Key result
Differences in baseline renal function and cardiovascular disease inclusion criteria likely explain the varying cardiorenal event rates and effect sizes across the three major SGLT2 inhibitor trials.
Why the study?
Do SGLT2 inhibitors as a class reduce major adverse cardiovascular events and cardiorenal outcomes in adult patients with Type 2 Diabetes Mellitus?
Systematic Review (n=34,322)
Do SGLT2 inhibitors as a class reduce major adverse cardiovascular events and cardiorenal outcomes in adult patients with Type 2 Diabetes Mellitus?
Differences in baseline renal function and cardiovascular disease history across SGLT2 inhibitor trials likely explain the variations in their cardiorenal event rates and relative risk reductions.
Supports SGLT2 inhibitor use in T2DM; confirms class MACE reduction while attributing absolute rate differences to baseline eGFR and CVD history.
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.
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Kluger et al. (2018) conducted a systematic review in Type 2 diabetes mellitus (n=34,322). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) vs. Placebo was evaluated on Major adverse cardiovascular events (MACE). Differences in baseline renal function and cardiovascular disease inclusion criteria likely explain the varying cardiorenal event rates and effect sizes across the three major SGLT2 inhibitor trials.
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