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Chapter 3 Hypoglycemia

Linda Gonder-Frederick, PhD, Daniel J. Cox, PhD, ABPP,

Harsimran Singh, PhD, and Jaclyn A. Shepard, PsyD

The Problem of Hypoglycemia: Definitions and Prevalence

Hypoglycemic episodes, the most common acute complication of diabetes, are almost unavoidable, especially for patients using insulin. Hypoglycemia can be defined both biologically and symptomatically. The biological definition, based on blood glucose (BG) levels, is any reading <3.9 mmol/l (70 mg/dl) (Workgroup on Hypoglycemia, American Diabetes Association [ADA] 2005). This, however, treats all BG levels <70 as symptomatically equal, which is misleading. Symptomatically, hypoglycemia is defined in terms of its impact on the central nervous system. The Diabetes Control and Complications Trial (DCCT) defined three levels of hypoglycemia: mild, moderate, and severe (DCCT Research Group 1997). Mild hypoglycemia is characterized by symptoms caused by counterregulatory hormones and mild neuroglycopenia that do not significantly disrupt cognitive-motor functioning and are quickly alleviated by consuming carbohydrates. Moderate hypoglycemia can disrupt routine functioning, but the individual maintains the executive capacity to recognize symptoms and initiate treatment.

When mild or moderate episodes are not recognized or treated in a timely manner, severe hypoglycemia (SH) can occur. With SH, extreme neuroglycopenia precludes the ability to self-treat due to cognitive impairment, unconsciousness, or seizure. Episodes of SH are inherently dangerous, especially when no one else is present to provide emergency assistance or when the individual is engaging in potentially dangerous activities such as driving a vehicle (Cox 2006b). Mortality due to SH, albeit uncommon, does occur, accounting for an estimated 2 to 4% of deaths in individuals with type 1 diabetes (T1D) (Swade 1997, Allen 2003, Dagogo-Jack 2004, Friedrich 2004, Cox 2006b). Some of these mortalities are associated with nocturnal hypoglycemia, which can lead to what has been called the “dead in bed” phenomenon (Sovik 1999).

There are no definitive statistics on the frequency of hypoglycemia, but it has been estimated that individuals with T1D have an average of two episodes per week, most of these mild or moderate (Allen 2001, Cryer 2003). For SH, estimates of prevalence vary widely across studies. In the DCCT, SH occurred at least once per year in 65% of patients on intensive insulin regimens, with an average of 61.2 episodes per 100 patient years (DCCT Research Group 1997). Other prospective studies have reported frequencies ranging from 4.8 to 19 episodes per 100 patient years (Bognetti 1997, Davis 1997, Allen 2001, Rewers 2002, Leese 2003). However, prevalence rates do not accurately reflect the fact that the majority of episodes are concentrated in a minority subgroup of patients who have frequent and recurrent SH (Cox 1999, Honkasalo 2011). This is true not only for adults, but also for children, where 80 to 100% of episodes occur in 20 to 33% of patients (Bognetti 1997, Rewers 2002). The occurrence of SH is also not evenly distributed across times of day, with 50% or more episodes occurring at night in both children and adults (DCCT Research Group 1991, Bognetti 1997, Davis 1997).

In type 2 diabetes (T2D), some studies have reported a much lower frequency of hypoglycemia, especially when patients on all treatment regimens, including dietary therapy alone and low-dose oral medications, are included in the study (Katakura 2003). Hypoglycemia is less common during the initial years following diagnosis of T2D, presumably due to intact counterregulatory hormone mechanisms (Cryer 2003, Henderson 2003, Zammitt 2005). However, it seems that after insulin use begins, the frequency of hypoglycemia, including SH, is equivalent in T1D and T2D (Holstein 2003, Leese 2003). The use of oral sulfonylureas also greatly increases hypoglycemia in patients with T2D (Chelliah 2004, Steppel 2004, Zammit 2005).

The Impact of Hypoglycemia on Physical and motional Well-Being

The practical implications of hypoglycemia can range from patients’ personal lives to their working and social relationships, with potential negative consequences for their overall quality of life (Cryer 2004, Frier 2008, Singh 2010). Episodes of hypoglycemia are typically associated with negative consequences, including unpleasant symptoms, potential embarrassment, and inconvenience (Gonder-Frederick 1997a, Cox 2002, Jørgensen 2003). Scientific studies of the prevalence of physical injury due to SH are somewhat rare (Graveling 2010, Griffith 2011); however, clinical experience indicates that this is not uncommon. Recent retrospective and prospective surveys have demonstrated that a subgroup of patients is at a higher risk for hypoglycemia-related driving mishaps and automobile accidents (Cox 2003, Sommerfield 2003, Cox 2006b).

In people with T1D, acute hypoglycemia may produce impairment in various cognitive domains, including immediate and visual memory, delayed memory, prospective memory, and visual-motor and spatial skills (Holmes 1984, Wirsén 1992, Draelos 1995, Ewing 1998, Sommerfield 2003, Amiel 2009). There has been concern that frequent episodes of SH may also have long-term negative effects on the brain and cognitive function; however, research in this area has produced mixed results (Wredling 1990, Perros 1997, Deary 2003, Hershey 2003, DCCT Research Group 2007). These equivocal findings may be in part due to sample differences in the age of diabetes onset. Studies examining associations between SH and its impact on cognitive functioning and other development processes have shown that SH may have a more damaging effect on the developing brain in young children with T1D than in older children or adults. Children and adolescents diagnosed with T1D before the age of 5 or 6 years exhibit poorer cognitive function compared with those diagnosed later in life (Ryan 1985, Ryan 1988, Bjørgaas 1996; also see Chapter 5). For older people with T2D, there is increasing evidence to suggest that occurrence of SH is associated with a greater subsequent risk of dementia (Whitmer 2009), but this may be a result of a combination of factors, including chronic hyperglycemia and hypoglycemia (Strachan 2011).

Recurrent hypoglycemia and SH can also have negative impact on psychosocial functioning, health status, and overall quality of life in both individuals with diabetes and their significant others (Gold 1994, Gonder-Frederick 1997a, Davis 2005, Leiter 2005, Nordfeldt 2005a, Laiteerapong 2011, Pettersson 2011, Williams 2011). In adults with diabetes, there is evidence that ongoing problems with SH are associated with chronic mood changes, reduced happiness and energy levels, and feelings of helplessness, anxiety, and depression, and they can be a risk factor for affective disorders (Gold 1997, Strachan 2000, Hermanns 2003, Hermanns 2005). Treatment and management of SH can also pose a significant economic burden for patients and the health care system in terms of health care expenses and indirect costs due to decreased productivity (DCCT Research Group 1995, Lundkvist 2005, Reviriego 2008).

Unpleasant symptoms and experiences related to hypoglycemia can cause considerable anxiety in patients with diabetes and their significant others, which may lead to fear of hypoglycemia (FOH) (Myers 2007, Wild 2007, Gonder-Frederick 2011). High levels of FOH can impair quality of life in families of children with T1D (Nordfeldt 2005b, Jaser 2009, Haugstvedt 2010), and parents can exhibit particularly high levels of fear when their children have experienced seizures or comas (Clarke 1998). High FOH may adversely impact glycemic control in children with T1D, as parents may encourage higher BG levels than clinically desirable to avoid future occurrences (Barnard 2010; also see Chapter 14). In spouses and partners of patients who experience recurrent SH, there are not only higher levels of FOH but also more sleep disturbances (due to anxiety about nocturnal hypoglycemia) and reported marital conflict (Gonder-Frederick 1997a, Stahl 1998, Jørgensen 2003). Although numerous studies have investigated FOH, it has been difficult to empirically document its impact on diabetes management (Wild 2007). However, there is some scientific evidence, and much clinical evidence, that high levels of FOH in individuals with T1D or insulin-treated T2D, as well as in parents of youth with T1D, can contribute to treatment behaviors that maintain higher BG levels (Cox 1987, Cox 1990, Wild 2007, Patton 2008). Survey data have also shown that FOH is the most common reason for not adjusting insulin doses, as hypoglycemia is the most feared complication of intensive insulin therapy (McCrimmon 1994, Reach 2005). FOH is also a primary barrier to exercise in patients with type 1 and type 2 diabetes (Brazeau 2008, Shahar 2008).

