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 Analogues in CKD: Use with Insulin for Insulin Resistance

Yes, GLP-1 receptor agonists can and should be used in patients with CKD and can be safely combined with insulin, though insulin doses must be reduced by approximately 20% to prevent hypoglycemia. 1

Use of GLP-1 RAs Across CKD Stages

Efficacy Maintained Across All CKD Stages

• GLP-1 receptor agonists retain full glucose-lowering potency across the entire range of eGFR, including patients with eGFR as low as 15 ml/min/1.73 m² and those on dialysis. 1, 2
• Unlike SGLT2 inhibitors which lose glycemic efficacy below eGFR 30 ml/min/1.73 m², GLP-1 RAs maintain their antihyperglycemic effects even in advanced CKD and end-stage renal disease. 1
• Meta-analyses demonstrate that cardiovascular risk reduction with GLP-1 RAs is at least as effective, if not more so, in patients with eGFR <60 ml/min/1.73 m² compared to those with higher eGFR. 1

Agent-Specific Dosing in CKD

Preferred agents with proven cardiovascular benefits: 1, 3

• Semaglutide: No dose adjustment required at any level of kidney function, including dialysis; available in both injectable and oral formulations. 1, 2
• Dulaglutide: No dose adjustment needed; can be used with eGFR >15 ml/min/1.73 m². 1, 2
• Liraglutide: No dose adjustment required, though limited data exists for severe CKD; shows enhanced cardiovascular benefit in patients with eGFR <60 ml/min/1.73 m². 1, 2

Agents to avoid in advanced CKD: 2

• Exenatide: Contraindicated with CrCl <30 ml/min due to renal elimination. 1, 2
• Lixisenatide: Contraindicated in severe renal impairment and ESRD. 2

Combination with Insulin: Practical Algorithm

Step 1: Assess Current Insulin Regimen

• Document total daily insulin dose (basal + bolus if applicable). 1
• Review recent hypoglycemia frequency and severity. 1

Step 2: Initiate GLP-1 RA with Insulin Dose Reduction

• Reduce insulin dose by approximately 20% when starting GLP-1 RA therapy. 2, 3
• For patients on basal insulin alone: reduce basal insulin by 20%. 1
• For patients on basal-bolus regimens: reduce both components proportionally or consider eliminating bolus insulin first. 1

Step 3: Titrate GLP-1 RA Slowly

• Start with the lowest available dose to minimize gastrointestinal side effects (nausea, vomiting, diarrhea occur in 15-20% of CKD patients). 1
• Titrate upward every 1-4 weeks based on tolerability and glycemic response. 1

Step 4: Monitor and Adjust

• Hypoglycemia risk is reduced by 50% when GLP-1 RAs are used with insulin in moderate-to-severe CKD (stages G3-G4) compared to insulin alone. 1
• GLP-1 RAs do not cause hypoglycemia when used alone, but risk increases when combined with insulin or sulfonylureas. 1, 4
• Monitor blood glucose closely during the first 2-4 weeks; further reduce insulin if hypoglycemia occurs. 1

Mechanism: Addressing Insulin Resistance in CKD

Direct Effects on Insulin Sensitivity

• Thiazolidinediones (not GLP-1 RAs) are the primary agents that directly improve insulin sensitivity in advanced CKD. 1
• GLP-1 RAs reduce insulin resistance indirectly through weight loss (mean reduction 1.41 kg), which is particularly beneficial in CKD where insulin resistance is common. 5

Glucose-Dependent Insulin Secretion

• GLP-1 RAs augment glucose-dependent insulin secretion from pancreatic beta cells, meaning they only stimulate insulin release when glucose is elevated. 6
• This mechanism explains the low intrinsic hypoglycemia risk and allows for safe combination with basal insulin. 1, 6

Additional Metabolic Benefits

• Suppress inappropriate glucagon secretion at hyper- or euglycemia. 6
• Slow gastric emptying (more pronounced with short-acting agents like exenatide and lixisenatide). 6
• Reduce calorie intake independent of nausea. 6

Clinical Positioning in CKD Treatment Algorithm

For eGFR ≥30 ml/min/1.73 m²

1. First-line: Metformin + SGLT2 inhibitor. 1
2. If glycemic targets not met: Add GLP-1 RA (semaglutide, liraglutide, or dulaglutide preferred). 1
3. If still inadequate control: Continue GLP-1 RA and add/optimize insulin with dose reduction as above. 1

