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Hypoglycemia in adults with diabetes mellitus

Hypoglycemia in adults with diabetes mellitus
Literature review current through: Jan 2024.
This topic last updated: Jan 02, 2024.

INTRODUCTION — Hypoglycemia is the most common acute complication of glucose-lowering therapy and is associated with poor outcomes and quality of life in people with type 1 and type 2 diabetes. Hypoglycemia is more common among patients with type 1 diabetes than those with type 2 diabetes and is usually limited to patients with type 2 diabetes treated with specific medication classes (eg, insulin, sulfonylureas, or meglitinides) [1,2]. Reducing the risk of hypoglycemia involves patient education and empowerment, frequent blood glucose monitoring (BGM; usually with fingerstick measurements or continuous glucose monitoring [CGM]), individualized glycemic goals, flexible and rational insulin (and other drug) regimens, and ongoing professional guidance and support.

The symptoms, risk factors, and treatment of hypoglycemia in adults with diabetes are reviewed in this topic, as are general strategies for hypoglycemia risk reduction. Specific strategies to mitigate the risk of hypoglycemia in the inpatient and ambulatory settings, as well as the physiologic response to hypoglycemia, are discussed separately:

(See "Management of diabetes mellitus in hospitalized patients".)

(See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus".)

(See "Continuous subcutaneous insulin infusion (insulin pump)".)

(See "Insulin therapy in type 2 diabetes mellitus".)

(See "Management of blood glucose in adults with type 1 diabetes mellitus".)

(See "Treatment of type 2 diabetes mellitus in the older patient".)

(See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

SYMPTOMS — Hypoglycemia causes neurogenic (autonomic) and neuroglycopenic symptoms. Older adults and patients with longstanding diabetes may have more neuroglycopenic than neurogenic manifestations of hypoglycemia.

The neurogenic symptoms include tremor, palpitations, and anxiety/arousal (catecholamine mediated, adrenergic) and sweating, hunger, and paresthesias (acetylcholine mediated, cholinergic) [2,3].

The neuroglycopenic symptoms include dizziness, weakness, drowsiness, delirium, confusion, and, at lower plasma glucose concentrations, seizure and coma [3,4]. Profound, prolonged hypoglycemia can cause brain death if unwitnessed and left untreated, but the vast majority of episodes are reversed after the glucose level is raised. The rare, fatal episodes are generally thought to be the result of ventricular arrhythmia [4].

In patients with diabetes, the onset of symptoms of hypoglycemia may occur at glucose levels less than 70 mg/dL (3.9 mmol/L), although the specific value varies between and within individuals over time.

The lower limit of the laboratory reference range for fasting plasma glucose level in individuals without diabetes is typically 70 mg/dL (3.9 mmol/L). The glycemic thresholds for neurogenic and neuroglycopenic responses shift to higher plasma glucose concentrations in patients with chronic hyperglycemia and to lower plasma glucose concentrations in patients with repeated episodes of hypoglycemia, which may be caused by intensive diabetes treatment [5]. The degree of hypoglycemia at which symptoms arise varies across individuals. Symptoms may be absent because of impaired awareness of hypoglycemia, which is thought to result from reduced sympathoadrenal (predominantly sympathetic neural) responses. These blunted responses may be caused by recent antecedent hypoglycemia, prior exercise, or sleep in patients with diabetes [1,2]. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus", section on 'Hypoglycemia-associated autonomic failure'.)

DEFINITION AND CLASSIFICATION — Hypoglycemia is the result of the interplay between absolute or relative therapeutic insulin excess and compromised physiologic and behavioral defenses against falling plasma glucose concentrations (defective glucose counterregulation and impaired awareness of hypoglycemia). (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus".)

Definition — Hypoglycemia in patients with diabetes is defined as all episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm [1,6]. Although glycemic thresholds that induce symptoms (and counterregulatory responses) vary within and between individuals, professional societies and workgroups generally agree on the following definitions of three levels of hypoglycemia [6-9]:

Level 1 hypoglycemia – A blood glucose level <70 mg/dL (3.9 mmol/L) but ≥54 mg/dL (3 mmol/L) should alert the patient to take action. This glucose threshold approximates the lower limit of the physiologic, nondiabetic fasting range, the normal glycemic threshold for glucose counterregulatory hormone secretion, and the highest antecedent low glucose level reported to reduce sympathoadrenal responses to subsequent hypoglycemia [1]. It should alert the patient to take action such as ingestion of carbohydrate (see 'Reversing hypoglycemia' below) or, at the very least, repeated measurements of the glucose level and temporary avoidance of critical tasks such as driving.

