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Hypoglycemia in Patients With Diabetes

Summary
Basic Information
Diagnosis
Workup
Differential Diagnosis
Treatment
Special Considerations
Follow-up
Screening and Prevention

Jan.17.2023

Hypoglycemia in Patients With Diabetes

Summary

Key Points

It is important to minimize the risk of hypoglycemia in the management of any person with diabetes
In type 2 diabetes, if possible, avoid insulin and insulin secretagogues (sulfonylureas, meglitinides); there are other classes that lower the blood glucose level equally effectively and do not increase risk of hypoglycemia (metformin, pioglitazone, dipeptidyl peptidase 4 inhibitors, sodium-glucose transport protein 2 inhibitors, glucagonlike peptide 1 receptor agonists)
In type 2 diabetes, if insulin is required, use basal insulin analogues.^{33,34,35,36,37} If mealtime insulin is also needed, use prandial rapid-acting insulin analogues³⁵
In type 1 diabetes, favor insulin pumps and CGM (continuous glucose monitoring) sensors, particularly integrated hybrid closed-loop systems, (over MDI [multiple daily injections]) to reduce risk of hypoglycemia.^43,44,45,46 If an insulin pump cannot be used, use basal insulin analogues and rapid-acting insulin analogues before meals
More intensive regimens generally increase the risk of hypoglycemia. For certain patients (eg, older adults or those with CKD [chronic kidney disease]), the risk of hypoglycemia may well outweigh benefits of intensive glycemic control^52,58
Proper patient education about at-risk situations, and prompt recognition and treatment of hypoglycemia should occur when insulin or insulin secretagogues are prescribed⁷

Alarm Signs and Symptoms

Frequent episodes of hypoglycemia, especially when severe, mandate a complete reassessment of the overall glucose-lowering strategy and the specific glucose-lowering regimen

Basic Information

Terminology

Hypoglycemia is the physical state defined by an abnormally low circulating blood glucose concentration, which, in the patient with diabetes, is almost always induced by specific glucose-lowering therapies that augment insulin supply in a glucose-independent fashion. These include:
- Multiple injectable (and inhaled) insulin formulations
- Insulin secretagogues (ie, sulfonylureas, meglitinides)
Patients at higher risk for hypoglycemia include older people and those with CKD (chronic kidney disease) and pancreatic insufficiency
Blood glucose level is the concentration of glucose in mg/dL (or mmol/L) measured in the whole blood
Plasma (or serum) glucose level is the concentration of glucose in mg/dL (or mmol/L) measured in the plasma (or serum), which is approximately 11% higher than the blood glucose level^1,2
- Prevailing hematocrit can affect this difference, which is less in anemia and more in polycythemia
Hypoglycemia unawareness refers to the absence of adrenergic symptoms of hypoglycemia due to autonomic nervous system dysfunction and loss of the body's usual counterregulatory response to a low blood glucose level^3,4
- This condition is caused by multiple repeated episodes of hypoglycemia and is particularly dangerous, because the onset of cognitive dysfunction (including loss of consciousness) may be rapid

Background

Glucose Measurement Issues

Unless the venous blood sample is collected in a tube that includes a glycolytic inhibitor (eg, sodium fluoride in a "gray-top tube"), the measured glucose concentration may decline by approximately 5% per hour, due to ongoing glycolysis by RBCs^1,2
There are also differences in measured glucose level depending on the source of the blood, with arterial blood glucose level being higher than venous blood glucose level, particularly in the postprandial setting where the differences can approach 5%^1,2
- They are more similar in the fasting state, because less glucose is extracted from the blood
- Capillary blood glucose level, the source for home glucose meters (ie, "fingersticks"), approximates arterial blood glucose level^1,2
Most conventional measurements are venous plasma/serum and capillary blood
- Of note, most modern home glucose meters are plasma adjusted, meaning that the measured blood glucose concentration is multiplied by a fixed factor, increasing the value to the equivalent plasma concentration²
CGM (continuous glucose monitoring) devices^1,5 are becoming increasingly popular
- CGM devices use indwelling subcutaneous sensor microcatheters to frequently assay the prevailing glucose concentration in the interstitial fluid compartment, which, in a steady state, approximates the concurrent plasma glucose level
- During periods of rapid fluctuations in plasma glucose concentrations (eg, increasing after meals or decreasing after correction doses of insulin are administered), a lag between the plasma and interstitial compartments of about 10 minutes occurs^1,5
  - Can also vary based on the prevailing plasma glucose level
For clarity, this Clinical Overview refers to blood glucose levels unless specifically discussing CGM sensors, in which case it refers to interstitial glucose levels

