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Hypoglycemia in adults with diabetes mellitus

Hypoglycemia in adults with diabetes mellitus
Author:
Philip E Cryer, MD
Section Editor:
Irl B Hirsch, MD
Deputy Editor:
Katya Rubinow, MD
Literature review current through: Dec 2022. | This topic last updated: Aug 03, 2022.

INTRODUCTION — Hypoglycemia is the limiting factor in the glycemic management of patients with type 1 diabetes, in whom the risk of severe hypoglycemia increases as glycated hemoglobin (A1C) levels are reduced with intensive therapy (figure 1) [1,2]. Less commonly, hypoglycemia affects patients with type 2 diabetes, usually in those who are treated with a sulfonylurea, a meglitinide, or insulin. Reducing the risk of hypoglycemia while maintaining or improving glycemic control involves patient education and empowerment, frequent self-monitoring of blood glucose (SMBG; usually with fingerstick measurements or with continuous glucose monitoring [CGM] in type 1 diabetes), individualized glycemic goals, flexible and rational insulin (and other drug) regimens, and ongoing professional guidance and support.

The symptoms, risk factors, prevention, and treatment of hypoglycemia in adults with diabetes are reviewed in this topic. The physiologic response to hypoglycemia as well as hypoglycemia in children and adolescents is discussed elsewhere. (See "Physiologic response to hypoglycemia in healthy individuals and patients with diabetes mellitus" and "Hypoglycemia in children and adolescents with type 1 diabetes mellitus".)

SYMPTOMS — Hypoglycemia causes neurogenic (autonomic) and neuroglycopenic symptoms. Older adults and patients with long-term 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]. Although profound, prolonged hypoglycemia can cause brain death in the unobserved patient with diabetes, 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 65 mg/dL (3.6 mmol/L), although the specific value varies between and within individuals over time.

The lower limit of the normal fasting plasma glucose value is typically 70 mg/dL (3.9 mmol/L). The glycemic thresholds for these responses shift to higher plasma glucose concentrations in patients with poorly controlled diabetes and to lower plasma glucose concentrations in patients with repeated episodes of hypoglycemia, such as may be caused by intensive therapy of diabetes [5]. Symptoms may be absent because of impaired awareness of hypoglycemia (which is thought to be the result of reduced sympathoadrenal [predominantly sympathetic neural] responses) to a given degree of hypoglycemia 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 of 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 — American Diabetes Association (ADA) Workgroups have defined hypoglycemia in patients with diabetes as all episodes of an abnormally low plasma glucose concentration (with or without symptoms) that expose the individual to harm [1]. They did not identify a specific glucose level that defines hypoglycemia, as the glycemic thresholds that induce symptoms (and counterregulatory responses) vary within and between individuals.

Alert value – The Workgroups identified instead an alert glucose level of ≤70 mg/dL (3.9 mmol/L). This glucose concentration approximates the lower limit of the physiologic fasting nondiabetic 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 the possibility of developing clinically important hypoglycemia, and prompt appropriate actions 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.

Clinically important biochemical hypoglycemia – In 2017, The International Hypoglycaemia Study Group (a joint working group of the ADA and the European Association for the Study of Diabetes) proposed a glucose level of <54 mg/dL (3 mmol/L) as sufficiently low to indicate serious, clinically important biochemical hypoglycemia [6]. This value identifies an unequivocally low glucose level, one that occurs rarely, if at all, in nondiabetic individuals under physiologic conditions and one that should be avoided because of immediate and long-term consequences to the individual. The Group recommended that the frequency of detection of a glucose level <54 mg/dL be included when reporting hypoglycemia in clinical trials of glucose-lowering drugs.

Classification of severity — ADA and the Endocrine Society Workgroups classify the severity of hypoglycemia in diabetes is as follows [1]:

Severe hypoglycemia – An event requiring 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 restoration of plasma glucose to normal is considered sufficient evidence that the event was induced by a low plasma glucose concentration.

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 that was presumably caused by hypoglycemia).

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 chronically poorly controlled diabetes can experience symptoms of hypoglycemia as glucose levels fall into the physiologic range. (This term is also used to describe artifactually low plasma or serum glucose concentrations due to continued metabolism of glucose after the sample is drawn as can occur when the sample tube does not include an inhibitor of glycolysis and when separation of the plasma or serum is delayed.)

MAGNITUDE OF THE PROBLEM

Frequency

Type 1 diabetes — Patients with type 1 diabetes report an average of up to three episodes of severe hypoglycemia (episodes requiring the assistance of another person) per year [1,7]. 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 [8-11]. 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 glycemia, 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) [12], compared with the shorter-acting 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, such as metformin, alpha-glucosidase inhibitors, thiazolidinediones, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl peptidase-4 (DPP-4) inhibitors, and sodium-glucose co-transporter 2 (SGLT2) inhibitors do not usually cause hypoglycemia [13,14]. 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.

