Out of Sight, Out of Mind: A Call to Action for the Treatment of Hypoglycemia Free

Ready-to-use glucagon options are available in a powdered formulation for intranasal administration (Baqsimi); a liquid, room-temperature stable formulation (Gvoke) in three delivery methods (autoinjector, prefilled syringe, and vial-and-syringe kit) for subcutaneous (SC) administration; and a room-temperature stable glucagon analog (dasiglucagon [Zegalogue]) in two delivery methods (autoinjector and prefilled syringe) for SC administration (Table 1). These formats are intended to help family members, friends, coworkers, school personnel, and post-acute and long-term care (LTC) nursing assistants successfully administer full doses of glucagon to those affected by severe hypoglycemia, especially at times when stress is high and judgment is clouded. Additionally, these glucagon formulations and delivery devices make self-administration feasible, especially when people with nonsevere hypoglycemia are alone, and consumed carbohydrates alone are not restoring euglycemia.

Level 1 and level 2 hypoglycemia are commonly considered nonsevere hypoglycemia. These levels are defined by blood glucose concentrations (level 1: <70 but ≥54 mg/dL; level 2: <54 mg/dL). Level 3 hypoglycemia is synonymous with severe hypoglycemia and is defined by the need for assistance from another person regardless of blood glucose level (e.g., if the affected person is unable or unwilling to swallow, unconscious, or in a coma) (1).

The estimated ratio of SHEs to mild-to-moderate (nonsevere) hypoglycemic events ranges from 1:20 to 1:60 (2,3), and the rates for severe hypoglycemia vary among studies on the basis of its definition, patient age, type of diabetes, clinical complexity, and types of glucose-lowering medications (2,4,5). Individuals taking insulin may not always record their insulin doses, which makes the probability of hypoglycemia (and hyperglycemia) high. For example, in a recent survey of 540 people with diabetes on a multiple daily injection insulin regimen, 257 (47.6%) did not record insulin doses (6). Both dose recording and glucose management could be improved through the use of a smart insulin pen connected to an integrated digital app and a continuous glucose monitoring (CGM) system (7).

Yet, despite these findings and despite the increasing use of insulin pumps (8,9), CGM (10–13), and automated insulin delivery systems (14), severe hypoglycemia defined as a loss of consciousness/coma and convulsions/seizures remains a concern. A high percentage of survey respondents sourced from the T1D Exchange clinic registry, most of whom used insulin pump therapy, CGM, or both, reported between 2011 and 2021 to have had at least 1 SHE within the past 12 months (8–10,13,15). Furthermore, a meta-analysis of 40 studies involving 582,310 participants with type 2 diabetes yielded a pooled prevalence of 6% for severe hypoglycemia (3).

Any level of hypoglycemia is of concern because of its numerous, possibly lifechanging, consequences, eight of which are described below.

Next-day functioning may be affected by overnight glucose concentrations (16). The CGM metric percent coefficient of variation (%CV)—a measure of glycemic variability—that was limited to only overnight hours was predictive for overall next-day functioning. Higher %CV predicted poorer sustained attention and lower engagement in demanding daily activities. One possible reason for high levels of glycemic variability may be sleep disrupted by CGM system alarms for hypoglycemic and hyperglycemic events. For example, consuming carbohydrates with each hypoglycemia alarm and later reawakening to give insulin with each hyperglycemia alarm could trigger a vicious cycle of glycemic variability.

Nonsevere hypoglycemia may affect work productivity (17). Just over half (51%) of people with type 1 diabetes and 28% of those with type 2 diabetes report having nonsevere hypoglycemic events between once daily and once weekly in the past month. If these nonsevere hypoglycemic events occurred at work, nearly one in five people missed on average 10 hours of work due to leaving work early or missing an entire day; if these events occurred outside of work, one in seven missed on average 13 hours of work. As a result of these missed work hours, some affected individuals missed meetings or appointments or did not finish projects on time (17).

Overall, these data help to demonstrate that hypoglycemia affects both people with diabetes and their workplace colleagues because of the resulting suboptimal work performance and absenteeism. Furthermore, according to the American Diabetes Association, reduced productivity due to diabetes also affects the U.S. economy, costing $106.3 billion in 2022 (18,19).

Frequent SHEs may lead to cognitive decline. For example, among 718 individuals ≥60 years of age with type 1 diabetes, those who experienced at least one SHE within the previous 12 months, compared with those who did not, had lower global cognition scores and lower scores for three of the four domains that comprise global cognition: language, executive function, and episodic memory (20). Additionally, those with four or more SHEs within the past 12 months had even lower global cognition scores and individual domain scores for the same three domains (20).