Blood Glucose Ranges and Classification

Normal blood glucose concentrations are typically 70 to 99 mg/dL fasting and generally less than 130 to 140 mg/dL postprandially⁶
- However, lower readings (50-69 mg/dL) can be considered normal in patients without diabetes if asymptomatic
Symptomatic hypoglycemia is defined as a blood glucose level less than 70 mg/dL (3.9 mmol/L) with classic symptoms^7,8
Asymptomatic hypoglycemia is defined as a blood glucose level less than 70 mg/dL (3.9 mM) but without symptoms^7,8
- While less concerning to the patient, asymptomatic hypoglycemia may still portend adverse consequences, since it is associated with an increased risk of symptomatic hypoglycemia
Levels of hypoglycemia per the 2017 International Hypoglycemia Study Group,⁷ with a specific eye toward definitions for clinical trials, were classified as follows:
- Level 1: less than 70 mg/dL (3.9 mmol/L) but greater than or equal to 54 mg/dL (3.0 mmol/L) (usually asymptomatic)
- Level 2: less than 54 mg/dL (3.0 mmol/L) (associated with some impairment of cognitive function)
- Level 3: a severe event characterized by altered mental and/or physical status requiring assistance of another person, irrespective of the prevailing blood glucose level

Epidemiology

More commonly encountered in type 1 diabetes than in type 2 diabetes^8,9
Type 1 diabetes
- Annual prevalence of severe hypoglycemia in patients with type 1 diabetes is approximately 30% to 40%, and the annual incidence is 1.0 to 1.7 episodes per person-year^9,10
- Mild/moderate but still symptomatic hypoglycemia is much more frequent, occurring several times per week
- With the advent of CGM, it became apparent that hypoglycemia, usually asymptomatic, occurs at multiple times per day, with time in range typically around 5%⁷
Type 2 diabetes
- Rates of hypoglycemia in patients with type 2 diabetes are quite variable in the literature, depending on definitions, severity, treatment strategy and intensiveness, and patient population
- In clinical trials, severe hypoglycemia rates also range widely from 0.7 to 12 episodes per 100 patient-years, with higher rates seen in insulin trials¹¹
  - In observational studies, hospitalizations or emergency department visits for hypoglycemia are approximately 2 episodes per 100 patient-years in those using insulin or sulfonylureas.¹¹ Severe episodes that did not prompt medical evaluation are much more common (4%-17% of insulin-treated patients)¹¹
  - 1 large meta-analysis of 46 observational studies and more than 500,000 patients with type 2 diabetes found that the prevalence of mild/moderate hypoglycemia was 45% and 6% for severe hypoglycemia¹²
    - Corresponding incidence rates were 19 and 0.8 episodes per person-year. Rates were highest in those using insulin: mild/moderate, 50% prevalence and incidence of 23 episodes per person-year; severe, 21% prevalence and incidence of 1 episode per person-year.¹² For those on sulfonylureas: mild/moderate, 30% prevalence and incidence of 2 episodes per person-year; severe, 5% prevalence and incidence of 0.01 episodes per person-year¹²
- Older people, those with CKD, especially end-stage renal disease, and patients afflicted with pancreatic insufficiency (eg, chronic pancreatitis or postpancreatectomy) and hypoadrenalism are at higher risk

Etiology and Risk Factors

Etiology

Occurs when the ambient insulin supply exceeds the carbohydrate nutrient supply, resulting in excess movement of glucose molecules from the plasma into cells and concurrent suppression of endogenous glucose production, limiting the ability of (primarily) the liver to produce glucose via glycogenolysis and gluconeogenesis
Result is insufficient glucose to meet the body's energy needs, leading to classic symptoms involving autonomic stimulation and neurologic alterations

Risk Factors

As follows (Table 1):
- In type 2 diabetes, prevalent therapy with insulin or insulin secretagogues (ie, sulfonylureas, meglitinides)
- After mealtimes, mismatch between amount of insulin administered and amount of carbohydrates consumed (eg, with interrupted or curtailed meals)
- Periods of prolonged fasting, particularly when the basal (long acting) insulin dose is in excess
- Unanticipated increase in activity level in those on insulin (or insulin secretagogues)
- Prior episodes of severe hypoglycemia
- Hypoglycemia unawareness
- CKD
- Ethanol ingestion without concurrent consumption of food calories
- Rare and unrelated to diabetes per se: hepatic failure, adrenal insufficiency (including hypopituitarism), sepsis, insulinoma, nesidioblastosis, non–islet cell tumor hypoglycemia

