Page 414 - Read Online

Shamliyan et al. Vessel Plus 2020;4:35 I http://dx.doi.org/10.20517/2574-1209.2020.34 Page 5 of 13

Canagliflozin improved diastolic function in patients with type 2 diabetes in two Japanese non-randomized
controlled clinical trials [64,65] . One trial of canagliflozin in outpatients with chronic heart failure and
diabetes (CANOSSA trial: prospective, open-label, add-on trial of canagliflozin for diabetes mellitus and
[65]
stable chronic heart failure) enrolled 94% of patients with HFpEF (exact definition was not provided) .
Canagliflozin improved echocardiographic parameters of diastolic function at 6 and 12 month (P <
[65]
0.001) . The second pilot study reported improved left ventricular diastolic function after 3 months of
[64]
canagliflozin treatment although it did not specify baseline HFpEF .
Dapagliflozin
Dapagliflozin did not improve all-cause or cardiovascular death or hospitalization for heart failure in adults
[58]
with type 2 diabetes and HFpEF (LVEF ≥ 45%) [Table 1] .

DECLARE-TIMI 58 investigators conducted a prospective baseline assessment of ejection fraction in all
enrolled patients with established atherosclerotic cardiovascular disease (ASCVD) or multiple risk factors
[58]
for ASCVD and with a creatinine clearance ≥ 60 mL/min . The authors acknowledged the absence of
universally accepted definitions of HFpEF and reported outcomes in subpopulations with various baseline
LVEF thresholds (< 45%, ≥ 45%, and 45%-55%). Based on post hoc interaction model and protective
effects from dapagliflozin in heart failure with reduced ejection fraction, the authors concluded similar
[58]
dapagliflozin benefits in overall trial population .
We identified two RCTs that examined the effects from dapagliflozin on diastolic function in adults with
type 2 diabetes [66,67] . The RCT enrolling patients with heart failure reported that dapagliflozin significantly
[66]
improved diastolic function in those with baseline LVEF ≥ 45% . The second RCT that enrolled patients
without prior history of heart failure, reported that dapagliflozin had no effect on diastolic function when
[67]
compared with placebo .
Ongoing registered studies reported different definitions of HFpEF, exclusion of adults with various
thresholds of reduced LVEF (e.g., < 45% or < 50%) and various definitions of primary and secondary
outcomes [Table 2]. Available protocols did not provide details on estimated statistical power and required
sample size to detect statistically significant differences in primary outcomes.

Empagliflozin
Empagliflozin did not improve exercise tolerance, patient-reported outcomes related to the quality of life
and patient satisfaction, congestion, diuretic use and all-cause healthcare resource utilization in adults
with HFpEF enrolled in the pivotal EMPERIAL trials [59-61] . Trials enrolled adults with heart failure with
[45]
or without diabetes . The authors defined HFpEF as symptomatic heart failure with LVEF > 40% and
elevated N-Terminal Pro-Brain Natriuretic Peptide [Table 3]. The unpublished results have been presented
in the meeting of the European Society of Cardiology in June 2020 [59,60] . Some positive trends in improving
congestion after empagliflozin in HFpEF did not achieve statistical significance, possibly due to insufficient
[59]
statistical power .

The pivotal Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients
(EMPA-REG OUTCOME Trial) did not examine baseline ejection fraction but reported improvement
in diastolic dysfunction as a possible mechanism in the observed reduced cardiovascular mortality and
[68]
morbidity .
Ongoing registered studies reported different definitions of HFpEF (e.g., LVEF ≥ 40 or ≥ 50%), exclusion
of adults with various thresholds of the reduced LVEF (e.g., < 30% or < 40%) and various definitions of
primary and secondary outcomes [Table 3]. Available protocols did not provide details on estimated
statistical power and required sample size to detect statistically significant differences in primary outcomes.