Risk Factors for Hypoglycemia

All hypoglycemic episodes in diabetes are caused by a surplus of insulin or other BG-lowering medications relative to food intake and physical activity. Physiologically, factors such as greater insulin sensitivity, higher BG variability, and impaired renal function increase the risk for hypoglycemia, as do some medications that delay gastric emptying (Chelliah 2004, Workgroup on Hypoglycemia ADA 2005, Honkasalo 2011). Numerous studies have documented that glycemic control and variables that lower A1C (e.g., more intensive insulin therapy) result in increased risk for hypoglycemia in both youth and adults (Davis 1997, DCCT Research Group 1997, Allen 2001). Some studies have attempted to go beyond these broad relationships and identify the immediate, discrete precursors of hypoglycemic episodes. This research shows that diabetes management plays a critical role in hypoglycemia risk, with 75% or more episodes being behaviorally induced in people with both T1D and T2D. For youth and adults, the majority of episodes were attributed to reduced food intake, including missed meals, and increased physical activity (Bognetti 1997, Davis 1997, Murata 2005). A recent retrospective study of 84 children and adolescents found that most SH episodes occurred when meals (carbohydrates) were delayed, followed by intense physical activity and excessive insulin administration (Cosmescu 2008). Another retrospective study involving >1,300 adults with T1D and T2D identified daily exercise as a major risk factor for SH (Honkasalo 2011). The occurrence of unexpected vigorous activity has also been highlighted as a common precipitant (Clarke 1999).

Clinical experience indicates that many patients have only a rudimentary understanding of the effects of food and exercise on BG levels. Clinicians cannot assume that patients and their caregivers know about more complex behavioral risk factors for hypoglycemia, such as eating foods high in fat content, which can result in a delayed and/or depressed glycemic response, or engaging in elongated sessions of moderate physical activity, which can utilize as much (or more) glucose than shorter bouts of intense exercise. Maladaptive decisions and behaviors leading to hypoglycemia can also occur in patients who are nonadherent or nonconscientious about their diabetes management, including those who may skip meals or snacks, or fail to count carbohydrate content when calculating meal boluses. Psychiatric conditions that result in disordered behavior can also greatly increase patient risk, especially disordered eating behavior characterized by undereating, or binge eating accompanied by purging (Young-Hyman 2010).

For some patients, frequent and recurrent episodes of hypoglycemia may be related to emotional or cognitive problems that contribute to poor decision making and judgments, or risky behaviors in dealing with low BG. Patients may minimize or dismiss the potential seriousness of episodes, experience secondary gain through the care and concern of family members, or perceive delaying treatment as a form of “winning” in a power struggle with diabetes.

Another understudied but important risk factor is patient cognitions: beliefs, attitudes, and judgments about hypoglycemia and its treatment. Clinically, it is not uncommon to encounter patients who believe they can function fine at very low BG levels (e.g., <54 mg/dl) or that hypoglycemia is a necessary part of having good diabetes control. Other beliefs and attitudes can lead patients to have lower personal glycemic thresholds for treating hypoglycemia or a tendency to delay treatment, which greatly increase risk.

Some patients also engage in overtreatment of hyperglycemia, or what is sometimes called diabetes “micro-management,” often resulting in insulin overbolusing or “stacking.” These individuals may be highly conscientious in their diabetes management and highly motivated to avoid hyperglycemia and long-term complications. However, high anxiety about hyperglycemia can become maladaptive and lead to extreme behaviors to avoid high BG (e.g., increased insulin dosing), which may increase hypoglycemic episodes (Ritholtz 2008, Singh 2010).

Episodes of SH occur when milder or more moderate levels of hypoglycemia are not recognized and treated quickly enough or adequately. The probability of SH occurrence has been described in a biopsychobehavioral model that attempts to integrate the complex physiological, psychological, and behavioral processes that determine risk level (Gonder-Frederick 1997b, Cox 1999). The first step of this model is the occurrence of mild or moderate hypoglycemia, which triggers certain physiological reactions, including hormonal counterregulation and neuroglycopenia. These, in turn, cause adrenergic and neuroglycopenic symptoms, followed by patient detection and recognition of these symptoms, which ideally leads to appropriate decision making and self-treatment, thereby avoiding SH.

However, the potential for SH is not avoided when hypoglycemic symptoms are not produced, recognized, or treated in a timely manner, which often occurs when a patient has hypoglycemic-associated autonomic failure (HAAF). With HAAF, frequent low-BG episodes lead to defective counterregulatory (epinephrine) responses to hypoglycemia and reduced hypoglycemic awareness (HA) (Cryer 2002, Cryer 2004, Kubiak 2004). This can cause BG to drop lower during hypoglycemia and fail to produce warning symptoms until levels are very low, which greatly increases the probability for significant neuroglycopenia and mental confusion, possibly preventing timely self-treatment. The relationship between reduced HA and SH risk has been well documented in people with both T1D and T2D, and it has been estimated that up to 60% of SH episodes are not associated with warning symptoms (DCCT Research Group 1991, Cryer 2002, Henderson 2003). Approximately 25% of patients with T1D appear to have some degree of reduced HA (Hepburn 1990, Geddes 2007).

Factors contributing to HAAF, reduced HA, and SH risk include frequent hypoglycemic episodes, intensive insulin regimens, lower A1C levels, longer diabetes duration, physical exercise, suppressed nocturnal counterregulation, and alcohol consumption (Avogaro 1989, Kerr 1990, DCCT Research Group 1991, Davis 1997, DCCT Research Group 1997, Rewers 2002, Cryer 2003, Banarer 2004, Bulsara 2004, Sandoval 2004, Workgroup on Hypoglycemia ADA 2005, Richardson 2005, Schultes 2007). Smoking is another risk factor for SH, although it is unclear at this point whether it is related to HAAF (Hirai 2007). Even in the absence of HAAF and reduced HA, patients may fail to detect early warning signs of hypoglycemia. Field studies have found that both adults and children with T1D may fail to recognize half or more of BG levels lower than 70 mg/dl (3.9 mmol/l) (Clarke 1995, Gonder-Frederick 2008). Another field study prospectively followed adults with T1D with and without a recent history of SH (Cox 1999) over a 6-month period. The study replicated the relationship between HAAF-related factors (e.g., reduced HA, frequent low BG ) and SH risk; however, individuals in the high-risk group also showed cognitive and behavioral differences. Specifically, individuals with SH history showed more cognitive impairment during hypoglycemia and a tendency to treat episodes with food rather than faster-acting carbohydrates.

Parents have been shown to demonstrate poor ability to detect low BG in their children (Gonder-Frederick 2008). Factors that can contribute to parents’ and their children’s failure to detect hypoglycemia include attention and perceptual processes, inaccurate beliefs about low-BG symptoms, and misattribution of symptoms to non-BG-related causes. Emotional distress may also have a negative impact; for example, school-aged children with depressive symptoms show poorer hypoglycemia detection (Gonder-Frederick 2008).

Age is a major factor in SH, with older people and younger children at highest risk (Bognetti 1997, Bulsara 2004, Chelliah 2004). Increased risk in the elderly often occurs due to impaired renal function and/or medications (Chelliah 2004), and the elderly in poor glycemic control have more frequent episodes (Munshi 2011). Adolescents are at higher risk than adults with T1D (DCCT Research Group 1994), and children under 6 years of age are at higher risk than those over 6 years old (Davis 2001). One prospective study has documented the relationship between psychiatric disorders and higher SH risk in older children (Rewers 2002), and another investigated surreptitious intentional insulin overdosing by adolescents with emotional disturbance and family problems (Boileau 2006). A recent study of over 1,000 adults with T1D and T2D found that depression was a risk factor for SH (Honkasalo 2011). In the elderly, cognitive impairment and dementia also significantly increases risk (Brauser 2011). Adults in lower socioeconomic status (SES) groups are at higher risk, including those who are “food-insecure” and vulnerable to experiencing hunger secondary to inability to afford food (Bulsara 2004, Seligman 2010). For children and adolescents, being underinsured significantly increases risk (Ratner 2000, Bulsara 2004).