Table 1. Factors contributing to risk of hypoglycemia in patients with diabetes.
Diabetes complexity	Multimorbidity	Pharmacotherapy	Patient context and environment	Health care system
Diabetes duration Impaired hypoglycemia awareness High glycemic variability Prior hypoglycemic events Severe and nonsevere Glycemic control U-shaped relationship with hemoglobin A1C Fear of hypoglycemia Fear of hyperglycemia	Functional impairment, frailty Comorbid health conditions Microvascular complications (autonomic, peripheral, and kidney disease, cardiovascular disease, heart failure, cerebrovascular disease, liver disease, depression) Cognitive impairment, dementia	High-risk medications Insulin, sulfonylurea Glucose-lowering polypharmacy Nondiabetes medications For example: β-blockers Complex treatment regimens Medication mistakes Dosing errors, discordance with meals	Inadequate caregiver support or supervision Food insecurity Poor health literacy Financial burden Nonclinical or competing clinical demands Fasting, either for medical tests/procedures or person/religious reasons For example: Ramadan	Performance measurement, reporting, and benchmarking that focus on lowering hemoglobin A1C Inadequate diabetes support/resources, including DSME and clinical monitoring Payer decisions regarding DSME, glucose monitoring, drug formulary, and diabetes technologies Lack of integration of patient health information, including glucose monitoring data and self-reported hypoglycemia, into clinical EHR

Risk Models and Risk Scores

No widely used risk model or risk score used to determine hypoglycemia risk
Several have been published however and appear to be moderately discriminating
- Hypoglycemia risk calculator^13,14
- Hypoglycemia risk score^15,16,17

Diagnosis

Approach to Diagnosis

Diagnosis of hypoglycemia in patients with diabetes is straightforward in most circumstances given easy access to rapid glucose measurement tools
Hypoglycemia should be suspected in patients with diabetes who report classic symptoms
- Classic symptoms are divided into the counterregulatory or adrenergic response and those due to neuroglycopenia
- Adrenergic symptoms include tachycardia/palpitations, sweating, tremors, hunger, slowing and/or slurring of speech
  - β-Blockers can inhibit tachycardia/palpitation and tremor which can masks signs and symptoms of hypoglycemia
- Neuroglycopenic symptoms include various degrees of cognitive dysfunction, including personality change, disorientation, disagreeable behavior, lethargy, and coma
- Severity of symptoms typically relates to the degree of hypoglycemia but also its rapidity of onset
- Occasionally, particularly in those people under poor glycemic control, symptoms may emerge even when the blood glucose levels are in the reference range, felt to be related to the brain sensing "relative" hypoglycemia compared with recent ambient levels
For the purpose of identifying hypoglycemia in people with known diabetes, standardized glucose measuring devices (glucometers, continuous glucose monitors) are sufficient in everyday, real-world settings
Laboratory confirmation of a low blood glucose level is unnecessary in most cases, with the following exceptions:
- When there is uncertainty regarding the accuracy of a rapid test result
- When it is important to determine whether prevailing symptoms should be attributed to hypoglycemia or an alternate diagnosis (Tables 2 and 3)
- Convenience of concordant measurement with additional laboratory studies of relevant interest (eg, as might occur with inpatients or critically ill patients)

Table 2. Other conditions to consider in patients with diabetes with altered mental status.
Condition	Factors relevant to diabetes
Stroke	Sudden acute neurologic deficits should prompt concern for stroke, because diabetes is an independent risk factor for ischemic stroke Lacunar infarcts are common in patients with diabetes; MRI is usually required to show these smaller lesions^18,19
Seizure	Epilepsy or seizures are observed in patients with diabetes at higher rates than people without diabetes Patients with type 1 diabetes who experience episodes of DKA also have seizures more frequently²⁰
Drug overdose	Toxicology screen may be informative Reversibility with naloxone supports acute opioid intoxication²¹
Ethanol intoxication	Acute ethanol intoxication can potentially induce hypoglycemia in children or in malnourished people who consume ethanol regularly Inebriation is usually identified by history or behavior²²
Encephalitis/meningitis	Fever and focal neurologic abnormalities suggest CNS infection, formally diagnosed by CSF culture
Intracerebral hemorrhage	Patients with diabetes are more prone to deep subcortical intracerebral hemorrhage than lobar hemorrhage¹⁸
Delirium (eg, from acute illness)	Delirious states (due to sepsis, uremia, postoperative state) may be exacerbated by wide glycemic excursions in patients with diabetes
Severe hypothyroidism	Noncompliance with levothyroxine therapy elevates risk Patients with established ongoing care are, however, unlikely to present initially with severe hypothyroidism if regularly screened
Hyperglycemic crisis	Hyperosmolarity and/or acidosis contributes to altered sensorium²³

