What to do if a patient on a Glucagon-like peptide-1 (GLP-1) receptor agonist has elevated creatinine levels and decreasing estimated Glomerular Filtration Rate (eGFR)?

Management of Rising Creatinine and Declining eGFR in Patients on GLP-1 Receptor Agonists

When a patient on a GLP-1 receptor agonist shows elevating creatinine and declining eGFR, continue the GLP-1 RA if eGFR remains above 15 mL/min/1.73 m² and evaluate for other causes of kidney function decline, as GLP-1 RAs are generally nephroprotective and not directly nephrotoxic. 1

Initial Assessment

When faced with worsening kidney function in a patient on GLP-1 RA therapy:

1. Rule out dehydration and volume depletion

   • Assess for symptoms of nausea, vomiting, diarrhea (common GLP-1 RA side effects)
   • Check for clinical signs of dehydration
   • Review medication list for other agents that may affect kidney function

2. Evaluate for other causes of acute kidney injury

   • Review recent medication changes (NSAIDs, diuretics, nephrotoxic agents)
   • Check for urinary tract obstruction
   • Consider contrast-induced nephropathy if recent imaging
   • Assess for intercurrent illness

Action Plan Based on eGFR Level

For eGFR >15 mL/min/1.73 m²:

• Continue GLP-1 RA therapy - Most GLP-1 RAs (dulaglutide, liraglutide, semaglutide) can be safely continued 1
• Increase monitoring frequency of kidney function:
  • Every 3-6 months if eGFR 30-44 mL/min/1.73 m²
  • More frequently if eGFR <30 mL/min/1.73 m²

For eGFR <15 mL/min/1.73 m²:

• Consider discontinuation of GLP-1 RA due to limited data in severe kidney disease
• Consult nephrology for management recommendations

Important Considerations

Medication-Specific Adjustments:

• Exenatide and exenatide extended-release: Discontinue if eGFR <30 mL/min/1.73 m² 1
• Dulaglutide: Can be used down to eGFR >15 mL/min/1.73 m² 1
• Liraglutide, lixisenatide, semaglutide: No dosage adjustment required, but limited data in severe CKD 1

Evaluate Concurrent Medications:

• If on SGLT2 inhibitor:

  • A reversible decrease in eGFR (3-10%) is expected and generally not an indication to discontinue 1
  • Continue SGLT2i even if eGFR falls below 30 mL/min/1.73 m² unless not tolerated 1
  • Only discontinue if eGFR decrease >30% or kidney replacement therapy is initiated 1

• If on metformin:

  • Reduce dose if eGFR <45 mL/min/1.73 m² 1
  • Discontinue if eGFR <30 mL/min/1.73 m² 1

Monitoring and Follow-up

1. Hydration status:

   • Ensure adequate fluid intake
   • Consider reducing diuretic doses if applicable 1

2. Follow-up laboratory testing:

   • Repeat creatinine and eGFR within 1-2 weeks if significant decline
   • Monitor electrolytes, especially if on RAS inhibitors or diuretics

3. Watch for warning signs:

   • Severe nausea/vomiting that may worsen dehydration
   • Signs of volume depletion (orthostatic hypotension, dizziness)

Clinical Perspective

GLP-1 RAs are generally considered nephroprotective rather than nephrotoxic 2, 3. Multiple studies have shown that GLP-1 RAs can reduce the risk of composite renal outcomes by approximately 17% and new-onset macroalbuminuria by 25% 3. The kidney benefits appear to be mediated through both direct effects on renal hemodynamics and indirect effects via improved glycemic control, blood pressure reduction, and weight loss 4, 5.

However, acute kidney injury has been reported in post-marketing surveillance of GLP-1 RAs, primarily in the setting of severe gastrointestinal side effects leading to dehydration 6, 7. Therefore, careful monitoring of kidney function and hydration status is essential, especially when initiating therapy or increasing doses.

Key Pitfalls to Avoid

1. Don't automatically discontinue GLP-1 RA therapy when seeing mild to moderate eGFR decline without investigating other causes
2. Don't overlook dehydration as a common reversible cause of kidney function decline in patients on GLP-1 RAs
3. Don't fail to adjust other medications (metformin, SGLT2i) according to eGFR thresholds
4. Don't miss the opportunity to optimize other aspects of kidney protection (blood pressure control, RAS inhibition)

By following this approach, you can appropriately manage patients on GLP-1 RAs who develop worsening kidney function while maintaining the cardiorenal benefits of these important medications.