Interventions to Reduce SH Risk

Any intervention that reduces the frequency of hypoglycemia and/or improves timely detection and treatment of episodes will be effective in reducing SH risk. Also, interventions that reduce the frequency of hypoglycemia and SH typically reduce FOH. The essential foundation for reducing SH risk is adequate diabetes education to provide patients with an understanding of how imbalances in insulin, food, and physical activity occur, and ways to avoid such imbalances. This type of patient education and training (especially educating patients regarding HA) may not be implemented because of limited personnel resources, despite being part of recommended diabetes self-management education (DSME). Some authors have even suggested that inadequate patient education is a major reason why patients experience increased hypoglycemia when they transition to intensive insulin therapies (Mühlhauser 1993). In addition to hypoglycemia prevention, patients need education on the appropriate treatment of episodes and the importance of responding immediately and appropriately to avoid SH. Such education should include training in hypoglycemic symptomatology, including the physiological basis of symptoms and their impact on the ability to adequately self-treat.

When an individual presents with problems with SH, the first target of intervention is often the insulin regimen. Numerous studies show that long-lasting insulin analogs decrease the occurrence of both diurnal and nocturnal hypoglycemia in people with T1D and T2D (Brunelle 1998, Ratner 2000, Yki-Jarvinen 2000, Davis 2004, Home 2004, Alemzadeh 2005, Rosenstock 2005). Many studies have also demonstrated that continuous subcutaneous insulin infusion (CSII) therapy or insulin pump therapy significantly reduces the frequency of hypoglycemia and SH risk in both adults and children (Boland 1999, Bode 2002, Linkeschova 2002, Litton 2002, Rami 2003, Bulsara 2004, Colquitt 2004). However, two recent meta-analyses of this literature point out that CSII does not always reduce hypoglycemia (Weissberg-Benchell 2003, Hirsch 2005). Other changes in insulin may also be indicated; for example, discontinuing basal insulin doses during exercise may significantly decrease hypoglycemia in children (Tansey 2006). For patients who have tried a variety of different insulin regimens but continue to have serious problems with SH, transplant surgery may be considered. However, there are significant surgical and postoperative complications, and islet cell transplant does not result in long-term insulin independence for the majority of patients (Shapiro 2006, Meloche 2007). And, although glycemic thresholds for counterregulation and symptoms improve after islet cell transplant, the magnitude of the epinephrine response (signaling hypoglycemia) may remain impaired (Rickels 2007).

In addition to reducing episode frequency, interventions can focus on improving the ability to detect hypoglycemia when it occurs. There is research aimed at developing pharmacological agents that increase hypoglycemic awareness (Heller 2008), but these agents are not yet available. Several studies have found that, if patients can rigorously avoid BG levels <70 mg/dl (3.9 mmol/l) for just a few weeks, timely hormonal counterregulation and adrenergic warning symptoms are restored (Cranston 1994, Fanelli 1994). Unfortunately, there have been no large-scale clinical trials evaluating this intervention to determine what proportion of patients might respond to treatment or what types of support programs are needed for patient success. In addition, only one long-term follow-up study has investigated whether a single course of treatment (3-month physician-supervised avoidance of hypoglycemia) produces long-lasting results (Dagogo-Jack 1999).

With recent technological advances in diabetes management, continuous glucose monitoring (CGM) has been increasingly used in the detection and reduction of hypoglycemia. CGM can provide patients with warnings when BG trends indicate that hypoglycemia is imminent (Boland 2001, Chico 2003, Jeha 2004). An early randomized trial (Garg 2006) showed that patients with T1D and insulin-requiring T2D who wore continuous glucose monitors for three consecutive 72-hour periods experienced significant improvements in glycemic excursions compared with patients using traditional BG monitoring. Specifically, those using continuous glucose monitors spent 21% less time in hypoglycemia and 26% more time within BG target range. More recent clinical trials have focused on the impact of longer-duration use of continuous glucose monitors on hypoglycemic risk. In a recent study of both adults and youth with T1D who did CGM for 26 weeks, time spent in hypoglycemia was significantly shorter and time spent in euglycemia (normal glucose content) was significantly longer compared with control subjects using self-monitoring of blood glucose (SMBG) (Battelino 2011). Though these results are promising, other findings suggest that CGM may not effectively reduce hypoglycemia for all patients. Results from the Juvenile Diabetes Research Foundation (JDRF) trial did not find a statistically significant difference in time spent in hypoglycemia or in the frequency of SH over 6 months of CGM as compared with SMBG for any age-group (JDRF Continuous Glucose Monitoring Study Group 2008). However, adults in this study were able to achieve better glycemic control without increasing hypoglycemic risk.

Sensor-augmented pump (SAP) therapy, which integrates CGM use and insulin pump therapy, is a first step toward the development of a closed-loop control system (or “artificial pancreas”) and one of the newest diabetes technologies aimed at reducing hyperglycemia while preventing hypoglycemia. A number of studies, including two large clinical trials (Sensor-Augmented Pump Therapy for A1C Reduction [STAR 3]; Sensing With Insulin Pump Therapy to Control HbA1c [SWITCH]), are underway to evaluate the feasibility and efficacy of SAP therapy with adults and, most recently, youth with T1D (Fisher 2006, Kordonouri 2010, Conget 2011, Scaramuzza 2011). Early findings have indicated beneficial effects on metabolic control in both adults and children, including improved A1C (Hermanides 2011, Scaramuzza 2011), without increasing hypoglycemia (Buse 2011, Slover 2011). A possible negative effect on diabetes management is overtreating hypoglycemia due to delays in glucose feedback (Wolpert 2007, Block 2008). When this technology is introduced, however, this time lag should be addressed in the context of its use (see Chapter 11).

Because diabetes management behaviors play a critical role in hypoglycemia and SH, it is not surprising that behavioral interventions are effective in reducing risk. The behavioral intervention receiving the most scientific study is Blood Glucose Awareness Training (BGAT), designed to improve patients’ ability to recognize symptoms and other cues that signal low BG and to anticipate the effect of treatment factors such as insulin, food, and physical activity on glucose levels (Cox 1989, Gonder-Frederick 2000, Cox 2006a, Cox 2008). BGAT is a structured, manualized training program that integrates diabetes didactics, self-monitoring and self-assessment strategies, and evaluation of personal diabetes management behaviors. A recent article reviewed 15 studies of BGAT in the U.S. and Europe showing that the intervention can have numerous treatment benefits, such as improved hypoglycemia detection, decreased frequency of low BG and SH, and reduced FOH (Cox 2006a). Patients who complete BGAT after initiating intensive insulin therapy have been shown to maintain integrity of counterregulation and avoid the typical increase in frequency of hypoglycemia with improved diabetes control (Kinsley 1999).

Despite evidence for its effectiveness, BGAT is not widely disseminated. It is an intensive and demanding training program, there are reimbursement issues, and there are not enough trained and experienced health care professionals to offer BGAT. To make it more widely available, BGAT has been translated for Internet delivery as BGATHome, and the initial tests are encouraging (Cox 2008). A similar psychobehavioral intervention, also using strategies such as BG symptom diaries and BG estimation with accuracy evaluation, has been developed and tested in controlled trials in Germany (Kubiak 2006, Hermanns 2010). Long-term follow-up after this intervention found significantly lower rates of SH in the experimental group with no increase in A1C.