Level 2 hypoglycemia – A blood glucose level <54 mg/dL (3 mmol/L) indicates serious hypoglycemia requiring immediate action [7]. This value identifies an unequivocally low glucose level, one that occurs rarely, if at all, in individuals without diabetes under physiologic conditions and one that should be avoided because of immediate and long-term consequences to the individual. This level of hypoglycemia is typically associated with cognitive impairment [10]. The frequency of detection of a glucose level <54 mg/dL (3 mmol/L) has been recommended for inclusion when reporting hypoglycemia in clinical trials of glucose-lowering drugs [7].

Level 3 hypoglycemia – Level 3 hypoglycemia is defined as a hypoglycemic event that requires the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions. Plasma glucose measurements may not be available during such an event, but neurologic recovery attributable to normalization of plasma glucose is considered sufficient evidence that the event was induced by a low plasma glucose concentration.

These definitions of hypoglycemia assume accurate and reliable measurement of glucose levels. Blood glucose monitoring (BGM) provides information about capillary glucose levels at a specific point in time. Notably, BGM readings may not be accurate in patients with poor capillary blood flow, such as those with shock, hypothermia, Raynaud phenomenon, or peripheral vascular disease [11,12]. Continuous glucose monitoring (CGM) measures interstitial glucose and therefore provides distinct information from BGM. CGM may be helpful for patients in whom BGM is consistently unreliable. It also may be helpful for capturing time spent in hypoglycemia as well as hypoglycemia missed by BGM, especially during sleep. Although there is no consensus for defining level 1 and 2 hypoglycemia based on CGM data, several studies have used 15 consecutive minutes with sensor glucose values below the respective thresholds (ie, <70 mg/dL [3.9 mmol/L] or <54 mg/dL [3 mmol/L]) for this purpose [13,14].

Clinical classification — Clinical classification of hypoglycemic events can be helpful for identifying and tracking hypoglycemia:

Documented symptomatic hypoglycemia – An event during which typical symptoms of hypoglycemia are accompanied by a measured glucose level <70 mg/dL (3.9 mmol/L).

Asymptomatic hypoglycemia – An event not accompanied by typical symptoms of hypoglycemia but with a measured glucose level <70 mg/dL (3.9 mmol/L).

Probable symptomatic hypoglycemia – An event during which typical symptoms of hypoglycemia are not accompanied by measurement of the glucose level but resolve after action taken to reverse hypoglycemia (eg, carbohydrate ingestion).

Pseudohypoglycemia – An event during which the person with diabetes reports typical symptoms of hypoglycemia but has a measured glucose level ≥70 mg/dL (3.9 mmol/L).

This category reflects the fact that patients with chronic hyperglycemia can experience sympathoadrenal symptoms as glucose levels fall into the physiologic range. (This term is also used to describe artifactually low plasma or serum glucose concentrations due to poor capillary blood flow or continued metabolism of glucose after sample collection due to absence of a glycolysis inhibitor or delayed sample processing.)

MAGNITUDE OF THE PROBLEM

Frequency

Type 1 diabetes — Patients with type 1 diabetes report an average of two to five episodes of severe hypoglycemia (episodes requiring the assistance of another person) per year [1,15,16]. Studies using continuous glucose monitoring (CGM) show much more frequent episodes of clinically important hypoglycemia (<54 mg/dL [3 mmol/L]), ranging from every two to three days to every six days [13,17-19]. Clinically important hypoglycemia detected with CGM is much more common than prior estimates based on self-reported events or fingerstick glucose assessments. Of note, CGM may over-report hypoglycemia, especially in the lower range of normoglycemia, which suggests that the frequency of clinically important hypoglycemia may be overstated with CGM. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'Reliability'.)

Type 2 diabetes — Hypoglycemia is substantially less frequent in type 2 diabetes, although patients with type 2 diabetes treated with insulin, a sulfonylurea or a meglitinide are generally at higher risk than those treated with diet or other medications [1,2]. Among the commonly used insulin secretagogues (sulfonylureas, meglitinides), hypoglycemia is most often reported in patients taking long-acting drugs, such as glyburide (glibenclamide) [20], compared with sulfonylureas with lower risk for hypoglycemia (eg, glipizide, glimepiride, and gliclazide) (see "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus"). In contrast to insulin and insulin secretagogues, agents that do not cause unregulated hyperinsulinemia (eg, metformin, alpha-glucosidase inhibitors, thiazolidinediones, glucagon-like peptide 1 [GLP-1] receptor agonists, dual GLP-1 and gastric inhibitory polypeptide [GIP] receptor agonists, dipeptidyl peptidase 4 [DPP-4] inhibitors, and sodium-glucose co-transporter 2 [SGLT2] inhibitors) do not usually cause hypoglycemia [21,22]. However, they increase the risk if used with insulin or an insulin secretagogue [2].

