What are the considerations for using GLP-1 (Glucagon-like peptide-1) receptor agonists, such as liraglutide (Victoza) or semaglutide (Ozempic), in patients with proteinuria?

GLP-1 Receptor Agonists in Patients with Proteinuria

GLP-1 receptor agonists can be safely used in patients with proteinuria and may actually provide renoprotective benefits, particularly in those with diabetic kidney disease, though caution is warranted in patients with severe renal impairment. 1, 2

Renal Benefits of GLP-1 Receptor Agonists

GLP-1 receptor agonists have demonstrated several beneficial effects on kidney function in patients with proteinuria:

• Reduction in albuminuria: Pooled analysis of SUSTAIN 6 and LEADER trials showed that semaglutide/liraglutide reduced albuminuria by 24% versus placebo, with the largest reduction (33%) observed with semaglutide 1.0 mg 2

• Slowed eGFR decline:

  • Semaglutide 1.0 mg slowed eGFR decline by 0.87 mL/min/1.73 m²/year
  • Liraglutide slowed eGFR decline by 0.26 mL/min/1.73 m²/year 2
  • These effects were more pronounced in patients with baseline eGFR <60 mL/min/1.73 m²

• Reduced risk of persistent eGFR reductions: Combined semaglutide/liraglutide therapy significantly lowered the risk of persistent 40% and 50% eGFR reductions versus placebo 2

• Specific benefits in diabetic nephropathy: Liraglutide has been shown to decrease proteinuria from 2.53 g/g creatinine to 1.47 g/g creatinine and substantially reduce the rate of eGFR decline from 6.6 to 0.3 mL/min/1.73 m²/year in patients with overt diabetic nephropathy 3

Safety Considerations and Contraindications

When considering GLP-1 receptor agonists in patients with proteinuria, the following safety considerations should be noted:

1. Renal impairment considerations:

   • Exenatide and lixisenatide are contraindicated in severe renal impairment or end-stage renal disease 1
   • Liraglutide and semaglutide should be used with caution in patients with severe renal impairment or ESRD 1
   • Liraglutide pharmacokinetics are not significantly altered by renal dysfunction, suggesting no dose adjustment is required in patients with renal impairment 4

2. Potential for acute kidney injury:

   • Case reports exist of acute kidney injury in patients taking GLP-1 receptor agonists, particularly in those with pre-existing chronic kidney disease 5
   • Patients experiencing adverse gastrointestinal symptoms (nausea, vomiting, diarrhea) may be at higher risk for acute kidney injury due to volume depletion 5

3. Gastrointestinal side effects:

   • Nausea, vomiting, and diarrhea are the most common adverse effects 1
   • These effects are dose-dependent and more frequent with short-acting than long-acting GLP-1 receptor agonists 1
   • Gradual dose titration is recommended to improve gastrointestinal tolerability 1

Practical Recommendations for Use in Patients with Proteinuria

1. Patient selection:

   • Best candidates: Patients with diabetic kidney disease and proteinuria who may benefit from both glycemic control and renoprotective effects
   • Use caution in: Patients with severe renal impairment (eGFR <30 mL/min/1.73 m²)
   • Avoid exenatide/lixisenatide in: Patients with severe renal impairment or ESRD

2. Monitoring recommendations:

   • Baseline assessment: Measure eGFR, urine albumin-to-creatinine ratio, and electrolytes
   • Regular monitoring: Check renal function periodically, especially after initiation and dose increases
   • Increased vigilance: Monitor more closely if patient develops significant gastrointestinal symptoms

3. Dose titration:

   • Start with lower doses and titrate slowly to minimize gastrointestinal side effects
   • For semaglutide: Start at 0.25 mg weekly for 4 weeks, then increase gradually to target dose
   • For liraglutide: Start at 0.6 mg daily for 7 days, then increase gradually to target dose 1

4. Risk mitigation:

   • Ensure adequate hydration, especially if gastrointestinal side effects occur
   • Consider temporary dose reduction or discontinuation if acute kidney injury is suspected
   • Educate patients to report severe or persistent gastrointestinal symptoms

Common Pitfalls and Caveats

• Overestimating safety in severe CKD: While GLP-1 receptor agonists have renoprotective effects, caution is still warranted in advanced CKD due to limited kidney reserve in the event of adverse effects

• Ignoring volume status: Dehydration from gastrointestinal side effects can worsen kidney function in vulnerable patients

• Overlooking drug interactions: GLP-1 receptor agonists may delay gastric emptying, potentially affecting absorption of concomitantly administered medications 1

• Failure to adjust concomitant medications: Patients on insulin or sulfonylureas may require dose adjustments to prevent hypoglycemia when starting GLP-1 receptor agonists 1

By carefully selecting patients, monitoring kidney function, and managing side effects appropriately, GLP-1 receptor agonists can be valuable therapeutic options for patients with proteinuria, particularly those with diabetic kidney disease.