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Rev Cardiovasc Med. 2018 Jun 30;19(2):41-49. doi: 10.31083/j.rcm.2018.02.907.

Cardiorenal Outcomes in the CANVAS, DECLARE-TIMI 58, and EMPA-REG OUTCOME Trials: A Systematic Review.

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Baylor Heart and Vascular Institute, Dallas, TX, 75226.
Baylor Scott & White Research Institute, Dallas, TX, 75226.
Texas A & M College of Medicine Health Science Center, Dallas, TX, 75226.
Baylor University Medical Center, Dallas, TX, 75226.
Baylor Heart and Vascular Hospital, Dallas, TX, 75226.
UIC/Advocate Christ Medical Center, Oak Lawn, IL, 60453.
Einstein Medical Center, Philadelphia, PA, 19141.
Sidney Kimmel College of Thomas Jefferson University, Philadelphia, PA, 19107.
David Geffen School of Medicine at UCLA, Los Angeles, CA, 90095.
Cedars-Sinai Medical Center, Los Angeles, CA, 90048.
University of Utah School of Medicine, Salt Lake City, UT, 84132.


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 Assessment Study (CANVAS) Program, and Empagliflozin, Cardiovascular 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 relative risk reductions, were 22.6, 24.2, 7%; 26.9, 31.5, 14%; 37.4, 43.9, 14% for DECLARE-TIMI 58, CANVAS, and EMPA-REG OUTCOME, respectively. DECLARETIMI 58 had the fewest cardiorenal events (across treatment and control arms) and EMPA-REG OUTCOME the most. DECLARE-TIMI 58 used alternative inclusion criterion for baseline renal function (creatinine clearance ≧ 60 mL/min) compared to the other trials (estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 bodysurface area). Therefore, the DECLARE-TIMI 58 study cohort had higher eGFR (mean eGFR 85.2 mL/min/1.73 m2 compared to 76.5 and 74 in CANVAS and EMPAREG 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.


CANVAS; EMPAREG OUTCOME; DECLARETIMI 58; SGLT-2 inhibitor; canagliflozin; dapagliflozin; empagliflozin; ertugliflozin; sotagliflozin

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Conflict of interest statement

The authors declare no competing interests.

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