There is also compelling evidence that less-intensive behavioral interventions may be effective, suggesting that more effort should be directed at developing, testing, and disseminating these types of programs. For example, structured outpatient education specifically designed to teach patients about the causes, effects, and treatment of hypoglycemia may prevent the increased risk associated with intensive insulin regimens (Plank 2004, Samann 2005). Another intervention combined a case-management approach with psychoeducation, and it decreased episodes of SH by 60% (Svoren 2003). Also encouraging are studies from Norway showing that mass distribution of patient education materials (videotapes and brochures) reduced episodes of SH without compromising metabolic control in children with T1D. This randomized, controlled trial followed more than 200 pediatric patients over a 24-month period and found that episodes of SH were reduced from 45 to 24% in the experimental intervention group (Nordfeldt 2003, Norfeldt 2005a).

The successful results of these relatively simple interventions focusing on didactics suggest that inadequate patient education is an underrecognized but major risk factor for SH. The positive findings for several educational and behavioral interventions, combined with the difficulty of finding these for many patients, suggest that programs with demonstrated effectiveness at reducing SH risk are underimplemented in diabetes health care. Such programs are likely to be cost-effective because of the significant financial burden of hypoglycemia on the individual and the health care system (Brito-Sanfiel 2010). Given its impact on the quality of life, emotional well-being, and physical safety and health of people with diabetes, the problem of hypoglycemia has not received the attention it deserves, and the availability of interventions to reduce episodes is inadequate. Clearly, much more effort on several fronts, including research, clinical care, e-health efforts, and diabetes advocacy, needs to be directed at finding ways to implement effective interventions to address the problem of hypoglycemia in diabetes.

Recommendations for Care

1. Hypoglycemia is common in patients with both T1D and T2D, and patients should be assessed at each clinical encounter to determine whether this is a problem area for them. If there are problems, more detailed assessment should be conducted to determine whether or not referral is needed for patient education or other interventions, following the example of a comprehensive hypoglycemia interview provided by Cradock and Frier (2010). Often patients are reluctant to discuss SH episodes with health care professionals due to fears that their ability to engage in certain activities and/or occupations (e.g., driving, piloting airplanes) will be restricted (Davis 1997, DCCT Research Group 1997, Leese 2003, Workgroup on Hypoglycemia ADA 2005, Zammitt 2005).

2. FOH is common and should be periodically assessed in both patients and family members, including parents of children with diabetes, especially following distressing or traumatic episodes of SH. When patients present with chronically high BG levels, the possibility of very high FOH should be considered (Gonder-Frederick 1997b, Nordfeldt 2005b, Wild 2007, Barnard 2010).

3. During hypoglycemia assessments at clinic visits, potential problems in diabetes management behaviors related to episodes (e.g., missed meal, increased physical activity, variable work schedule that changes insulin dosing schedule) should be identified to guide patient counseling/education (Bognetti 1997, Workgroup on Hypoglycemia ADA 2005, Honkasalo 2011).

4. Individuals who exhibit risky behavior associated with increased episodes of hypoglycemia that are found to be associated with clinically significant emotional or cognitive problems will benefit from referral to a psychotherapist or counselor with expertise in diabetes management and behavioral intervention.

5. Beliefs about hypoglycemia and its treatment need to be assessed to identify attitudes and behaviors that increase risk. Some questions that may be helpful include: “How low does your BG need to be before you believe you need to raise it?” and “How low does your BG need to be before it affects your ability to think and function?”

6. When concerns regarding hyperglycemia appear to be contributing to increased hypoglycemic events, the practitioner might consider additional education sessions with a diabetes educator and modification of the care regimen that encourages more monitoring as well as compensatory strategies such as modification of the patient’s MNT.

7. Hypoglycemic awareness/detection should be assessed at each clinic visit given that hormonal counterregulation and symptom thresholds can change over time. Assess ability to recognize hypoglycemia in patients who do not report traditional hypoglycemic unawareness, because even these patients may fail to detect up to 50% of episodes. Ability to recognize hypoglycemia should also be assessed in pediatric patients as well as their parents, since research indicates that poor ability to identify low BG may be a risk factor for SH (Cox 1999, Cryer 2002, Workgroup on Hypoglycemia ADA 2005, Gonder-Frederick 2008).

8. Patients with comorbid psychiatric or cognitive problems, as well as those in lower-SES groups, may warrant closer monitoring for problems with SH given their higher risk level (Rewers 2002, Seligman 2010, Honkasalo 2011).

9. Ideally, all patients should receive comprehensive education on hypoglycemia, including its causes, its impact on cognitive functioning, and the need for immediate treatment. For the subset of patients who have recurrent problems with hypoglycemia, this education should be a continuing part of clinical care. Education regarding HAAF and the impact of frequent episodes of mild hypoglycemia on the ability to counterregulate and recognize warning symptoms should be provided, with care taken to present information in a manner that translates to behavior change strategies. Further, routine screening regarding incidence and identification may need to be accompanied by suggestions regarding accessible treatment resources (such as print or web-based information) when the practitioner is not able to provide these ongoing services.

10. Patients should be assessed for frequency of mild hypoglycemic events during clinic visits given that these can be a risk factor for HAAF and SH. Education regarding the impact of frequent mild hypoglycemia on symptoms and hormonal response should be provided to patients who have one or more weekly episodes, and the possibility of following a regimen aimed at avoiding these events to improve counterregulation should be discussed with the patient (Cranston 1994, Heller 2008).

11. CGM or SAP therapy should be considered for patients who have recurrent SH due to hypoglycemic unawareness, problems with nocturnal hypoglycemia, very high levels of FOH, or hypoglycemia that interferes with quality of life, and for those who live alone. Given the complexity of these technologies, patients considering using CGM or SAP therapy should receive comprehensive and systematic training from diabetes educators (Hermanides 2011, JDRF Research Group 2011).

12. Some of the strategies used in BGAT and BGATHome (e.g., BG Awareness Diaries) have been published previously for use by health care providers including psychologists, diabetes educators, nurses, and physicians (Cox 2006a) and can be suggested as intervention resources, especially when trained providers are not geographically available.

ACKNOWLEDGMENTS

This manuscript was supported in part by NIH/NIDDK Grants R01DK60039 and R21DK080896. The authors thank Karen Vajda and Kelli McFarling for their editorial assistance.

BIBLIOGRAPHY

Alemzadeh R, Berhe T, Wyatt DT: Flexible insulin therapy with glargine insulin improved glycemic control and reduced severe hypoglycemia among preschool-aged children with type 1 diabetes mellitus. Pediatrics 115:1320–1324, 2005

Allen C, LeCaire T, Palta M, Daniels K, Meredith M, D’Alession DJ: Risk factors for frequent and severe hypoglycemia in type 1 diabetes. Diabetes Care 24:1878–1881, 2001

Allen KV, Frier BM: Nocturnal hypoglycemia: clinical manifestations and therapeutic strategies toward prevention. Endocr Prac 9:530–543, 2003

Amiel SA: Hypoglycemia: from the laboratory to the clinic. Diabetes Care 32:1364–1371, 2009

Avogaro AJ, Bristow D, Bier DM, Cobelli C, Toffolo G: Stable-label intravenous glucose tolerance test minimal model. Diabetes 38:1048–1055, 1989

Banarer S, Cryer PE: Hypoglycemia in type 2 diabetes. Med Clin North Am 88:1107–1116, 2004

Barnard K, Thomas S, Royle P, Noyes K, Waugh N: Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review. BMC Pediatr 10:50, 2010

Battelino T, Phillip M, Bratina N, Nimri R, Oskarsson P, Bolinder J: Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Diabetes Care 34:795–800, 2011

Bjørgaas M, Sand T, Gimse R: Quantitative EEG in type 1 diabetic children with and without episodes of severe hypoglycemia: a controlled, blind study. Acta Neurol Scand 93:398–402, 1996

Block JM, Buckingham B: Use of real-time continuous glucose monitoring technology in children and adolescents. Diabetes Spectr 21:84–90, 2008

Bode BW, Tamborlane WV, Davidson PC: Insulin pump therapy in the 21st century: strategies for successful use in adults, adolescents, and children with diabetes. Postgrad Med 111:69–77, 2002

Bognetti E, Brunelli A, Meschi F, Viscardi M, Bonfanti R, Chiumello G: Frequency and correlates of severe hypoglycaemia in children and adolescents with diabetes mellitus. Eur J Pediatr 156:589–591, 1997

