Network Meta-Analysis on the Effects of Finerenone Versus SGLT2 Inhibitors and GLP-1 Receptor Agonists on Cardiovascular and Renal Outcomes in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease

Objective: To evaluate the cardiovascular and renal benefits of finerenone, sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagonlike peptide-1 receptor agonists (GLP-1 RA) in patients with Type 2 Diabetes Mellitus (T2DM) and chronic kidney disease (CKD) with network meta-analysis.Methods: Systematic literature searches were conducted of PubMed, Cochrane Library, Web of Science, Medline and Embase covering January 1, 2000 to December 30, 2021. Randomized control trials (RCTs) comparing finerenone, SGLT-2i and GLP-1 RA in diabetics with CKD were selected. We performed a network meta-analysis to compare the three drugs indirectly. Results were reported as risk ratio (RR) with corresponding 95% confidence interval (CI).Results: In all, 17 RCTs were selected, including 51,496 patients. Finerenone reduced the risk of major adverse cardiovascular events (MACE), renal events and hospitalization for heart failure (HHF) (RR [95%CI]; 0.88 [0.80-0.97], 0.86 [0.79–0.93], 0.79 [0.67,0.92], respectively). SGLT-2i were associated with reduced risks of MACE (RR [95%CI]; 0.84 [0.78–0.90]), renal events (RR [95%CI]; 0.67 [0.60–0.74], HHF (RR [95%CI]; 0.60 [0.53–0.68]), all-cause death (ACD) (RR [95%CI]; 0.89 [0.81–0.91]) and cardiovascular death (CVD) (RR [95%CI]; 0.86 [0.77–0.96]) compared to placebo. GLP-1 RA were associated with a lower risk of MACE (RR [95%CI]; 0.88 [0.80–0.97]). As for renal outcomes and HHF, SGLT2i had significant effect in comparison to finerenone (finerenone vs SGLT2i: RR [95%CI]; 1.29 [1.13–1.47], 1.31 [1.07–1.61], respectively) and GLP-1 RA (GLP-1 RA vs SGLT2i: RR [95%CI]; 1.36 [1.16–1.59], 1.49 [1.18–1.89], respectively). It can be concluded that all three kinds of drugs were comparable in MACE, ACD and CVD. When the risk of cardiovascular events arise in DM patients with CKD, SGLT2i，finerenone and GLP-1 analogues can be considered, as all three drugs share resemblance in the ability of lowering cardiovascular risks, but should renal events becomes a priority, then SGLT2i should be recommended. Compared with placebo, there was a trend toward reduction in ACD with finerenone (RR [95%CI]; 0.90 [0.80–1.00]). GLP-1 RA did not reduce the risk of renal events, HHF, CVD and ACD, but the analysis based on chemical structure showed that a GLP-1 analogues, liraglutide (RR [95%CI]; 0.79 [0.67–0.92], 0.69 [0.52–0.90], 0.76 [0.62–0.93], respectively) showed significant effect in HHF, CVD and ACD, while an exendin-4 analogues, exenatide (RR [95%CI]; 1.10 [0.83–1.46], 1.19 [0.84–1.69], 1.10 [0.87–1.39], respectively), did not.Conclusions: In patients with T2DM and CKD, finerenone led to a risk reduction in MACE, renal events and HHF, SGLT2i were associated with a decreased risk of cardiovascular and renal events. GLP-1 RA were associated with a decreased risk of MACE. And all three kinds of drugs were comparable in MACE, ACD and CVD. SGLT2i significantly decreased the risk of renal events and HHF compared with finerenone and GLP-1 RA. Among GLP-1 RA, GLP-1 analogues showed significantly reduced cardiovascular events compared with exendin-4 analogues.