What causes hypoglycemia?

Causes of Hypoglycemia

Hypoglycemia is primarily caused by medications (particularly insulin and sulfonylureas), with other major causes including endocrine disorders, critical illness, and nutritional factors that create an imbalance between insulin levels and glucose availability. 1

Medication-Related Causes

• Insulin therapy is the most common risk factor for hypoglycemia, especially intensive insulin regimens with multiple daily injections or insulin pumps 1, 2
• Sulfonylureas and meglitinides are oral antidiabetic agents that stimulate insulin release and can cause hypoglycemia 1
• Other medications that may induce hypoglycemia include:
  • NSAIDs, analgesics, antibacterials, antimalarials
  • Antiarrhythmics and antidepressants
  • These drugs may stimulate insulin release, reduce insulin clearance, or interfere with glucose metabolism 3

Clinical and Biological Risk Factors

Major Risk Factors

• Recent history of severe hypoglycemia (within past 3-6 months) 1
• Impaired hypoglycemia awareness - reduced ability to perceive warning symptoms 1
• End-stage kidney disease - decreased renal gluconeogenesis and impaired insulin clearance 1
• Cognitive impairment or dementia - inability to recognize or respond to hypoglycemic symptoms 1

Other Risk Factors

• Age ≥75 years - elderly patients have reduced counterregulatory hormone responses 1
• Female sex 1
• High glycemic variability 1
• Chronic kidney disease (eGFR <60 mL/min/1.73 m²) - reduces renal glucose production 1
• Cardiovascular disease 1
• Neuropathy and retinopathy 1
• Major depressive disorder 1

Physiological and Pathological Causes

• Impaired counterregulatory hormone responses:

  • Deficient glucagon release during hypoglycemia
  • Reduced epinephrine response
  • These defects are particularly common in long-standing diabetes 4

• Spontaneous hypoglycemia (non-iatrogenic):

  • Insulinoma - insulin-secreting pancreatic tumor
  • Post-bariatric surgery hypoglycemia - altered gut hormone secretion
  • Non-islet cell tumor hypoglycemia - tumors producing IGF-2 5, 6
  • Autoimmune hypoglycemia - antibodies against insulin or insulin receptors 6

• Endocrine deficiencies:

  • Adrenal insufficiency
  • Hypopituitarism
  • Growth hormone deficiency 5

Social, Cultural, and Economic Risk Factors

• Food insecurity - irregular access to adequate nutrition 1
• Low-income status - limited resources for proper diabetes management 1
• Housing insecurity - unstable living conditions affecting medication adherence and meal timing 1
• Fasting for religious or cultural reasons - prolonged periods without food 1
• Alcohol or substance use disorder - alcohol inhibits gluconeogenesis 1

Hospital-Specific Risk Factors

• Interruptions in nutritional intake - NPO status, delayed meals 1
• Changes in medication regimens - new drugs or altered dosing 1
• Critical illness - altered metabolism and increased insulin resistance 1
• Sepsis - dysregulated glucose metabolism 1
• Low albumin levels - altered drug binding and pharmacokinetics 1

Genetic Causes

• Monogenic disorders:
  • Congenital hyperinsulinism
  • Glucokinase-activating gene mutations
  • Inborn errors of metabolism affecting glycogen storage or fatty acid oxidation 6

Prevention Considerations

• Hypoglycemia risk assessment should be performed at every clinical encounter for patients on insulin or insulin secretagogues 1
• Prior episodes of hypoglycemia are the strongest predictor of future events 1
• Avoidance of hypoglycemia for 2-3 weeks can help reverse hypoglycemia unawareness in many patients 4

Understanding these causes is essential for preventing hypoglycemia, which is associated with increased morbidity and mortality, particularly in hospitalized and elderly patients 1.