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Page 4 of 13 Shamliyan et al. Vessel Plus 2020;4:35 I http://dx.doi.org/10.20517/2574-1209.2020.34

Table 1. Sodium-glucose cotransporter 2 inhibitors in adults with heart failure with preserved ejection fraction, the results
from post-hoc subgroup analyses of the randomized controlled clinical trials
Population Definition Outcome Treatment effect
Canagliflozin vs. Placebo the CANVAS Program [57] * ClinicalTrials.gov/NCT01032629/NCT01989754
Heart failure event with documented Fatal or hospitalized heart failure HR 0.83 (0.55-1.25)
EF of ≥ 50% at the HF admission
Heart failure event with documented Fatal or hospitalized heart failure HR 0.71 (0.52-0.97) 1
EF of ≥ 50% or assumed to be ≥ 50%
Dapagliflozin, 10 mg vs. Placebo DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial
Infarction 58) [58] ** ClinicalTrials.gov/NCT01730534
Heart failure with EF of ≥ 45% or Cardiovascular death or hospitalization for heart failure HR 0.88 (0.66-1.17)
without known reduced ejection Hospitalization for heart failure HR 0.72 (0.5-1.04)
fraction Cardiovascular death HR 1.41 (0.93-2.13)
All-cause mortality HR 1.02 (0.75-1.38)
Heart failure with EF of ≥ 45% Cardiovascular death or hospitalization for heart failure HR 0.79 (0.56-1.13)
Hospitalization for heart failure HR 0.74 (0.48-1.14)
Cardiovascular death HR 1.44 (0.83-2.49)
All-cause mortality HR 1.06 (0.71-1.59)
Heart failure with EF 45-< 55% Cardiovascular death or hospitalization for heart failure HR 0.83 (0.58-1.2)
Hospitalization for heart failure HR 0.76 (0.48-1.19)
Cardiovascular death HR 1.18 (0.69-2.01)
All-cause mortality HR 0.98 (0.66-1.46)
Ertugliflozin, 5 mg, 15 mg vs. Placebo (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) [62] *** ClinicalTrials.
gov/NCT01986881
Heart Failure with EF > 45% Cardiovascular death or hospitalization for heart failure HR 0.92 (0.61-1.39)
Cardiovascular death HR 1.08 (0.64-1.8)
All-cause mortality HR 1.01 (0.66-1.56)
Hospitalization for heart failure HR 0.70 (0.39-1.26)

1 Statistically significant differences at 95%confidence level. *Ejection fraction was assessed during retrospective secondary review
of the medical record data by one of the members of the original adjudication committee who was blinded to individual participant
treatment assignment; **Prospective baseline assessment of ejection fraction was conducted in all participants; ***Ejection fraction was
assessed from medical records when available. EF: ejection fraction; HR: hazard rate ratio

for the reduction in cardiovascular mortality, morbidity or heart failure hospitalizations in patients with
HFpEF.

Canagliflozin
Canagliflozin did not reduce the risk of fatal or hospitalized heart failure when compared with placebo in
[57]
adults with type 2 diabetes and heart failure with documented LVEF of ≥ 50% [Table 1] . Canagliflozin
reduced the risk of fatal or hospitalized heart failure in a subpopulation with heart failure and documented
LVEF of ≥ 50% [Table 1] .
[57]
The CANVAS RCTs did not examine LVEF at baseline in enrolled adults of ≥ 30 years of age with a history
of symptomatic atherosclerotic cardiovascular disease or aged ≥ 50 years with 2 or more risk factors for
cardiovascular disease [44,63] . Post hoc subgroup analysis was based on retrospective secondary review of
the medical hospitalization record data by one of the members of the original adjudication committee to
[57]
identify patients with HFpEF defined as heart failure with documented LVEF of ≥ 50% (101 patients) .
The authors conducted a sensitivity analysis assuming that patients with unknown LVEF had HFpEF (61
[57]
patients) and found a significant protective effects from canagliflozin in this combined subpopulation .

Based on post hoc interaction model and protective effects from canagliflozin in heart failure with reduced
ejection fraction (LVEF < 50%), the authors concluded similar canagliflozin benefits in the overall trial
population .
[57]