Causes of Hypoglycemia
Hypoglycemia is primarily caused by medications (particularly insulin and sulfonylureas), endocrine disorders, critical illness, and nutritional factors, with medication-related causes being the most common in clinical practice. 1
Medication-Related Causes
- Insulin therapy is the most common cause of hypoglycemia, especially intensive insulin regimens with multiple daily injections or insulin pumps 1, 2
- Sulfonylureas and meglitinides stimulate insulin release and can cause prolonged hypoglycemia 3, 1
- Combining insulin and sulfonylureas further increases hypoglycemia risk 3
- Non-diabetes medications that can cause hypoglycemia include NSAIDs, analgesics, antibacterials, antimalarials, antiarrhythmics, and antidepressants 4
Clinical and Biological Risk Factors
- Recent severe hypoglycemia (within past 3-6 months) is a major risk factor 3, 1
- Impaired hypoglycemia awareness (reduced ability to perceive warning symptoms) significantly increases risk 3, 1
- End-stage kidney disease increases risk due to decreased renal gluconeogenesis and impaired insulin clearance 3, 5
- Cognitive impairment or dementia limits ability to recognize or respond to 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 risk 3, 1
- Chronic kidney disease (eGFR <60 mL/min/1.73 m² or albuminuria) reduces renal glucose production 3, 5
- Cardiovascular disease is associated with increased risk 3, 1
- Neuropathy and retinopathy are associated risk factors 3, 1
- Major depressive disorder and severe mental illness increase risk 3, 1
Endocrine and Metabolic Causes
- Adrenal insufficiency with cortisol deficiency impairs counterregulatory responses 5, 6
- Insulinoma (insulin-secreting tumor) can cause spontaneous hypoglycemia 2, 7
- Defective glucose counterregulation due to failure of decreasing insulin and increasing counterregulatory hormones 6, 7
Social, Cultural, and Economic Risk Factors
- Food insecurity with irregular access to adequate nutrition 3, 1
- Low-income status with limited resources for proper diabetes management 3, 1
- Housing insecurity affecting medication adherence and meal timing 3, 1
- Fasting for religious or cultural reasons leading to prolonged periods without food 3, 1
- Underinsurance limiting access to appropriate medications and monitoring supplies 3
Hospital-Specific Risk Factors
- Interruptions in nutritional intake (NPO status, delayed meals) 1, 5
- Changes in medication regimens (new drugs or altered dosing) 1
- Critical illness with altered metabolism and increased insulin resistance 1, 5
- Sepsis with dysregulated glucose metabolism 1, 5
- Low albumin levels affecting drug binding and pharmacokinetics 1, 5
Physiological Mechanisms
- In healthy individuals, decreasing insulin and increasing glucagon and epinephrine prevent hypoglycemia 7
- In diabetes, especially type 1 and advanced type 2, this counterregulatory system is compromised 6, 7
- Hypoglycemia-associated autonomic failure occurs when recent hypoglycemia impairs future counterregulatory responses, creating a vicious cycle 7
Clinical Implications
- Hypoglycemia can cause cognitive impairment, accidents, falls, cardiac complications (arrhythmias, myocardial ischemia), and potentially permanent neurological damage 8
- Fear of hypoglycemia often prevents optimal glycemic control 9, 8
- Recurrent hypoglycemia can lead to hypoglycemia unawareness, further increasing risk 7
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
- Continuous glucose monitoring can help identify patterns of hypoglycemia, especially in high-risk populations 5