The frequency of serious, clinically important hypoglycemia in type 2 diabetes, particularly in advanced type 2 diabetes, is uncertain. The frequency of hypoglycemia increases over time as patients approach the insulin-deficient end of the spectrum of type 2 diabetes. In a global observational study, the rate of severe hypoglycemia among insulin-treated patients with type 2 diabetes was 2.5 events per person-year [16].

Although observational studies suggest that CGM detects higher numbers of hypoglycemic events in insulin-treated patients with type 2 diabetes than reported using fingerstick measurements [23], clinical trial data suggest that hypoglycemia is infrequent in such patients irrespective of glucose monitoring strategy. As an example, in a trial evaluating CGM or usual care (blood glucose monitoring [BGM] at least four times daily) in 158 adults with type 2 diabetes (median duration 17 years) and treated with multiple daily insulin injections, hypoglycemia was infrequent in both groups (eg, percentage of time spent <60 mg/dL [<3.3 mmol/L], 0 percent) [24].

Consequences — Recurrent hypoglycemia is a strong risk factor for impaired awareness of hypoglycemia. In turn, impaired awareness of hypoglycemia increases the risk of severe hypoglycemia sixfold in people with type 1 diabetes and 17-fold in individuals with type 2 diabetes who are taking insulin [25,26].

Health-related quality of life — Hypoglycemia, particularly nocturnal or severe episodes, has been associated with reduced health-related quality of life [27,28]. Severe hypoglycemia has been associated with diabetes distress and fear of hypoglycemia [29]. In turn, fear of hypoglycemia can lead to behaviors that are detrimental to diabetes management [30]. Nonsevere hypoglycemia may also diminish quality of life. In middle-aged adults (mean age 53.5 years), nonsevere hypoglycemia has been shown to increase time away from work [31]. Recurrent episodes of hypoglycemia may impact driving privileges, employment, and interpersonal relationships [30]. (See 'Fear of hypoglycemia' below.)

Health-related outcomes — Hypoglycemia is associated with multiple other adverse consequences. Whether hypoglycemia directly causes these adverse outcomes or is a marker of greater vulnerability to these outcomes is not always clear.

Mortality and cardiovascular disease – Acute hypoglycemic episodes can be life-threatening and account for up to 10 percent of deaths in people with type 1 diabetes under 40 years of age [32]. In clinical trials and observational studies, severe hypoglycemia is associated with a roughly 1.5- to 6-fold increased risk of cardiovascular events and mortality [33-38]. Whether hypoglycemia plays a causal role in cardiovascular disease is unclear, as confounders including comorbid illness may contribute to this observed association. A direct relationship between hypoglycemia and cardiovascular disease, particularly coronary heart disease, has been posited in part based on the biological effects of hypoglycemia, including adverse regulation of sympathoadrenal, immune, and endothelial function [34]. In a meta-analysis of observational studies with bias analysis, comorbid illness alone did not fully explain the association between hypoglycemia and cardiovascular disease [34]. (See "Treatment of type 2 diabetes mellitus in the older patient", section on 'Avoiding hypoglycemia'.)

Cognitive impairment and dementia – The extent to which recurrent hypoglycemia causes cognitive impairment is uncertain and may depend in part on patient age [1,39]. In older adults, severe hypoglycemia has been associated with an increased risk of dementia [40-43]. In turn, older adults with diabetes who develop dementia have a higher risk of hypoglycemia. In younger adults, however, the results from the Diabetes Control and Complications Trial (DCCT; mean age on study entry 27 years) are reassuring. Although the frequency of severe hypoglycemia in the DCCT was >3-fold higher in the intensive treatment group as compared with the conventional treatment group, the two groups did not differ in multiple psychosocial and neurobehavioral parameters measured at 2, 5, 7, and 18 years; furthermore, patients with repeated episodes of hypoglycemia did not perform differently from those who rarely had hypoglycemia [44,45].

Falls and fractures — In frail, older adults, mild episodes of hypoglycemia may lead to episodes of dizziness or weakness, increasing the risk of falls and fracture [46,47]. Severe hypoglycemia has also been associated with increased risk of falls and fractures in both type 1 and type 2 diabetes [48-50]. (See "Treatment of type 2 diabetes mellitus in the older patient", section on 'Avoiding hypoglycemia'.)

RISK FACTORS FOR HYPOGLYCEMIA — The precipitants of hypoglycemia are rarely documented in observational studies or clinical trials. In more than half of hypoglycemic events, a direct precipitant is not clearly identified [51,52].