Diagnostic Criteria

Symptomatic hypoglycemia is defined as a blood glucose level less than 70 mg/dL (3.9 mmol/L) with classic symptoms^7,8
Asymptomatic hypoglycemia is defined as a blood glucose level less than 70 mg/dL (3.9 mmol/L) only but without symptoms^7,8
- Although less concerning to the patient, asymptomatic hypoglycemia may still portend adverse consequences, because it is associated with an increased risk of symptomatic hypoglycemia

Workup

History

Adrenergic symptoms include episodes of unprovoked sweating, tachycardia/palpitations, tremors, and hunger especially sugar craving
Neuroglycopenic symptoms include confusion/disorientation, personality changes, lethargy, or loss of consciousness
Constellation of these symptoms are especially likely to reflect hypoglycemia if they coincide with the timing of either the peak effect of insulin (or insulin secretagogues) previously administered and/or the nadir of calories consumed and/or an unanticipated increase in activity level

Physical Examination

Episodic and otherwise unexplained tachycardia, diaphoresis, tremulousness, mental status changes, including loss of consciousness

Laboratory Tests

Plasma (serum or blood) venous glucose concentrations
- Laboratory-based determinations of plasma, serum, or whole blood glucose level may be obtained in emergency department or hospital-based settings under some circumstances
- Threshold for hypoglycemia is set at a blood glucose level less than 70 mg/dL (3.9 mmol/L)^7,8
- Concentration of glucose in mg/dL (or mmol/L) as measured in the plasma (or serum) is approximately 11% higher than the blood glucose level^1,2
- Prevailing hematocrit can affect this difference, with less of a difference found in anemia and greater difference in polycythemia
- Although uncommon, low blood glucose level may occur because of an erroneous test result (see Table 3)

Imaging Studies

None in most circumstances
In the rare circumstance where an insulinoma is suspected (recurrent hypoglycemia in the patient who is not taking any insulin or insulin secretagogues), imaging may include abdominal CT or MRI or endoscopic ultrasound²⁴

Evaluation for Contributory or Alternative Causes

None in most circumstances
If hypoglycemia events do not follow the usual pattern, are severe, recurrent, or otherwise unexplained, especially if accompanied by other symptoms, consider concurrent either primary or secondary adrenal insufficiency²⁵
Other conditions, such as fulminant hepatic failure, sepsis, and so on, should, of course, be accompanied by other obvious features
In a rare circumstance where an insulinoma is suspected (recurrent hypoglycemia in the patient with diabetes who is not taking any insulin or insulin secretagogues), measuring insulin and C-peptide levels during hypoglycemia is invaluable and instrumental for securing that diagnosis²⁴

Differential Diagnosis

Hypoglycemia is usually easily identified by measurement of blood (or interstitial) glucose level at the time of a suspected event
Other conditions to consider in patients with altered mental status should include those listed in Table 2
Table 3 explores causes of erroneous blood glucose measurements

Table 3. Differential Diagnosis: Erroneous low blood glucose measurement.
Condition	Description	Differentiated by
Malfunctioning/inaccurate blood glucose meter or CGM sensor	Home blood glucose meters or CGM sensors have inherent error rates FDA regulations allow for 15%-20% deviation from plasma glucose levels, depending on the specific glucose range²⁶ Insufficient droplet size and/or poorly perfused fingers may result in falsely low blood glucose level	Patient is asymptomatic and hypoglycemia is not confirmed on repeat testing or by the assessment of glucose levels through a separate method

Treatment

Approach to Treatment

Treatment of Acute Hypoglycemic Episodes

Acute Episodes in Patients Who Are Conscious

Urgent treatment of hypoglycemia is ideally accomplished by ingestion of rapidly absorbed carbohydrates, if feasible²⁷
- Patients should be instructed to ingest 15 g of carbohydrates. For more severe episodes, 30 g should be ingested²⁸
  - Good options include ingesting 15 g of glucose tablets (3-4 tablets depending on product) or glucose gel (15-g packet/tube) or by drinking 4-oz fruit juice or sugared soda (12-15 g) or 8 oz of milk (12 g) or 5 to 7 pieces of candy. These contain glucose and other simple sugars that are broken down to glucose
  - Patients taking α-glucosidase inhibitors (acarbose, miglitol) must use dextrose tablets, honey, or milk, since juice, soda, and candy will not work due to mechanism of action of medication
  - 1 systematic review found that consuming glucose tablets provided a higher rate of relief from symptomatic hypoglycemia compared with other dietary forms of sugar, such as juices, various types of candy, or milk²⁹
- Blood glucose level increases substantially within 10 to 15 minutes after ingestion
  - As a rule of thumb, 15 g of carbohydrates will increase the blood glucose level approximately 25 mg/dL
  - Patients should be instructed to recheck the blood glucose level 15 minutes after ingesting carbohydrates³⁰ at which point, depending on how severe the hypoglycemia is, the blood glucose level should rise above 70 mg/dL
  - Additional carbohydrates can be consumed to increase the blood glucose level to a more comfortable level of greater than 100 mg/dL
- Depending on timing of the event, once the glucose pattern is trending up, the patient should consume a meal or snack as soon as able to prevent recurrent episodes^4,30

