High-dose Tirzepatide (10-15 mg/week) increases AKI risk, while Lixisenatide, Canagliflozin, Empagliflozin, and Dapagliflozin reduce it
Background
While glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose co-transporter 2 inhibitors (SGLT2is) are known for their protective effects against chronic kidney disease (CKD), their specific impact on acute kidney injury (AKI) has remained unclear. AKI and CKD share some clinical features but differ in their underlying pathogenesis and risk profiles. Previous analyses often broadly categorized these agents, potentially masking individual drug- and dose-specific renal safety profiles. This study addresses the critical need to evaluate the comparative AKI risk of these widely used medications at a granular level, moving beyond general assumptions of renoprotection.
Study Design
Researchers conducted a Bayesian network meta-analysis (NMA) following Cochrane-recommended methodology, specifically focusing on safety assessments. A comprehensive systematic literature search across eight databases identified 67 randomized controlled trials (RCTs), encompassing a total of 199,877 participants. Eligible trials reported AKI outcomes or explicit acute renal injury-related events associated with GLP-1RA or SGLT2i interventions. The primary outcome measured was the incidence of AKI, with all-cause dropout analyzed as a general tolerability measure. Odds ratios (ORs) with 95% credible intervals (CrIs) were calculated, and surface under the cumulative ranking curves (SUCRA) were utilized to estimate relative safety rankings.
Results
The network meta-analysis revealed differential acute kidney injury (AKI) profiles among various GLP-1RAs and SGLT2is. Notably, only high-dose tirzepatide (10-15 mg/week) was significantly associated with an increased risk of AKI when compared to control groups. This increased risk translated to an absolute risk difference of 0.28%, with a number needed to harm (NNH) of 357. Conversely, several other agents demonstrated a protective effect against AKI. > Lixisenatide, high-dose canagliflozin (300 mg/day), empagliflozin, and dapagliflozin were all associated with a reduced risk of AKI. These findings highlight the importance of evaluating individual drug and dose levels for renal safety, rather than generalizing renoprotective effects across entire drug classes.
Key Findings
- High-dose tirzepatide (10-15 mg/week) significantly increased AKI risk compared to controls.
- The absolute risk difference for AKI with high-dose tirzepatide was 0.28%, with a number needed to harm of 357.
- Lixisenatide was associated with a reduced risk of AKI.
- High-dose canagliflozin (300 mg/day) was associated with a reduced risk of AKI.
- Empagliflozin and dapagliflozin were associated with a reduced risk of AKI.
Why It Matters
This network meta-analysis provides crucial insights for both clinicians and peptide users, emphasizing that renoprotection is not uniform across all GLP-1RAs and SGLT2is, particularly concerning acute kidney injury. The finding that high-dose tirzepatide may increase AKI risk suggests a need for heightened vigilance and potentially closer renal function monitoring in patients prescribed 10-15 mg/week, especially those with pre-existing risk factors for AKI. Conversely, the identified protective effects of lixisenatide, canagliflozin, empagliflozin, and dapagliflozin against AKI could inform drug selection for individuals at higher risk of acute renal events. This study refines our understanding of these agents' safety profiles, moving beyond their established benefits in chronic kidney disease to consider acute renal outcomes, thereby impacting prescribing patterns and patient counseling.
glp-1ra
sglt2i
tirzepatide
lixisenatide
canagliflozin
empagliflozin