Direct precipitants – In studies that evaluated precipitating events of hypoglycemia, the following factors were most commonly cited [51-54]:

Delayed or missed meals, or low carbohydrate content of meals

Excessive physical activity

Medication errors (eg, miscalculated doses, wrong insulin type)

Overcorrection of hyperglycemia (eg, intentionally taking additional insulin)

Illness

Patient- and treatment-related factors – Beyond the immediate precipitants of hypoglycemic events, multiple patient- and treatment-related factors can increase the risk of hypoglycemia. Patient-related risk factors include the following [1,2,55-61]:

Hypoglycemia-associated autonomic failure (including the syndromes of impaired awareness of hypoglycemia and deficient glucose counterregulation)

History of severe or nonsevere hypoglycemia

Longer duration of diabetes

Older age

Alcohol ingestion

Chronic kidney disease

Dementia or cognitive impairment

Malnutrition with glycogen depletion

Treatment-related risk factors for iatrogenic hypoglycemia include insulin therapy in patients with either type 1 or type 2 diabetes and sulfonylurea or meglitinide therapy in patients with type 2 diabetes [2,62]. Multiple studies have demonstrated that the risk of hypoglycemia increases with the duration of insulin use [61,63]. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Hypoglycemia' and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Hypoglycemia'.)

Randomized trials in type 1 [64,65] and type 2 [66-68] diabetes have consistently demonstrated that patients treated to lower glycated hemoglobin (A1C) levels (to reduce long-term microvascular complications) have two- to threefold higher rates of hypoglycemia. However, in observational studies, the relationship between A1C level and hypoglycemia is not linear. For example, in the Type 1 Diabetes Exchange Clinic Registry, the risk of severe hypoglycemia that required the assistance of another person was lowest among those with A1C levels of 7 to 7.5 percent and higher in those with A1C levels <7 or >7.5 percent [69]. Similarly, the relationship between A1C and severe hypoglycemia in patients with type 2 diabetes appears to be U-shaped, with greater risk at both low and high A1C levels (figure 1) [70,71].

Other factors — Finally, other important factors have been associated with hypoglycemia. These include [72-74]:

Food insecurity

Limited health literacy

Low socioeconomic status

STRATEGIES TO MANAGE HYPOGLYCEMIA — Our approach to the management of hypoglycemia outlined below is largely consistent with the American Diabetes Association (ADA) Standards of Care and the Endocrine Society Clinical Practice Guidelines [6,9,75]. (See 'Society guideline links' below.)

Strategies to reduce the risk of hypoglycemia in the ambulatory setting are reviewed below. The approach to mitigating hypoglycemia in the inpatient setting is reviewed separately. (See "Management of diabetes mellitus in hospitalized patients".)

General approach to reduce risk — The prevention of hypoglycemia involves identifying precipitants and risk factors contributing to hypoglycemia, addressing these (when possible), and tailoring treatment regimens to reduce risk. At each visit, the provider should inquire about any:

Episodes of symptoms consistent with hypoglycemia

Low measured glucose levels

Episodes requiring the assistance of another person

All available blood glucose monitoring (BGM) or continuous glucose monitoring (CGM) data should be reviewed to determine the frequency and details (eg, time of day, severity) of any documented episodes of hypoglycemia. Insulin and other glucose-lowering medications should be adjusted based on glucose patterns with focus on reducing hypoglycemia, which sometimes may require adjusting the target glucose and A1C levels. Any clear precipitants (eg, exercise, overcorrection of hyperglycemia) or other risk factors (eg, cognitive impairment, food insecurity) should be specifically addressed.

Reducing the risk of hypoglycemia involves application of the following principles [1,2,76]:

Patient education and empowerment

Frequent monitoring of glucose levels (with fingerstick measurements or CGM)

Individualized glycemic goals

Flexible and rational regimens for insulin and other drugs

Ongoing professional guidance and support

In a meta-analysis of 43 studies (randomized trials and observational studies), both educational interventions (eg, flexible insulin therapy, behavioral techniques) and technological interventions (continuous subcutaneous insulin infusion [CSII], CGM, sensor-augmented pump) reduced severe hypoglycemia and improved glycemic management in patients with type 1 diabetes [77].

Patient education — There is increasing evidence that structured patient education focused on implementation of flexible insulin therapy can reduce the incidence of severe hypoglycemia in patients with type 1 diabetes [6,78-81]. Although data are sparse, similar results could reasonably be expected for patients with type 2 diabetes. Patients should be taught to adjust their medications, meal plans, and exercise based on glucose patterns. Clinicians should review how to treat (but not overtreat) evolving hypoglycemia with oral carbohydrate ingestion or glucagon. In addition, close associates, such as a spouse or a partner, should be taught to recognize severe hypoglycemia and administer treatment with glucagon. (See 'Reversing hypoglycemia' below.)

