What are the recommendations for using Oral Hypoglycemic Agents (OHAs) in diabetic patients with Chronic Kidney Disease (CKD)?

Oral Hypoglycemic Agents in Diabetic Patients with CKD

For diabetic patients with CKD, metformin and SGLT2 inhibitors should be used as first-line therapy when eGFR ≥30 mL/min/1.73m², with dose adjustments for metformin and specific SGLT2 inhibitor selection based on eGFR levels. 1

First-Line Therapy Selection Based on Kidney Function

Metformin

• eGFR ≥45 mL/min/1.73m²: Standard dosing
• eGFR 30-44 mL/min/1.73m²: Reduce dose (typically to half the maximum dose)
• eGFR <30 mL/min/1.73m²: Discontinue 1

SGLT2 Inhibitors

• For glucose lowering:
  • Not recommended when eGFR <30 mL/min/1.73m² 1
• For cardiovascular/kidney protection:
  • Dapagliflozin: Can be used for heart failure or CKD indications with eGFR ≥25 mL/min/1.73m² 1
  • Canagliflozin: Can be used with eGFR ≥30 mL/min/1.73m² with albuminuria >300 mg/day 1
• Contraindicated in dialysis 1

Second-Line and Additional Agents

GLP-1 Receptor Agonists

• Preferred as add-on therapy when additional glycemic control is needed 1
• No dosage adjustments required for most GLP-1 RAs 1
• Particularly beneficial for patients with high cardiovascular risk 1

DPP-4 Inhibitors

• Most require dose reduction in CKD 2
• Exception: Linagliptin does not require dose adjustment in any stage of CKD 3, 4
• Safe to use in severe renal impairment and dialysis 3

Sulfonylureas

• First generation (chlorpropamide, tolazamide, tolbutamide): Avoid in all CKD stages 1
• Second generation:
  • Glipizide: Preferred sulfonylurea in CKD as it doesn't have active metabolites 1, 5
  • Glyburide: Should be avoided in renal impairment 1
  • Glimepiride: Use with caution at reduced doses when eGFR <30 mL/min/1.73m² 1

Insulin

• Can be used in all stages of CKD including dialysis 6
• Dose reduction often required as kidney function declines due to decreased insulin clearance 1
• Monitor closely for hypoglycemia 1

Special Considerations for Advanced CKD (eGFR <30) and Dialysis

1. Hypoglycemia Risk:

   • Risk increases significantly due to:
     • Decreased clearance of insulin and some oral agents
     • Impaired renal gluconeogenesis 1
   • Patients with significant creatinine elevations have a 5-fold increase in severe hypoglycemia frequency 1

2. Preferred Agents in Advanced CKD/Dialysis:

   • Insulin (with dose adjustment) 6
   • Glipizide (at reduced doses) 1
   • DPP-4 inhibitors (especially linagliptin) 3
   • Repaglinide (short-acting insulinotropic agent) 7

3. Monitoring:

   • More frequent blood glucose monitoring
   • Regular assessment of kidney function
   • Vigilance for hypoglycemia symptoms 1

Treatment Algorithm Based on CKD Stage

CKD Stage 1-3a (eGFR ≥45 mL/min/1.73m²)

1. Metformin + SGLT2i as first-line therapy
2. Add GLP-1 RA if additional glycemic control needed
3. Consider DPP-4 inhibitor or glipizide as third-line options

CKD Stage 3b (eGFR 30-44 mL/min/1.73m²)

1. Reduced-dose metformin + SGLT2i
2. Add GLP-1 RA or DPP-4 inhibitor if needed
3. Consider glipizide at low dose or insulin if further control needed

CKD Stage 4-5 (eGFR <30 mL/min/1.73m²) and Dialysis

1. Discontinue metformin and SGLT2i
2. Use insulin as primary therapy
3. Consider linagliptin or reduced-dose glipizide as alternatives
4. Avoid most other oral agents

Pitfalls and Caveats

• Metformin: Risk of lactic acidosis increases with declining kidney function; controversial cutoff for use 4
• Sulfonylureas: Increased risk of prolonged and severe hypoglycemia in CKD; use with extreme caution 7
• SGLT2 inhibitors: Reduced glucose-lowering efficacy with lower eGFR, though cardiovascular and renal benefits may persist 1
• HbA1c interpretation: May be less reliable in advanced CKD, particularly in dialysis patients, potentially underrepresenting actual glycemic control 1
• Glycemic targets: Consider less stringent targets (HbA1c ~7-8%) in patients with CKD due to increased hypoglycemia risk and limited life expectancy 1

By following these evidence-based recommendations and considering the specific characteristics of each medication class, clinicians can optimize glycemic control while minimizing risks in diabetic patients with CKD.