Causes of Hypoglycemia
Hypoglycemia is primarily caused by medications used to treat diabetes (particularly insulin, sulfonylureas, and meglitinides), but can also result from various clinical, biological, and social factors that disrupt the balance between glucose production and utilization. 1
Medication-Related Causes
Diabetes Medications
- Insulin therapy: Highest risk, especially intensive insulin regimens 1
- Sulfonylureas (e.g., glyburide, glipizide): Second highest risk 2, 3
- Meglitinides (e.g., repaglinide): Similar mechanism to sulfonylureas 4
Non-Diabetes Medications
- Beta-blockers: Can mask hypoglycemic symptoms and impair recovery 1
- Alcohol: Impairs gluconeogenesis 1
- Salicylates: Can potentiate hypoglycemic effects of other medications 5
- Pentamidine, quinine, and disopyramide: Less common but significant causes 5
Clinical and Biological Risk Factors
Major Risk Factors
- Recent (within 3-6 months) moderate or severe hypoglycemia 1
- Impaired hypoglycemia awareness 1
- End-stage kidney disease 1
- Cognitive impairment or dementia 1
Other Clinical Risk Factors
- Age ≥75 years 1
- Female sex 1
- High glycemic variability 1
- Polypharmacy 1
- Cardiovascular disease 1
- Chronic kidney disease (eGFR <60 mL/min/1.73 m² or albuminuria) 1
- Neuropathy 1
- Retinopathy 1
- Major depressive disorder 1
- Severe mental illness 1
Social, Cultural, and Economic Risk Factors
Major Risk Factors
- Food insecurity 1
- Low-income status 1
- Housing insecurity 1
- Fasting for religious or cultural reasons 1
- Underinsurance 1
Other Social Risk Factors
Rare and Endocrine Causes
- Insulinoma: Tumor of pancreatic beta cells producing excess insulin 6
- Post-bariatric surgery hypoglycemia: Altered gut hormone secretion after weight loss surgery 7
- Autoimmune hypoglycemia: Antibodies against insulin or insulin receptors 6
- Non-islet cell tumor hypoglycemia: Large tumors producing IGF-2 6
- Adrenal insufficiency: Cortisol deficiency impairs gluconeogenesis 6
- Hypopituitarism: Multiple hormone deficiencies affecting glucose regulation 6
- Genetic disorders: Congenital hyperinsulinism, glycogen storage diseases, fatty acid oxidation disorders 6
Situational Triggers
- Skipped or delayed meals 4
- Intense exercise without adequate carbohydrate intake 1
- Sleep (nocturnal hypoglycemia) 1
- Critical illness 1
- Reduced caloric intake during illness 3
Pathophysiological Mechanisms
Hypoglycemia occurs when glucose counterregulatory mechanisms fail. These mechanisms include:
- Decreased insulin secretion
- Increased glucagon release
- Increased epinephrine secretion
- Cortisol and growth hormone release
In diabetes, these mechanisms are often impaired, leading to defective glucose counterregulation and hypoglycemia unawareness, creating a vicious cycle of recurrent hypoglycemia 8.
Clinical Pearls
- Always consider hypoglycemia in any patient with altered mental status, especially those on diabetes medications 5
- Recurrent hypoglycemia can lead to hypoglycemia unawareness, making future episodes more dangerous 1
- Kidney and liver disease significantly increase hypoglycemia risk due to impaired drug clearance and reduced gluconeogenesis 3
- The combination of insulin with sulfonylureas substantially increases hypoglycemia risk 1
- Elderly patients may not recognize hypoglycemic symptoms, making detection more difficult 1
Understanding these causes and risk factors is essential for preventing hypoglycemia, which can lead to significant morbidity and mortality, especially in vulnerable populations.