Acute Episodes in Patients Who Are Unconscious

If the patient is unconscious or in situations where safe oral consumption of carbohydrates is not possible, treatment depends on the availability of IV access³⁰
- If IV access is available, use dextrose-containing infusion
  - In adults, use 25 g (50 mL) of D50W solution (50% dextrose in water)
- If there is no IV access, the treatment of choice is glucagon, which can be administered via an intramuscular or a subcutaneous injection or by a nasal spray
- After IV dextrose or intramuscular/subcutaneous/intranasal glucagon, blood glucose level should be rechecked after 15 minutes, and repeat treatment considered if the blood glucose level has not increased adequately (at least greater than 70 mg/dL) with improving sensorium
- Additional ongoing administration of dextrose may be required to successfully restore and maintain euglycemia, depending upon the cause and severity
- Sulfonylurea-induced hypoglycemia, which can be prolonged and refractory if overdosed, may require additional pharmacologic agents such as octreotide³¹

Strategies to Reduce Hypoglycemia

In patients with diabetes, particularly those using medications that can result in hypoglycemia, blood glucose concentrations should always be kept greater than 70 mg/dL, and actually, more comfortably above 80 to 90 mg/dL, allowing for inherent inaccuracies in blood glucose measurement tools such as home glucose meters using fingersticks
Hypoglycemia prevention almost always requires an adjustment in therapy or in self-management habits⁴
Preventive strategies differ to some degree between patients with type 1 and type 2 diabetes
For patients using CGM (continuous glucose monitoring) devices, recommended targets from a recent international consensus statement³² for time in range are as follows:
- Time below range (ie, below 70 mg/dL or 3.9 mmol/L) should be less than 4% (or less than 1 hour/day)
- Corresponding target for below 54 mg/dL (less than 3 mmol/L) should be less than 1% (or less than 15 minutes/day)
- For high-risk groups, below 70 mg/dL (3.9 mmol/L) target should be less than 1% (or less than 15 minutes/day)

For Patients With Type 2 Diabetes

Best strategy to prevent hypoglycemia is, logically, to avoid those glucose-lowering medications that may induce hypoglycemia (insulin, sulfonylureas, meglitinides). All other antihyperglycemic drug categories do not increase the risk of hypoglycemia (when used as monotherapy or in conjunction with each other) (Table 4)
- Medications with low risk of hypoglycemia include:
  - Biguanide: metformin
  - Thiazolidinedione: pioglitazone
  - Dipeptidyl peptidase 4 inhibitors: sitagliptin, saxagliptin, alogliptin, linagliptin
  - Sodium-glucose transport protein 2 inhibitors: canagliflozin, dapagliflozin, empagliflozin, ertugliflozin
  - Glucagonlike peptide 1 receptor agonists: exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide
- Glucose-lowering agents that are much less commonly used but are also not associated with hypoglycemia include:
  - α-Glucosidase inhibitors: acarbose, miglitol
  - Bile acid sequestrant: colesevelam
  - Amylin mimetic: pramlintide
  - Dopamine agonist: bromocriptine
When medications that do not lead to hypoglycemia are used in conjunction with those that do (particularly in people who are tightly controlled), it is possible that hypoglycemia rates may be increased, because the former may accentuate this effect of the latter
However, compared with a more aggressively titrated insulin regimen, adding a medication not associated with hypoglycemia to basal insulin therapy may actually reduce the dose of insulin required, and, as a result, hypoglycemia rates
In general, the higher the insulin dose, relative to weight, and the more frequent the injections, the greater the risk of hypoglycemia
For those on insulin, higher (ie, more relaxed) glycemic target reduces the risk of hypoglycemia
For those on basal insulin once or twice daily, the use of long-acting basal insulin analogues (glargine, detemir, degludec) reduces the risk of symptomatic (especially nocturnal) hypoglycemia over human NPH (neutral protamine Hagedorn) insulin^33,34,35
Longer-acting basal insulin, degludec, has been shown to decrease the risk of hypoglycemia further over glargine^36,37
For those requiring mealtime insulin, rather than regular human insulin, the use of rapid-acting insulin analogue could conceivably decrease the risk of hypoglycemia before the next meal, although the data are limited³⁵
In general, adding mealtime rapid-acting insulin analogues to basal insulin will increase hypoglycemia rates. However, clinicians should recognize the signs of a patient taking too high a basal insulin dose (usually beginning around 0.5 units/kg). These include hypoglycemia before meals and hypoglycemia overnight. In this circumstance, reducing the basal insulin dose and adding mealtime rapid-acting insulin analogues will reduce hypoglycemia rates
- Note that too high a basal dose can occur at lower amounts than 0.5 units/kg in lean people, insulin naïve people, and those with advanced CKD (chronic kidney disease), especially end-stage renal disease, and concurrent adrenal insufficiency
In general, using premixed insulin formulations, such as 70/30, which are a combination of intermediate-acting insulin and regular/rapid insulin analogues, increases the risk of hypoglycemia compared with basal insulin alone³⁸
More frequent glucose monitoring and comprehensive diabetes education, including specific training about the avoidance of hypoglycemia, may reduce the risk of severe episodes²⁷
- Use of CGM devices should reduce the risk of severe hypoglycemia, but the evidence for this is not strong in type 2 diabetes. It may be more effective in those at risk for hypoglycemia³⁹

