Causes of Persistent Hypoglycemia
Persistent hypoglycemia is primarily caused by medications (especially insulin and sulfonylureas), endocrine disorders, advanced chronic kidney disease, critical illness, and nutritional factors. 1
Medication-Related Causes
- Insulin therapy is the most common cause of hypoglycemia, particularly with intensive insulin regimens using multiple daily injections or insulin pumps 1, 2
- Sulfonylureas and meglitinides stimulate insulin release and can cause prolonged hypoglycemia, especially first-generation sulfonylureas 1, 3
- Medication errors including accidental mix-ups between insulin products or inappropriate dosing can lead to severe hypoglycemia 2
- Changes in insulin regimen (strength, manufacturer, type, injection site) can predispose to hypoglycemia 2
Disease-Related Causes
Kidney Disease
- Advanced chronic kidney disease significantly increases risk for persistent hypoglycemia due to:
Endocrine Disorders
- Insulinoma (insulin-producing pancreatic tumor) causes fasting hypoglycemia with inappropriate insulin secretion 5, 6
- Non-islet cell tumors producing IGF-2 (NICTH syndrome) with low insulin and C-peptide levels 5
- Adrenal insufficiency with cortisol deficiency impairs counterregulatory responses 1, 7
- Hypopituitarism affecting multiple hormone axes 5
Autoimmune Causes
- Antibodies against insulin (HIRATA syndrome), especially in patients with Graves' disease 5
- Antibodies against insulin receptors 5
Genetic Causes
- Monogenic congenital hyperinsulinism (activating mutations of glucokinase gene) 5
- Inborn errors of metabolism that persist into adulthood:
Risk Factors and Clinical Contexts
Patient-Specific Risk Factors
- History of severe hypoglycemia in past 3-6 months 1
- Impaired hypoglycemia awareness (reduced ability to perceive warning symptoms) 4, 1
- Advanced age (≥75 years) with reduced counterregulatory hormone responses 1
- Cognitive impairment or dementia limiting ability to recognize or respond to symptoms 1
- High glycemic variability 1
- Cardiovascular disease 1
- Diabetic neuropathy and retinopathy 1
Hospital-Specific Risk Factors
- Interruptions in nutritional intake (NPO status, delayed meals) 4, 1
- Critical illness with altered metabolism 4, 8
- Sepsis with dysregulated glucose metabolism 1, 8
- Low albumin levels affecting drug binding and pharmacokinetics 1
- Acute kidney injury (important risk factor for in-hospital hypoglycemia) 4
Social and Nutritional Factors
- Food insecurity with irregular access to adequate nutrition 1
- Alcohol consumption (especially with insufficient food intake) 3, 5
- Fasting for religious or cultural reasons 1
Special Considerations
- Recurrent hypoglycemia creates a vicious cycle by impairing counterregulatory responses, leading to hypoglycemia unawareness and increased risk of future episodes 7
- In patients with diabetes and advanced chronic kidney disease, clinicians should aim to optimize glycemic management while minimizing hypoglycemia 4
- For patients with hypoglycemia unawareness, a 2-3 week period of scrupulous avoidance of hypoglycemia is recommended to restore awareness 7
- Continuous glucose monitoring can help identify patterns of persistent hypoglycemia, especially in high-risk populations like those with advanced kidney disease 4
Clinical Pitfalls to Avoid
- Failing to adjust insulin doses in patients with declining kidney function 4
- Not recognizing that hypoglycemic symptoms may be atypical or absent in patients with autonomic neuropathy or recurrent hypoglycemia 4, 7
- Overlooking multifactorial causes of hypoglycemia, especially in hospitalized, underfed elderly patients with severe illness 5, 6
- Continuing the same insulin regimen when nutrition is interrupted in hospitalized patients 4
- Not investigating for insulinoma or other rare causes when hypoglycemia persists despite appropriate medication adjustments 5