What is the role of GLP-1 (Glucagon-Like Peptide-1) receptor agonists in the treatment of type 2 diabetes in patients with End-Stage Renal Disease (ESRD)?

GLP-1 Receptor Agonists in Type 2 Diabetes with ESRD

Liraglutide and semaglutide should be used with caution in patients with ESRD, while exenatide and lixisenatide are contraindicated. 1

Agent-Specific Recommendations by Renal Function

Contraindicated in ESRD

• Exenatide (both immediate and extended-release formulations) is contraindicated in severe renal impairment and ESRD due to renal elimination 1, 2
• Lixisenatide is contraindicated in severe renal impairment and ESRD 1

Use with Caution in ESRD

• Liraglutide can be used with caution in ESRD, though limited data exists for this population 1
• Semaglutide (subcutaneous) can be used with caution in ESRD, with limited data available 1
• Dulaglutide can be used without dose adjustment in patients with eGFR >15 ml/min/1.73 m² 1, 3

The American College of Cardiology explicitly lists severe renal impairment or ESRD as a contraindication for exenatide and lixisenatide, while recommending caution (not contraindication) for liraglutide and semaglutide in this population. 1

Efficacy in ESRD

GLP-1 receptor agonists retain glucose-lowering efficacy even in advanced CKD and ESRD, including dialysis patients. 1, 3

• Real-world data from 46 ESRD patients showed mean A1C reduction of 0.8% with GLP-1 receptor agonists 4
• The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines confirm that GLP-1 receptor agonists maintain antihyperglycemic effects across the full range of eGFR, including dialysis patients 1
• These agents work through glucose-dependent insulin secretion, which remains functional regardless of kidney function 1

Preferred Agents in ESRD

Prioritize liraglutide, semaglutide, or dulaglutide in ESRD patients, as these have cardiovascular outcome trial data and can be used with caution in this population. 1, 3

The ADA/KDIGO consensus specifically recommends GLP-1 receptor agonists with proven cardiovascular benefit (liraglutide, semaglutide, dulaglutide) for patients with type 2 diabetes and CKD who do not meet glycemic targets with metformin and/or SGLT2 inhibitors. 1 While metformin is contraindicated with eGFR <30 ml/min/1.73 m², and SGLT2 inhibitors have minimal glycemic effects at this level of kidney function, GLP-1 receptor agonists remain effective. 1

Safety Considerations in ESRD

Hypoglycemia Risk

• GLP-1 receptor agonists do not cause hypoglycemia when used alone 1
• In moderate-to-severe CKD, hypoglycemia rates are reduced by 50% even with concurrent insulin therapy 1
• When combining with insulin or sulfonylureas, reduce doses of these agents by approximately 20% for insulin to prevent hypoglycemia 1
• Real-world data showed emergent hypoglycemia occurred only in 3 patients, all on concomitant insulin 4

Acute Kidney Injury

• Case reports have associated exenatide with acute kidney injury 2
• In a retrospective study of 64 GLP-1 receptor agonist prescriptions in ESRD patients, 10 cases of AKI occurred, but notably none in the semaglutide cohort 4
• Monitor for dehydration, as nausea and vomiting can precipitate volume depletion 1

Gastrointestinal Effects

• Nausea and vomiting are common, which raises concern in ESRD patients at risk for malnutrition 1
• Start at low doses and titrate slowly to minimize gastrointestinal side effects 1, 3
• Exercise caution in patients with or at risk for malnutrition, as GLP-1 receptor agonists induce weight loss 1

Contraindications to Screen

• Personal or family history of medullary thyroid cancer 1, 3
• Multiple endocrine neoplasia syndrome type 2 (MEN2) 1, 3
• History of serious hypersensitivity reaction to the drug 1
• History of pancreatitis (use liraglutide with particular caution) 1

Clinical Algorithm for ESRD Patients

Step 1: Assess Current Glycemic Control

• If A1C is not at individualized target despite available therapies, consider GLP-1 receptor agonist 1
• Metformin is contraindicated with eGFR <30 ml/min/1.73 m² 1
• SGLT2 inhibitors have minimal glycemic effects in ESRD (though may be continued for cardiovascular/renal benefits if previously initiated) 1

Step 2: Select Appropriate Agent

• First choice: Liraglutide, semaglutide, or dulaglutide (cardiovascular outcome trial data) 1, 3
• Avoid: Exenatide and lixisenatide (contraindicated) 1
• No dose adjustment needed for liraglutide, semaglutide, or dulaglutide in ESRD 1, 3

Step 3: Adjust Concomitant Medications

• Reduce insulin dose by approximately 20% when initiating GLP-1 receptor agonist 1
• Consider stopping or reducing sulfonylurea dose 1
• Do not combine with DPP-4 inhibitors 1

Step 4: Initiate and Titrate

• Start at lowest available dose 1
• Titrate slowly over weeks to minimize nausea and vomiting 1, 3
• Monitor for gastrointestinal symptoms and signs of dehydration 3

Step 5: Monitor

• Check kidney function every 3-6 months 3
• Monitor for hypoglycemia, especially if on insulin or sulfonylureas 1
• Watch for signs of acute pancreatitis (rare but serious) 3
• Assess nutritional status given weight loss effects 1

Special Consideration: Transplant Candidacy

In ESRD patients with obesity exceeding BMI limits for kidney transplant listing, GLP-1 receptor agonists can facilitate weight loss to meet transplant eligibility criteria. 1

This represents a unique and important indication in the ESRD population, as achieving transplant eligibility can dramatically improve long-term outcomes. 1

Cardiovascular and Renal Benefits

While the primary cardiovascular outcome trials did not specifically target ESRD populations, meta-analyses show that cardiovascular risk reduction with GLP-1 receptor agonists is at least as effective in patients with eGFR <60 ml/min/1.73 m² compared to those with higher eGFR. 1 The composite renal outcome risk is reduced by 17%, primarily driven by reduction in new-onset macroalbuminuria (25% reduction). 5 However, GLP-1 receptor agonists have not demonstrated significant effects on progression to ESRD or doubling of serum creatinine in clinical trials. 5

Practical Pitfalls to Avoid

• Do not use exenatide or lixisenatide in ESRD—these are absolute contraindications, not just cautions 1
• Do not forget to reduce insulin/sulfonylurea doses when initiating therapy to prevent hypoglycemia 1
• Do not combine with DPP-4 inhibitors—this combination is not recommended 1
• Do not ignore gastrointestinal symptoms—severe nausea/vomiting can lead to dehydration and AKI in vulnerable ESRD patients 1, 4
• Do not overlook nutritional status—weight loss may be detrimental in malnourished ESRD patients 1