What is the approach to using tirzepatide (glucagon-like peptide-1 (GLP-1) receptor agonist) in patients with Chronic Kidney Disease (CKD) stage 3?

Tirzepatide Use in CKD Stage 3

Tirzepatide can be safely used in patients with CKD stage 3 (eGFR 30-59 mL/min/1.73 m²) without dose adjustment, and should be considered as add-on therapy when glycemic targets are not met with metformin and SGLT2 inhibitors, or when these agents cannot be used. 1

Pharmacokinetic Safety Profile

• No dose adjustment is required for CKD stage 3. Renal impairment does not impact tirzepatide pharmacokinetics, as demonstrated in studies showing similar drug exposure across all stages of renal impairment including moderate CKD (eGFR 30-59 mL/min/1.73 m²) compared to normal renal function 2, 3

• The FDA label explicitly states that renal impairment does not change tirzepatide pharmacokinetics, and this has been confirmed in patients with type 2 diabetes and renal impairment based on clinical trial data 2

• A pharmacokinetic study found only a 25-29% increase in drug exposure in moderate renal impairment, which is not clinically significant and does not warrant dose modification 3

Positioning in Treatment Algorithm

Tirzepatide is recommended as third-line therapy after metformin and SGLT2 inhibitors in CKD stage 3. The treatment hierarchy is:

1. First-line: Metformin (if eGFR ≥30 mL/min/1.73 m²) plus SGLT2 inhibitor 1, 4

2. Second-line: If SGLT2 inhibitor cannot be used, add a GLP-1 receptor agonist with proven cardiovascular benefit (semaglutide, liraglutide, or dulaglutide) 1

3. Third-line: Tirzepatide can be added when individualized glycemic targets are not achieved despite metformin and SGLT2 inhibitor use, or when these medications cannot be used 1

Evidence for Kidney Benefits

• Tirzepatide reduces albuminuria in CKD stage 3. Meta-analysis shows tirzepatide 10 mg reduces UACR by 26.95% and 15 mg reduces it by 18.03% compared to placebo over 26-72 weeks 5

• eGFR is preserved with tirzepatide. Studies show no detrimental effects on eGFR, with changes comparable to insulin (ranging from +0.36 to +1.42 mL/min/1.73 m² across doses) 5

• The KDOQI commentary notes that emerging evidence shows tirzepatide reduces albuminuria and slows eGFR decline in persons with type 2 diabetes, though dedicated kidney outcomes trials have not yet been published 1

Important Clinical Considerations

Monitor renal function when initiating or escalating tirzepatide doses in CKD stage 3 patients who report severe gastrointestinal reactions. 2

• Tirzepatide has a reassuring renal safety profile with no increased risk of acute kidney injury, urinary tract infections, nephrolithiasis, or renal cancer compared to placebo, insulin, or GLP-1 receptor agonists 5

• The drug is highly protein-bound (99% to albumin) and metabolized by proteolytic cleavage rather than renal excretion, explaining why renal impairment does not affect its clearance 2

Specific Caution for CKD Stage 3

In patients on chronic thiazide diuretics (particularly hydrochlorothiazide) with CKD stage 3, monitor serum calcium within 1-2 weeks of initiating tirzepatide. A case report documented severe symptomatic hypercalcemia (corrected calcium 4.58 mmol/L) in a patient with CKD3 on chronic HCTZ who started tirzepatide 6

Glycemic Efficacy in CKD Stage 3

• Tirzepatide maintains its glucose-lowering efficacy across all stages of CKD, unlike SGLT2 inhibitors whose glycemic effects decline when eGFR falls below 45 mL/min/1.73 m² 1

• In a small study of CKD patients on hemodialysis, tirzepatide significantly reduced glycated albumin from 22.7% to 18.3% (p=0.028), demonstrating preserved glycemic control even in advanced kidney disease 7

• The drug's glucose-dependent mechanism results in low hypoglycemia risk, which is particularly important in CKD where hypoglycemia risk is elevated 1

Practical Dosing

• Start tirzepatide at 2.5 mg subcutaneously once weekly for 4 weeks, then increase to 5 mg weekly 2

• Escalate by 2.5 mg increments every 4 weeks as needed for glycemic control, up to a maximum of 15 mg weekly 2

• No dose reduction is required for CKD stage 3 2