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 [15], this is not necessarily borne out in clinical trials. As an example, in a trial evaluating CGM or usual care (self-monitoring of blood glucose [SMBG] at least four times daily) in 158 adults with type 2 diabetes (median duration 17 years), treated with multiple daily insulin injections, there was no difference in hypoglycemia, which was infrequent in both groups (eg, percentage of time spent <60 mg/dL [<3.3 mmol/L], 0 percent) [16].

Consequences — The extent to which recurrent hypoglycemia causes cognitive impairment is uncertain [1,17]. In older adults, severe hypoglycemia has been associated with an increased risk of dementia [18,19]. Furthermore, 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 over three times higher in the intensive treatment group as compared with the conventional treatment group, there were no differences between the two groups 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 [20,21]. Severe hypoglycemia may also be associated with an increased risk of cardiovascular disease in patients with type 2 diabetes, although whether hypoglycemia is causal is not clear [22]. (See "Treatment of type 2 diabetes mellitus in the older patient", section on 'Avoiding hypoglycemia'.)

In middle-aged adults (mean age 53.5 years), nonsevere hypoglycemia has been shown to increase time away from work [23]. In frail, older adults, mild episodes of hypoglycemia may lead to episodes of dizziness or weakness, increasing the risk of falls and fracture [24]. (See "Treatment of type 2 diabetes mellitus in the older patient", section on 'Avoiding hypoglycemia'.)

Fear of hypoglycemia and its consequences can result in poor glycemic control. (See 'Fear of hypoglycemia' below.)

RISK FACTORS FOR HYPOGLYCEMIA — Risk factors for hypoglycemia include the following [1,2,25,26]:

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

Longer duration of diabetes

Older age

Lower levels of glycemia, when achieved with medications

Erratic timing of meals, including missed meals and low carbohydrate content of meals

History of recent severe hypoglycemia

Exercise

Alcohol ingestion

Chronic kidney disease

Malnutrition with glycogen depletion

Iatrogenic hypoglycemia occurs in patients with type 1 diabetes and in patients with type 2 diabetes treated with insulin, a sulfonylurea, or a meglitinide [2]. Randomized controlled clinical trials in type 1 [27,28] and type 2 [29-31] diabetes have consistently documented that patients treated to lower A1C levels (to reduce long-term microvascular complications) have two- to threefold higher rates of severe hypoglycemia. In the Type 1 Diabetes Exchange Clinic Registry, the risk of severe hypoglycemia that required the assistance of another person was also shown to be higher in males, adolescents, and in those with longstanding diabetes (>40 years duration), a history of severe hypoglycemia, and greater glucose variability [28,32].

STRATEGIES TO MANAGE HYPOGLYCEMIA — Our approach to the management of hypoglycemia outlined below is largely consistent with reports from a joint workgroup of the American Diabetes Association (ADA) and the Endocrine Society [1] and the International Hypoglycaemia Study Group [33].

General approach to reduce risk — The prevention of hypoglycemia involves assessing for risk factors and tailoring treatment regimens to reduce risk. At each visit, the provider should inquire about any:

Low measured glucose levels

Episodes requiring the assistance of another person

Episodes of symptoms consistent with hypoglycemia

All self-monitoring of blood glucose (SMBG) or continuous glucose monitoring (CGM) data that are available should be reviewed and the frequency and details of any recognized episodes of hypoglycemia determined. The insulin regimen is adjusted based on glucose patterns, with an eye to reducing hypoglycemia, while at the same time achieving target glucose and A1C levels.

Reducing the risk of hypoglycemia while maintaining or improving glycemic control involves application of the following principles [1,2,33]:

Patient education and empowerment

Frequent SMBG (usually with fingerstick measurements or with CGM [CGM primarily in type 1 diabetes or high-risk type 2 diabetes patients])

Individualized glycemic goals

Flexible and rational insulin (and other drug) regimens

Ongoing professional guidance and support

In a meta-analysis of 43 studies (randomized trials and observational studies), educational interventions (eg, flexible insulin therapy, behavioral techniques) and technological interventions (continuous subcutaneous insulin infusion, CGM, sensor-augmented pump) reduced severe hypoglycemia and improved glycemic control [34].

