Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review
*Correspondence: aaron.kluger@bswhealth.org (Aaron Y. Kluger)
In this systematic review, we sought to summarize the 3 recent sodium-glucose cotransporter 2 inhibitor (SGLT2i) trials (Dapagliflozin Effect on CardiovasculAR Events (DECLARE-TIMI 58), Canagliflozin Cardiovascular Assess-ment Study (CANVAS) Program, and Empagliflozin, Car-diovascular Outcomes, and Mortality in Type 2 Diabetes (EMPA-REG OUTCOME)) and to explore the potential causes for their different results. We found that the major adverse cardiovascular event rates per 1000 patient-years for drug and placebo, as well as the corresponding rela-tive risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14% for DECLARE-TIMI 58, CAN-VAS, and EMPA-REG OUTCOME, respectively. DECLARE-TIMI 58 had the fewest cardiorenal events (across treat-ment and control arms) and EMPA-REG OUTCOME the most. DECLARE-TIMI 58 used alternative inclusion crite-rion for baseline renal function (creatinine clearance ≥ 60 mL/min) compared to the other trials (estimated glomeru-lar filtration rate (eGFR) > 30 mL/min/1.73 m2 body-surface area). Therefore, the DECLARE-TIMI 58 study co-hort had higher eGFR (mean eGFR 85.2 mL/min/1.73 m2 compared to 76.5 and 74 in CANVAS and EMPA-REG OUTCOME, respectively); this may have caused the difference in results. Additionally contributing to the high event rate in EMPA-REG OUTCOME was the requirement of prior confirmed cardiovascular disease (CVD), resulting in 99.2% of patients with CVD compared to only 65.6%and 40.6% in CANVAS and DECLARE-TIMI 58, respectively (which did not require CVD). In conclusion, there is a need for large-scale studies of SGLT2i with matching inclusion/exclusion criteria and appropriate endpoints to ensure a truly direct comparison of the drugs.