As the amount of time spent in hypoglycemia increases, so does the likelihood of impaired awareness of hypoglycemia (IAH) (21). Severe hypoglycemia can develop quickly because IAH-affected individuals have hypoglycemia symptoms, if any, at a lower blood glucose level than individuals without IAH (e.g., they may develop symptoms at level 2 hypoglycemia [<54 mg/dL] but not at level 1 hypoglycemia [<70 but ≥54 mg/dL]). This delay in symptoms can leave IAH-affected people with only one opportunity, or no opportunity at all, to eat carbohydrates in an attempt to raise their blood glucose level to >70 mg/dL before their hypoglycemia escalates to an SHE. Hypoglycemic events and IAH can become a vicious cycle, with frequent events leading to worsening IAH and worsening IAH leading to more frequent events (1).

Car accidents are an often forgotten consequence of SHEs. The American Diabetes Association (ADA) recommends assessing people with diabetes for their ability to drive safely (22). However, in a 2023 study (23), only 40% of adults >18 years of age with type 1 diabetes reported receiving education or information about resources dealing with safe driving practices for people with diabetes. Furthermore, one education session may not sufficiently inform people about the dangers of driving when experiencing hypoglycemia. Also, in a recent systematic literature review (24), 13 identified guidelines for drivers with diabetes, from 11 countries, were found to vary greatly. Differences included recommendations for minimum blood glucose levels, the time window to check blood glucose before driving, frequency of blood glucose testing, target blood glucose level, and time to wait before resuming driving after a hypoglycemic event. Based on the results of a preliminary study (25), individuals’ responses to hypoglycemic events while driving could be improved by using an in-vehicle warning system.

In the aforementioned systematic review (24), 72% of participants reported having had an undefined hypoglycemic event while driving and ∼4% reported having had a car accident because of hypoglycemia within the past 2 years. For comparison, ∼3% (11 million/332 million) of the U.S. population in 2021 (26) had police-reported crashes (27).

Also, in a 2020 study of people with diabetes aged 15–22 years, 47% reported having biochemical or symptomatic hypoglycemia while driving at least once within the past month. Additionally, only 43% of those who reported hypoglycemia while driving reported pulling over, treating the hypoglycemia, and resuming driving only when they had euglycemia or symptom resolution (28).

Hypoglycemia is known to cause cardiac arrhythmias through various mechanisms, including hypokalemia and activation of the sympathetic nervous system (29). A recent meta-analysis of 14 studies revealed the risk for cardiac arrhythmias among people with diabetes and any level of hypoglycemia was 42% greater than the risk for cardiac arrhythmias among people with diabetes but without hypoglycemia; the risk for cardiac arrhythmias was 27% greater for those with diabetes and severe hypoglycemia (29).

Severe hypoglycemic events may precede the development of cardiovascular disease (CVD), especially in people with type 2 diabetes in whom CVD is a common comorbidity. However, some people will have an SHE after a cardiovascular event or after hospitalization for heart failure (30–33).

For people ≥55 years of age with a history of major macrovascular disease (e.g., nonfatal myocardial infarction or nonfatal stroke) or a history of major microvascular disease (e.g., nephropathy or retinopathy), an SHE was associated with a 200% increased risk for having new major macrovascular disease or new or progressive major microvascular disease (30,33).

SHEs frequently lead to 911 calls for dispatching emergency medical services (EMS) personnel, to subsequent EMS transport and treatment in an emergency department (ED), and then possibly to hospitalization. Yet, not all EMS personnel carry glucagon because of state regulations that prohibit them from administering it (34). Specifically, emergency medical technicians may be prohibited, which is problematic because they are the second most common first responders (35). In situations where glucagon is not available, first responders must attempt venipuncture to administer intravenous dextrose, which was most common in 2015, at 50% of EMS encounters (36), but may also be problematic because venous access may be difficult or impossible. Additionally, individuals who reside in rural locations may not have immediate access to EMS, and the arrival of EMS personnel may take longer, potentially leading to poor outcomes (37).

Between 2016 and 2018 at a single urban ED, 232 people with diabetes, 84% of whom had type 2 diabetes, were seen because of hypoglycemia. Sixty-two percent had been receiving insulin, and 34.5% had a blood glucose level <54 mg/dL (38). Between 2018 and 2020 among people with type 1 diabetes (n = 110), people with type 2 diabetes (n = 109), and caregivers of people with diabetes (n = 210), 20% indicated use of a health care resource, such as calling for EMS or an HCP or going to an ED, because of an SHE (39). Forty percent of those who arrived at the ED reported that the SHE precipitated an overnight hospital stay. Thus, use of health care resources because of hypoglycemia remains high. Furthermore, in the United States in 2022, use of EMS and ED services because of diabetes contributed to ∼3.9% of the $306.6 billion overall direct health care cost attributed to diabetes (18).

When people with diabetes and hypoglycemia are not treated in a timely manner, they may suffer an unrecoverable seizure or coma. SHEs are associated with an increased risk for death days to months after they occur (30–33,40). Based on 2011–2020 claims data from a U.S. database, all-cause mortality within 30 days and 12 months of an ED visit because of hypoglycemia was estimated at 0.2 and 1.7%, respectively, for ∼4,200 people with type 1 diabetes and 1.5 and 13.5%, respectively, for ∼50,000 people with type 2 diabetes (40).

