Systematic Review of Cardiovascular Outcome Trials Using New Antidiabetic Agents in CKD Stratified by Estimated GFR

INTRODUCTION: Cardiovascular benefits observed with new antidiabetic agents may not extend to chronic kidney disease (CKD) patients. This study performed a systematic review and meta-analysis of cardiovascular outcome trials (CVOTs) using new antidiabetic agents stratified by kidney function. METHODS: MEDLINE (via PubMed) and the Cochrane Central Register of Controlled Trials were searched for eligible studies up to November 16, 2020. Data were stratified by the trial entry estimated glomerular filtration rate (eGFR) and albuminuria. Primary major cardiovascular event (MACE) outcomes were extracted, and a meta-analysis with a random effects model was performed to estimate overall risk ratios (RRs). RESULTS: Our search identified 16 studies for inclusion (glucagon-like peptide-1 [GLP-1] analogues, n = 6; dipeptidyl-peptidase 4 [DPP-4] inhibitors, n = 4; and sodium-glucose cotransporter-2 [SGLT-2] inhibitors, n = 6) with a combined total of 150,816 participants (28.2% with eGFR <60 ml/min per 1.73 m(2), n = 42,534). The RR for MACE with GLP-1 analogues with an eGFR ≥60 ml/min per 1.73 m(2) was 0.87 (95% confidence interval [CI], 0.77–0.98; P = 0.02) and 0.90 (95% CI, 0.78–1.04; P = 0.14) with an eGFR <60 ml/min per 1.73 m(2). The RR for MACE with DPP-4 inhibitors with eGFR ≥60 ml/min per 1.73 m(2) was 0.99 (95% CI, 0.92–1.07; P = 0.86) and 0.99 (95% CI, 0.91–1.08; P = 0.86) with an eGFR <60 ml/min per 1.73 m(2). The RR for MACE with SGLT-2 inhibitors with an eGFR ≥60 ml/min per 1.73 m(2) was 1.01 (95% CI, 0.92–1.10; P = 0.87) and 0.85 (95% CI, 0.75–0.95; P = 0.005) with an eGFR <60 ml/min per 1.73 m(2). Most analyses had significant heterogeneity. Sufficient albuminuria data were unavailable to analyze empirically. CONCLUSION: Clear evidence for MACE prevention in diabetes patients with an eGFR <60 ml/min per 1.73 m(2) currently exists for SGLT-2 inhibitors only. However, similar GLP-1 analogue effect sizes suggest a lack of sufficient power rather than a lack of effect.