What could be causing orange urine in an adult patient with a history of diabetes or metabolic disorders, currently taking a GLP-1 (Glucagon-like peptide-1) receptor agonist, such as liraglutide (Victoza) or semaglutide (Ozempic)?

Orange Urine in Patients Taking GLP-1 Receptor Agonists

Orange urine is not a recognized side effect of GLP-1 receptor agonists and requires evaluation for alternative causes including dehydration (which can occur secondary to GLP-1-induced gastrointestinal effects), medications, dietary factors, or underlying hepatobiliary or renal pathology.

GLP-1 Receptor Agonists Do Not Directly Cause Orange Urine

The comprehensive safety profiles of GLP-1 receptor agonists documented in major guidelines and clinical trials do not list urine discoloration as an adverse effect 1, 2. The most common side effects are gastrointestinal (nausea, vomiting, diarrhea) occurring in 30-45% of patients, along with recognized risks including gallbladder disease, pancreatitis concerns, and cardiovascular effects like modest heart rate elevation 1, 2.

Evaluate for Dehydration-Related Concentrated Urine

The most likely GLP-1-related mechanism for orange urine is dehydration from severe gastrointestinal side effects leading to concentrated urine.

• GLP-1 receptor agonists can cause acute kidney injury from dehydration secondary to severe nausea, vomiting, and diarrhea, particularly in patients with pre-existing kidney disease 2, 3.
• Concentrated urine from inadequate fluid intake appears darker and may have an orange tint 2.
• Ensure adequate fluid intake and monitor renal function closely, especially when initiating or escalating doses 2.

Assess for Gallbladder and Hepatobiliary Pathology

GLP-1 receptor agonists increase the risk of gallbladder disease, which can cause bilirubinuria manifesting as dark orange or brown urine.

• The American College of Cardiology states that GLP-1 receptor agonists may increase the risk of gallbladder disease, including acute cholecystitis, by slowing gallbladder emptying and prolonging the refilling phase, leading to bile stasis 1, 4.
• Monitor for right upper quadrant pain, fever, nausea, and jaundice 2.
• Check liver enzymes, bilirubin levels, and consider hepatobiliary imaging if cholestasis or obstruction is suspected 4.

Rule Out Other Common Causes of Orange Urine

Systematically exclude non-GLP-1 causes:

• Medications: Rifampin, phenazopyridine, sulfasalazine, and certain laxatives containing senna commonly cause orange urine.
• Dietary factors: High intake of carotene-rich foods (carrots, sweet potatoes) or vitamin B supplements.
• Hepatic dysfunction: Elevated conjugated bilirubin from any cause of cholestasis or hepatocellular injury.
• Hematuria: Concentrated blood in urine may appear orange rather than red.
• Urinary tract infection: Particularly with certain bacteria producing pigments.

Renal Function Monitoring in Context

• GLP-1 receptor agonists have demonstrated renoprotective effects, with liraglutide showing a 20% reduction in composite renal outcomes and semaglutide showing a 36% reduction in persistent macroalbuminuria 1.
• However, acute kidney injury can occur from dehydration-related mechanisms 2, 3.
• Liraglutide is not eliminated by renal mechanisms and can be used with caution in renal impairment, while exenatide should not be given in severe renal impairment 3.

Practical Diagnostic Approach

Obtain the following immediately:

• Urinalysis with microscopy to assess for bilirubin, urobilinogen, blood, and specific gravity 2.
• Serum creatinine and electrolytes to evaluate renal function and dehydration 2.
• Liver function tests including direct and indirect bilirubin if hepatobiliary pathology is suspected 4.
• Medication reconciliation for other drugs causing urine discoloration.
• Assess hydration status and severity of gastrointestinal symptoms 2.

Management Considerations

• If dehydration is identified, ensure aggressive fluid repletion and consider temporarily holding or reducing the GLP-1 receptor agonist dose until gastrointestinal symptoms resolve 2.
• If gallbladder disease is confirmed, surgical consultation may be warranted 4.
• Continue GLP-1 therapy only after the underlying cause of orange urine is identified and addressed, as the medication itself is not the direct cause 1.