SHEs can be scary (39) and stressful (41); induce panic (42) and feelings of helplessness (39), shame, and embarrassment (41); and negatively affect sleep health (43). After an SHE, some people may fear future reoccurrences, which is known as fear of hypoglycemia (FoH). Affected people may feel like they have to scramble to resolve hypoglycemia, and their judgment and decision-making are most likely suboptimal (42).

Fear can overwhelm people with diabetes such that they limit their activities and have blood glucose levels much higher than their prescribed upper limit target to avoid hypoglycemia reoccurrences (e.g., they may reduce their basal or bolus insulin doses or snack excessively to keep glucose levels high) (44). At its core, FoH most likely affects individuals’ confidence in their ability to avoid or address severe hypoglycemia (44).

In 2005, Leiter et al. (45) reported that, to avoid hypoglycemia reoccurrence, 23% of people with type 1 diabetes and 12% of those with type 2 diabetes among 335 survey respondents indicated that they always modified their insulin dose after a nonsevere hypoglycemic event; 34.5% of those with type 1 diabetes and 10.5% of those with type 2 diabetes reported always modifying their insulin dose after an SHE (45). Ten years later, Leiter et al. (46) reported on another survey of 156 respondents with type 2 diabetes who were diagnosed on average 12 years earlier. They found that, after a self-treated hypoglycemic event (i.e., hypoglycemia symptoms that resolved after drinking a glass of juice, eating something, or taking a glucose tablet), 8% purposely missed and 9% purposely decreased at least one dose of basal insulin. Also, 43.5% of respondents were very or somewhat worried about self-treated hypoglycemic events if they were in a location where they would not have access to food or drink, and 24% were very or somewhat worried about hypoglycemia occurring if they were alone at home (46).

People with IAH may also have FoH because they have hypoglycemia symptoms at lower blood glucose levels than do people with normal awareness of hypoglycemia, and they worry that they will not be able to remedy hypoglycemia quickly enough to keep it from escalating to an SHE (21,44). For people with normal awareness and for some with IAH, however, FoH may instead be the result of hypervigilance for body sensations, which can be associated with hypoglycemia but can also overlap with anxiety (47,48). Therefore, they may interpret body sensations as catastrophic regardless of whether the sensations are mild or even normal (physiologic). Yet, individuals’ early recognition of their own typical symptoms for hypoglycemia is important, allowing them to address hypoglycemia as quickly as possible (47,48).

FoH also extends to caregivers. Sixty-five percent of partners of adults with type 1 diabetes reported moderate or extreme worry about future hypoglycemic events, and 56% of partners had personally helped their loved one to recover from at least one SHE in the previous 6 months (49). Partners worry about hypoglycemia occurring specifically while their loved ones are sleeping, alone, or driving (49).

Given these eight possibly lifechanging consequences of hypoglycemia, preventing hypoglycemia is crucially important. Approaches to preventing hypoglycemia are described elsewhere (1,50,51). When hypoglycemia occurs, however, treatment is needed to reduce the time spent in hypoglycemia and to allow individuals to recover quickly. Therefore, we highlight below guidelines for the treatment of hypoglycemia from the ADA, the American Association of Clinical Endocrinology (AACE), the Endocrine Society, and the American Society of Consultant Pharmacists (ASCP). By following these guidelines, we can help people at high risk for hypoglycemia develop a treatment plan that includes ready-to-use glucagon.

The ADA’s Standards of Care in Diabetes—2024 (1), the Endocrine Society’s 2023 guidelines for the management of people with diabetes at high risk for hypoglycemia (51), and a 2022 update of the AACE clinical practice guideline for developing a diabetes comprehensive care plan (50) indicate that glucagon should be prescribed and available for all people at increased risk for level 2 or level 3 hypoglycemia.

New to the ADA’s 2024 Standards of Care and included in the 2023 Endocrine Society guidelines is the favored status of ready-to-use glucagon rather than traditional lyophilized glucagon that requires reconstitution before use. Ready-to-use glucagon is favored because caregivers such as family members, friends, teachers, and coworkers, rather than trained medical personnel, are often responsible for administering glucagon (51). In separate head-to-head studies between each of the ready-to-use glucagon formulations and the traditional lyophilized glucagon, many more caregivers in simulated hypoglycemia emergency situations successfully gave a full dose of the ready-to-use formulations than of the traditional formulation (52–54).

Also new in the ADA’s 2024 Standards of Care are recommendations for patient education about hypoglycemia prevention and treatment, for modifying diabetes treatment plans for people who have level 2 or level 3 hypoglycemic events, and for HCPs to use evidence-based interventions to reestablish awareness of hypoglycemia (1,55). Patient education, ideally through a diabetes self-management education and support program or delivered by a trained diabetes educator, should include defining hypoglycemia, explaining various situations that may precipitate hypoglycemia such as fasting and physical activity, demonstrating how to self-monitor blood glucose levels, and reviewing the patient-centric hypoglycemia treatment protocol that includes ready-to-use glucagon. For people who have had level 2 or level 3 hypoglycemic events since their last clinic visit, diabetes therapies may need to be deintensified. HCPs should consider enrolling people with IAH in an evidence-based training program such as the Blood Glucose Awareness Training Program or the Dose Adjusted for Normal Eating program (1).