Boileau P, Aboumrad B, Bougnères P: Recurrent comas due to secret self-administration of insulin in adolescents with type 1 diabetes. Diabetes Care 29:430–431, 2006

Boland E, Monsod T, Delucia M, Brandt CA, Fernando S, Tamborlane WV: Limitations of conventional methods of self-monitoring of blood glucose: lessons learned from 3 days of continuous glucose sensing in pediatric patients with type 1 diabetes. Diabetes Care 24:1858–1862, 2001

Boland EA, Grey M, Oesterle A, Fredrickson L, Tamborlane WV: Continuous subcutaneous insulin infusion: a new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care 22:1779–1784, 1999

Brauser D: Elderly dementia patients at serious risk for hypoglycemia. Paper presented at the annual meeting of the American Association for Geriatric Psychiatry (AAGP), San Antonio, TX, Abstract NR-20, March 2011

Brazeau A-S, Rabasa-Lhoret R, Strychar I, Mircescu H: Barriers to physical activity among patients with type 1 diabetes. Diabetes Care 31:2108–2109, 2008

Brito-Sanfiel M, Diago-Cabezudo JI, Calderon A: Economic impact of hypoglycemia on healthcare in Spain. Expert Rev Pharmacoecon Outcomes Res 10:649–660, 2010

Brunelle RL, Llewelyn J, Anderson JH Jr, Gale EAM, Koivisto VA: Meta-analysis of the effect of insulin lispro on severe hypoglycemia in patients with type 1 diabetes. Diabetes Care 21:1726–1731, 1998

Bulsara MK, Holman CD, Davis EA, Jones TW: The impact of a decade of changing treatment on rates of severe hypoglycemia in a population-based cohort of children with type 1 diabetes. Diabetes Care 27:2293–2298, 2004

Buse JB, Dailey G, Ahmann AA, Bergenstal RM, Green JB, Peoples T, Tanenberg RJ, Yang Q: Baseline predictors of A1C reduction in adults using sensor-augmented pump therapy or multiple daily injection therapy: the STAR 3 experience. Diabetes Technol Ther 13:601–606, 2011

Chelliah A, Burge MR: Hypoglycaemia in elderly patients with diabetes mellitus: causes and strategies for prevention. Drugs Aging 21:511–530, 2004

Chico A, Vidal-Rios P, Subira M, Novials A: The continuous glucose monitoring system is useful for detecting unrecognized hypoglycemias in patients with type 1 and type 2 diabetes but is not better than frequent capillary glucose measurements for improving metabolic control. Diabetes Care 26:1153–1157, 2003

Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Kovatchev B, Young-Hyman D: The biopsychobehavioral model of risk of severe hypoglycemia II: self-management behaviors. Diabetes Care 22:580–584, 1999

Clarke WL, Gonder-Frederick LA, Snyder AL, Cox DJ: Maternal fear of hypoglycemia in their children with insulin dependent diabetes mellitus. J Pediatr Endocrinol Metab 11:189–194, 1998

Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W: Reduced awareness of hypoglycemia in adults with IDDM: a prospective study of hypoglycemic frequency and associated symptoms. Diabetes Care 18:517–522, 1995

Colquitt JL, Green C, Sidhu MK, Hartwell D, Waugh N: Clinical and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes. Health Technol Assess 8:1–171, 2004

Conget I, Battelino T, Giménez M, Gough H, Castañeda J, Bolinder J; SWITCH Study Group: The SWITCH study (sensing with insulin pump therapy to control HbA(1c)): design and methods of a randomized controlled crossover trial on sensor-augmented insulin pump efficacy in type 1 diabetes suboptimally controlled with pump therapy. Diabetes Technol Ther 13:49–54, 2011

Cosmescu A, Felea D, M˘at˘asaru S: [Severe hypoglycemia in children and adolescents suffering from type 1 diabetes mellitus]. Rev Med Chir Soc Med Nat Iasi 112:955–958, 2008

Cox DJ, Ritterband L, Magee J, Clarke W, Gonder-Frederick L: Blood glucose awareness training delivered over the internet. Diabetes Care 31:1527–1528, 2008

Cox DJ, Gonder-Frederick L, Ritterband L, Patel K, Schachinger H, Fehm-Wolfsdorf G, Hermanns N, Snoek F, Zrebiec J, Polonksy W, Schlundt D, Kovatchev B, Clarke WL: Blood glucose awareness training: what is it, where is it, and where is it going? Diabetes Spectr 19:43–49, 2006a

Cox DJ, Kovatchev B, Vandecar K, Gonder-Frederick L, Ritterband L, Clarke W: Hypoglycemia preceding fatal car collisions. Diabetes Care 29:467–468, 2006b

Cox DJ, Penberthy JK, Zrebiec J, Weinger K, Aikens JE, Frier BM, Stetson B, DeGroot M, Trief P, Schaechinger H, Hermanns N, Gonder-Frederick L, Clarke WL: Incidence of driving mishaps and their correlates among drivers with diabetes. Diabetes Care 26:2329–2334, 2003

Cox DJ, Gonder-Frederick L, McCall A, Kovatchev B, Clarke WL: The effects of glucose fluctuation on cognitive function and QOL: the functional costs of hypoglycaemia and hyperglycaemia among adults with type 1 or type 2 diabetes. Int J Clin Pract Suppl 129:20–26, 2002

Cox DJ, Gonder-Frederick L, Kovatchev B, Young-Hyman D, Donner TW, Julian DM, Clarke W: Biopsychobehavioral model of severe hypoglycemia II: understanding the risk of severe hypoglycemia. Diabetes Care 22:2018–2025, 1999

Cox DJ, Gonder-Frederick L, Antoun B, Clarke WL, Cryer P: Psychobehavioral metabolic parameters of severe hypoglycemic episodes. Diabetes Care 13:458–459, 1990

Cox DJ, Gonder-Frederick L, Lee JH, Julian DM, Carter WR, Clarke WL: Effects and correlates of blood glucose awareness training among patients with IDDM. Diabetes Care 12:313–318, 1989

Cox DJ, Irvine A, Gonder-Frederick L, Nowacek G, Butterfield J: Fear of hypoglycemia: quantification, validation, and utilization. Diabetes Care 10:617–621, 1987

Cradock S, Frier B: Determining the risk of hypoglycaemia people with type 2 diabetes: an approach for clinical practice. Br J Diabetes Vasc Dis 10:44–46, 2010

Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA: Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet 344:283–287, 1994

Cryer PE: Diverse causes of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med 350:2272–2279, 2004

Cryer PE, Davis SN, Shamoon H: Hypoglycemia in diabetes. Diabetes Care 26:1902–1912, 2003

Cryer PE: Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia 45:937–948, 2002

Dagogo-Jack S: Hypoglycemia in type 1 diabetes mellitus: pathophysiology and prevention. Treat Endocrinol 3:91–103, 2004

Dagogo-Jack S, Fanelli CG, Cryer PE: Durable reversal of hypoglycemia unawareness in type 1 diabetes. Diabetes Care 22:866–867, 1999

Davis CL, Delamater AM, Shaw KH, La Greca AM, Edison MS, Perez-Rodriguez JE, Nemery R: Parenting styles, regimen adherence, and glycemic control in 4- to 10-year-old children with diabetes. J Pediatr Psychol 26:123–129, 2001

Davis EA, Keating B, Byrne G, Russell M, Jones TW: Hypoglycemia: incidence and clinical predictors in a large population-based sample of children and adolescents with IDDM. Diabetes Care 20:22–25, 1997

Davis RE, Morrissey M, Peters JR, Wittrup-Jensen K, Kennedy-Martin T, Currie CJ: Impact of hypoglycaemia on quality of life and productivity in type 1 and type 2 diabetes. Curr Med Res Opin 21:1477–1483, 2005

Davis S, Alonso MD: Hypoglycemia as a barrier to glycemic control. J Diabetes Complications 18:60–68, 2004

