Is GLP-1 (Glucagon-like peptide-1) receptor agonist appropriate for patients with end-stage renal disease?

GLP-1 Receptor Agonists in End-Stage Renal Disease

GLP-1 receptor agonists can be used with caution in patients with end-stage renal disease, with liraglutide and semaglutide being preferred agents that do not require dose adjustment in ESRD, while exenatide and lixisenatide are contraindicated in severe renal impairment or ESRD. 1

Safety and Efficacy in ESRD

GLP-1 receptor agonists have been studied with eGFR as low as 15 ml/min/1.73 m² and retain their glucose-lowering potency across the range of eGFR, including in dialysis patients 1. The 2022 consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO) specifically addresses this issue:

• Liraglutide and semaglutide should be used with caution in patients with severe renal impairment or ESRD 1
• Exenatide and lixisenatide are contraindicated in severe renal impairment or ESRD 1
• GLP-1 RAs retain glucose-lowering efficacy even in advanced kidney disease 1

Benefits in Renal Disease

GLP-1 receptor agonists offer several benefits for patients with diabetic kidney disease:

• Reduced albuminuria and slower eGFR decline 1
• Cardiovascular risk reduction that is at least as significant in patients with eGFR <60 ml/min/1.73 m² compared to those with higher eGFR 1
• Potential renoprotective effects through anti-inflammatory and anti-fibrotic mechanisms 2, 3

A meta-analysis of cardiovascular outcomes trials showed that GLP-1 receptor agonists significantly reduced the risk for composite kidney disease outcomes (macroalbuminuria, eGFR decline, progression to kidney failure, or death from kidney disease) compared with placebo, largely driven by reduction in albuminuria 1.

Practical Considerations for Use in ESRD

When using GLP-1 receptor agonists in ESRD patients:

1. Agent selection:

   • Prefer liraglutide or semaglutide over exenatide or lixisenatide 1
   • Recent evidence suggests semaglutide may have a more favorable safety profile in ESRD patients 4

2. Dosing approach:

   • Start with the lowest dose and titrate slowly to minimize gastrointestinal side effects 5
   • For semaglutide: Start at 0.25 mg weekly and gradually increase 5
   • For liraglutide: Start at 0.6 mg daily and gradually increase 5

3. Monitoring:

   • Watch for gastrointestinal side effects (nausea, vomiting, diarrhea) which occur in 15-20% of patients with moderate-to-severe CKD 1
   • Monitor for acute kidney injury, especially with severe gastrointestinal symptoms that could lead to dehydration 6
   • Reduce doses of concomitant insulin or insulin secretagogues to prevent hypoglycemia 1

4. Special considerations:

   • In ESRD patients with obesity exceeding BMI limits required for kidney transplant listing, GLP-1 RAs can help with weight loss to facilitate qualification for transplant 1
   • For patients on dialysis, a 2023 retrospective study showed a mean A1C reduction of 0.8% with GLP-1 RA use 4

Cautions and Contraindications

Important safety considerations include:

• Contraindications: Personal or family history of medullary thyroid cancer, multiple endocrine neoplasia syndrome type 2, and history of serious hypersensitivity reaction to the drug 1, 6

• Cautions:

  • History of pancreatitis (particularly with liraglutide) 1
  • Risk of hypoglycemia when used with insulin or insulin secretagogues 1
  • Potential for gastrointestinal side effects that may worsen nutritional status in already vulnerable ESRD patients 1
  • Monitor for diabetic retinopathy complications with semaglutide, especially with rapid glucose reduction 6

Conclusion

The evidence supports the use of certain GLP-1 receptor agonists (particularly liraglutide and semaglutide) in ESRD patients, with appropriate monitoring and dose adjustments. These agents not only provide glycemic control but may offer additional cardiovascular and renal benefits in this high-risk population.