Causes of Hypoglycemia
Hypoglycemia is primarily caused by medications, particularly insulin and sulfonylureas, as well as endocrine disorders, critical illness, and nutritional factors. 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 (especially chlorpropamide and glyburide) and meglitinides stimulate insulin release and are major causes of hypoglycemia 1, 3
- Combination therapy with insulin and sulfonylureas further increases hypoglycemia risk 2
- Other medications that can cause hypoglycemia include alcohol, propranolol, salicylates, quinine, pentamidine, ritodrine, and disopyramide 4
Clinical and Biological Risk Factors
- Recent history of severe hypoglycemia (within past 3-6 months) significantly increases risk of future episodes 2, 1
- Impaired hypoglycemia awareness (reduced ability to perceive warning symptoms) creates a vicious cycle of recurrent hypoglycemia 1, 5
- End-stage kidney disease increases risk due to:
- Cognitive impairment or dementia increases risk due to inability to recognize or respond to hypoglycemic symptoms 2, 1
- Age ≥75 years is a major risk factor as elderly patients have:
- Female sex is associated with higher hypoglycemia risk 2, 1
- High glycemic variability increases risk 2, 1
- Chronic kidney disease (eGFR <60 mL/min/1.73 m²) reduces renal glucose production 2, 6
- Cardiovascular disease is a risk factor 2, 1
- Neuropathy and retinopathy are associated with increased hypoglycemia risk 2, 1
- Major depressive disorder increases risk 2, 1
Social, Cultural, and Economic Risk Factors
- Food insecurity (irregular access to adequate nutrition) is a major risk factor 2, 1
- Low-income status limits resources for proper diabetes management 2, 1
- Housing insecurity affects medication adherence and meal timing 2, 1
- Fasting for religious or cultural reasons creates prolonged periods without food 2
- Underinsurance limits access to appropriate diabetes care 2
- Low health literacy impairs understanding of hypoglycemia prevention 2
- Alcohol or substance use disorder increases risk (alcohol inhibits gluconeogenesis) 2, 1
Hospital-Specific Risk Factors
- Interruptions in nutritional intake (NPO status, delayed meals) are common in hospitals 2
- Changes in medication regimens during hospitalization 2
- Critical illness alters metabolism and increases insulin resistance 2, 1
- Sepsis dysregulates glucose metabolism 2, 1
- Low albumin levels alter drug binding and pharmacokinetics 2
- Polypharmacy increases risk of drug interactions 2
Non-Diabetic Causes of Hypoglycemia
- Insulinoma (insulin-secreting pancreatic tumor) 7, 8
- Post-bariatric surgery hypoglycemia 7, 8
- Non-islet cell tumor hypoglycemia (NICTH) caused by Big-IGF2 secretion 8
- Autoimmune hypoglycemia (antibodies against insulin or insulin receptors) 8
- Adrenal insufficiency (cortisol deficiency) 8
- Hypopituitarism 8
- Genetic disorders:
- Monogenic congenital hyperinsulinism
- Inborn errors of metabolism
- Glycogen storage disorders 8
- Factitious/surreptitious hypoglycemia (deliberate insulin or sulfonylurea administration) 8
Classification of Hypoglycemia
- Level 1: Glucose <70 mg/dL (<3.9 mmol/L) and ≥54 mg/dL (≥3.0 mmol/L) 2
- Level 2: Glucose <54 mg/dL (<3.0 mmol/L) 2
- Level 3: Severe event characterized by altered mental/physical status requiring assistance for treatment, irrespective of glucose level 2
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, 5
- Short-term avoidance of hypoglycemia (2-3 weeks) can reverse hypoglycemia unawareness in most affected patients 5
- Understanding these causes is essential for preventing hypoglycemia, which is associated with increased morbidity and mortality, particularly in hospitalized and elderly patients 2, 1