For Patients With Type 1 Diabetes

For those on MDIs (multiple daily injections), use of long-acting basal insulin analogues (glargine, detemir, degludec) reduces the risk of symptomatic (especially nocturnal) hypoglycemia over NPH.^33,40 Here, too, degludec has shown advantage over glargine⁴¹
For those on MDI, use of rapid-acting insulin analogues (lispro, aspart, glulisine) over regular human insulin before meals may also reduce the risk of hypoglycemia⁴²
Use of continuous subcutaneous insulin infusion devices ("insulin pumps") alone (versus MDI) does not appear to reduce the risk of hypoglycemia, although they may allow the achievement of a lower hemoglobin A1c without increasing hypoglycemia risk⁴³
More modern insulin pumps communicating with CGM sensors in hybrid-closed loop systems, however, do reduce the risk of severe hypoglycemia over MDI^44,45,46
Use of integrated hybrid closed-loop systems involving an insulin pump communicating and partially driven by a CGM device has also shown advantages over open-loop pumps (ie, not integrated with CMG) in reducing the risk of severe hypoglycemia⁴⁵
Although intuitive, it remains debatable whether the use of CGM alone (without an insulin pump) also reduces the risk of hypoglycemia.^46,47 The data appear to be strongest in those at risk for hypoglycemia³⁹

Table 4. Major glucose-lowering drug classes in type 2 diabetes and risk of hypoglycemia.
Classes	Drug names	Mechanism(s)	Usual hemoglobin A1c reduction	Hypoglycemia risk
Insulin	Degludec, glargine, detemir, NPH, regular, lispro, aspart, glulisine	Replaces deficient insulin supply	Theoretically limitless	High
Sulfonylureas	Glyburide, glipizide, glimepiride	↑ endogenous insulin production	1%-1.5%	Moderate
Biguanide	Metformin	↓ hepatic glucose production	1%-1.5%	Low
Thiazolidinediones	Pioglitazone	↑ peripheral insulin sensitivity	1%-1.5%	Low
DPP-4 inhibitors	Sitagliptin, saxagliptin, alogliptin, linagliptin	↓ DPP-4 activity↑ incretin levels (GLP-1, GIP)	0.5%-1%	Low
GLP-1 receptor agonists	Exenatide, liraglutide, dulaglutide, lixisenatide, semaglutide	↑ insulin levels (glucose dependent)↓ glucagon levelsSlows gastric emptying↑ satiety	1%-1.5%	Low
SGLT2 inhibitors	Canagliflozin, dapagliflozin, empagliflozin, ertugliflozin	↑ urinary glucose excretion	0.5%-1%	Low

Nondrug and Supportive Care

Treatment will almost always require an adjustment in therapy or in self-management habits
Advise patients who are experiencing frequent, severe, or nocturnal hypoglycemia to perform more frequent glucose monitoring
Following recurrent, severe, or nocturnal episodes of hypoglycemia, the patient and/or clinicians should try to determine why hypoglycemia occurred
- Usual explanation is a mismatch between the insulin or insulin secretagogue dose, calories (particularly carbohydrate calories), and activity level
- Corrective measures should be taken to prevent recurrent events
Hypoglycemia unawareness or 1 or more episodes of hypoglycemia that require assistance should prompt reevaluation of the treatment regimen. Refer such patients for (additional) comprehensive diabetes education including specific training about the avoidance of hypoglycemia²⁷
Insulin-treated patients with hypoglycemia unawareness should be advised to aim for less stringent glycemic targets to strictly avoid hypoglycemia for a few weeks to regain partial counterregulatory responses and reduce risk of future episodes^27,48
Education about hypoglycemia is especially important for those at greatest risk, especially those with advanced CKD, especially end-stage renal disease

