Page 411 - Read Online

Page 2 of 13 Shamliyan et al. Vessel Plus 2020;4:35 I http://dx.doi.org/10.20517/2574-1209.2020.34

regardless of heart failure type, small number of events, and probable publication bias hampered the quality of
evidence.

Conclusion: Existing evidence is insufficient to support definitive clinical recommendations for use of SGLT2-
inhibitors in adults with HFpEF. Future research should employ consistent definitions of HFpEF and examine the
effects from SGLT2- Inhibitors in patients with various HFpEF phenotypes and underlying causes.

Keywords: Sodium-glucose cotransporter-2 - inhibitors, heart failure with preserved ejection fraction,
cardiovascular mortality, heart failure hospitalization, systematic literature review, grading of recommendations
assessment, development and evaluation methodology

INTRODUCTION
Heart failure with preserved ejection fraction (HFpEF) presents a significant and growing clinical and
[1-4]
economic burden in aging populations, specifically with prevalent arterial hypertension and diabetes .
Estimated 1-year all-cause mortality rates of 33% and all cause readmission rates of 67% in patients with
[3]
HFpEF have not improve over the last decade in the US . Diabetes is a widely recognized risk factor
[5,6]
for cardiovascular morbidity and mortality . Although emerging treatments improved cardiovascular
[7,8]
outcomes in people with diabetes , no treatments have been proven to improve survival and reduce
health care utilization in people with HFpEF [9-14] . Sodium-glucose cotransporter-2 (SGLT2)- inhibitors
are found to improve survival in heart failure with reduce ejection fraction and reduce the risk of
major cardiovascular events including heart failure hospitalizations in adults with type 2 diabetes [15-19] .
Empagliflozin and canagliflozin have been approved by the US Food and Drug Administration (FDA) to
reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease
while dapagliflozin has also been approved to reduce the risk of cardiovascular death and hospitalization
for heart failure in adults with reduced left ventricular ejection fraction (LVEF ≤ 40%) [20-25] . Recent
evidence-based guidelines recommend SGLT2- inhibitors for the improvement in cardiovascular outcomes
in adults with type 2 diabetes [26-29] . However, the evidence regarding the benefits from SGLT2- inhibitors in
adults with HFpEF has not been systematically reviewed and appraised. We conducted a systematic rapid
literature review of all completed and ongoing clinical studies aimed at patient outcomes in adults with
HFpEF.

METHODS
We conducted our review according to the developed priori protocol [30-32] . We hypothesized that SGLT2-
inhibitors improve cardiovascular mortality, morbidity and hospitalizations in adults with HFpEF, with or
without diabetes [33-38] .

Eligible interventions included SGLT2- inhibitors regardless of country’ approval [Supplementary Table 1]
focusing on the availability in the US, for example dapagliflozin, canagliflozin, empagliflozin and
ertugliflozin [Supplementary Table 2]. We included studies that compared SGLT2- inhibitors with
antidiabetic medications or placebo. We abstracted reported number of events or rates of all-cause and
cardiovascular mortality, incident or progressing of heart failure, and hospitalizations for heart failure [14,39] .
We also looked at the reported intermediate outcomes, e.g., exercise tolerability and the quality of life or
other patient reported outcomes as defined in the primary studies [40-45] .

We conducted a comprehensive search with MeSH terms and key words in PubMed, Scopus, the Cochrane
Library, www.clinicaltrials.gov, the World Health organization International Clinical Trials Registry
Platform, Health Technology Assessment databases, and regulatory agencies up to October 2020 to find