What are the considerations for using Zepbound (tirzepatide) in patients with Chronic Kidney Disease (CKD)?

Zepbound (Tirzepatide) for Chronic Kidney Disease

Tirzepatide can be safely used in patients with CKD and does not require dose adjustment regardless of renal function, including in end-stage renal disease (ESRD), as renal impairment does not impact its pharmacokinetics. 1

Key Pharmacokinetic Considerations

• No dose adjustment is needed for any degree of renal impairment, including ESRD, as tirzepatide pharmacokinetics remain unchanged across all stages of kidney disease 1
• Tirzepatide is metabolized by proteolytic cleavage and beta-oxidation, with intact drug not appearing in urine or feces 1
• The drug is 99% albumin-bound with a 5-day half-life, enabling once-weekly dosing 1

Role in CKD Management Algorithm

While tirzepatide is safe in CKD, current KDIGO 2024 guidelines prioritize long-acting GLP-1 receptor agonists (not dual GIP/GLP-1 agonists like tirzepatide) for patients with type 2 diabetes and CKD who haven't achieved glycemic targets despite metformin and SGLT2 inhibitor use 2. The guideline specifically recommends choosing GLP-1 RAs with documented cardiovascular benefits 2.

Positioning in Treatment Hierarchy

For patients with type 2 diabetes and CKD, the evidence-based treatment sequence is:

1. First-line: SGLT2 inhibitors for eGFR ≥20 mL/min/1.73 m² (strong recommendation) 2, 3
2. Second-line: RAS inhibitors (ACEi or ARB) at maximum tolerated doses for albuminuria 2, 3
3. Third-line: Nonsteroidal MRAs for eGFR >25 mL/min/1.73 m² with persistent albuminuria >30 mg/g despite RASi 2, 3
4. For glycemic control: Long-acting GLP-1 RAs with proven cardiovascular benefits if targets not met 2

Clinical Efficacy Data in CKD

Real-world evidence demonstrates tirzepatide provides significant benefits in CKD patients, including:

• Hemoglobin A1c reduction of 1.15% in patients with diabetes and CKD 4
• Weight reduction of nearly 10% over 13.89 months of use 4
• Significant reductions in systolic and diastolic blood pressure and total cholesterol 4
• UACR reduction of 26.95% with 10 mg dose and 18.03% with 15 mg dose compared to placebo over 26-72 weeks 5
• Greater UACR reduction in patients with type 2 diabetes (-33.25%) compared to those with obesity alone (-7.93%) 5
• No detrimental effects on eGFR with comparable changes to insulin across all doses 5

Renal Safety Profile

Tirzepatide demonstrates an excellent renal safety profile with no increased risk of adverse renal events 5:

• No increased risk of acute kidney injury compared to placebo, insulin, or GLP-1 RAs 5
• No increased risk of urinary tract infections, nephrolithiasis, or renal cancer 5
• Safe and effective in patients undergoing hemodialysis, with significant glycemic control improvement (glycated albumin decreased from 22.7% to 18.3%) 6

Monitoring Requirements

When initiating or escalating tirzepatide doses in CKD patients, monitor renal function if severe gastrointestinal reactions occur 1:

• Check renal function at baseline
• Monitor for severe nausea, vomiting, or diarrhea that could lead to volume depletion
• Assess volume status and adjust as needed
• No routine additional monitoring beyond standard CKD care is required 1

Special Considerations for Advanced CKD

In patients with eGFR <45 mL/min/1.73 m², recognize that:

• SGLT2 inhibitors lose glucose-lowering efficacy below this threshold, though kidney and cardiovascular benefits persist 2
• Tirzepatide maintains glucose-lowering efficacy regardless of kidney function 1, 7
• Metformin should be dose-reduced at eGFR <45 and stopped at eGFR <30 mL/min/1.73 m² 2

For hemodialysis patients, tirzepatide at doses of 2.5-7.5 mg weekly effectively reduces fat mass without decreasing skeletal muscle mass, avoiding increased frailty risk 6

Contraceptive Considerations

Advise patients using oral hormonal contraceptives to switch to non-oral methods or add barrier contraception for 4 weeks after tirzepatide initiation and after each dose escalation, as delayed gastric emptying may reduce oral contraceptive efficacy 1. This effect is largest after the first dose and diminishes over time 1.

Common Pitfalls to Avoid

• Do not withhold tirzepatide based solely on reduced eGFR, as no dose adjustment is needed even in ESRD 1
• Do not combine tirzepatide with DPP-4 inhibitors, as there is no added glucose-lowering benefit beyond tirzepatide alone 2
• Do not use creatinine-based eGFR alone to assess renal function changes in obese patients receiving tirzepatide, as changes in muscle mass confound creatinine measurements; cystatin C-based eGFR provides more accurate assessment 8
• Do not discontinue SGLT2 inhibitors when adding tirzepatide, as the combination provides complementary benefits for CKD progression and cardiovascular outcomes 2

Evidence Gaps

No dedicated kidney outcomes trials for tirzepatide have been published 2, unlike SGLT2 inhibitors (empagliflozin, canagliflozin, dapagliflozin) and semaglutide, which have demonstrated hard renal endpoint benefits in CKD populations 2. Current evidence is limited to surrogate markers (UACR, eGFR) and short-term observational data 4, 5.