Patient education — There is increasing evidence that structured patient education focused on implementation of flexible insulin therapy can reduce the incidence of severe hypoglycemia [35-38]. Patients should be taught to adjust their medications, meal plans, and exercise based on glucose patterns. Clinicians should review how to treat (and not overtreat) developing hypoglycemia with oral carbohydrate or glucagon. In addition, close associates, such as a spouse or a partner, should be taught to recognize severe hypoglycemia and treat it with glucagon. (See 'Reversing hypoglycemia' below.)

Regular SMBG is critical to the glycemic management of type 1 diabetes as well as intensively treated (basal/bolus insulin) type 2 diabetes. CGM is usually used in type 1 diabetes, but some patients with type 2 diabetes may benefit as well. The use of CGM, or periodically performing SMBG before and two to three hours after each meal, bedtime, in the middle of the night, and before and after exercise can help identify glycemic patterns and hypoglycemia [39]. 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 control can minimize 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 2 diabetes should be tailored to the individual, balancing the reduction in microvascular complications with the risk of hypoglycemia [40-43]. 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.

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'.)

Insulin regimens — More than half of episodes of iatrogenic hypoglycemia, including severe hypoglycemia, occur during the night [2,44]. 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 in individuals using long-acting insulin analogs (glargine, detemir, degludec) rather than NPH as the basal insulin. (See "Management of blood glucose in adults with type 1 diabetes mellitus", section on 'Choosing basal/prandial insulin'.)

Although many clinicians believe continuous subcutaneous insulin infusion (CSII) in type 1 diabetes reduces hypoglycemia, at comparable A1C levels, CSII has not been found to consistently result in less hypoglycemia than a basal-bolus regimen with insulin analogs [45,46]. However, CSII in conjunction with CGM, particularly devices that are programmed to interrupt insulin delivery at a preset sensor glucose value (threshold-suspend feature) or incorporate the predictive low-glucose suspend feature, have been shown to reduce nocturnal hypoglycemia [47]. (See "Continuous subcutaneous insulin infusion (insulin pump)", section on 'Sensor-augmented insulin pump'.)

In patients with type 2 diabetes, long-acting insulin analogs may reduce symptomatic and nocturnal hypoglycemia compared with NPH. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Choice of basal insulin'.)

When addressing nocturnal (and fasting) hypoglycemia, in addition to adjusting the basal rate, it is important to question the patient concerning bedtime insulin bolusing for food and/or overcorrection of hyperglycemia, as well as exercise patterns and alcohol use.

Specific settings

Impaired awareness of hypoglycemia — If there is 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 [48-54]. 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, based on serial estimates of glucose levels prior to their measurement by patients with diabetes, has been reported to improve detection of hypoglycemia [55].

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, including frequent SMBG 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 [56]. 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 in patients with type 1 diabetes [57].

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 [2,58-61]. 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, fear of hypoglycemia is understandable. At its best, this concern should prompt diabetic patients to be aware of early symptoms and to ingest carbohydrate before symptoms progress. In some cases, however, fear of hypoglycemia can become a major barrier to lowering blood glucose concentrations substantially. 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 [62]. As a result, it is important to explore the patient's past experience with hypoglycemia before embarking on an intensified insulin regimen. Educational strategies need to focus on how to help the patient live safely with the increased risk.

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 values, 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 controlled research study. (See "Pancreas and islet transplantation in diabetes mellitus", section on 'Indications for transplantation'.)

REVERSING HYPOGLYCEMIA — The goal of the treatment of hypoglycemia is to raise the plasma glucose concentration to normal by providing dietary or parenteral carbohydrate (specifically glucose), or in cases of severe hypoglycemia outside of a medical center, by stimulating endogenous glucose production by administering glucagon. 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 more consistently effective (table 1) [63]. Patients with type 1 diabetes should have a glucagon kit, which should be checked regularly and replaced when it is beyond its expiration date.

Asymptomatic — For a person with drug-treated diabetes, we suggest defensive actions when self-monitoring reveals a glucose level ≤70 mg/dL (3.9 mmol/L). Defensive 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 [64].

Symptomatic — Patients with symptomatic hypoglycemia 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. This can be followed by long-acting carbohydrate (a meal or a snack) to prevent recurrent symptoms.

In patients taking 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.

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

With IV access — Patients already in the hospital can usually be treated quickly by giving 25 g of 50 percent glucose (dextrose) 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. Therefore, the glucagon dose should be followed promptly by oral intake of concentrated carbohydrates, immediately upon awakening from the confused state and before the development of nausea.

Glucagon therapy requires that the glucagon can be located and that the relative or friend is able to recognize hypoglycemia, remain calm, and administer it.

