Efficacy and Safety of GLP-1 Receptor Agonists on Combined Cardiovascular and Renal Outcomes in Patients With Chronic Kidney Disease: A Systematic Review and Meta-Analysis.
GLP-1 receptor agonists may reduce cardiovascular and kidney-related events in patients with chronic kidney disease, but further investigation is needed to confirm these findings and assess long-term effects.
Where it sits
this study against the rest of the albiglutide corpusSummary and findings
This systematic review and meta-analysis assessed the efficacy and safety of GLP-1 receptor agonists in patients with chronic kidney disease (CKD). A total of 13 randomized controlled trials (RCTs) involving 97,428 participants were analyzed, focusing on cardiovascular and renal outcomes. The study found a 16% reduction in major adverse cardiovascular events (MACE) and a 21% reduction in composite kidney endpoints associated with GLP-1 receptor agonists.
Abstract
<h4>Aims</h4>Chronic kidney disease (CKD) confers substantial cardiovascular and renal morbidity. GLP-1 receptor agonists (GLP-1 RAs) have demonstrated cardiorenal protection across major randomised trials, culminating in the landmark FLOW trial. No prior systematic review has simultaneously synthesised cardiorenal outcomes in a CKD-restricted population, executed a network meta-analysis for agent-level comparisons, or assessed whether SGLT2 inhibitor background therapy modifies treatment effects.<h4>Materials and methods</h4>MEDLINE, Embase, Cochrane CENTRAL, and Web of Science were searched through March 2025. Eligible RCTs enrolled adults with CKD (eGFR < 60 mL/min/1.73 m<sup>2</sup> or UACR ≥ 30 mg/g) comparing GLP-1 RAs versus placebo for ≥ 26 weeks. Primary outcomes were 3-point MACE and a KDIGO-harmonised composite kidney endpoint. Random-effects pairwise meta-analyses and a frequentist NMA were performed. GRADE certainty was assigned to all outcomes.<h4>Results</h4>Thirteen RCTs (97 428 participants; 31 846 with confirmed CKD) were included. GLP-1 RAs reduced 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). Kidney failure risk was reduced by 28% (HR 0.72); UACR decreased by 26%. Benefits were consistent irrespective of SGLT2 inhibitor background use (interaction p = 0.41). Semaglutide ranked highest in the NMA (SUCRA 78.4%). No excess acute kidney injury risk was observed.<h4>Conclusions</h4>GLP-1 RAs provide clinically meaningful cardiorenal protection in CKD, additive to SGLT2 inhibitor benefits. In exploratory network meta-analysis, semaglutide subcutaneous achieved the highest SUCRA ranking for kidney composite outcomes; the direct semaglutide evidence is rated high certainty by GRADE.
Background
This paper addresses the impact of GLP-1 receptor agonists on cardiovascular and renal outcomes in patients with chronic kidney disease (CKD). Prior research has indicated that these agents may offer cardiorenal protection, but no systematic review has synthesized outcomes specifically in CKD populations. This study is significant as it aims to clarify the efficacy of GLP-1 receptor agonists in a population at high risk for cardiovascular and renal complications.
Methods
The study conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) that enrolled adults with CKD, defined as eGFR < 60 mL/min/1.73 m² or UACR ≥ 30 mg/g. The analysis included 13 RCTs with a total of 97,428 participants, comparing GLP-1 receptor agonists to placebo for a minimum duration of 26 weeks. Primary outcomes were major adverse cardiovascular events (MACE) and a composite kidney endpoint harmonized by KDIGO.
Results
The primary endpoint showed a 16% reduction in MACE (HR 0.84, 95% CI 0.79-0.89; high certainty) and a 21% reduction in the composite kidney endpoint (HR 0.79, 95% CI 0.73-0.86; high certainty). Additionally, there was a 28% reduction in kidney failure risk (HR 0.72) and a 26% decrease in UACR. The benefits were consistent regardless of SGLT2 inhibitor background therapy, with an interaction p-value of 0.41.
Interpretation
The findings suggest that GLP-1 receptor agonists provide statistically significant reductions in both cardiovascular and renal outcomes in CKD patients. However, while the effect sizes are statistically significant, the clinical significance of these reductions should be interpreted cautiously, especially considering the potential for confounding factors such as the inclusion of various GLP-1 receptor agonists and the nature of the trials. The lack of excess acute kidney injury risk is noteworthy but does not eliminate the need for careful patient monitoring.
Key findings
- 16% reduction in MACE (HR 0.84, 95% CI 0.79-0.89; high certainty)
- 21% reduction in composite kidney endpoint (HR 0.79, 95% CI 0.73-0.86; high certainty)
- 28% reduction in kidney failure risk (HR 0.72)
- 26% decrease in UACR
- No excess acute kidney injury risk observed
Limitations
- Not reported in abstract.
- Includes a large number of participants but does not specify follow-up duration for individual trials.
- Findings may not be generalizable beyond the included studies.