What are the considerations for using Glucagon-like peptide-1 (GLP-1) receptor agonists in patients with Immunoglobulin A (IgA) nephropathy and impaired renal function?

GLP-1 Receptor Agonists in IgA Nephropathy

GLP-1 receptor agonists are not established therapy for IgA nephropathy but may be considered as add-on treatment in patients with concurrent type 2 diabetes and IgA nephropathy, particularly when proteinuria persists despite optimized supportive care with RAS inhibition and SGLT2 inhibitors. 1

Primary Treatment Framework for IgA Nephropathy

The foundation of IgA nephropathy management remains optimized supportive care, which takes absolute priority over any consideration of GLP-1 receptor agonists 1:

• RAS blockade should be instituted regardless of hypertension if proteinuria exceeds 0.5 g/day 1
• Blood pressure control to target levels 1
• SGLT2 inhibitors are emerging as important adjunctive therapy for IgA nephropathy, though formal guidelines have not yet incorporated them as standard of care 1
• Corticosteroids (6-month course) may be considered if proteinuria remains 0.75-1 g/day or higher after at least 90 days of optimized supportive care, but only in patients with eGFR ≥30 ml/min/1.73 m² 1

Role of GLP-1 Receptor Agonists in IgA Nephropathy

When to Consider GLP-1 RAs

GLP-1 receptor agonists should be considered specifically in the following clinical scenario 1:

• Patient has both IgA nephropathy AND type 2 diabetes 1
• Glycemic targets are not met despite metformin and/or SGLT2 inhibitor therapy 1
• OR the patient cannot tolerate metformin or SGLT2 inhibitors 1

Agent Selection

Choose GLP-1 receptor agonists with proven cardiovascular benefit 1, 2:

• Liraglutide - can be used with caution even in ESRD 2
• Semaglutide (injectable or oral) - no dose adjustment needed across all levels of kidney function 2, 3
• Dulaglutide - can be used without dose adjustment when eGFR >15 ml/min/1.73 m² 2

Avoid these agents in severe renal impairment 2:

• Exenatide - contraindicated in severe renal impairment and ESRD 2
• Lixisenatide - contraindicated in severe renal impairment and ESRD 2

Renal Benefits Beyond Glycemic Control

GLP-1 receptor agonists provide kidney-protective effects that extend beyond glucose lowering 1, 4, 5:

• Reduce albuminuria as demonstrated in cardiovascular outcomes trials 1, 4
• Slow eGFR decline compared to placebo and even compared to insulin glargine 1, 4
• Reduce composite kidney disease outcomes (macroalbuminuria, eGFR decline, progression to kidney failure, or death from kidney disease) by meta-analysis of 8 cardiovascular outcomes trials 1
• Cardiovascular risk reduction is actually greater in patients with eGFR <60 ml/min/1.73 m² compared to those with preserved kidney function 1, 4

Emerging Evidence Specific to IgA Nephropathy

Recent case report and genetic evidence suggest potential benefit 6, 7:

• A diabetic patient with biopsy-proven nephrotic IgA nephropathy showed rapid, meaningful, and persistent proteinuria reduction for 2 years when GLP-1 RA was added to ACE inhibitor and SGLT2 inhibitor 6
• Mendelian randomization analysis found genetically proxied GLP-1R agonist associated with decreased risk of IgA nephropathy (OR = 0.58,95% CI = 0.36-0.94, p = 0.027) 7
• The protective effect may be mediated through anti-inflammatory mechanisms, specifically through signaling lymphocytic activation molecule family member 1 (SLAMF1), accounting for 34% of the total effect 7

Practical Implementation Algorithm

Step 1: Confirm Indication

• Biopsy-proven IgA nephropathy 1
• Concurrent type 2 diabetes 1
• Inadequate glycemic control on metformin and/or SGLT2 inhibitor 1

Step 2: Check for Contraindications 3

• Personal or family history of medullary thyroid carcinoma 3
• Multiple endocrine neoplasia syndrome type 2 3
• History of pancreatitis (relative contraindication) 3
• Severe gastroparesis 3

Step 3: Select Agent and Initiate

• First choice: Semaglutide (no dose adjustment needed regardless of eGFR) 2, 3
• Alternative: Dulaglutide if eGFR >15 ml/min/1.73 m² 2
• Start at lowest dose and titrate slowly over weeks to minimize gastrointestinal side effects 1

Step 4: Adjust Concomitant Medications

• Reduce insulin dose by approximately 20% when initiating GLP-1 RA to prevent hypoglycemia 2
• Reduce sulfonylurea dose if used concomitantly 1
• Do not combine with DPP-4 inhibitors 1

Step 5: Monitor Response

• Glycemic control (HbA1c every 3 months) 2
• Kidney function (eGFR every 3-6 months) 2
• Proteinuria (urine protein-to-creatinine ratio every 3-6 months) 1
• Gastrointestinal symptoms (nausea, vomiting, diarrhea occur in 15-20% but usually resolve with continued use) 1, 4

Critical Pitfalls to Avoid

Medication Errors

• Do not use exenatide or lixisenatide in patients with eGFR <30 ml/min/1.73 m² - these are absolute contraindications 2
• Do not forget to reduce insulin/sulfonylurea doses when initiating therapy - failure to do so significantly increases hypoglycemia risk 2
• Do not combine with DPP-4 inhibitors - this combination provides no additional benefit and is not recommended 1

Monitoring Failures

• Do not ignore severe gastrointestinal symptoms - severe nausea, vomiting, or diarrhea can lead to dehydration and acute kidney injury in vulnerable patients with pre-existing kidney disease 1, 3
• Monitor renal function closely when initiating or escalating doses in patients reporting severe gastrointestinal reactions 3

Nutritional Concerns

• Do not overlook nutritional status - GLP-1 RAs cause weight loss which may be detrimental in malnourished patients with advanced CKD 1
• However, in obese patients exceeding BMI limits for kidney transplant listing, GLP-1 RAs can facilitate weight loss to meet transplant eligibility criteria 1

Misunderstanding the Evidence Base

• GLP-1 RAs are NOT established therapy for IgA nephropathy itself - the primary indication remains type 2 diabetes management 1
• The kidney benefits demonstrated in trials were in diabetic kidney disease, not specifically IgA nephropathy 1, 4, 5
• Emerging evidence is promising but limited to case reports and genetic studies 6, 7

Special Considerations for Advanced CKD

GLP-1 receptor agonists retain glucose-lowering efficacy even in advanced CKD and dialysis 1, 2:

• Can be used with eGFR as low as 15 ml/min/1.73 m² 1, 2
• Maintain antihyperglycemic effects across the full range of eGFR, including dialysis patients 2
• Do not cause hypoglycemia when used alone 2
• Particularly valuable when metformin is contraindicated (eGFR <30 ml/min/1.73 m²) and SGLT2 inhibitors have minimal glycemic effects 1

Positioning in Overall Treatment Strategy

GLP-1 receptor agonists should be viewed as adjunctive therapy in the specific context of diabetic patients with IgA nephropathy 1, 6:

• They do not replace optimized supportive care (RAS inhibition, blood pressure control) 1
• They do not replace consideration of corticosteroids in high-risk patients meeting criteria 1
• They should be added when diabetes management requires additional glucose-lowering beyond metformin and SGLT2 inhibitors 1
• The anti-proteinuric and kidney-protective effects observed in diabetic kidney disease may provide additional benefit in IgA nephropathy, but this remains investigational 6, 7