What are the considerations for administering glucagon injection to an adult patient with diabetes mellitus (DM) taking sulfonylurea (e.g. glyburide) who is at risk for hypoglycemia?

Glucagon Administration in Sulfonylurea-Treated Patients

Glucagon should be prescribed to all adult patients with diabetes taking sulfonylureas who are at increased risk of severe hypoglycemia, particularly those aged 65 years or older, those with chronic kidney disease (GFR ≤30 mL/min/1.73 m²), or those with a history of severe hypoglycemia. 1

Risk Stratification for Glucagon Prescription

High-Risk Criteria Requiring Glucagon Prescription

Patients on sulfonylureas meeting ANY of the following criteria should receive a glucagon prescription:

• Age ≥65 years (3-fold increased risk of hypoglycemia) 2
• Chronic kidney disease with GFR ≤30 mL/min/1.73 m² (3.6-fold increased risk) 2
• Previous episode of Level 2 hypoglycemia (glucose <54 mg/dL) 1
• Any episode of Level 3/severe hypoglycemia (requiring external assistance) 1
• Hypoglycemia unawareness 1
• Concurrent use of intermediate- or long-acting insulin (3-fold increased risk) 2
• Irregular eating habits or living alone 3
• Multiple comorbidities or frailty 1

Sulfonylurea-Specific Considerations

Glyburide should be avoided entirely in older adults due to its longer duration of action and higher hypoglycemia risk. 1 If a sulfonylurea must be used, shorter-acting agents like glipizide, glimepiride, or gliclazide are preferred as they carry lower hypoglycemia risk. 1

The overall incidence of hypoglycemia in hospitalized patients on sulfonylureas is approximately 19%, with glyburide having the highest rate at 22%. 2

Glucagon Dosing and Administration

For Severe Hypoglycemia Treatment

Adults and patients weighing >25 kg or ≥6 years:

• Administer 1 mg (1 mL) subcutaneously, intramuscularly (upper arm, thigh, or buttocks), or intravenously 4
• If no response after 15 minutes, administer an additional 1 mg dose using a new kit while waiting for emergency assistance 4

Pediatric patients weighing <25 kg or <6 years:

• Administer 0.5 mg (0.5 mL) by the same routes 4
• Repeat 0.5 mg dose after 15 minutes if no response 4

Critical Post-Administration Steps

1. Call emergency services immediately after administering glucagon 4
2. Once patient can swallow, provide oral carbohydrates to restore liver glycogen and prevent recurrence 4
3. Trigger immediate medication regimen reevaluation after any Level 2 or Level 3 hypoglycemic episode 1, 5

Mechanism and Effectiveness in Sulfonylurea-Induced Hypoglycemia

Glucagon works by stimulating hepatic glucose production, which is effective even in sulfonylurea-induced hypoglycemia. 6 Unlike insulin-induced hypoglycemia where hepatic glycogen stores may be depleted, sulfonylurea-induced hypoglycemia results from excessive endogenous insulin secretion, making glucagon particularly effective. 3

Important caveat: Sulfonylurea-induced hypoglycemia can be prolonged due to the drugs' long half-lives, particularly with glyburide and chlorpropamide. 3 Patients may require repeated glucagon doses or prolonged carbohydrate administration even after initial recovery. 4

Patient and Caregiver Education Requirements

All patients prescribed glucagon must receive comprehensive training:

• Caregivers, family members, and household contacts should know the location of glucagon and how to administer it 1
• Glucagon administration is not limited to healthcare professionals 1
• Patients should inform those around them about their glucagon prescription and hypoglycemia risk 4
• Review signs and symptoms of severe hypoglycemia at every clinical encounter 1, 7

Alternative Formulations

Intranasal glucagon represents a major advancement, being as effective as injectable glucagon while eliminating technical difficulties associated with reconstitution and injection. 6 This formulation may improve caregiver confidence and treatment success rates, particularly in non-medical settings.

When to Consider Stopping Sulfonylureas

Strongly consider discontinuing sulfonylurea therapy in patients with:

• Documented hypoglycemia episodes despite dose reduction 1
• HbA1c significantly below individualized target (suggesting overtreatment) 8
• Progressive renal impairment (GFR declining toward 30 mL/min/1.73 m²) 2
• Development of hypoglycemia unawareness 1

Switch to non-hypoglycemic medication classes (metformin, GLP-1 receptor agonists, SGLT2 inhibitors, DPP-4 inhibitors, or TZDs) when feasible. 1

Common Clinical Pitfalls

• Continuing maximum-dose sulfonylureas in poorly controlled patients rather than transitioning to insulin therapy represents misuse 9
• Combining sulfonylureas with insulin without clear benefit increases hypoglycemia risk without improving control 2, 9
• Failing to prescribe glucagon prophylactically in high-risk patients, waiting until after a severe event occurs 1
• Not adjusting sulfonylurea doses in patients with declining renal function, as both parent drugs and active metabolites accumulate 3, 2