What are the causes of hypoglycemia (low blood sugar) apart from insulin?

Causes of Hypoglycemia Apart from Insulin

Beyond insulin, the most important causes of hypoglycemia include sulfonylureas and meglitinides (insulin secretagogues), acute kidney injury with impaired insulin clearance, nutritional interruptions, adrenal insufficiency, and alcohol consumption—with sulfonylureas being particularly problematic due to their prolonged duration of action. 1, 2, 3, 4

Medication-Related Causes

Sulfonylureas and Meglitinides

• Sulfonylureas (glyburide, glipizide) are capable of producing severe hypoglycemia because they stimulate insulin release in a glucose-independent manner 3, 4, 5
• First-generation sulfonylureas carry especially high risk for prolonged hypoglycemia 2
• These agents increase hypoglycemia risk particularly in elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency 3, 4
• Renal or hepatic insufficiency causes elevated drug levels and diminished gluconeogenic capacity, both increasing serious hypoglycemic reactions 3, 4

Drug Interactions Potentiating Hypoglycemia

• Nonsteroidal anti-inflammatory agents, azoles, salicylates, sulfonamides, chloramphenicol, probenecid, coumarins, monoamine oxidase inhibitors, quinolones, and beta-adrenergic blocking agents can all potentiate sulfonylurea-induced hypoglycemia 4
• Beta-blockers additionally mask hypoglycemia symptoms, making recognition difficult 3, 4

Renal Dysfunction

Acute and Chronic Kidney Disease

• Acute kidney injury is an important risk factor for hospital hypoglycemia, likely due to decreased insulin clearance 1, 2
• Advanced chronic kidney disease significantly increases persistent hypoglycemia risk through multiple mechanisms: decreased renal gluconeogenesis (kidneys normally contribute 20-40% of glucose production), impaired insulin clearance, poor nutritional status, and accumulation of uremic toxins 2, 6
• Reduced insulin degradation by kidney, liver, and muscle due to uremia extends insulin half-life 6
• Insulin requirements typically decrease by 40-50% when patients transition to dialysis 6

Dialysis-Specific Mechanisms

• Increased erythrocyte glucose uptake during hemodialysis creates an additional glucose sink depleting plasma glucose 6
• Glucose-free or low-glucose dialysate significantly increases hypoglycemia risk 6
• Impaired counterregulatory hormone responses result in blunted hormonal responses to falling glucose 6

Endocrine Disorders

Adrenal Insufficiency

• Cortisol deficiency impairs counterregulatory responses to hypoglycemia 2
• Patients with adrenal or pituitary insufficiency are particularly susceptible to hypoglycemic action of glucose-lowering drugs 3, 4

Nutritional and Metabolic Factors

Interruptions in Nutrition

• Nutrition-insulin mismatch is a common preventable source of iatrogenic hypoglycemia, often related to unexpected interruption of nutrition 1
• NPO status, delayed meals, or interrupted enteral/parenteral feedings without corresponding medication adjustment 1, 2
• Reduced oral intake or emesis without medication dose adjustment 1
• Caloric intake deficiency increases hypoglycemia likelihood 3, 4

Alcohol Consumption

• Alcohol ingestion increases hypoglycemia risk, particularly when combined with glucose-lowering medications 3, 4, 7

Food Insecurity

• Irregular access to adequate nutrition increases hypoglycemia risk 2, 8

Hepatic Dysfunction

• Hepatic insufficiency diminishes gluconeogenic capacity and may cause elevated drug levels of glucose-lowering medications 3, 4
• Reduced insulin degradation capacity 6

Exercise-Related Hypoglycemia

• Severe or prolonged exercise increases hypoglycemia risk, especially without carbohydrate adjustment 3, 4
• Physical activity can cause hypoglycemia if medication dose or carbohydrate consumption is not altered 1

Stress and Illness-Related Factors

Critical Illness and Sepsis

• Critical illness with altered metabolism increases hospital hypoglycemia risk 2
• Sepsis causes dysregulated glucose metabolism 2
• Low albumin levels affect drug binding and pharmacokinetics 2

Corticosteroid Withdrawal

• Sudden reduction of corticosteroid dose can induce iatrogenic hypoglycemia 1

High-Risk Patient Populations

Patient-Specific Risk Factors

• History of severe hypoglycemia in past 3-6 months predicts recurrent events 2, 8
• Impaired hypoglycemia awareness (reduced ability to perceive warning symptoms) increases severe hypoglycemia risk 6-20 fold 8
• Advanced age (≥75 years) with reduced counterregulatory hormone responses 2
• Cognitive impairment or dementia limiting ability to recognize or respond to symptoms 2
• High glycemic variability 2
• Cardiovascular disease 2
• Diabetic neuropathy and retinopathy 2

Hemolytic Anemia Risk

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency with sulfonylurea treatment can lead to hemolytic anemia; a non-sulfonylurea alternative should be considered 3, 4
• Hemolytic anemia has been reported in patients without known G6PD deficiency on sulfonylureas 3, 4

Common Clinical Pitfalls to Avoid

• Failing to adjust sulfonylurea or insulin doses in patients with declining kidney function is a critical error 2, 6
• Continuing the same medication regimen when nutrition is interrupted in hospitalized patients 2
• Not recognizing that elderly patients may fail to perceive hypoglycemic symptoms despite significant neuroglycopenia 6
• Overlooking medication interactions that potentiate hypoglycemia 4
• Missing the diagnosis in patients on beta-blockers who have masked autonomic symptoms 3, 4

Prevention Strategies

• Any blood glucose value <70 mg/dL should trigger immediate treatment and review of the patient's regimen, as such readings predict subsequent severe hypoglycemia 1
• Provide carbohydrate-rich snacks during dialysis for patients with pre-dialysis glucose ≤100 mg/dL 6
• Proactive surveillance of glycemic outliers and interdisciplinary data-driven approaches can reduce hypoglycemic events by 56-80% 1