The ADA also added two new tables to its Standards of Care section on glycemic goals and hypoglycemia (1). Table 6.6 in the Standards of Care includes the median 30-day average wholesale prices (AWPs) and national average drug acquisition costs (NADACs) for the ready-to-use glucagon formulations and the traditional lyophilized glucagon formulation (Table 1). Table 6.7 in the Standards of Care summarizes the components of hypoglycemia prevention to assess at the initial visit, every follow-up visit, and annually for people at risk for hypoglycemia (1,55). Among these components are assessing for hypoglycemia awareness and cognition and providing a glucagon prescription and glucagon training.

Added in 2023 and maintained in the 2024 ADA Standards of Care is the specific inclusion of glucagon in a flowchart for intensifying diabetes management to injectable therapies for people with type 2 diabetes (56). When basal insulin is added because A1C remains above a patient’s target, the flowchart indicates that a glucagon prescription should be considered for the treatment of emergent hypoglycemia (Figure 1). Many adults with longstanding type 2 diabetes require basal insulin therapy, with the principal aims of limiting hyperglycemia between meals and overnight and reducing glucose production by the liver (56). Individuals using one of the newer basal insulin formulations, such as glargine 300 units/mL or degludec, may have lower rates of symptomatic hypoglycemia, but the risk remains elevated with insulin use (57,58).

Overbasalization—the titration of basal insulin beyond an appropriate dose in an attempt to achieve glycemia targets—is to be avoided because it could precipitate frequent hypoglycemic events (59). Indicators of possible overbasalization include doses >0.5 units/kg of body weight, a bedtime-to-morning or postprandial glucose differential ≥50 mg/dL, hypoglycemia with or without IAH, and high glucose variability (56,59). In a post hoc analysis of data from the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, 32.4% (903/2,791) of all insulin users were considered overbasalized (59), and 7% (717/10,251) and 11% (1,091/10,251) of participants experienced hypoglycemic events that required medical assistance and any type of assistance, respectively (60).

According to the ADA (18), ∼283,000 Americans <20 years of age have been diagnosed with type 1 or type 2 diabetes, representing 0.35% of all people in this age cohort, with 24,000 new diagnoses in youth every year. The youngest individuals in this cohort are especially susceptible to SHEs because they may not recognize hypoglycemia symptoms and report them to their parents. Youth and adolescents may also experience IAH (61). While in school, they may be reluctant to tell a teacher that they have hypoglycemia symptoms because of embarrassment or fear of social stigma (62). Hypoglycemia preparedness in daycare centers and schools is important. Youth and adolescents spend ∼30 hours/week in these settings, and mild hypoglycemia often occurs once or twice per week even in youth and adolescents who meet glycemia targets (62); thus, hypoglycemia can certainly happen during school or daycare hours.

Ready-to-use glucagon formulations can be used in children. Each formulation has a different lower age limit. The powder is available as 3 mg for intranasal administration to children >4 years of age. The liquid-stable glucagon analog dasiglucagon is available as 0.6 mg in an autoinjector and a prefilled syringe for SC administration to children ≥6 years of age. The liquid room-temperature stable glucagon is available in an autoinjector, a prefilled syringe, and a vial-and-syringe kit, with 0.5 mg for children 2 to <12 years of age and 1 mg for children ≥12 years of age (Table 1) (63).

Federal law, through Section 504 of the Americans with Disabilities Act, gives students the right to receive appropriate diabetes care to enable them to safely and equitably participate in school activities along with their schoolmates who do not have diabetes (64). Therefore, schools should provide trained staff to monitor students’ blood glucose levels, give insulin, and, in case of an SHE, administer glucagon. Among other support tools the ADA furnishes, its bulletin “ADA Safe at Schools: Helping the Student With Diabetes Succeed: A Guide for School Personnel” helps to prepare school nurses and other school personnel to effectively support children in school (64).

Having at least one student with diabetes at a school is highly probable. In a survey of 1,796 school nurses in the New England region of the United States, 86% indicated that they had at least one student with type 1 diabetes (interquartile range, 1–4) (65). Ninety percent of respondents indicated a high degree of comfort with giving insulin injections, and 84% indicated being mostly or very comfortable with treating low blood glucose. However, the survey question did not specify the treatment of low blood glucose (65); therefore, we do not know whether they had the same comfort with administering glucagon, especially given that ready-to-use glucagon was not available before 2019, the last year in which the survey was fielded.

