What is the frequency of negative effects on kidney function in patients with impaired renal function or risk factors for kidney disease when treated with glucagon-like peptides (GLPs)?

Negative Effects of GLP-1 Receptor Agonists on Kidney Function

GLP-1 receptor agonists rarely cause negative effects on kidney function and instead demonstrate renoprotective benefits in the vast majority of patients, with acute kidney injury occurring in only 0.3-0.6% of cases, primarily in the setting of severe dehydration from gastrointestinal side effects. 1, 2

Frequency of Adverse Renal Events

Acute Kidney Injury Incidence

• Postmarketing reports document acute kidney injury and worsening of chronic renal failure in patients treated with GLP-1 receptor agonists, though the absolute frequency remains very low 1, 2
• The majority of reported acute kidney injury cases occurred in patients experiencing severe gastrointestinal reactions—specifically nausea, vomiting, diarrhea, or dehydration—rather than direct nephrotoxicity 1, 2
• Some acute kidney injury events required hemodialysis, particularly in patients without known underlying renal disease who developed severe volume depletion 1

Context: Predominant Renoprotective Effects

• In contrast to causing harm, GLP-1 receptor agonists reduce the risk of worsening kidney function by 16% (risk ratio 0.84,95% CI 0.77-0.91) across multiple large trials 3
• GLP-1 receptor agonists reduce albuminuria and slow eGFR decline, with liraglutide reducing the risk of new or worsening nephropathy by 22% 4
• The renoprotective effects appear independent of glycemic control and persist across patients with and without pre-existing chronic kidney disease 4, 3

Mechanism of Renal Events When They Occur

Volume Depletion as Primary Culprit

• Nausea occurs in 15-44% of patients taking GLP-1 receptor agonists, with vomiting in 5-25% and diarrhea in 8-32% 5
• These gastrointestinal effects are dose-dependent, typically transient, and most pronounced during initial titration 4, 5
• When severe and prolonged, these symptoms lead to dehydration and prerenal azotemia rather than intrinsic kidney damage 1, 2

Direct Renal Effects

• GLP-1 receptor agonists have direct effects on the kidney that reduce intraglomerular pressure and albuminuria through mechanisms independent of glycemia 4
• Animal studies suggest GLP-1 receptor agonists reduce oxidative stress in the kidney by >50% and blunt increases in angiotensinogen 4

Clinical Monitoring and Prevention

High-Risk Scenarios Requiring Vigilance

• Monitor renal function when initiating or escalating doses in patients reporting severe gastrointestinal reactions 1
• Patients with pre-existing moderate-to-severe chronic kidney disease (eGFR <45 mL/min/1.73 m²) require closer monitoring, though no dose adjustment is needed for semaglutide, liraglutide, or dulaglutide 5
• Exenatide and lixisenatide are not recommended if eGFR <30 mL/min/1.73 m², and exenatide weekly should be avoided with eGFR <45 mL/min/1.73 m² 5

Practical Prevention Strategies

• Slow titration starting at the lowest dose and increasing gradually every 4 weeks minimizes gastrointestinal side effects and subsequent dehydration risk 5
• Educate patients to maintain adequate hydration (at least 1.5 L/day) and seek medical attention if unable to tolerate oral fluids due to persistent vomiting 6
• Reducing meal portion sizes, limiting alcohol and carbonated beverages, and avoiding high-fat foods help manage gastrointestinal symptoms 5

Net Renal Benefit-Risk Profile

Overwhelming Evidence for Renoprotection

• GLP-1 receptor agonists reduce the composite kidney disease outcome (macroalbuminuria, eGFR decline, progression to kidney failure, or death from kidney disease) compared with placebo 4
• Treatment with GLP-1 receptor agonists significantly reduced the risk of developing persistent macroalbuminuria across multiple cardiovascular outcome trials 3
• The renoprotective effects remain consistent in patients with eGFR as low as 15-59 mL/min/1.73 m² 4

Recommendation for Patients with Kidney Disease

• GLP-1 receptor agonists are recommended for people with type 2 diabetes and chronic kidney disease, as they appear to possibly slow CKD progression while reducing cardiovascular disease risks 4
• The cardiovascular and renal benefits substantially outweigh the rare risk of acute kidney injury from volume depletion, particularly when appropriate monitoring and patient education are implemented 4, 6