Drug-Induced Hypoglycemia

Definition and EtiologyTop

Drug-induced hypoglycemia is a plasma glucose level <3.9 mmol/L (70 mg/dL) regardless of symptoms of hypoglycemia. Symptoms may first appear in patients with lower blood glucose levels (eg, in those with long-standing well-controlled type 1 diabetes mellitus (DM) [hypoglycemia unawareness]) or in patients with blood glucose levels still >5.6 mmol/L (100 mg/dL) when the level has rapidly decreased, that is, in relative hypoglycemia.

Hypoglycemia is an important treatment-related complication of DM. Repeated episodes of hypoglycemia increase the risk of cardiovascular and all-cause mortality and hypoglycemia unawareness in diabetes.

Causes:

1) An excessively high dose of antidiabetic therapy (insulin, sulfonylureas, or meglitinides) in relation to food intake and physical activity levels.

2) Impaired physiologic mechanisms preventing hypoglycemia recognition, such as in autonomic dysfunction.

3) Decreased insulin or medication clearance, such as in patients with renal impairment.

4) Decreased endogenous glucose production (eg, after alcohol intake or in hepatic dysfunction).

5) Increased insulin sensitivity (eg, after a decrease in body weight, as a delayed effect of exercise, or as a result of improved diabetes control).

6) Erratic glucose control, such as in gastroparesis associated with diabetes and in patients with associated adrenal insufficiency.

Caution: The risk of hypoglycemia is increased in patients in whom intensive insulin therapy is used to achieve normalization of blood glucose levels and glycated hemoglobin levels (HbA1c) <7.0%. Episodes of hypoglycemia are less frequent in patients with type 2 DM, even in those receiving intensive insulin therapy.

Hypoglycemia classification:

1) Level 1: Blood glucose levels <3.9 mmol/L (70 mg/dL) and ≥3.0 mmol/L (54 mg/dL).

2) Level 2: Blood glucose levels <3.0 mmol/L (54 mg/dL), sufficiently low to indicate serious, clinically important hypoglycemia.

3) Level 3 (defined by symptoms): A severe event characterized by altered mental and/or physical status requiring assistance of a third party for recovery. Repeated level 3 hypoglycemia may cause cognitive impairment in the long term.

Clinical Features and DiagnosisTop

1. Clinical features:

1) Autonomic symptoms: Dizziness, blurred vision, pallor, hunger, nausea, lightheadedness, palpitations, tremor, hunger, anxiety, and profuse perspiration are caused by sympathetic and vagal stimulation. These develop in patients with blood glucose levels of ~3.0 mmol/L (54 mg/dL).

2) Neuroglycopenic symptoms: Confusion, somnolence, dysarthria, abnormal coordination, atypical behavior, visual disturbances, migrant paresthesia, seizures, loss of consciousness, coma, and death. These symptoms may develop in patients with blood glucose levels <2.8 mmol/L (50 mg/dL), leading to glucose deficit in the central nervous system. They are usually seen in patients with level 3 hypoglycemia.

2. In some patients symptoms and signs of hypoglycemia may be absent despite very low glucose levels. This is referred to as hypoglycemia unawareness. Causes:

1) Autonomic nervous system dysfunction in patients with long-standing DM causes a loss of warning signs related to adrenergic stimulation. This leads to features of neuroglycopenia appearing without warning autonomic symptoms.

2) Other factors that increase the risk of hypoglycemia unawareness include repeated episodes of hypoglycemia, which may require temporary adoption of less stringent criteria of glycemic control, and the use of certain drugs, for example, beta-blockers.

Differential Diagnosis

1. Hypoglycemia caused by other factors: Insulinoma and other nondiabetic causes of hypoglycemia.

2. Loss of consciousness caused by other conditions: Coma in the course of DM (see Diabetic Ketoacidosis), syncope, epilepsy.

TreatmentTop

Acute Treatment

1. Level 1 and 2 hypoglycemia (conscious patients): Intake of fast-acting carbohydrates should be recommended at a blood glucose alert value of 3.9 mmol/L (70 mg/dL). Glucose (10-15 g) is the preferred treatment, although any foods or fluids that contain glucose (fruit juice, hard candy bar) will raise blood glucose levels; this may be repeated as necessary. Ingestion of fatty foods may delay and then prolong acute glycemic response. Subsequently, the patient should consume a meal or snack with complex (long-lasting) carbohydrates and added fat to prevent recurrent hypoglycemia (eg, bread, potatoes, cereal, nuts, peanuts). All patients, and particularly patients using insulin pumps or treated with insulin analogues as part of an intensive insulin therapy regimen, should consume 15 g of glucose and measure their blood glucose level after 15 minutes (the 15/15 rule; see Diabetes Mellitus); this should be repeated in case of persistent hypoglycemia. Glucagon should be prescribed for all individuals with level 2 hypoglycemia to have it available if needed.

