What is the appropriate workup for a patient with recurrent hypoglycemia?

Workup for Recurrent Hypoglycemia

Begin by documenting Whipple's triad at every clinical encounter—symptoms/signs of hypoglycemia, a measured low plasma glucose, and resolution after glucose correction—as this confirms true hypoglycemia and guides all subsequent evaluation. 1, 2, 3

Initial Documentation and Pattern Recognition

Document the complete hypoglycemia profile at each visit:

• Record frequency, severity (Level 1: <70 but ≥54 mg/dL; Level 2: <54 mg/dL; Level 3: requires assistance), timing, and precipitants of all episodes 1, 4
• Correlate home glucose meter and CGM readings with symptoms and treatments, as patients frequently treat symptoms without checking glucose, misinterpret normal values as hypoglycemic, or tolerate hypoglycemia without intervention 1, 4
• A Level 2 or 3 hypoglycemic event within the past 3-6 months is the strongest predictor of recurrence and mandates immediate comprehensive workup 4

Screen for Impaired Hypoglycemia Awareness

Screen annually (minimum) for impaired hypoglycemia awareness using validated tools:

• Use single-question Pedersen-Bjergaard or Gold questionnaires for rapid screening 1
• Ask directly: "Do you ever experience low blood glucose without feeling symptoms?" or "At what glucose level do you typically begin feeling symptoms?" 4
• Impaired awareness dramatically increases risk of severe hypoglycemia and requires immediate treatment modification 1, 4
• This condition presents as confusion being the first sign of hypoglycemia, occurring in patients with long-standing diabetes or recurrent hypoglycemia 1

Systematic Risk Factor Assessment

Evaluate clinical and biological risk factors:

• Recent (within 3-6 months) Level 2 or 3 hypoglycemia—the strongest predictor 4
• Intensive insulin therapy (multiple daily injections, pumps, automated insulin delivery systems) 4
• End-stage kidney disease with altered insulin clearance 4
• Cognitive impairment or dementia (bidirectional association with hypoglycemia) 4

Evaluate social and economic risk factors:

• Food insecurity—strongly associated with increased hypoglycemia-related emergency visits and hospitalizations 4
• Low-income status or residence in socioeconomically deprived areas 4

Medication-Related Evaluation

Review all medications systematically:

• Sulfonylureas interacting with antimicrobials (fluoroquinolones, clarithromycin, sulfamethoxazole-trimethoprim, metronidazole, fluconazole) dramatically increase effective dose and cause hypoglycemia 4
• Assess additive effects of multiple glucose-lowering agents (basal insulin + rapid-acting insulin + GLP-1 agonist combinations) 4
• Insulin secretagogues (sulfonylureas, meglitinides) stimulate endogenous insulin release for hours 5

Laboratory Evaluation During Hypoglycemic Episode

For patients with diabetes on insulin or secretagogues, the workup focuses on medication adjustment and risk factor modification as outlined above. 1, 4

For patients WITHOUT diabetes or those with unexplained hypoglycemia despite medication adjustment:

Obtain critical blood work during a symptomatic episode with documented low glucose:

• Plasma glucose, insulin, C-peptide, proinsulin 2, 6, 7
• Beta-hydroxybutyrate 2, 6
• Plasma/urine sulfonylurea screen 2, 6
• Insulin antibodies 2, 7

If spontaneous episodes cannot be captured, perform supervised provocative testing:

• 72-hour supervised fast test for patients with fasting or random hypoglycemia symptoms 2, 6, 3
• Mixed meal test for patients with predominantly postprandial symptoms 6, 3
• Measure the same panel (insulin, C-peptide, proinsulin, beta-hydroxybutyrate, sulfonylurea screen) when glucose falls below 55 mg/dL during testing 2, 6

Differential Diagnosis Based on Laboratory Results

Elevated insulin and C-peptide with low glucose indicates endogenous hyperinsulinism:

• Insulinoma 2, 6, 7
• Non-insulinoma pancreatogenous hypoglycemia syndrome 6, 3
• Postbariatric hypoglycemia 3

Elevated insulin with suppressed C-peptide indicates exogenous insulin:

• Factitious hypoglycemia from surreptitious insulin use 2, 6

Suppressed insulin and C-peptide with positive sulfonylurea screen:

• Surreptitious or accidental sulfonylurea ingestion 2, 6

Suppressed insulin and C-peptide without sulfonylurea:

• Critical illness 2, 6, 3
• Hepatic or renal dysfunction 3, 7
• Hormone deficiencies (cortisol, growth hormone) 2, 6, 3
• Non-islet cell tumors producing IGF-II 2, 6, 7

Common Pitfalls to Avoid

• Never pursue extensive workup without first documenting Whipple's triad—many patients report "hypoglycemia" symptoms at normal glucose levels 2, 3
• Do not rely solely on patient-reported glucose values—verify with simultaneous symptoms and laboratory confirmation 1, 4
• In older adults with recurrent hypoglycemia on insulin therapy, simplify the regimen regardless of A1C 1
• Do not overlook medication interactions, particularly sulfonylureas with common antimicrobials 4