Transition from childhood to young adulthood is a period in which adolescents are particularly vulnerable to SHEs. Recognizing this, Diabetes Link (formerly the College Diabetes Network) provides the resource “Off to College With Diabetes” to help with this transition (66). The resource describes glucagon as “your safety net,” reiterating the message noted in guidelines that anyone taking insulin is at high risk for hypoglycemia and that glucagon is needed when fast-acting carbohydrates are ineffective at resolving nonsevere hypoglycemia quickly enough to avoid escalation to an SHE.

Older adults (≥65 years of age) are affected by SHEs as much as, if not more than, younger adults. As the number of older adults increases, so will the number of those who have diabetes, especially type 2 diabetes. In 2022, the ADA estimated that ∼15.9 million people, which is about one in three adults ≥65 years of age, had diabetes (18). Also, in an observational study from 2016 to 2020 that annually involved up to 120,861 residents of LTC facilities who had type 2 diabetes and were ≥65 years of age, 35% had at least one episode of level 1 hypoglycemia, and ∼25% had at least one episode of level 2 hypoglycemia (67). Glucagon, a proxy for level 3 hypoglycemia, was given to 18–23% of the LTC residents each year (67).

In 2023, the ASCP released its recommendations for the management and treatment of older adults in LTC or assisted-living facilities (68). These guidelines advise the use of glucagon when blood glucose is <70 mg/dL and the LTC resident is unable or unwilling to consume nutrition orally, which aligns with the other organizations’ recommendations.

No head-to-head studies among the three ready-to-use glucagon formulations have been published, and without such studies, direct comparisons of their efficacy, safety, and tolerability cannot be made. In independent published studies, efficacy was demonstrated for each formulation. Additionally, each performed as well as traditional lyophilized glucagon requiring reconstitution (Table 1) (69–75). Generally, euglycemia returned or symptoms resolved as early as 10–15 minutes after glucagon administration.

Safety and tolerability profiles for each of the three ready-to-use glucagon formulations were deemed acceptable. The intranasal formulation has a few unique adverse events (e.g., nasal congestion and discomfort) because it is given intranasally; similarly, the adverse events unique to the SC formulations are at the injection site (e.g., discomfort and pain). Nausea and vomiting are common to all formulations (Table 1); therefore, people receiving glucagon should be placed on their side so they will not choke should they vomit.

It is also important to ensure that glucagon on hand has not yet expired. Shelf life and expiry dates are dictated by the specific dose and delivery method, along with manufacturer-recommended storage conditions (Table 1).

Self-administration of ready-to-use glucagon is feasible when a person with diabetes is alone and experiencing hypoglycemia, especially level 2 hypoglycemia (<54 mg/dL), and glucose has not risen to >70 mg/dL within 15 minutes after eating 15 g carbohydrates.

Consuming carbohydrates is the preferred method to resolve hypoglycemia. Glucose tablets and liquid may be the easiest and most effective fast-acting glucose forms to resolve nonsevere hypoglycemia (76–79). If hypoglycemia is confirmed or if symptoms consistent with hypoglycemia are present, the affected person—if able and willing to swallow—should consume 15 g fast-acting carbohydrates and recheck blood glucose 15 minutes later. This check ideally should be a fingerstick glucose measurement with a blood glucose meter because equilibrium is delayed between capillary blood glucose and CGM-based interstitial glucose readings. If blood glucose is still <70 mg/dL, the person should eat another 15 g carbohydrates and repeat this procedure until blood glucose is >70 mg/dL.

A common predicament arises when blood glucose does not increase and CGM shows a downward glucose trend despite the affected person consuming carbohydrates. In such instances, people may wonder whether they should consume more carbohydrates, whether they need glucagon, and whether someone is around to help them if need be. Complicating the predicament is that decision-making may be poor during a hypoglycemic event. Therefore, fast-acting carbohydrates and ready-to-use glucagon should be kept available in a nightstand drawer, purse, pants pocket, and car. Caregivers, family members, friends, and coworkers should know where these treatments are stored, and, for glucagon, they should know when and how to use it (1,44).

Nonsevere hypoglycemic events may be safely resolved by eating one or two 15-g servings of fast-acting carbohydrates. However, the window of time may be brief to resolve nonsevere hypoglycemic events with carbohydrates to avoid escalation to an SHE (Table 2) (76–79).

Published contemporaneous studies regarding the effectiveness of various carbohydrate sources to resolve hypoglycemia are few (78–80). In a 2023 study (79), which involved 32 people with type 1 diabetes, one 16-g serving of glucose tablets was effective at increasing blood glucose of 54–63 mg/dL to ≥72 mg/dL or blood glucose <54 mg/dL to ≥72 mg/dL within 15 minutes in only ∼20% of patients, whereas one 32-g serving as glucose tablets was effective at increasing blood glucose of 54–63 mg/dL to ≥72 mg/dL within 15 minutes in 47% of patients but was effective at increasing blood glucose from <54 mg/dL to ≥72 mg/dL in only 24% of patients (Table 2).