2. Level 3 hypoglycemia (unconscious or impaired patients): In patients with altered mental status or those unable or unwilling to consume carbohydrates by mouth, administer 20% glucose (dextrose) IV solution (0.2 g of glucose/kg, even up to 80-100 mL of the solution; in Canada up to 50 mL of a 50% glucose solution is used), followed by an IV infusion of a 10% glucose solution until the mental status improves and the patient is able to tolerate oral carbohydrates.

In case of level 3 hypoglycemia in patients with DM in whom it is difficult to establish IV access, administer glucagon 0.5 to 1 mg as an IM or subcutaneous injection; if there is no improvement, repeat the injection after 10 minutes. There is a new intranasal formulation of glucagon available, called Baqsimi, which can also be used for level 3 out-of-hospital hypoglycemic episodes by care providers. Glucagon should be used with caution in patients with type 2 diabetes. Do not use glucagon in patients with hypoglycemia caused by sulfonylureas (as it may paradoxically stimulate the secretion of endogenous insulin and worsen the hypoglycemic episode). Glucagon is also contraindicated in patients with recent alcohol use.

Long-Term Management

1. Assess the risk of recurrence: Hypoglycemia caused by long-acting sulfonylureas, intermediate-acting insulins, or long-acting insulin analogues may recur even after 16 to 20 hours (particularly in patients with impaired renal function). When using premixed insulins, note that they have 2 peaks of action (one after 2-4 h and another after 8-12 h). As older patients are at increased risk of hypoglycemia due to age-related reduction in glucagon secretion along with impaired awareness of symptoms, the use of premixed insulin pens as well as assistance with insulin administration and more frequent glucose monitoring (including continuous glucose monitoring or flash glucose monitoring) can help reduce this risk.

2. Driving: Patients are recommended to measure their blood glucose level before driving when on insulin, an insulin secretagogue, or both. For private driving, the blood glucose level should be ≥5.0 mmol/L and for commercial driving, ≥6.0 mmol/L. Patients should not drive if their blood glucose level is <5.0 mmol/L and should wait ≥40 minutes after successfully correcting their hypoglycemia. Drivers should measure their blood glucose every 4 hours while driving or should wear a continuous glucose monitor.

Diabetes Canada recommends that health-care providers notify the driving licensing body if a patient has had a severe hypoglycemic episode while driving in the past 12 months or if they have had >1 episodes of severe hypoglycemia while awake but not driving in the past 6 months for private drivers and in the past 12 months for commercial drivers. Health-care providers should refer to their local driving licensing body for specific reporting requirements in their region.

3. Assess the frequency and time of occurrence of hypoglycemia and adjust treatment of DM appropriately:

1) Hypoglycemia occurring at a specified time: Adjust nutrition management and insulin doses.

2) Hypoglycemia occurring at irregular intervals: Identify and address the causes, including irregular meals, inappropriate or variable insulin injection techniques and administration, lipohypertrophy, variable intensity of exercise, alcohol use, gastric motility disorders, gastroparesis, and variable rates of carbohydrate absorption from the gastrointestinal tract.

3) Hypoglycemia unawareness: Adjust treatment to reduce the incidence of episodes of hypoglycemia for ≥3 months. Educate patients and their caregivers or family members on how to recognize the less typical prodromal symptoms of hypoglycemia. Consider the use of a continuous glucose monitoring system or flash glucose monitoring system. Consider the risk of hypoglycemia unawareness at work or when driving. Patients with hypoglycemia unawareness and level 2 hypoglycemia should be advised to raise their glycemic targets for several weeks. This may prevent hypoglycemia and partially reverse hypoglycemia unawareness. Hypoglycemia unawareness or repeated level 3 hypoglycemia should prompt reevaluation of the patient’s treatment regimen.

4. Assess chronic sequelae of hypoglycemia, such as cognitive impairment.