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 and meglitinides are oral antidiabetic agents that stimulate insulin release and can cause hypoglycemia 3, 1
- Other medications that can cause hypoglycemia include:
- NSAIDs, analgesics, antibacterials (particularly sulfa antibiotics), antimalarials 4
- Antiarrhythmics, antidepressants (especially monoamine oxidase inhibitors and SSRIs) 2
- ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic blockers 2
- Pentamidine, disopyramide, fibrates, fluoxetine, propoxyphene 2
Clinical and Biological Risk Factors
- Recent history of severe hypoglycemia (within past 3-6 months) is a significant predictor of future episodes 3, 1
- Impaired hypoglycemia awareness (reduced ability to perceive warning symptoms) is a major risk factor 3, 5
- End-stage kidney disease increases risk due to decreased renal gluconeogenesis and impaired insulin clearance 3, 1
- Cognitive impairment or dementia increases risk due to inability to recognize or respond to hypoglycemic symptoms 3, 1
- Advanced age (≥75 years) is associated with reduced counterregulatory hormone responses 3, 1
- Female sex has been identified as a risk factor 3, 1
- High glycemic variability increases hypoglycemia risk 3, 1
- Chronic kidney disease (eGFR <60 mL/min/1.73 m²) reduces renal glucose production 3, 1
- Cardiovascular disease is associated with increased hypoglycemia risk 3, 1
- Autonomic neuropathy impairs counterregulatory responses 2, 5
- Alcohol consumption inhibits gluconeogenesis 2
Endocrine and Metabolic Causes
- Insulinoma (insulin-producing pancreatic tumor) 6
- Post-bariatric surgery hypoglycemia 6
- Non-insulinoma pancreatogenous hypoglycemia syndrome 6
- Autoimmune hypoglycemia syndrome (associated with high levels of insulin antibodies) 6
- Hormonal deficiencies (adrenal insufficiency, hypopituitarism) 1, 6
Social, Cultural, and Economic Risk Factors
- Food insecurity leads to irregular access to adequate nutrition 3, 1
- Low-income status limits resources for proper diabetes management 3, 1
- Housing insecurity affects medication adherence and meal timing 3, 1
- Fasting for religious or cultural reasons creates prolonged periods without food 3, 1
- Underinsurance limits access to appropriate medications and monitoring supplies 3
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 alters metabolism and increases insulin resistance 1
- Sepsis causes dysregulated glucose metabolism 1
- Low albumin levels alter drug binding and pharmacokinetics 1
Hypoglycemia Classification
- Level 1: Blood glucose <70 mg/dL (3.9 mmol/L) and ≥54 mg/dL (3.0 mmol/L) 3
- Level 2: Blood glucose <54 mg/dL (3.0 mmol/L) 3
- Level 3: Severe event characterized by altered mental and/or physical status requiring assistance for treatment, irrespective of glucose level 3
Clinical Implications
- Hypoglycemia can cause cognitive impairment, accidents, falls, and in severe cases, death 3, 7
- Recurrent hypoglycemia can lead to hypoglycemia unawareness, creating a vicious cycle of further episodes 5, 7
- Fear of hypoglycemia may lead to defensive behaviors that result in suboptimal glycemic control 7
- Hypoglycemia is associated with increased risk of cardiovascular events and mortality 7, 6
Understanding these causes is essential for preventing hypoglycemia, which significantly impacts morbidity, mortality, and quality of life, particularly in patients with diabetes and other high-risk conditions.