Drug Therapy

If the patient is unconscious or in situations where safe oral consumption of carbohydrates is not possible, treatment depends on the availability of IV access, in which case dextrose-containing infusion is used. If there is no IV access in this setting, the treatment of choice is glucagon, which can be administered via an intramuscular or a subcutaneous injection or, more recently, by a nasal spray
IV dextrose (25 g/50 mL)
- For mild/moderate hypoglycemia, administer 25 mL of D50 (50% dextrose; 12.5 g). This will typically raise the blood glucose level by 25 to 50 mg/dL
- For very severe episodes, where a greater increase in blood glucose level is needed, give IV 50 mL of D50 (25 g). This will typically raise the blood glucose level by greater than 50 mg/dL⁴⁹
- In the absence of D50, 100 to 200 mL of D10 (10% dextrose; 10-20 g) can be used instead⁵⁰
Glucagon
- May be given via intramuscular or subcutaneous or IV injection
- For adults or pediatric patients weighing more than 25 kg, administer 1 mg intramuscularly/subcutaneously/IV
  - If there has been no response after 15 minutes, an additional dose of 1 mg may be administered
- For adults and pediatric patients 4 years or older, administer 3 mg of intranasal spray as one actuation of the intranasal device into 1 nostril
  - If there has been no response after 15 minutes, an additional dose of 3 mg from a new device may be given
- Both will increase blood glucose level by 25 to 50 mg/dL within 15 minutes, with blood glucose level continuing to rise by 100 mg/dL or more at 1 hour⁵¹
After dextrose or glucagon, the blood glucose level should be rechecked after 15 minutes and treatment readministered if the blood glucose level has not increased adequately (at least greater than 70 mg/dL, but preferably greater than 100 mg/dL)

Persistent or Recurrent Disease

Any severe acute episode of hypoglycemia should be evaluated in the emergency department for documentation of sustained normalization of blood glucose level, for exploration as to cause, and for the consideration of possible admission
Any recurrent episode of hypoglycemia not responding to routine measures should also be evaluated in the emergency department

Admission Criteria

Severe episodes not responding to routine corrective measures warrant admission
Episodes that are felt to be potentially persistent, as might occur after obvious excess dosing of a long-acting insulin (eg, glargine, detemir, degludec) or a long-acting sulfonylurea (eg, glyburide, glibenclamide)
Episodes related to insulin pump malfunction that may require comprehensive assessment of the device and reeducation of the patient
Episodes that have led to significant neurologic sequelae (seizure, coma, persistently altered mental status after resuscitation)
Episodes that have led to significant orthopedic injury, head trauma, or motor vehicle accident

Special Considerations

Older Adults

It is more important to avoid hypoglycemia in older adults due to frequently concurrent cardiovascular disease, potential effects of recurrent severe episodes on cognitive function, and also due to greater fall risk
Consider deintensifying treatment regimen and relaxing glycemic goals, especially in those with multiple coexisting chronic illnesses, cognitive impairment, or functional dependence⁵²
Avoid glyburide and short-acting insulin sliding scales⁵³

Pregnancy

Glycemic targets are generally lower in pregnant patients with diabetes, including gestational diabetes^27,54
Because of alterations in substrate delivery to the liver, hepatic glucose production may be impaired and a female using insulin may be predisposed to hypoglycemia
Although it is unknown if there is any deleterious effect on fetal development with hypoglycemia, for a variety of reasons, hypoglycemia should be avoided as much as possible

Chronic Kidney Disease

Patients with renal insufficiency are susceptible to hypoglycemia, particularly those using insulin⁵⁵
- Risk of hypoglycemia is exacerbated by several mechanisms, including impaired renal gluconeogenesis, reduced clearance by the kidney of insulin or certain insulin secretagogues (eg, glyburide), defective insulin degradation due to uremia, and in more advanced stages of uremia, decreased caloric intake⁵⁶
Additional measures to limit risk of hypoglycemia may be warranted in patients with advanced kidney disease, such as:
- Relaxing glycemic control (ie, raising hemoglobin A1C targets)
- Reducing doses of insulin and/or eliminating drugs that are renally cleared, especially sulfonylureas^57,58

Physical Activity/Exercise

Engaging in physical activity increases hypoglycemia, particularly in type 1 diabetes
Several factors affect glycemic control during exercise in patients with diabetes including:
- Insulin delivery method
- Amount of insulin on board
- Blood glucose level before exercise
- Composition of the meal before exercise
- Type, duration, and intensity of exercise⁵⁹
Various approaches to prevent or limit hypoglycemia include:
- Increasing carbohydrate intake before or during exercise
- Reducing basal insulin
- Reducing bolus insulin for the meal before exercise
- Suspending basal insulin delivered from an insulin pump altogether^60,61,62
Ideal approach must be individualized based on all of these factors, and determining the most effective can take an extended period of trial and error
- Use of hybrid closed-loop automated insulin delivery system may attenuate exercise-induced decreases in plasma glucose level and limit glycemic variability in patients with type 1 diabetes⁶³