Deary IJ, Sommerfield AJ, McAulay V, Frier B: Moderate hypoglycaemia obliterates working memory in humans with and without insulin treated diabetes. J Neurol Neurosurg Psychiatry 74:278–279, 2003

Diabetes Control and Complications Trial Research Group: Long-term effect of diabetes and its treatment on cognitive function. N Engl J Med 356:1842–1852, 2007

Diabetes Control and Complications Trial Research Group: Hypoglycemia in the Diabetes Control and Complications Trial. Diabetes 46:271–286, 1997

Diabetes Control and Complications Trial Research Group: Resource utilization and costs of care in the Diabetes Control and Complications Trial. Diabetes Care 18:1468–1478, 1995

Diabetes Control and Complications Trial Research Group: Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. J Pediatr 125:177–188, 1994

Diabetes Control and Complications Trial Research Group: Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Am J Med 90:450–459, 1991

Draelos MT, Jacobson AM, Weinger K, Widom B, Ryan CM, Finkelstein DM, Simonson DC: Cognitive function in patients with insulin-dependent diabetes mellitus during hyperglycemia and hypoglycemia. Am J Med 98:135–144, 1995

Ewing FM, Deary IJ, McCrimmon RJ, Strachan MWJ, Frier BM: Effect of acute hypoglycemia on visual information processing in adults with type 1 diabetes mellitus. Physiol Behav 64:653–660, 1998

Fanelli C, Pampanelli S, Epifano L, Rambotti AM, Ciofetta M, Modarelli F, Di Vincenzo A, Annibale B, Lepore M, Lalli C: Relative roles of insulin and hypoglycaemia on induction of neuroendocrine responses to, symptoms of, and deterioration of cognitive function in hypoglycaemia in male and female humans. Diabetologia 37:797–807, 1994

Fisher LK, Halvorson M: Future developments in insulin pump therapy: progression from continuous subcutaneous insulin infusion to a sensor-pump system. Diabetes Educ 32 (Suppl. 1):47S–52S, 2006

Friedrich LV, Dougherty R: Fatal hypoglycemia associated with levofloxacin. Pharmacother 24:1807–1812, 2004

Frier BM: How hypoglycaemia can affect the life of a person with diabetes. Diabetes Metab Res Rev 24:87–92, 2008

Garg S, Zisser H, Schwartz S, Bailey T, Kaplan R, Ellis S, Jovanovic L: Improvement in glycemic excursions with a transcutaneous, real-time continuous glucose sensor: a randomized controlled trial. Diabetes Care 29:44–50, 2006

Geddes J, Wright RJ, Zammitt NN, Deary IJ, Frier B: An evaluation of methods of assessing impaired awareness of hypoglycemia in type 1 diabetes. Diabetes Care 30:1868–1870, 2007

Gold AE, Frier BM, MacLeod KM, Deary IJ: A structural equation model for predictors of severe hypoglycaemia in patients with insulin-dependent diabetes mellitus. Diabet Med 14:309–315, 1997

Gold AE, Deary IJ, Jones RW, O’Hare JP, Reckless JPD, Frier BM: Severe deterioration in cognitive function and personality in five patients with long-standing diabetes: a complication of diabetes or a consequence of treatment? Diabet Med 11:499–505, 1994

Gonder-Frederick L, Schmidt K, Vajda K, Greear M, Singh H, Shepard J, Cox D: Psychometric properties of the Hypoglycemia Fear Survey-II for adults with type 1 diabetes mellitus. Diabetes Care 34:801–806, 2011

Gonder-Frederick L, Zrebiec J, Bauchowitz A, Lee J, Cox D, Kovatchev B, Ritterband L, Clarke W: Detection of hypoglycemia by children with type 1 diabetes 6 to 11 years of age and their parents: a field study. Pediatrics 121:e489–e495, 2008

Gonder-Frederick L, Cox DJ, Clarke W: Helping patients understand, recognize, and avoid hypoglycemia. In Practical Psychology for Diabetes Clinicians. Anderson BJ, Rubin RR, Eds. Alexandria, VA, American Diabetes Association, 2002, p. 113–124

Gonder-Frederick L, Cox DJ, Clarke W, Julian D: Blood glucose awareness training. In Psychology in Diabetes Care. Snoek F, Skinner TC, Eds. London, John Wiley and Sons, 2000, p. 169–206

Gonder-Frederick L, Cox DJ, Kovatchev B, Julian D, Clarke W: The psychosocial impact of severe hypoglycemic episodes on spouses of patients with IDDM. Diabetes Care 20:1543–1546, 1997a

Gonder-Frederick L, Cox DJ, Kovatchev B, Schlundt D, Clarke W: A biopsychobehavioral model of risk of severe hypoglycemia. Diabetes Care 20:661–669, 1997b

Graveling AJ, Frier B: Risks of marathon running and hypoglycaemia in type 1 diabetes. Diabet Med 27:585–588, 2010

Griffith R, Tengnah C: Legal basis for standards of driving with diabetes. Br J Community Nurs 16:19–22, 2011

Haugstvedt A, Wentzel-Larsen T, Graue M, Søvik O, Rokne B: Fear of hypoglycaemia in mothers and fathers of children with type 1 diabetes is associated with poor glycaemic control and parental emotional distress: a population-based study. Diabet Med 27:72–78, 2010

Heller SR: Minimizing hypoglycemia while maintaining glycemic control in diabetes. Diabetes 57:3177–3183, 2008

Henderson JN, Allen KV, Deary IJ, Frier BM: Hypoglycaemia in insulin-treated type 2 diabetes: frequency, symptoms and impaired awareness. Diabet Med 20:1016–1021, 2003

Hepburn DA, Patrick AW, Eadington DW, Ewing DJ, Frier B: Unawareness of hypoglycaemia in insulin-treated diabetic patients: prevalence and relationship to autonomic neuropathy. Diabet Med 7:711–717, 1990

Hermanides J, Nørgaard K, Bruttomesso D, Mathieu C, Frid A, Dayan CM, Diem P, Fermon C, Wentholt IM, Hoekstra JB, Devries JH: Sensor-augmented pump therapy lowers HbA(1c) in suboptimally controlled type 1 diabetes: a randomized controlled trial. Diabet Med. doi: 10.1111/j.1464-5491.2011.03256.x

Hermanns N, Kulzer B, Krichbaum M, Kubiak T, Haak T: Long-term effect of an education program (HyPOS) on the incidence of severe hypoglycemia in patients with type 1 diabetes. Diabetes Care 33:e36, 2010

Hermanns N, Kulzer B, Krichbaum M, Kubiak T, Haak T: Affective and anxiety disorders in a German sample of diabetic patients: prevalence, comorbidity and risk factors. Diabet Med 22:293–300, 2005

Hermanns N, Kubiak T, Kulzer B, Haak T: Emotional changes during experimentally induced hypoglycaemia in type 1 diabetes. Biol Psychol 63:15–44, 2003

Hershey T, Lillie R, Sadler M, White NH: Severe hypoglycemia and long-term spatial memory in children with type 1 diabetes mellitus: a retrospective study. J Int Neuropsychol Soc 9:740–750, 2003

Hirai FE, Moss SE, Klein BEK, Klein R: Severe hypoglycemia and smoking in a long-term type 1 diabetic population: Wisconsin Epidemiologic Study of Diabetic Retinopathy. Diabetes Care 30:1437–1441, 2007

Hirsch IB: Insulin analogues. N Engl J Med 352:174–183, 2005

Holmes CS, Koepke KM, Thompson RG, Gyves PW, Weydert JA: Verbal fluency and naming performance in type 1 diabetes at different blood glucose concentrations. Diabetes Care 7:454–459, 1984

Holstein A, Egberts E-H: Risk of hypoglycaemia with oral antidiabetic agents in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes 111:405–414, 2003

Home P, Bartley P, Russell-Jones D, Hanaire-Brouton H, Heeg J-E, Abrams P, Landin-Olsson M, Hylleberg B, Lang H, Draeger E; Study to Evaluate the Administration of Detemir Insulin Efficacy, Safety and Suitability (STEADINESS) Study Group: Insulin detemir offers improved glycemic control compared with NPH insulin in people with type 1 diabetes: a randomized clinical trial. Diabetes Care 27:1081–1087, 2004