In a 2024 open-label, three-arm crossover study (80), researchers described the effectiveness of one, 16-g serving of carbohydrates as four dextrose tablets in its ability to prevent hypoglycemia when consumed at a plasma glucose (PG) level <70, ≤80, and ≤90 mg/dL. With nadir PG levels, which occurred ∼10 minutes after consuming the 16-g serving, of 57, 64, and 74 mg/dL, respectively, the 16-g serving effectively increased PG to ≥70 mg/dL for 9 of 29 (31%), 14 of 29 (48%), and 20 of 29 (69%) participants, respectively. Based on PG values measured for 60 minutes after consuming the serving, time spent in hypoglycemia was significantly longer for those with PG <70 mg/dL compared with those with PG ≤80 mg/dL (mean 26 vs. 18 minutes) and for those with PG <70 mg/dL compared with those with PG ≤90 mg/dL (mean 26 vs. 7 minutes). The remainder of participants in each arm who did not attain a PG ≥70 mg/dL required two or three total 16-g servings, with servings consumed every 20 minutes. The researchers indicated that patients may benefit from consuming carbohydrates at a blood glucose level >70 mg/dL rather than waiting until their blood glucose is <70 mg/dL. Additionally, positive results with earlier carbohydrate consumption were only rarely associated with rebound hyperglycemia; only one participant in the intervention PG <70 mg/dL group and one participant in the intervention PG ≤80 mg/dL group experienced a PG >180 mg/dL within 60 minutes of the intervention (Table 2) (80).

Other studies are aged and involved small numbers of patients (Table 2). A study published in 1984 that involved 16 patients with insulin-treated diabetes revealed that 20 g glucose tablets worked best to increase blood glucose from ≤55 to ≥75 mg/dL within 20 minutes (7 of 9 patients), compared with whole milk (0 of 5 patients), 6 oz orange juice (1 of 3 patients), or 12 oz orange juice (2 of 5 patients) (76). A study published in 1990 that involved 32 patients revealed that, of seven carbohydrate sources—15 g glucose tablets, 15 g sucrose tablets, 15 g glucose in water, 15 g sucrose in water, 15 g glucose as 40 g 40% dextrose gel, 15 g cornstarch hydrolysate containing 2–3% glucose, or 15 g glucose as orange juice—glucose tablets worked to resolve hypoglycemia symptoms in 15 minutes in 4 of 6 patients, whereas glucose or sucrose in water worked to resolve symptoms in 5 of 6 patients, all from a nadir blood glucose between 38 and 50 mg/dL. However, orange juice was the least effective to resolve hypoglycemia symptoms (0 of 6 patients) (77).

In our experience, some patients may eat <15 g glucose tablets (i.e., eat one tablet rather than three or four tablets) and are more likely to take the proper dose of glucose as a liquid. Plus, patients can simply swallow the liquid; they do not have to work (i.e., chew) to take 15 g glucose tablets.

The outcomes of the aforementioned studies indicate that people most likely respond differently to various carbohydrate sources, and sometimes a second serving of ≥15 g is necessary. Yet, having ready-to-use glucagon available is important so that people with diabetes and their caregivers have a backup method when consuming carbohydrates is not working fast enough (or at all) to resolve hypoglycemia.

Insulin use is a major risk factor for developing hypoglycemia. This fact is important given that ∼8.3 million people with diabetes (1.6 million with type 1 diabetes and 6.7 million with type 2 diabetes) in the United States use insulin (18). Other risk factors include treatment with an insulin secretagogue or another glucose-lowering drug combined with insulin or a secretagogue, recent level 2 or level 3 hypoglycemia, age ≥75 years, impaired cognition or dementia (also a consequence of hypoglycemia), IAH (also a consequence of hypoglycemia), inappropriate tight glycemic control, fasting or erratic meal consumption, alcohol consumption, and various social determinants of health (SDOH) (1).

Inappropriate tight control refers to setting the same glycemic goals for individuals in poor health as for those in good health, which could contribute to hypoglycemia. The ADA recommends a framework for considering glycemic targets based on whether a person with diabetes is in good, intermediate, or poor health, with generally higher A1C targets for those in poor health to reduce the risk for hypoglycemia (81). Health status is based on the number of coexisting chronic illnesses, presence of intact cognition, degree of treatment burden, and risk for hypoglycemia.

Unfortunately, A1C levels may not predict the level of risk for SHEs; people with type 1 or type 2 diabetes with various A1C levels have reported having SHEs (9,82). Also, A1C levels in older adults may be inaccurate because these individuals may have comorbidities that affect red blood cell turnover, such as severe kidney disease or gastrointestinal bleeding (33).

Alcohol consumption is associated with a high risk for hypoglycemia, most likely because of impaired counterregulatory response, IAH, and impaired cognition (83). Risk may be elevated up to 24 hours after alcohol consumption (83).

