Should peptide therapy be stopped in a patient with declining kidney function who is currently on a GLP-1 (Glucagon-Like Peptide-1) receptor agonist, such as dulaglutide (Trulicity), liraglutide (Victoza), or semaglutide (Ozempic)?

GLP-1 Receptor Agonist Management in Declining Kidney Function

Direct Recommendation

Do not routinely stop GLP-1 receptor agonists (dulaglutide, liraglutide, or semaglutide) when kidney function is declining—these medications can be safely continued even with severe chronic kidney disease (eGFR <30 mL/min/1.73 m²) and may provide renal protection. 1

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Evidence-Based Rationale

GLP-1 Receptor Agonists Are Safe Across All Stages of CKD

• No dose adjustment is required for dulaglutide, liraglutide, or semaglutide regardless of kidney function, including end-stage renal disease (ESRD). 1, 2, 3
• The FDA labels for dulaglutide and semaglutide explicitly state that no clinically relevant change in pharmacokinetics occurs in patients with renal impairment, including ESRD. 2, 3
• Liraglutide pharmacokinetic studies demonstrate no increased drug exposure with declining creatinine clearance, even in patients requiring continuous ambulatory peritoneal dialysis (CAPD). 4

GLP-1 Receptor Agonists Provide Renal Protection

• GLP-1 receptor agonists reduce albuminuria and slow eGFR decline, as demonstrated in cardiovascular outcomes trials and dedicated renal studies. 1
• Liraglutide significantly improved eGFR slopes from -2.75 to -1.42 mL/(min·1.73 m²·year) over 7 years, with more pronounced benefits in patients with baseline eGFR <45 mL/min/1.73 m². 5
• Semaglutide reduced urinary albumin-to-creatinine ratio (UACR) by 26-34% compared to placebo across the SUSTAIN trials, with greater reductions in patients with pre-existing microalbuminuria or macroalbuminuria. 6
• A meta-analysis of 8 cardiovascular outcomes trials showed GLP-1 receptor agonists significantly reduced risk for composite kidney disease outcomes (macroalbuminuria, eGFR decline, progression to kidney failure, or death from kidney disease). 1

Preferred Agents for Advanced CKD

For patients with eGFR <20 mL/min/1.73 m², GLP-1 receptor agonists are the preferred glucose-lowering agents over SGLT2 inhibitors. 1

• Weekly formulations (dulaglutide, semaglutide) or daily liraglutide are specifically recommended for this population. 1
• If a patient is already on canagliflozin or dapagliflozin when eGFR falls below 20 mL/min/1.73 m², continue the SGLT2 inhibitor for cardiovascular and renal benefits, but do not initiate new SGLT2 inhibitor therapy at this level. 1

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Clinical Decision Algorithm

Step 1: Assess Current eGFR and Trajectory

• eGFR ≥30 mL/min/1.73 m²: Continue current GLP-1 receptor agonist at standard dose. 1, 2, 3
• eGFR 20-29 mL/min/1.73 m²: Continue current GLP-1 receptor agonist; consider adding or continuing SGLT2 inhibitor if already prescribed. 1
• eGFR <20 mL/min/1.73 m²: Continue GLP-1 receptor agonist; prefer GLP-1 receptor agonist over initiating new SGLT2 inhibitor. 1

Step 2: Monitor for Gastrointestinal Adverse Events

The primary safety concern is not declining kidney function itself, but rather gastrointestinal symptoms that could lead to volume depletion and acute kidney injury. 7

• Monitor patients experiencing severe nausea, vomiting, or diarrhea with laboratory tests (serum creatinine, eGFR). 2
• Discontinue GLP-1 receptor agonist temporarily if acute worsening of kidney function occurs in the setting of severe gastrointestinal symptoms. 7
• Most adverse kidney events with GLP-1 receptor agonists have occurred in patients with gastrointestinal symptoms leading to dehydration. 7

Step 3: Understand Expected eGFR Changes

An initial transient decline in eGFR may occur with semaglutide but does not indicate harm. 6

• Semaglutide causes an initial eGFR decrease of 2-3 mL/min/1.73 m² from baseline to week 12-16, which then plateaus. 6
• After the initial dip, eGFR stabilizes and long-term decline is similar to or better than placebo. 6
• In SUSTAIN 6, overall eGFR decline from baseline to week 104 was similar between semaglutide and placebo (ETD 0.07-0.97 mL/min/1.73 m²). 6

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Critical Caveats and Pitfalls

Do Not Confuse Initial eGFR Dip with Drug Toxicity

• The initial eGFR decline with GLP-1 receptor agonists (particularly semaglutide) is hemodynamic and reversible, not nephrotoxic. 6
• This pattern mirrors the beneficial "eGFR dip" seen with SGLT2 inhibitors and RAS inhibitors. 1
• Do not discontinue therapy based solely on this initial decline unless accompanied by severe gastrointestinal symptoms or signs of acute kidney injury. 6

Limited Experience Does Not Equal Contraindication

• While FDA labels note "limited clinical experience" in patients with severe renal impairment, this reflects study enrollment criteria, not safety concerns. 2, 3, 4
• The available pharmacokinetic and clinical data support safe use across all stages of CKD. 2, 3, 4

Specific Considerations for Each Agent

Dulaglutide:

• Use with caution in ESRD, but no dose adjustment required. 2
• Monitor renal function in patients reporting severe gastrointestinal reactions. 2

Liraglutide:

• Can be used in patients with eGFR as low as 15 mL/min/1.73 m² based on cardiovascular outcomes trial data. 1
• Regression analysis showed no significant effect of decreasing creatinine clearance on liraglutide pharmacokinetics. 4

Semaglutide:

• No dose adjustment required for any degree of renal impairment, including ESRD. 3
• Expect initial eGFR decline that stabilizes after 12-16 weeks. 6

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When to Actually Stop GLP-1 Receptor Agonists

Absolute Indications for Discontinuation

1. Severe gastrointestinal symptoms with acute kidney injury: Discontinue if patient develops severe nausea/vomiting/diarrhea AND acute worsening of kidney function. 7
2. Initiation of kidney replacement therapy (dialysis): While not contraindicated, clinical experience is limited and benefit may be reduced. 2
3. Pregnancy: Discontinue at least 2 months before planned pregnancy due to long washout period. 3

Relative Indications for Caution (Not Discontinuation)

• Pre-existing gastroparesis: Use with caution but not contraindicated. 2
• History of pancreatitis: Consider alternative agents but not an absolute contraindication. 8

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Combination Therapy Considerations

When eGFR is declining, optimize multi-drug renal protection rather than stopping individual agents. 1

• Continue RAS inhibitor (ACE inhibitor or ARB) even when eGFR falls below 30 mL/min/1.73 m². 1
• Continue SGLT2 inhibitor if already prescribed, even if eGFR falls below 20 mL/min/1.73 m². 1
• Add GLP-1 receptor agonist if not already prescribed, particularly for patients with eGFR <20 mL/min/1.73 m² who cannot initiate SGLT2 inhibitors. 1
• Consider nonsteroidal mineralocorticoid receptor antagonist (finerenone) for patients with persistent albuminuria despite RAS inhibitor and SGLT2 inhibitor. 1