Regular glucose monitoring is critical for glycemic management in patients with type 1 diabetes as well as insulin-treated patients with type 2 diabetes. CGM is usually used in type 1 diabetes, but some evidence suggests that many insulin-treated patients with type 2 diabetes may benefit as well [82,83]. The use of CGM can help identify glycemic patterns and hypoglycemia [84]. Alternatively, patients may perform BGM before and two to three hours after each meal, at bedtime, in the middle of the night, and before and after exercise. For patients with diabetes who may have asymptomatic hypoglycemia due to repeated episodes of hypoglycemia and/or impaired awareness of hypoglycemia, intermittent use of CGM may be valuable for the detection and management of hypoglycemia. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus", section on 'CGM systems'.)

Glycemic targets — Glycemic management can reduce the risks for retinopathy, nephropathy, and neuropathy in both type 1 and type 2 diabetes and may decrease the risk for cardiovascular disease. Target A1C levels in patients with type 1 and type 2 diabetes should be individualized and based on patient preferences, balancing the reduction in microvascular complications with the risk of hypoglycemia and burden and cost of therapy [85-88]. Less stringent treatment goals may be appropriate for patients with a history of severe hypoglycemia, risk factors for hypoglycemia, or limited life expectancies, as well as very young children or older adults and individuals with comorbid conditions. De-escalation of therapy in some individuals may be appropriate. However, given that severe hypoglycemia is common in patients with poor glycemia, simply relaxing the glycemic target may not reduce hypoglycemia risk (figure 1).

Glycemic goals are reviewed in detail elsewhere. (See "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target' and "Glycemic control and vascular complications in type 1 diabetes mellitus", section on 'Glycemic targets'.)

Glucose-lowering regimens

Type 1 diabetes – More than half of episodes of iatrogenic hypoglycemia, including severe hypoglycemia, occur during the night [2,89]. Nocturnal hypoglycemia in type 1 diabetes is less common in individuals using rapid-acting insulin analogs (lispro, aspart, glulisine) rather than regular insulin before meals and slightly lower in individuals using long-acting insulin analogs (glargine, detemir, degludec) rather than NPH as the basal insulin. Nocturnal and/or fasting hypoglycemia warrants assessment not only of the basal insulin dose but also of any bedtime insulin boluses for food and/or correction of hyperglycemia. Patients also should be queried about exercise patterns and alcohol use. (See "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Choosing basal/prandial insulin'.)

Although many clinicians believe CSII in type 1 diabetes reduces hypoglycemia, in patients at comparable A1C levels, CSII has not consistently reduced hypoglycemia relative to a basal-bolus regimen with insulin analogs [90,91]. However, CSII in conjunction with CGM (including sensor-augmented insulin pump therapy and hybrid closed-loop systems) can reduce time in hypoglycemia. The trials that demonstrate this benefit are reviewed separately. (See "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Sensor-augmented insulin pump' and "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Insulin only, partially automated system'.)

Type 2 diabetes – In patients with type 2 diabetes, clinicians should consider using medications that are not associated with hypoglycemia whenever possible. In a single-arm study of older patients with type 2 diabetes on multiple daily insulin injections, simplification to once-daily basal insulin with or without noninsulin medications reduced hypoglycemia without compromising glycemic management [92]. Choice of insulin may also impact hypoglycemia risk; for example, long-acting insulin analogs may reduce nocturnal hypoglycemia (but not always total hypoglycemia) compared with NPH. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Choice of basal insulin'.)

Specific settings

Impaired awareness of hypoglycemia — In patients with a history of impaired awareness of hypoglycemia, a two- to three-week period of scrupulous avoidance of hypoglycemia is advisable since that often restores awareness [93-99]. That can be accomplished by more intensive professional involvement (eg, by telephone); in practice, it may require higher glycemic goals in the short term. Blood glucose awareness training, focused on cultivating patient awareness and anticipation of hypoglycemia, has been reported to both reduce hypoglycemic episodes and improve detection of hypoglycemia [100].

Exercise-induced hypoglycemia — Exercise-induced hypoglycemia can occur during, shortly after, or many hours after exercise, and therefore, patients should remain vigilant for its occurrence, utilizing frequent BGM or CGM.

Measures to reduce early post-exercise hypoglycemia include interspersing brief episodes of intense exercise (which tends to raise plasma glucose concentrations), adding carbohydrate ingestion (eg, 1 g/kg/h), and reducing insulin doses [101]. In one study in patients with type 1 diabetes, a subcutaneous injection of mini-dose (150 mcg) glucagon prevented exercise-induced hypoglycemia without producing hyperglycemia [102]. (See "Exercise guidance in adults with diabetes mellitus", section on 'Glycemic management during exercise'.)

Exercise increases glucose utilization by muscle and, therefore, can cause hypoglycemia in patients with insulin-deficient diabetes who have near-normal or moderately elevated plasma glucose levels at the start of exercise [2,103-106]. In addition, exercise, like hypoglycemia, can shift the glycemic threshold for the sympathoadrenal response to subsequent hypoglycemia to a lower plasma glucose concentration hours later. This shift causes defective glucose counterregulation by reducing epinephrine responses in the setting of absent insulin and glucagon responses. It also causes impaired awareness of hypoglycemia by reducing symptom responses. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus", section on 'Exercise'.)

