GLP-1 Receptor Agonists Cut Cardiorenal Events 16-21% in CKD Patients, Semaglutide Ranks Highest

Patients with chronic kidney disease (CKD) face substantial cardiovascular and renal morbidity, often progressing to end-stage renal disease. While SGLT2 inhibitors have shown significant cardiorenal protection, there remains a need for additional therapies. GLP-1 receptor agonists (GLP-1 RAs) have demonstrated cardiorenal benefits in broader populations, but a comprehensive synthesis of their effects specifically in a CKD-restricted population, including agent-level comparisons and interaction with SGLT2 inhibitor background therapy, has been lacking.

This systematic review and meta-analysis included 13 randomized controlled trials (RCTs) with 97,428 participants, of whom 31,846 had confirmed CKD. Eligible RCTs enrolled adults with CKD (eGFR <60 mL/min/1.73 m2 or UACR ≥30 mg/g) comparing GLP-1 RAs versus placebo for at least 26 weeks. Primary outcomes were 3-point MACE (major adverse cardiovascular events) and a KDIGO-harmonised composite kidney endpoint. Random-effects pairwise meta-analyses and a frequentist network meta-analysis (NMA) were performed to assess efficacy and safety.

GLP-1 RAs significantly reduced 3-point MACE by 16% (HR 0.84, 95% CI 0.79-0.89; high certainty) and the composite kidney endpoint by 21% (HR 0.79, 95% CI 0.73-0.86; high certainty) in patients with CKD.

The risk of kidney failure was reduced by a substantial 28% (HR 0.72), and urinary albumin-to-creatinine ratio (UACR) decreased by 26%. These cardiorenal benefits were consistent and not modified by background SGLT2 inhibitor use (interaction p=0.41), indicating additive protection. In the exploratory network meta-analysis, semaglutide achieved the highest SUCRA ranking (78.4%) for kidney composite outcomes, with its direct evidence rated as high certainty by GRADE. No excess risk of acute kidney injury was observed with GLP-1 RA therapy.