Honkasalo MT, Elonheimo OM, Sane T: Severe hypoglycaemia in drug-treated diabetic patients needs attention: a population-based study. Scand J Prim Health Care. doi: 10.3109/02813432.2011.580090

Jaser SS, Whittemore R, Ambrosino JM, Lindemann E, Grey M: Coping and psychosocial adjustment in mothers of young children with type 1 diabetes. Child Health Care 38:91–106, 2009

Jeha GS, Karaviti LP, Anderson B, Smith EO, Donaldson S, McGirk T, Haymond MW: Continuous glucose monitoring and the reality of metabolic control in preschool children with type 1 diabetes. Diabetes Care 27:2881–2886, 2004

Jørgensen HV, Pedersen-Bjergaard U, Rasmussen AK, Borch-Johnsen K: The impact of severe hypoglycemia and impaired awareness of hypoglycemia on relatives of patients with type 1 diabetes. Diabetes Care 26:1106–1109, 2003

Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group, Tamborlane WV, Beck RW, Bode BW, Buckingham B, Chase HP, Clemons R, Fiallo-Scharer R, et al.: Continuous glucose monitoring and intensive treatment of type 1 diabetes. N Engl J Med 359:1464–1476, 2008

Katakura M, Naka M, Kondo T, Nishii N, Komatsu M, Sato Y, Yamauchi K, Hiramatsu K, Ikeda M, Aizawa T, Hashizume K: Prospective analysis of mortality, morbidity, and risk factors in elderly diabetic subjects: Nagano study. Diabetes Care 26:638–644, 2003

Kerr D, Macdonald IA, Heller SR, Tattersall RB: Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulin-dependent) diabetes. Diabetologia 33:216–221, 1990

Kinsley BT, Weinger K, Bajaj M, Levy CJ, Simonson DC, Quigley M, Cox DJ, Jacobson AM: Blood glucose awareness training and epinephrine responses to hypoglycemia during intensive treatment in type 1 diabetes. Diabetes Care 22:1022–1028, 1999

Kordonouri O, Pankowska E, Rami B, Kapellen T, Coutant R, Hartmann R, Lange K, Knip M, Danne T: Sensor-augmented pump therapy from the diagnosis of childhood type 1 diabetes: results of the Paediatric Onset Study (ONSET) after 12 months of treatment. Diabetologia 53:2487–2495, 2010

Kubiak T, Hermanns N, Schreckling H-J, Kulzer B, Haak T: Evaluation of a self-management-based patient education program for the treatment and prevention of hypoglycemia-related problems in type 1 diabetes. Patient Educ Couns 60:228–234, 2006

Kubiak T, Hermanns N, Schreckling H-J, Kulzer B, Haak T: Assessment of hypoglycaemia awareness using continuous glucose monitoring. Diabet Med 21:487–490, 2004

Laiteerapong N, Karter AJ, Liu JY, Moffet HH, Sudore R, Schillinger D, John PM, Huang ES: Correlates of quality-of-life in older adults with diabetes: the Diabetes and Aging Study. Diabetes Care. doi: 10.2337/dc10-2424

Leese GP, Wang J, Broomhall J, Kelly P, Marsden A, Morrison W, Frier BM, Morris A: Frequency of severe hypoglycemia requiring emergency treatment in type 1 and type 2 diabetes: a population-based study of health service resource use. Diabetes Care 26:1176–1180, 2003

Leiter LA, Yale J-F, Chiasson J-L, Harris SB, Kleinstiver P, Sauriol L: Assessment of the impact of fear of hypoglycemic episodes on glycemic and hypoglycemic management. Can J Diabetes 29:186–192, 2005

Linkeschova R, Raoul M, Bott U, Berger M, Spraul M: Less severe hypoglycaemia, better metabolic control, and improved quality of life in type 1 diabetes mellitus with continuous subcutaneous insulin infusion (CSII) therapy: an observational study of 100 consecutive patients followed for a mean of 2 years. Diabet Med 19:746–751, 2002

Litton J, Rice A, Friedman N, Oden J, Lee MM, Freemark M: Insulin pump therapy in toddlers and preschool children with type 1 diabetes mellitus. J Pediatr 141:490–495, 2002

Lundkvist J, Berne C, Bolinder B, Jönsson L: The economic and quality of life impact of hypoglycemia. Eur J Health Econ 6:197–202, 2005

McCrimmon RJ, Frier BM: Hypoglycaemia, the most feared complication of insulin therapy. Diabetes Metab 20:503–512, 1994

Meloche RM: Transplantation for the treatment of type 1 diabetes. World J Gastroenterol 13:6347–6355, 2007

Mühlhauser I, Berger M: Diabetes education and insulin therapy: when will they ever learn? J Intern Med 233:321–326, 1993

Munshi MN, Segal AR, Suhl E, Staum E, Desrochers L, Sternthal A, Giusti J, McCarthy R, Lee Y, Bonsignore P, Weinger K: Frequent hypoglycemia among elderly patients with poor glycemic control. Arch Intern Med 171:362–364, 2011

Murata GH, Duckworth WC, Shah JH, Wendel CS, Mohler MJ, Hoffman RM: Hypoglycemia in stable, insulin-treated veterans with type 2 diabetes: a retrospective study of 1662 episodes. J Diabetes Complications 19:10–17, 2005

Murata GH, Hoffman RM, Shah JH, Wendel CS, Duckworth WC: A probabilistic model for predicting hypoglycemia in type 2 diabetes mellitus. Arch Intern Med 164:1445–1450, 2004

Myers VH, Boyer BA, Herbert JD, Barakat LP, Scheiner G: Fear of hypoglycemia and self-reported posttraumatic stress in adults with type I diabetes treated by intensive regimens. J Clin Psychol Med Settings 14:11–21, 2007

Nordfeldt S, Johansson C, Carlsson E, Hammersjo J-A: Persistent effects of a pedagogical device targeted at prevention of severe hypoglycaemia: a randomized, controlled study. Acta Paediatr 94:1395–1401, 2005a

Nordfeldt S, Ludvigsson J: Fear and other disturbances of severe hypoglycaemia in children and adolescents with type 1 diabetes mellitus. J Pediatr Endocrinol Metab 18:83–91, 2005b

Nordfeldt S, Johansson C, Carlsson E, Hammersjo J-A: Prevention of severe hypoglycaemia in type I diabetes: a randomised controlled population study. Arch Dis Child 88:240–245, 2003

Patton SR, Dolan LM, Henry R, Powers SW: Fear of hypoglycemia in parents of young children with type 1 diabetes mellitus. J Clin Psychol Med Settings 15:252–259, 2008

Perros P, Frier BM: The long-term sequelae of severe hypoglycemia on the brain in insulin-dependent diabetes mellitus. Horm Metab Res 29:197–202, 1997

Pettersson B, Rosenqvist U, Deleskog A, Journath G, Wändell P: Self-reported experience of hypoglycemia among adults with type 2 diabetes mellitus (Exhype). Diabetes Res Clin Pract 92:19–25, 2011

Plank J, Kohler G, Rakovac I, Semlitsch BM, Horvath K, Bock G, Kraly B, Pieber TR: Long-term evaluation of a structured outpatient education programme for intensified insulin therapy in patients with type 1 diabetes: a 12-year follow-up. Diabetologia 47:1370–1375, 2004

Rami B, Nachbaur E, Waldhoer T, Schober E: Continuous subcutaneous insulin infusion in toddlers. Eur J Pediatr 162:721–722, 2003

Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson C, on behalf of the U.S. Study Group of Insulin Glargine in Type 1 Diabetes: Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care 23:639–643, 2000

Reach G, Zerrouki A, Leclercq D, d’Ivernois J-F: Adjusting insulin doses: from knowledge to decision. Patient Educ Couns 56:98–103, 2005