Fear of hypoglycemia — Hypoglycemia can be a frightening, unpleasant, and potentially lethal complication of diabetes, and therefore, concerns about hypoglycemia are understandable. At its best, this concern should prompt patients to be aware of early symptoms and to ingest carbohydrate before symptoms progress. Fear of hypoglycemia is defined as an excessive worry/discomfort that interferes with diabetes management through behavioral avoidance and distress. In one survey, patients who had a frightening episode of severe hypoglycemia in the previous year often became so fearful that they kept their blood glucose excessively high for several months afterwards [107]. As a result, it is important to explore the patient's experience with hypoglycemia, particularly before intensifying insulin or other glucose-lowering therapy. Educational strategies need to focus on how to help the patient manage the risk of hypoglycemia. Blood glucose awareness training can reduce fear of hypoglycemia [108].

Severe, intractable hypoglycemia — Patients with severe, intractable hypoglycemia may be candidates for pancreas transplantation. Successful pancreas transplantation can result in independence from exogenous insulin therapy and improvements in glucose metabolism, A1C, acute insulin responses to intravenous (IV) glucose, and counterregulatory responses of glucagon and epinephrine to insulin-induced hypoglycemia. Islet transplantation, an evolving technology, can also result in insulin independence and reduce the incidence of hypoglycemia. Islet transplantation can be performed currently only within the context of a clinical research study. (See "Pancreas and islet transplantation in diabetes mellitus", section on 'Indications for transplantation'.)

Older patients — Older patients with diabetes have increased vulnerability to hypoglycemia. Many older adults experience delayed recognition of hypoglycemia and suffer more serious consequences of hypoglycemic events. Strategies for mitigating the risk of hypoglycemia in older adults are similar to those employed for other patients with diabetes. The treatment of diabetes in older patients in reviewed separately. (See 'Strategies to manage hypoglycemia' above and "Treatment of type 2 diabetes mellitus in the older patient", section on 'Avoiding hypoglycemia'.)

REVERSING HYPOGLYCEMIA — The goal of hypoglycemia treatment is to restore a normal plasma glucose concentration by providing dietary or parenteral carbohydrate (specifically glucose), or, in cases of severe hypoglycemia, by administering glucagon to stimulate hepatic glucose production. In order to treat early symptoms of hypoglycemia, patients should be certain that fast-acting carbohydrate (such as glucose tablets, hard candy, or sweetened fruit juice) is available at all times, although treatment with glucose tablets is most consistently effective (table 1) [109]. Patients with type 1 diabetes and those with type 2 diabetes at high risk for severe hypoglycemia should be prescribed glucagon. (See 'Level 3 hypoglycemia (requiring assistance)' below.)

Level 1 hypoglycemia (<70 but ≥54 mg/dL) — When glucose monitoring reveals a glucose level <70 mg/dL (3.9 mmol/L), patients with drug-treated diabetes should take action. Options include repeating the measurement within 15 to 60 minutes (depending on the setting), avoiding critical tasks such as driving, ingesting carbohydrates, and adjusting the treatment regimen [110].

Level 2 hypoglycemia (<54 mg/dL) — Patients with level 2 hypoglycemia (glucose level <54 mg/dL [3 mmol/L]) should ingest 15 to 20 grams of fast-acting carbohydrate (table 1), which is usually sufficient to raise the blood glucose into a safe range without inducing hyperglycemia. Patients should be instructed to retest after 15 minutes. If the glucose remains <70 mg/dL (3.9 mmol/L), repeat treatment may be necessary. Acute treatment can be followed by long-acting carbohydrate (a meal or a snack) to prevent recurrent symptoms.

In patients using insulin or an insulin secretagogue in combination with an alpha-glucosidase inhibitor (acarbose, miglitol, voglibose), only pure glucose (eg, glucose tablets) should be used to treat symptomatic hypoglycemia. Other forms of carbohydrates, such as table sugar (sucrose), will be less effective in raising blood sugar as alpha-glucosidase inhibitors slow digestion of disaccharides.

Level 3 hypoglycemia (requiring assistance) — Severe hypoglycemia requires the assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions.

With IV access — Hospitalized patients can usually be treated quickly with 25 g of 50 percent glucose (dextrose) administered intravenously (IV).

Without IV access

Glucagon available – For the treatment of hypoglycemia in a person with impaired consciousness and no established IV access, we suggest the immediate administration of glucagon, rather than waiting to establish IV access. Administration of glucagon (subcutaneous, intramuscular, or nasal) will usually lead to recovery of consciousness within approximately 15 minutes, although it may be followed by marked nausea or even vomiting. To prevent these side effects, the glucagon dose should be followed promptly by oral intake of concentrated carbohydrates, ideally immediately upon the patient's emergence from impaired consciousness and before the development of nausea.