SDOH are the conditions in which people are born, grow, live, work, and age and are often attributed to health inequities across various populations (84). Food insecurity (i.e., not having adequate quantity and quality of food at all times for all household members to have an active, healthy life) (84) is one SDOH relevant to hypoglycemia risk. Interviewed adults who were food insecure were twice as likely as those who were not food insecure to report having ≥4 SHEs (85). Among the 28% of participants who reported having at least 1 SHE, 43% attributed hypoglycemia to their inability to afford food, whereas among 514 who did not report having an SHE, 7% attributed hypoglycemia to their inability to afford food (85).

Although the ADA now recommends prescribing glucagon in conjunction with basal insulin for people with type 2 diabetes (56) and the ADA (1) and the Endocrine Society (51) emphasize the use of ready-to-use glucagon, rates of prescribing and filling prescriptions for glucagon are woefully low (13,39,86). Even after glucagon prescriptions are filled, the glucagon someone has on hand may expire. For example, even among the highly motivated participants in the T1D Exchange clinic registry, glucagon on hand was >2 years old for 8% (20 of 251) of surveyed members who owned a glucagon kit. One reason given for not using glucagon at the time of an SHE was that the glucagon had expired (13).

Between 2013 and 2017, quarterly prescription rates for traditional lyophilized glucagon averaged only 1.6% among >250,000 adults ≥18 years of age with diabetes (87.9% with type 2 diabetes) (86). Between 2018 and 2020, only 3.7% (16 of 429) of people reported obtaining glucagon or keeping glucagon close after their most recent SHE (39). Between 2011 and 2021 among ∼2.8 million people with diabetes (type 1 diabetes 89,200, type 2 diabetes 2,725,264), only 1.5% (41,514) had filled at least one glucagon prescription, and prescription fill rates in 2021 were 22% lower than in 2011, despite the 2019 availability of ready-to-use intranasal and liquid-stable glucagon formulations (87). Additionally, only 8.7% of people treated with short-acting insulin, 2.3% of those treated with long-acting insulin, and 8.6% of those with a history of SHEs had filled at least one glucagon prescription (87).

In addition to the challenges of increasing rates of prescribing and filling prescriptions for glucagon are challenges of keeping glucagon on hand for immediate use when needed and ensuring its proper use and storage. Increasingly, HCPs and other stakeholders have been recognizing glucagon as a lifesaving treatment for people experiencing severe hypoglycemia. This recognition has led to some novel approaches to increase prescribing and filling prescriptions for glucagon.

Pharmacists practicing in North Carolina are able to prescribe glucagon for people they have proactively identified as being at high risk for severe hypoglycemia. The North Carolina law defines severe hypoglycemia as blood glucose <54 mg/dL or altered mental and/or physical functioning that requires assistance from another person for recovery. The law specifies prescribing either traditional lyophilized glucagon for reconstitution or ready-to-use glucagon Baqsimi or Gvoke, with the latter specified as delivery via an autoinjector or a prefilled syringe. Within 72 hours after a pharmacist has prescribed and dispensed glucagon, the pharmacist must notify the person’s primary care provider. Whether other states will enact similar legislation to permit pharmacist prescribing for glucagon is unknown; however, readers are encouraged to contact their state representatives or search their state government’s website to learn about any similar legislation.

A study performed between October 2020 and January 2021 (thus pre-dating the enacted law) at a single center in North Carolina showed that pharmacist-initiated outreach to primary care providers or endocrinologists about prescribing traditional lyophilized glucagon led to glucagon prescribing in 56% (61 of 109) of patients within 1 month of their appointments (88). In contrast, among those providers who did not receive this outreach, only 1 of 113 (0.9%) patients was prescribed glucagon within 1 month of the appointment. The pharmacist-led outreach consisted of a simple, brief electronic communication informing the provider that the undersigned pharmacist has pended a glucagon prescription for the patient who has an upcoming appointment and is available for provider and patient questions (88).

In the ASCP hypoglycemia treatment protocol, glucagon is considered undesignated (i.e., prescribed to the facility rather than to a specific patient) and as part of a standing order (i.e., an open order signed by a physician for getting the drug when needed) (68).

Personnel at a single LTC facility studied the effects of a quality improvement (QI) project that included a protocol with a standing order for glucagon and appropriate aftercare to treat severe hypoglycemia in the facility’s residents (89). The facility personnel hoped to decrease the number of hypoglycemia-related 911 calls, EMS transports, and hospitalizations. Over a 3-month baseline period, 39% of the facility’s residents had diabetes, and 15 residents reported hypoglycemic episodes, two of which resulted in EMS transport and hospitalization. Before the QI project, nursing staff was required to contact residents’ HCP to directly authorize any treatments for severe hypoglycemia, and if the HCP did not immediately respond, the facility contacted EMS to transport the resident to the ED for evaluation and treatment. The protocol instructed staff to administer glucagon when a resident was unwilling or unable to swallow (e.g., if the resident was unconscious) because of severe hypoglycemia. Over a 3-month period with the QI protocol, seven hypoglycemic episodes resulted in no EMS transports and hospitalizations. Although the numbers were small, the authors noted that the ∼50% decrease in hypoglycemia episodes and 100% decrease in EMS transports represented clinically important benefits to residents and relevant cost savings (89).

