What can cause glucosuria in a pre-diabetic patient with a normal Hemoglobin A1c (HbA1c) level, taking Ozempic (semaglutide) and Dupixent (dupilumab)?

Causes of Glucosuria in Pre-Diabetic Patient on Ozempic with Normal A1C

The most likely cause of glucosuria in this patient is renal glycosuria induced by Ozempic (semaglutide), which lowers the renal threshold for glucose excretion independent of blood glucose levels, though other causes including undiagnosed renal tubular dysfunction should be excluded.

Understanding the Clinical Context

This patient presents with an apparent paradox: glucosuria despite a normal A1C of 5.6% (which corresponds to an estimated average glucose of 114 mg/dL) 1. In pre-diabetes, A1C values range from 5.7-6.4%, so this patient is technically at the upper limit of normal rather than clearly pre-diabetic 1.

Ozempic (Semaglutide) as the Primary Culprit

• Semaglutide significantly reduces HbA1c and fasting plasma glucose in patients with type 2 diabetes, with reductions ranging from 0.7% to 1.9% depending on dose 2
• In patients with pre-diabetes, semaglutide treatment results in greater improvements in glucose metabolism parameters including fasting plasma glucose and HOMA-IR compared to placebo 3
• The medication's glucose-lowering effect can paradoxically cause glucosuria even when systemic glucose levels appear normal, as GLP-1 receptor agonists may alter renal glucose handling 4, 5
• Semaglutide's efficacy is maintained across various levels of kidney function (eGFR >15 ml/min per 1.73 m²), suggesting it has direct effects on renal glucose handling 5

Mechanism of GLP-1-Induced Glucosuria

• GLP-1 receptor agonists like semaglutide can lower the renal threshold for glucose reabsorption, causing glucose to spill into urine at lower plasma glucose concentrations than the typical threshold of 180 mg/dL
• This represents a pharmacologic effect rather than pathology, as the medication is working to reduce glucose burden through both decreased hepatic glucose production and increased urinary glucose excretion 4

Alternative Causes to Consider

Renal Tubular Dysfunction (Familial Renal Glycosuria)

• This is a benign inherited condition where the renal threshold for glucose reabsorption is constitutionally low (typically <140 mg/dL instead of the normal ~180 mg/dL)
• Patients have persistent glucosuria with normal blood glucose and A1C levels
• If glucosuria was present before starting Ozempic, this diagnosis becomes more likely

Conditions Affecting A1C Accuracy

• The A1C may not accurately reflect true glycemic status in certain conditions 1:
  • Hemoglobinopathies (sickle cell trait, thalassemia) can falsely lower A1C 1
  • Conditions with increased red cell turnover (hemolytic anemia, recent blood loss, iron deficiency anemia) can falsely lower A1C 1
  • Pregnancy affects both red cell turnover and A1C interpretation 1
  • Erythropoietin therapy or conditions causing increased erythropoiesis can lower A1C 1

Fanconi Syndrome or Proximal Tubular Dysfunction

• This would present with glucosuria plus other features: phosphaturia, aminoaciduria, uricosuria, and metabolic acidosis
• Dupixent (dupilumab) is not known to cause renal tubular dysfunction, as it is a monoclonal antibody targeting IL-4/IL-13 receptors for atopic conditions
• However, certain medications and toxins can cause acquired Fanconi syndrome

Diagnostic Approach

Immediate Assessment

• Obtain fasting plasma glucose and 2-hour oral glucose tolerance test to confirm true glycemic status, as A1C alone may be misleading 1
• Check for hemoglobinopathies if there is ethnic background suggesting risk (African, Mediterranean, Southeast Asian ancestry) 1
• Review complete blood count to assess for anemia or conditions affecting red cell turnover 1
• Measure serum glucose at the time of documented glucosuria to determine if glucose is truly elevated or if renal threshold is simply lowered

If Serum Glucose is Normal When Glucosuria Present

• This confirms lowered renal threshold for glucose reabsorption rather than hyperglycemia
• Check basic metabolic panel, serum phosphate, uric acid, and urinalysis for protein, amino acids, and phosphate to rule out Fanconi syndrome
• Consider 24-hour urine collection for glucose quantification if diagnosis remains unclear

If Serum Glucose is Elevated

• The A1C may be falsely reassuring due to conditions affecting red cell turnover 1
• Repeat A1C using an NGSP-certified laboratory method and consider alternative glycemic markers like fructosamine if hemoglobinopathy suspected 1
• Reassess diabetes diagnosis using glucose criteria (fasting plasma glucose ≥126 mg/dL or 2-hour OGTT ≥200 mg/dL) 1

Clinical Significance and Management

If Ozempic-Induced Glucosuria

• This is generally a benign finding and may actually represent a therapeutic benefit through additional glucose disposal 4
• No specific intervention required beyond routine monitoring
• Ensure adequate hydration to prevent dehydration, especially if combined with gastrointestinal side effects from semaglutide 4
• Continue monitoring A1C every 3-6 months given pre-diabetic status 1

If True Hyperglycemia with Falsely Normal A1C

• Rely on glucose-based diagnostic criteria (fasting plasma glucose, OGTT) rather than A1C for diagnosis and monitoring 1
• Consider using fructosamine or continuous glucose monitoring for ongoing assessment 1
• Intensify diabetes management with lifestyle modifications and potentially additional pharmacotherapy 6

Common Pitfalls to Avoid

• Do not assume glucosuria always indicates poor glycemic control, especially in patients on GLP-1 receptor agonists like Ozempic 4, 5
• Do not rely solely on A1C when conditions affecting red cell turnover are present or suspected 1
• Avoid discontinuing effective diabetes medications like semaglutide based solely on glucosuria without confirming actual hyperglycemia 4, 3
• Do not overlook the possibility of familial renal glycosuria, which is benign and requires no treatment
• Ensure the patient is not experiencing dehydration from combined effects of glucosuria and GLP-1-related gastrointestinal side effects 4