Glucagon administration requires that the glucagon be readily accessible and that a relative or friend can recognize hypoglycemia and administer the glucagon appropriately.

Intranasal glucagon – Intranasal glucagon can be delivered by placing the tip of the device in one nostril and depressing a small plunger that discharges the powder into the nostril without need for inhalation or other cooperation from the patient [111]. In a randomized, crossover trial comparing intranasal (3 mg) and intramuscular (1 mg) glucagon in 77 patients with type 1 diabetes and hypoglycemia (induced in a controlled setting by insulin administration), successful reversal of hypoglycemia occurred in 98.7 and 100 percent of intranasal glucagon and intramuscular glucagon treatments, respectively [112]. Mean time to success (glucose ≥70 mg/dL [3.9 mmol/L] or ≥20 mg/dL [1.1 mmol/L] from the glucose nadir) was slightly longer for intranasal than intramuscular administration (16 versus 13 minutes).

Stable, liquid glucagonGlucagon (or glucagon analog) can be administered using a prefilled syringe, an auto-injector pen, or a syringe kit with a single-dose vial, all of which contain a fixed-dose, stable liquid glucagon preparation that does not require reconstitution [113]. In trials in patients with type 1 diabetes, the successful reversal of hypoglycemia was similar in patients receiving 1 mg of stable liquid glucagon, 1 mg of reconstituted glucagon, or 0.6 mg of glucagon receptor agonist (dasiglucagon) [114-119]. Small doses (mini-doses) of stable, liquid glucagon that may be repeated if necessary are also in development [120,121].

Reconstituted glucagonGlucagon lyophilized powder requires reconstitution (mixing the powder with the diluent) immediately before use. It is administered (1 mg) either subcutaneously or intramuscularly. For caregivers who are not medical professionals, the reconstitution process may be challenging in an emergency setting. Consequently, glucagon preparations that do not require reconstitution are preferred for outpatient use [6].

Glucagon not available – There are no efficacy or safety data to guide the management of severe hypoglycemia (while awaiting emergency personnel) in patients with impaired consciousness and no immediate access to glucagon or IV dextrose. In a study of normoglycemic volunteers, the buccal absorption of glucose was minimal [122]. Therefore, some experts would not administer buccal or sublingual preparations due to concern about aspiration. In the absence of other options for such patients, other experts, including some UpToDate authors and editors, suggest that while awaiting emergency personnel, family members squeeze a glucose gel (eg, Insta-Glucose) or cake frosting in the space between the teeth and buccal mucosa, keeping the patient's head tilted slightly to the side. If a glucose gel or cake frosting is unavailable, some advocate sprinkling table sugar under the tongue as table sugar has been reported to raise plasma glucose concentrations to some extent in ill children with malaria [123,124].

Monitoring — The glycemic response to IV glucose and glucagon is transient. Therefore, effective initial treatment of hypoglycemia often must be followed by a continuous infusion of glucose (or food if the patient is able to eat). Further treatment and disposition vary depending on the class of agent causing the toxicity and the severity of symptoms. Sulfonylurea-caused hypoglycemia may be particularly long lasting or recurrent since the effects of sulfonylureas or their metabolites may continue to stimulate insulin secretion after initial carbohydrate treatment. (See "Sulfonylurea agent poisoning", section on 'Management'.)

There is little experience in treating "overdoses" of the newest longer-acting analogs, such as degludec or U-300 glargine; however, the durable effects of these insulins suggest that observation, continuous glucose monitoring (CGM), and prolonged treatment may be required.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hypoglycemia in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Type 1 diabetes (The Basics)" and "Patient education: Type 2 diabetes (The Basics)" and "Patient education: Low blood sugar in people with diabetes (The Basics)")

Beyond the Basics topics (see "Patient education: Type 1 diabetes: Overview (Beyond the Basics)" and "Patient education: Type 2 diabetes: Overview (Beyond the Basics)" and "Patient education: Hypoglycemia (low blood glucose) in people with diabetes (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Symptoms – Hypoglycemia causes neurogenic (eg, tremor, palpitations, and diaphoresis) and neuroglycopenic (eg, dizziness, weakness, delirium, and confusion) symptoms. (See 'Symptoms' above.)

Definition – Hypoglycemia in patients with diabetes can be defined as all episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm. Level 1 hypoglycemia is defined as blood glucose <70 mg/dL (3.9 mmol/L), and level 2 hypoglycemia is defined as blood glucose <54 mg/dL (3 mmol/L). Severe hypoglycemia requires the assistance of another person. (See 'Definition' above.)

