Can Glucagon-like peptide-1 (GLP-1) analogues be used in patients with Chronic Kidney Disease (CKD) and Diabetes Mellitus (DM) to reduce insulin resistance, and can they be given concurrently with insulin?

GLP-1 Receptor Agonists in CKD and Diabetes: Efficacy for Insulin Resistance and Concurrent Use with Insulin

Yes, GLP-1 receptor agonists can and should be used in patients with CKD and diabetes to improve glycemic control, and they can be safely combined with insulin when you reduce the insulin dose by approximately 20% at initiation. 1

Efficacy Across All Stages of CKD

GLP-1 receptor agonists retain full glucose-lowering potency across the entire spectrum of kidney function, including patients with eGFR as low as 15 ml/min/1.73 m² and those on dialysis. 2, 1 This is a critical distinction from SGLT2 inhibitors, which lose their glycemic efficacy below eGFR 30 ml/min/1.73 m² but maintain cardiovascular and kidney benefits. 2

Mechanism of Action on Insulin Resistance

• GLP-1 RAs address insulin resistance indirectly through multiple mechanisms, primarily via weight loss, which is particularly beneficial in CKD where insulin resistance is common. 1
• They enhance glucose-dependent insulin secretion while suppressing glucagon secretion, and slow gastric emptying to reduce postprandial glucose excursions. 3
• Thiazolidinediones directly improve insulin sensitivity in advanced CKD, but GLP-1 RAs achieve similar metabolic improvements through weight reduction and improved beta-cell function. 2

Concurrent Use with Insulin: Practical Algorithm

When initiating a GLP-1 RA in a patient already on insulin, you must reduce the insulin dose to prevent hypoglycemia. 1

Step-by-Step Approach:

1. For patients on basal insulin alone: Reduce the basal insulin dose by 20% when starting the GLP-1 RA. 1

2. For patients on basal-bolus regimens: Reduce both components proportionally, or consider eliminating bolus insulin first while maintaining basal insulin. 1

3. Titration strategy: Start the GLP-1 RA at the lowest dose and titrate every 4-7 days according to manufacturer guidelines. 1

4. Monitor closely: GLP-1 RAs do not cause hypoglycemia when used alone, but the combination with insulin or sulfonylureas requires vigilant glucose monitoring during the first 2-4 weeks. 2, 1

Real-World Evidence

A 2024 Canadian registry study demonstrated that adding a GLP-1 RA to patients with T2D and CKD already on SGLT2 inhibitors achieved superior HbA1c reduction (-1.3% vs -1.1%, P=0.03) compared to adding basal insulin, with the added benefits of significant weight loss (-3.4 kg vs +2.6 kg) and slower eGFR decline. 4

Agent-Specific Recommendations by CKD Stage

For eGFR ≥30 ml/min/1.73 m²:

• First choice: Semaglutide, liraglutide, or dulaglutide—all have proven cardiovascular benefits and require no dose adjustment. 1, 5
• Semaglutide can be used without dose adjustment at any eGFR level, including dialysis patients. 1

For eGFR 15-29 ml/min/1.73 m²:

• Preferred agent: Dulaglutide, as it demonstrated significantly slower GFR decline compared to insulin glargine in patients with moderate-to-severe CKD. 1, 5
• Metformin is contraindicated at this level of kidney function. 2, 1

For eGFR <15 ml/min/1.73 m² or dialysis:

• Use with caution: Liraglutide and semaglutide can be used, though data are limited. 1
• Absolutely contraindicated: Exenatide and lixisenatide due to renal elimination. 1

Cardiovascular and Kidney Benefits Beyond Glycemic Control

Meta-analyses of cardiovascular outcome trials demonstrate that GLP-1 RAs reduce major adverse cardiovascular events (MACE) by 12-26%, with the benefit being at least as effective—if not more so—in patients with eGFR <60 ml/min/1.73 m² compared to those with higher eGFR. 2, 1

• Liraglutide showed greater MACE reduction specifically in patients with eGFR <60 ml/min/1.73 m². 5
• GLP-1 RAs reduce composite kidney outcomes, primarily driven by reduction in albuminuria. 1, 6
• The 2024 FLOW trial demonstrated that semaglutide 1.0 mg reduced the primary kidney endpoint by 24% compared to placebo. 6

Clinical Positioning in Treatment Algorithm

For eGFR ≥30 ml/min/1.73 m²:

1. Start with metformin + SGLT2 inhibitor as first-line therapy. 1, 5
2. If glycemic targets are not met, add a GLP-1 RA (semaglutide, liraglutide, or dulaglutide). 1, 5
3. If still inadequate control, add or intensify insulin with appropriate dose reduction. 2

For eGFR 15-29 ml/min/1.73 m²:

1. Metformin is contraindicated; SGLT2 inhibitors can be continued if already initiated but have minimal glycemic effect. 2
2. GLP-1 RA becomes the primary glucose-lowering agent alongside insulin if needed. 2, 1
3. DPP-4 inhibitors (with dose adjustment) are an alternative if GLP-1 RAs are not tolerated. 2

Critical Safety Considerations and Pitfalls to Avoid

Gastrointestinal Side Effects:

• Nausea, vomiting, and diarrhea occur in 15-20% of patients with moderate-to-severe CKD but usually abate over several weeks with slow dose titration. 1, 5
• Pitfall: Severe vomiting can lead to dehydration and acute kidney injury in vulnerable CKD patients—monitor closely during initiation. 1

Hypoglycemia Prevention:

• Critical error to avoid: Failing to reduce insulin or sulfonylurea doses by 20% when initiating GLP-1 RA therapy. 1
• GLP-1 RAs alone do not cause hypoglycemia due to their glucose-dependent mechanism of action. 2, 1

Nutritional Status:

• Weight loss may be detrimental in malnourished ESRD patients—assess nutritional status before initiating therapy. 2, 1
• Conversely, in ESRD patients with obesity exceeding BMI limits for kidney transplant listing, GLP-1 RAs can facilitate weight loss to meet transplant eligibility criteria. 2, 1

Drug Interactions:

• Do not combine GLP-1 RAs with DPP-4 inhibitors—this combination is not recommended and provides no additional benefit. 1

Absolute Contraindications:

• Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN2). 7, 8
• Do not use exenatide or lixisenatide in ESRD—these are absolute contraindications, not just cautions. 1

Monitoring Strategy

• Check kidney function (eGFR and albuminuria) every 3-6 months while on GLP-1 RA therapy. 7
• Evaluate glycemic response and weight loss at each visit during dose titration (every 4 weeks). 7
• Monitor for gastrointestinal symptoms and adjust titration schedule accordingly. 1
• Assess for signs of acute pancreatitis, though causality has not been definitively established. 2