Cardiorenal effects of SGLT2 inhibitors, GLP-1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists in type 2 diabetes: a systematic review and meta-analysis

Type 2 diabetes mellitus (T2DM) is the leading cause of chronic kidney disease (CKD) and is associated with a markedly increased risk of cardiovascular morbidity and mortality. Sodium–glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and nonsteroidal mineralocorticoid receptor antagonists (NSMRAs) have independently demonstrated substantial cardiorenal benefits in large randomized controlled trials. Although these pharmacological classes act through distinct biological mechanisms, all have been incorporated into contemporary guideline-directed management of diabetic kidney disease. We performed a systematic review and meta-analysis to evaluate the overall cardiorenal effects of these contemporary therapeutic strategies while acknowledging the potential clinical heterogeneity among drug classes. This systematic review and meta-analysis was conducted according to the PRISMA 2020 statement. PubMed, Embase, Web of Science, Cochrane Library, and Google Scholar were systematically searched from January 2010 to March 2024. Randomized controlled trials enrolling adults with T2DM receiving SGLT2 inhibitors, GLP-1 receptor agonists, or NSMRAs and reporting renal and/or cardiovascular outcomes were eligible. Hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) were extracted and pooled using inverse-variance random-effects models. Clinical heterogeneity, publication bias, and sensitivity analyses were comprehensively assessed. Twenty-three randomized controlled trials comprising contemporary cardiovascular and renal outcome studies were included. Overall, treatment with SGLT2 inhibitors, GLP-1 receptor agonists, or NSMRAs was associated with significant reductions in renal adverse outcomes (pooled HR 0.72, 95% CI 0.67–0.78) and cardiovascular events (pooled HR 0.85, 95% CI 0.82–0.88). Moderate statistical heterogeneity was observed for renal outcomes (I²=43.7%), whereas cardiovascular outcomes demonstrated low heterogeneity (I²=26.3%). Sensitivity analyses confirmed the robustness of the pooled estimates. Publication bias was explored using Egger’s regression test and trim-and-fill analyses, and results were interpreted cautiously considering the limited number of included studies. Contemporary cardiorenal therapies, including SGLT2 inhibitors, GLP-1 receptor agonists, and NSMRAs, are consistently associated with improved renal and cardiovascular outcomes in adults with T2DM. Although pooling across pharmacologically distinct drug classes requires careful interpretation, the findings support current ADA and KDIGO recommendations advocating individualized use of these agents as complementary cardiorenal protective therapies. Future head-to-head trials and individual patient-data meta-analyses are warranted to better define comparative effectiveness.