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Page 8 of 13 Shamliyan et al. Vessel Plus 2020;4:35 I http://dx.doi.org/10.20517/2574-1209.2020.34

Other SGLT2 inhibitors
Limited evidence from small unpublished Japanese RCTs suggested that luseogliflozin (63 patients),
and tofogliflozin (62 patients) improved diastolic dysfunction from baseline in adults with diabetes and
[71]
HFpEF . However, luseogliflozin, when compared with voglibose, did not improve diastolic dysfunction
or brain natriuretic peptide (BNP) levels in type 2 diabetes patients with HFpEF ( defined as LVEF > 45%
2 [72]
and BNP =35 pg/mL ) .
We identified 60 registered studies of ipragliflozin, sotagliflozin, luseogliflozin, or tofogliflozin that did not
report enrolling patients with HFpEF.

DISCUSSION
Our review found insufficient evidence that SGLT2 inhibitors can improve cardiovascular mortality,
morbidity or hospitalizations in patients with HFpEF. We found no studies that reported adverse effects
[73]
from SGLT2 inhibitors specifically in adults with HFpEF . Limited evidence of some improvement in
intermediate outcomes of diastolic dysfunction lack clinical significance with valid prediction of better
patient-centered outcomes and healthcare utilization required in future studies [74,75] . The absence of RCTs
that met pooling criteria precluded planned meta-analyses. Previously published indirect net-work meta-
analyses focused on intermediate outcomes of diastolic dysfunction regardless of baseline HFpEF and did
not find consistent superiority of SGLT2 inhibitors when compared with placebo or other anti-diabetic
medications [74,75] . Previously published direct meta-analysis concluded that SGLT2 inhibitors reduced the
[15]
risk of cardiovascular death or heart-failure hospitalization regardless of baseline heart failure diagnosis .
However, this meta-analysis did not look at patient outcomes depending on baseline LVEF and specifically
in patients with HFpEF .
[15]

Various definitions of HFpEF preclude valid comparisons of patient outcomes among RCTs of the same
SGLT2 inhibitor and across RCTs of different SGLT2 inhibitors [Supplementary Table 2] [28,33,34,37,76-80] .
Ongoing studies use various inclusion and exclusion criterias with a potential threat to external validity of
[81]
completed in future studies . Consistent consensus definition of HFpEF in guidelines, RCTs, and real life
clinical practice and coding is essential for valid assessment of the best treatment options in adults with
HFpEF [35,82-85] . Patient outcomes can differ depending on HFpEF diagnostic criteria and should be assessed
by HFpEF phenotypes [38,79,80] . Subgroup analyses by HFpEF diagnostic criteria and phenotypes should be
conducted with prespecified evidence-based definitions, stratified randomization and adequate sample
size [86,87] . Known interactions between HFpEF phenotypes and treatment effects should guide future studies
aimed at efficacious treatments [11,83] . Registered protocols of ongoing RCTs are inconsistent in addressing
recommendations by guidelines hard clinical outcomes including all-cause and cardiovascular mortality,
morbidity, hospitalizations, or quality of life in people with HFpEF [88,89] . Such inconsistency indicates that
the most important clinical questions regarding the benefits from SGLT2 inhibitors on patient centered
outcomes may not be answered in the upcoming years.

Available heart failure guidelines recommend SGLT2 inhibitors to reduce cardiovascular mortality and
hospitalizations in patients with diabetes [Supplementary Table 3] [5,26-28,89,90] . Some guidelines specify
recommendations of SGLT2 inhibitors in heart failure with reduced ejection fraction [5,29] . Very few
guidelines including the Canadian Cardiovascular Society and Canadian Heart Failure Society guidelines
and the American Diabetes Association Standard of Care statement acknowledge uncertainty regarding
potential benefits of SGLT2 inhibitors for patients with midrange or preserved LVEF [5,29] . Older guidelines
do not make recommendations for or against SGLT2 inhibitors aimed at the prevention of heart failure
hospitalizations or mortality [33,34,88,91] .

We found no large observational studies of SGLT2 inhibitors in HFpEF. We can speculate that inconsistencies
in diagnostic and treatment recommendations for patients with HFpEF preclude optimal treatment choices