Given that nonsevere hypoglycemia can quickly escalate to severe hypoglycemia and not all school-aged children have their own glucagon device or are permitted to have an extra device to keep at school, advocates have alerted some state legislators to the need for undesignated glucagon in schools (90). An undesignated prescription in this case would be prescribed in the name of an authorized entity such as a school district, public school, or charter school, rather than in the name of a specific student. The school district provides and school personnel administer the medication as necessary according to state law (91). Legislation for undesignated glucagon in schools originated in Illinois in 2018 (90) and, through 2023, Ohio, Georgia, and Maine also have laws for undesignated glucagon in schools, with Georgia and Maine laws specifying ready-to-use glucagon (Figure 2) (92–95). New Jersey and West Virginia have introduced similar legislation, and Florida, Michigan, and Texas are considering introducing similar legislation (96). Parents of children with diabetes, school nurses, and other advocates could contact their state representatives to request that they consider similar legislation for undesignated glucagon in schools.

Individuals who are alone when an SHE occurs may panic as their CGM system shows a downward glucose trend even after they consume carbohydrates and they realize they do not have any more carbohydrates to consume. They may need —and feel empowered—to give themselves glucagon. Among adults with diabetes who experienced at least one SHE in the previous 3 years, 26% with type 1 diabetes and 38% with type 2 diabetes were alone during their last SHE (39). Even those ≥65 years of age could be alone during an SHE; within this age cohort, 22% of those with type 1 diabetes and 24% of those with type 2 diabetes reported being alone during their last SHE (97). Given that moderate hypoglycemia (blood glucose <54 mg/dL) occurs commonly and that rapid escalation to severe hypoglycemia is possible and unpredictable, these individuals may want agency over their diabetes management, which includes the ability to give themselves glucagon before they progress to a hypoglycemia-induced seizure and loss of consciousness and must rely on a stranger for help.

Consequences of hypoglycemia include poor functioning, cognitive decline, IAH, unsafe driving, cardiac arrhythmias and CVD, increased use of EMS and ED services and hospitalization, death, and FoH. Risk factors for hypoglycemia, some of which are also consequences of hypoglycemia, include insulin use with or without other glucose-lowering drugs, recent level 2 or level 3 hypoglycemia, age ≥75 years, impaired cognition or dementia, IAH, inappropriate tight glycemic control, fasting or erratic meal consumption, alcohol consumption, and various SDOH, especially food insecurity. Given these consequences of and risk factors for hypoglycemia, and the fact that nonsevere hypoglycemia can progress rapidly to an SHE, we recommend prescribing glucagon to people with diabetes so it will be available if and when needed. Severe hypoglycemia will inevitably occur. Having glucagon on hand and knowing when and how to use it will most likely help people with diabetes and their caregivers feel prepared to successfully manage SHEs when they arise.

Education is key to enable people to successfully treat their hypoglycemia. Education should emphasize being prepared, which means having prepositioned fast-acting carbohydrates and glucagon easily accessible at all times. Education should also explain that consuming carbohydrates does not always work to raise blood glucose sufficiently and that glucagon should be administered in such instances. Reserving glucagon until a person is unconscious can be too late to restore euglycemia. With the availability of ready-to-use glucagon products, family, friends, coworkers, and people with diabetes themselves can quickly administer glucagon when necessary.

Pharmacists proactively communicating with HCPs about a pended glucagon prescription before patient appointments (88), or having prescriptive authority for glucagon, as enacted in 2022 in North Carolina, could lead to improved prescribing and filling prescriptions for glucagon.

Analogous to the placement of automatic external defibrillators in airports, epinephrine autoinjectors in schools (98), and naloxone for intranasal administration in community settings, prepositioning ready-to-use glucagon in such places, including LTC facilities, may help to ensure the timely treatment of people experiencing an SHE who do not have their own glucagon with them.

Rates of glucagon prescribing are currently low; however, HCPs are increasingly recognizing the importance of glucagon, especially ready-to-use formulations, as evidenced by recent ADA, AACE, and Endocrine Society recommendations. These guidelines, combined with other efforts, could prompt more glucagon prescribing.

The authors acknowledge the editorial assistance of Matthew Krecic, DVM, MS, MBA, of Xeris Pharmaceuticals. The authors did not receive any funding for the preparation of this manuscript.

J.D.G. is a member of speakers bureaus for Abbott Diabetes, CeQur, Lilly, Novo Nordisk, Sanofi, and Xeris Pharmaceuticals. D.I. is a member of speakers bureaus for Abbott Diabetes, CeQur, Dexcom, Insulet, Lilly, Medtronic, and Novo Nordisk. No other potential conflicts of interest relevant to this article were reported.

Both authors wrote, reviewed, and edited the manuscript. Both are the guarantors of this work and, as such, take responsibility for the integrity of the content.