Risk factors for hypoglycemia – The direct precipitants of hypoglycemia may not always be identified but most commonly include delayed or missed meals, excessive physical activity, or medication errors. Clinical risk factors for hypoglycemia include hypoglycemia-associated autonomic failure (both impaired awareness of hypoglycemia and defective glucose counterregulation), a history of severe hypoglycemia, a long duration of diabetes, older age, dementia, chronic kidney disease, and malnutrition. Poor glycemic management (ie, chronic hyperglycemia) does not reduce the risk of hypoglycemia. (See 'Risk factors for hypoglycemia' above.)

General approach to reduce risk of hypoglycemia – The prevention of hypoglycemia involves assessing for precipitants and risk factors and addressing them through structured education, changes in the treatment regimen, or changes in glycemic targets when appropriate. (See 'General approach to reduce risk' above and 'Glucose-lowering regimens' above.)

Patient education – Patients should be taught and empowered to adjust their insulin doses based on glucose patterns, meal plans, and planned exercise. Clinicians should review how to treat (but not overtreat) evolving hypoglycemia with oral carbohydrate or glucagon. In addition, close associates or caregivers should be taught to recognize severe hypoglycemia and treat it with glucagon. Patients should be cautioned to be especially vigilant following an episode of hypoglycemia since both recognition of hypoglycemia and the attendant counterregulatory response will be impaired in the short term. (See 'Patient education' above.)

Adjustment of glycemic targets – We consider higher glycated hemoglobin (A1C) target values for patients with one or more previous episodes of severe hypoglycemia, risk factors for hypoglycemia, or little expected benefit from tighter glycemic management. If stringent glycemic management appears to contribute to hypoglycemic events, we continually reevaluate with the patient whether the benefits of improved blood glucose management outweigh the risk of hypoglycemia. (See 'Glycemic targets' above.)

Changes in the treatment regimen – In patients with type 1 diabetes, sensor-augmented insulin pump therapy and hybrid closed-loop systems can reduce time in hypoglycemia. In patients with type 2 diabetes, clinicians should consider using medications that are not associated with hypoglycemia whenever possible and simplifying or de-escalating insulin regimens. (See 'Glucose-lowering regimens' above.)

Reversing hypoglycemia – We routinely check that the patient's blood glucose monitoring (BGM) equipment is accurately calibrated and that the patient has filled a glucagon prescription within the past year. We also continually counsel patients about staying vigilant and keeping fast-acting carbohydrate readily available. (See 'Reversing hypoglycemia' above.)

Level 1 hypoglycemia (<70 mg/dL but ≥54 mg/dL) – For a person treated with insulin, a sulfonylurea, or a meglitinide, we suggest the individual take action when glucose monitoring reveals a glucose level <70 mg/dL (3.9 mmol/L) (Grade 2C). Options include repeating the measurement in the near term, avoiding critical tasks such as driving, ingesting carbohydrates, and adjusting the treatment regimen. (See 'Level 1 hypoglycemia (<70 but ≥54 mg/dL)' above.)

Level 2 hypoglycemia (<54 mg/dL) – Patients with glucose levels <54 mg/dL (3 mmol/L) should take immediate action to reverse hypoglycemia by ingesting carbohydrates. Fifteen to 20 grams of oral glucose is typically sufficient (table 1). Glucose may be ingested in the form of tablets, juice, soda, hard candies, or crackers (table 1). Patients should retest glucose after 15 minutes and re-treat if the glucose level is not ≥70 mg/dL (3.9 mmol/L). (See 'Level 2 hypoglycemia (<54 mg/dL)' above.)

Level 3 hypoglycemia (requiring assistance) – For patients with impaired consciousness and established intravenous (IV) access (typically in a hospital), IV dextrose (25 g of 50 percent glucose [dextrose]) can be administered to treat hypoglycemia. (See 'Level 3 hypoglycemia (requiring assistance)' above.)

For the treatment of hypoglycemia in a person with impaired consciousness and without established IV access, we suggest the immediate administration of glucagon, rather than waiting to establish IV access (Grade 2B). The usual dose is 3 mg given intranasally or 0.5 to 1 mg given as a subcutaneous or intramuscular injection. Glucagon formulations that do not require reconstitution are preferred for outpatient use. Education and training are necessary for clinicians, family, and other caregivers on the recognition and treatment of severe hypoglycemia, including the use of glucagon. (See 'Level 3 hypoglycemia (requiring assistance)' above.)

Monitoring initial treatment – The glycemic response to IV glucose and glucagon is transient. Therefore, effective initial treatment of hypoglycemia often needs to be followed by a continuous infusion of glucose (or food if the patient can eat). Further treatment and disposition depend on the class of agent causing the toxicity and the severity of symptoms. (See 'Monitoring' above.)

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Topic 1805 Version 42.0

References

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