Follow-up

Monitoring

Frequent glucose monitoring is imperative for assessing therapy and detecting hypoglycemia, especially in patients with type 1 diabetes or any patient treated with insulin
Desired frequency of monitoring depends upon several factors including:
- Type of diabetes (type 1 usually requires higher frequency than type 2)
- Use of medications that are associated with hypoglycemia (see Table 4)
- Comorbid conditions
- Presence of hypoglycemia unawareness
- Degree of glycemic variability
- Occupational hazards
Glucose measurement tools include home glucose monitors (ie, "glucometers" using fingersticks) and continuous glucose monitors (or "sensors")
- CGM (continuous glucose monitoring) devices may be used in real time (ie, continuous readouts) or require intermittent scanning
Patients with nocturnal or asymptomatic hypoglycemia may benefit from a safety standpoint by using real-time CGM devices, because most will identify hypoglycemic events without direct action and alert the patient (or family) via alarms
Patients who may not benefit from CGM include those who have difficulty operating technology, those who are not committed to wearing the device, or those who do not have the capability to understand and act on the data provided. Occasionally, a patient may note significant discrepancy between the CGM readings and fingerstick results, calling into question the utility of such devices (assuming the fingerstick readings are correct)
- Systematic reviews of CGM that pool data from heterogeneous studies do not consistently show reduced rates of hypoglycemia or time spent in hypoglycemia.⁶⁴ However, individual randomized controlled trials of patients with type 1 diabetes with hypoglycemic unawareness, nocturnal hypoglycemia, or frequent severe hypoglycemia show lower rates of hypoglycemia in patients who monitor glucose using CGM devices versus those using a glucometer^65,66,67
Analysis of CGM data can be complex, and interpretation of glucose patterns and subsequent decisions regarding changes in drug therapy, insulin dosing, or behavior requires significant expertise

Complications

Most common sequelae of severe episodes of hypoglycemia are injury during falls, or motor vehicle accidents
When episode is severe and prolonged, brain injury or seizures may occur
Hypoglycemia may also trigger tachyarrhythmias and bradyarrhythmias⁶⁸ and also myocardial injury to the point of myocardial infarction, each of which can be potentially lethal
Recurrent episodes may render the autonomic nervous system dysfunctional, such that repeat episodes do not induce the usual adrenergic symptoms ("hypoglycemia unawareness"³). In a vicious cycle, this may beget further hypoglycemia

Prognosis

Patients with mild hypoglycemia, even if frequent, do not appear to be at risk for increased mortality or other complications^69,70
Patients with severe hypoglycemia, especially when frequent, are at risk for both cardiovascular events and morality^69,70
- It is less clear if such a relationship is cause and effect or if recurrent hypoglycemia merely identifies people who are more vulnerable due to other medical conditions or less optimal self-management habits

Referral

Any patient with diabetes who has recurrent, significant hypoglycemia should be managed by an endocrinologist and/or a certified diabetes educator to fine-tune the treatment regimen to minimize future occurrences

Screening and Prevention

Screening

At each office visit, patients at risk should be queried about symptomatic and asymptomatic episodes of hypoglycemia. Data from fingerstick blood glucose meter outputs/downloads should be reviewed
Patients with very low hemoglobin A1c values who are using insulin or insulin secretagogues will frequently experience hypoglycemia, which may be asymptomatic⁷¹
If available, review CGM (continuous glucose monitoring) outputs/downloads to assess for time in range (ie, time spent with interstitial glucose, 70-180 mg/dL) and rates of hypoglycemia (time below range)
- Target is less than 4% (or less than 1 hour per day) for below 70 mg/dL (3.9 mmol/L) and less than 1% (or less than 15 minutes per day) for below 54 mg/dL (less than 3.0 mmol/L)³¹
- If a patient is at high risk for hypoglycemia, these targets may be too high and a preferable goal may be less than 1% for below 70 mg/dL (3.9 mmol/L)³¹

Prevention

Structured diabetes patient education is critical for preventing hypoglycemia⁷²
Key topics for patient education include informing them of situations that increase their risk of hypoglycemia, such as during certain illnesses when oral intake is curtailed, fasting for medical testing or religious holidays, with delayed meals, after drinking alcohol, during and after intense exercise, and while oversleeping²⁷

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