Reviriego J, Gomis R, Marañés JP, Ricart W, Hudson P, Sacristán JA: Cost of severe hypoglycaemia in patients with type 1 diabetes in Spain and the cost-effectiveness of insulin lispro compared with regular human insulin in preventing severe hypoglycaemia. Int J Clin Pract 62:1026–1032, 2008

Rewers A, Chase HP, Mackenzie T, Walravens P, Roback M, Rewers M, Hamman RF, Klingensmith G: Predictors of acute complications in children with type 1 diabetes. JAMA 287:2511–2518, 2002

Richardson T, Weiss M, Thomas P, Kerr D: Day after the night before: influence of evening alcohol on risk of hypoglycemia in patients with type 1 diabetes. Diabetes Care 28:1801–1802, 2005

Rickels MR, Schutta MH, Mueller R, Kapoor S, Markmann JF, Naji A, Teff KL: Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients. J Clin Endocrinol Metab 92:873–879, 2007

Ritholz M: Is continuous glucose monitoring for everyone? Consideration of psychosocial factors. Diabetes Spectr 21:287–289, 2008

Rosenstock J, Dailey G, Massi-Benedetti M, Fritsche A, Lin Z, Salzman A: Reduced hypoglycemia risk with insulin glargine: a meta-analysis comparing insulin glargine with human NPH insulin in type 2 diabetes. Diabetes Care 28:950–955, 2005

Ryan C: Does moderately severe hypoglycemia cause cognitive dysfunction in children? Pediatric Diabetes 5:59–62, 2004

Ryan C: Neurobehavioral complications of type 1 diabetes: examination of possible risk factors. Diabetes Care 11:86–93, 1988

Ryan C, Vega A, Drash A: Cognitive deficits in adolescents who developed diabetes early in life. Pediatrics 75:921–927, 1985

Samann A, Mühlhauser I, Bender R, Kloos C, Muller UA: Glycaemic control and severe hypoglycaemia following training in flexible, intensive insulin therapy to enable dietary freedom in people with type 1 diabetes: a prospective implementation study. Diabetologia 48:1965–1970, 2005

Sandoval DA, Guy DL, Richardson MA, Ertl AC, Davis SN: Effects of low and moderate antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes. Diabetes 53:1798–1806, 2004

Scaramuzza AE, Iafusco D, Rabbone I, Bonfanti R, Lombardo F, Schiaffini R, Buono P, Toni S, Cherubini V, Zuccotti GV; Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetology: Use of integrated real-time continuous glucose monitoring/insulin pump system in children and adolescents with type 1 diabetes: a 3-year follow-up study. Diabetes Technol Ther 13:99–103, 2011

Schultes B, Jauch-Chara K, Gais S, Hallschmid M, Reiprich E, Kern W, Oltmanns KM, Peters A, Fehm HL, Born J: Defective awakening response to nocturnal hypoglycemia in patients with type 1 diabetes mellitus. PLoS Med 4:e69, 2007

Seligman HK, Davis TC, Schillinger D, Wolf MS: Food insecurity is associated with hypoglycemia and poor diabetes self-management in a low-income sample with diabetes. J Health Care Poor Underserved 21:1227–1233, 2010

Shahar J: Helping your patients become active. Diabetes Spectr 21:59–62, 2008

Shapiro AM, Ricordi C, Hering BJ, Auchincloss H, Lindblad R, Roberston RP, Secchi A, et al.: International trial of the Edmonton protocol for islet transplantation. N Engl J Med 355:1318–1330, 2006

Singh H, Gonder-Frederick L, Shepard J, Cox DJ: Hypoglycemia-related cognitive dysfunction and its consequences in diabetes. Int Diabetes Monit 22:238–242, 2010

Slover RH, Welsh JB, Criego A, Weinzimer SA, Willi SM, Wood MA, Tamborlane WV: Effectiveness of sensor-augmented pump therapy in children and adolescents with type 1 diabetes in the STAR 3 study. Pediatr Diabetes. doi: 10.1111/j.1399-5448.2011.00793.x

Sommerfield AJ, Deary IKJ, McAulay V, Frier BM: Moderate hypoglycemia impairs multiple memory functions in healthy adults. Neuropsychology 17:125–132, 2003

Sovik O, Thordarsen H: Dead in bed syndrome in young diabetic patients. Diabetes Care 22 (Suppl. 2):B40–B42, 1999

Stahl M, Berger W, Schachinger H, Cox D: Spouse’s worries concerning diabetic partner’s possible hypoglycemia. Diabet Med 15:619–620, 1998

Steppel JH, Horton ES: Beta-cell failure in the pathogenesis of type 2 diabetes mellitus. Curr Diab Rep 4:169–175, 2004

Strachan MWJ, Reynolds RM, Marioni RE, Rice JF: Cognitive function, dementia and type 2 diabetes mellitus in the elderly. Nat Rev Endocrinol 7:108–114, 2011

Strachan MWJ, Deary IJ, Ewing FM, Frier BM: Recovery of cognitive function and mood after severe hypoglycemia in adults with insulin-treated diabetes. Diabetes Care 23:305–312, 2000

Svoren BM, Butler D, Levine B-S, Anderson BJ, Laffel LM: Reducing acute adverse outcomes in youths with type 1 diabetes: a randomized, controlled trial. Pediatrics 112:914–922, 2003

Swade TF, Emanuele NV: Alcohol and diabetes. Compr Ther 23:135–140, 1997

Tansey MJ, Tsalikian E, Beck RW, Mauras N, Buckingham BA, Weinzimer SA, Janz KF, et al., on behalf of The Diabetes Research in Children Network (DirecNet) Study Group: The effects of aerobic exercise on glucose and counterregulatory hormone concentrations in children with type 1 diabetes. Diabetes Care 29:20–25, 2006

Weissberg-Benchell J, Antisdel-Lomaglio J, Seshadri R: Insulin pump therapy: a meta-analysis. Diabetes Care 26:1079–1087, 2003

Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Selby JV: Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 301:1565–1572, 2009

Wild D, von Maltzahn R, Brohan E, Christensen T, Clauson P, Gonder-Frederick L: A critical review of the literature on fear of hypoglycemia in diabetes: implications for diabetes management and patient education. Patient Educ Couns 68:10–15, 2007

Williams SA, Pollack MF, Dibonaventura M: Effects of hypoglycemia on health-related quality of life, treatment satisfaction and healthcare resource utilization in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 91:363–370, 2011

Wirsén A, Tallroth G, Lindgren M, Agardh C-D: Neuropsychological performance differs between type 1 diabetic and normal men during insulin-induced hypoglycaemia. Diabet Med 9:156–165, 1992

Wolpert HA: Use of continuous glucose monitoring in the detection and prevention of hypoglycemia. J Diabetes Sci Technol 1:146–150, 2007

Workgroup on Hypoglycemia, American Diabetes Association: Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care 28:1245–1249, 2005

Wredling R, Levander S, Adamson U, Lins P-E: Permanent neuropsychological impairment after recurrent episodes of severe hypoglycaemia in man. Diabetologia 33:152–157, 1990

Yki-Jarvinen H, Dressler A, Ziemen M, on behalf of the HOE 901/3002 Study Group: Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 23:1130–1136, 2000

Young-Hyman DL, Davis CL: Disordered eating behavior in individuals with diabetes: importance of context, evaluation, and classification. Diabetes Care 33:683–689, 2010

Zammitt N, Frier BM: Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities. Diabetes Care 28:2948–2961, 2005

Linda Gonder-Frederick, PhD, is an Associate Professor in the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia School of Medicine in Charlottesville, VA.

Daniel J. Cox, PhD, ABPP, is a clinical psychologist and professor in the Department of Psychiatry and Neurobehavioral Sciences and the Department of Internal Medicine at the University of Virginia in Charlottesville, VA.

Harsimran Singh, PhD, is a Research Scientist in the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia School of Medicine in Charlottesville, VA.

Jaclyn A. Shepard, PsyD, is an Assistant Professor in the Department of Psychiatry and Neurobehavioral Sciences at the University of Virginia School of Medicine in Charlottesville, VA.