For eGFR 15-29 ml/min/1.73 m²

1. Metformin is contraindicated. 1
2. SGLT2 inhibitors can be continued if previously initiated but have minimal glycemic effect. 1
3. GLP-1 RA becomes the preferred glucose-lowering agent: Use dulaglutide (best data in this range) or semaglutide. 1, 2
4. Add insulin only if needed for glycemic control, reducing dose by 20% when initiating GLP-1 RA. 1, 2

For eGFR <15 ml/min/1.73 m² or Dialysis

1. GLP-1 RAs (semaglutide, dulaglutide, liraglutide) are preferred over insulin due to lower hypoglycemia risk and maintained efficacy. 1, 2
2. Insulin doses typically need reduction compared to earlier CKD stages due to decreased insulin clearance. 1
3. Combination therapy with reduced-dose insulin + GLP-1 RA is safe and effective. 1, 7

Cardiovascular and Renal Benefits Beyond Glycemic Control

Cardiovascular Protection

• Large cardiovascular outcome trials demonstrate that GLP-1 RAs with proven benefit (liraglutide, semaglutide, dulaglutide) reduce major adverse cardiovascular events (MACE) by 12-26%. 1
• Heart failure risk is reduced by 41% with SGLT2 inhibitors, but GLP-1 RAs also show benefit. 5
• Systolic blood pressure reduced by 4.68 mmHg and diastolic by 1.72 mmHg. 5

Renal Protection

• Composite kidney outcomes (macroalbuminuria, eGFR decline ≥50%, kidney failure, or kidney-related death) are reduced, primarily driven by albuminuria reduction. 1, 8
• The FLOW trial with semaglutide is evaluating prevention of ≥50% eGFR decline, kidney failure, or death due to kidney/cardiovascular causes. 1
• Albuminuria reduced by 8.14 mg/mmol creatinine. 5

Critical Safety Considerations and Pitfalls

Gastrointestinal Side Effects

• Nausea, vomiting, and diarrhea occur in 15-20% of patients with moderate-to-severe CKD but usually abate over several weeks to months with slow dose titration. 1, 2
• Severe vomiting can lead to dehydration and acute kidney injury in vulnerable CKD patients—this is the most important safety concern. 2
• Advise patients to maintain hydration and contact provider if unable to tolerate oral fluids. 1

Hypoglycemia Prevention

• Never combine GLP-1 RAs with DPP-4 inhibitors—this combination is contraindicated. 1, 2
• Always reduce insulin dose by ~20% when initiating GLP-1 RA. 2, 3
• Consider eliminating sulfonylureas entirely when starting GLP-1 RA, as they provide minimal benefit and increase hypoglycemia risk. 1

Contraindications

• Personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia type 2 (MEN2). 1, 4
• History of pancreatitis is a relative contraindication based on theoretical risk. 1, 2
• Avoid in patients at risk for malnutrition, as weight loss may be detrimental. 1, 2

Monitoring Parameters

• Do not discontinue GLP-1 RA if creatinine increases modestly (mean increase 3.82 μmol/L)—this is expected and not harmful. 5
• Heart rate increases by 2-5 bpm but has not been associated with adverse cardiovascular events. 1, 2
• Monitor for injection site reactions (<1% incidence). 1
• Check amylase/lipase if abdominal pain develops (mean increases of 13% and 22% respectively). 1

Special Population: Transplant Candidates

• In ESRD patients with obesity exceeding BMI limits for kidney transplant listing, GLP-1 RAs can facilitate weight loss to meet transplant eligibility criteria. 1
• This represents a critical indication where benefits clearly outweigh risks. 1

Real-World Evidence in ESRD

• A retrospective study of 46 patients with ESRD on GLP-1 RAs showed mean A1C reduction of 0.8% with no hypoglycemia in patients not on concomitant insulin. 7
• Ten cases of acute kidney injury occurred, but none in the semaglutide cohort, suggesting agent-specific safety profiles. 7
• Three patients experienced emergent hypoglycemia, all of whom were on concomitant insulin, reinforcing the need for insulin dose reduction. 7