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 [65]. 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 administering insulin), successful reversal of hypoglycemia occurred in 98.7 and 100 percent of intranasal glucagon and intramuscular glucagon visits, respectively [66]. 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 glucagon – Glucagon (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 (reconstitution not required) [67]. 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) [68-73]. The use of small doses (mini-doses) of stable, liquid glucagon, repeated if necessary, are also in development [74,75].

Reconstituted glucagon – Glucagon lyophilized powder requires reconstitution (mixing the powder with the diluent) immediately before use. It is administered (1 mg) either subcutaneously or intramuscularly. The reconstitution process is challenging for caregivers or friends in an emergency setting.

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 [76]. However, in the absence of other options for such patients, some 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 [77,78].

However, other experts, including the author of this topic review, would not administer buccal or sublingual preparations or foods, given the lack of supporting evidence showing that buccal absorption of glucose occurs in humans [76] and concerns about aspiration.

Monitoring — The glycemic response to intravenous 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 is able to eat, often not possible by the nausea often induced by glucagon). 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 sulfonylurea 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 analogues, such as degludec or glargine 300; however, the durable effects of these insulins suggest that observation, continuous glucose monitoring (CGM) and therapy may need to be prolonged, compared with hypoglycemia associated with shorter-acting insulins.

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. An alert value for hypoglycemia is defined as blood glucose <70 mg/dL (3.9 mmol/L). Clinically important hypoglycemia is defined as blood glucose <54 mg/dL (3 mmol/L), but the physiologic response to a low blood glucose can be quite variable. (See 'Definition' above.)

Risk factors for hypoglycemia – The clinical risk factors for hypoglycemia include hypoglycemia-associated autonomic failure (both impaired awareness of hypoglycemia and defective glucose counterregulation), a history of recent severe hypoglycemia, a long duration of diabetes, chronic kidney disease, malnutrition, and intensive glycemic therapy. (See 'Risk factors for hypoglycemia' above.)

General approach to reduce risk of hypoglycemia – The prevention of hypoglycemia involves assessing for risk factors and tailoring treatment regimens to reduce risk. (See 'General approach to reduce risk' above and 'Insulin regimens' above.)

Patient education – Patients should be taught to adjust their medications, meal plans, and exercise based on glucose patterns. Clinicians should review how to treat (and not overtreat) developing hypoglycemia with oral carbohydrate or glucagon. In addition, close associates, such as a spouse or a partner, should be taught to recognize severe hypoglycemia and treat it with glucagon. Patients should be told to be especially vigilant following an episode of hypoglycemia since both recognition of hypoglycemia and the counterregulatory response to it will be impaired during this time. (See 'Patient education' above.)

Adjust glycemic targets – The goal is to achieve the best degree of mean glycemia (glycated hemoglobin [A1C]) that can be accomplished safely. We consider more modest goals for A1C values in patients with one or more previous episodes of severe hypoglycemia, with risk factors for hypoglycemia, or in those with little expected benefit from glycemic control. We continually reevaluate with the patient whether the benefits of improved blood glucose control are worth the number of hypoglycemic episodes that are occurring. (See 'Glycemic targets' above.)

Reversing hypoglycemia We routinely check that the patient's blood glucose monitoring equipment is accurately calibrated, that fast-acting carbohydrate is being kept available, that the patient is staying vigilant, and that glucagon kits are not out of date. (See 'Reversing hypoglycemia' above.)

Asymptomatic – For a person treated with insulin, a sulfonylurea, or a meglitinide, we suggest defensive actions when self-monitoring reveals a glucose level ≤70 mg/dL (3.9 mmol/L) (Grade 2C). Defensive actions include repeating the measurement in the near term, avoiding critical tasks such as driving, ingesting carbohydrates, and adjusting the treatment regimen. (See 'Asymptomatic' above.)

Symptomatic – Patients with symptomatic hypoglycemia should ingest carbohydrates. Fifteen to 20 grams of oral glucose is typically sufficient (table 1). Glucose may be ingested in the form of tablets, juice, milk, other snacks, or a meal. Patients should retest glucose after 15 minutes and retreat if glucose is not improved. (See 'Symptomatic' above.)

Severe – 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 'Severe' above.)

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 (Grade 2B). The usual dose is 0.5 to 1 mg given as a subcutaneous or intramuscular injection or 3 mg given intranasally. Education and training for clinicians, friends, and family on the recognition and treatment of severe hypoglycemia, including the use of glucagon kits, is necessary. (See 'Severe' above.)

Monitoring initial treatment – The glycemic response to intravenous 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 is able to eat). Further treatment and disposition vary depending on the class of agent causing the toxicity and the severity of symptoms. (See 'Monitoring' above.)

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Topic 1805 Version 39.0

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