump are characterized by a lower FOH measured by the behavioral subscale than patients using multiple insulin injections with pens (Barnard & Skinner, 2008). The STAR 3 randomized clinical trial compared the metabolic control of diabetes in patients treated with a sensor-augmented personal insulin pump and the metabolic control of patients using multiple insulin pen injections with self-measured blood glucose. Patients' quality of life and satisfaction with treatment were also considered in this trial, including the FOH. After a 12-month follow-up, improved hypoglycemic behavior scores and a reduced level of worry were found in patients treated with a sensor-augmented personal insulin pump (Rubin & Peyrot, 2012).

Closed loop system
A closed loop system, also known as an artificial pancreas, aims to deliver insulin in the most physiological way possible. It consists of an insulin pump and a sensor that continuously measures blood glucose coordinated by an algorithm that allows insulin delivery in response to changes in blood glucose levels. In a study investigating the effect of an artificial pancreas on the level of FOH, the 4-day night time use of this system was associated with reduced fear and high treatment satisfaction in patients with type 1 diabetes (Ziegler et al., 2015).

Low glucose suspension function
The low glucose suspension function automatically suspends insulin delivery by the personal insulin pump at low blood glucose levels. In the CGM TIME trial, which involved 144 children with type 1 diabetes for at least 1 year, patients were treated using a sensor-augmented personal insulin pump with the LGS function, and parents completed the HFS-II questionnaire at baseline and after 12 months of treatment.
The study demonstrated that personal insulin pump therapy with the LGS function significantly reduced the FOH (Verbeeten et al., 2021).
Another technology used in sensor-augmented personal insulin pumps predicts drops in glucose levels 30 min before reaching a given value and allows insulin delivery to be automatically suspended and then automatically continued when the downward trend in blood glucose has subsided. A study on 21 children with type 1 diabetes investigating the effectiveness of this system for the prevention of hypoglycemia revealed that this function helped reduce the risk of hypoglycemia without a significant negative effect on the metabolic control of diabetes or an increased incidence of ketoacidosis (Villafuerte Quispe et al., 2017).

CONCLUSIONS
Adaptive FOH in a patient suffering from diabetes has positive aspects and allows for a response appropriate to the risk of hypoglycemia.
On the other hand, abnormal fear causing constant tension, anxiety, restriction of freedom, and reduced quality of life is pathological and should be identified early enough by the caregivers of patients with diabetes. The widespread use of hypoglycemia fear surveys in clinical practice to assess the level of fear during a visit to a diabetologist could improve the quality of diabetes care. Equally important is the competent and early identification of patients at risk of developing abnormal fear by analyzing the patient's history and treatment outcomes. An important issue that can prevent hypoglycemia, ensure good metabolic control and adequate self-control is ongoing patient education by qualified personnel, including with the use of psychoeducational training designed for this specific purpose. Advanced therapeutic technologies, such as continuous glucose monitoring, personal insulin pumps, the bolus calculator function, and the low glucose suspended function, especially when combined, also may help reduce the FOH. Offering participation in individual or group psychotherapeutic sessions aimed at cognitive-behavioral therapy to patients with FOH who meet the criteria for anxiety disorders at an appropriately early time may help reduce the level of fear and improve the quality of life of these patients.
Consideration of FOH is a vital aspect of diabetes care because the presence and level of this fear determine the type of therapy and management of patients with diabetes. The priority areas are to popularize knowledge about the FOH and its consequences among people who have direct contact with diabetes patients, as well as to conduct further studies to identify factors that determine the level of fear, which can be useful in planning personalized therapies for these patients.