Sodium/glucose cotransporter 2 (SGLT2) inhibitors reduce cardiovascular (CV) mortality and heart failure (HF) hospitalizations in patients with diabetes mellitus (DM) in studies were signs and symptoms of HF were not required for inclusion [
1,
2]. These findings led to the hypothesis that SGLT2 inhibitors may represent an effective treatment of HF independent of the DM status [
3]. Accordingly, prospective, controlled trials were designed to investigate the effect of SGLT2 inhibitors, dapagliflozin (DAPA-HF, 3) and empagliflozin (EMPEROR-Reduced, 4) in HF with reduced ejection fraction (HFrEF) patients. Dapagliflozin resulted in a 26% reduction in the primary endpoint of CV death, HF hospitalizations and urgent presentations for worsening HF [
3]. This resulted in a "number needed to treat" (NNT) of 21 patients, i.e., 21 patients need to be treated to prevent one of these events. In the DAPA-HF trial, all components of the primary endpoint were similarly reduced and there was no heterogeneity between subgroups [
3]. The treatment effects of dapagliflozin were not different across all groups of renal function at baseline [
5]. Recently, the EMPEROR-Reduced trial showed a consistent 25% reduction in the primary endpoint of CV death and HF hospitalizations when empagliflozin was added to established therapy in symptomatic patients with HFrEF [
4]. In EMPEROR-Reduced, there was a 30% reduction in all HF hospitalizations (the first and all subsequent) and a significant reduction in worsening of renal function over time, reflecting a nephro-protective effect. Similarly, endpoints consisting of dialysis requirement, decline in estimated glomerular filtration rate (eGFR) by > = 40% or death from renal or CV disease were reduced by 50% [
4,
6]. Since phase II trials have shown that a natriuretic and glucosuric effect occurs not only in DM but also in non-DM patients, DAPA-HF and EMPEROR-Reduced were conducted in patients with and without DM [
3‐
6]. Two large analyses showed that effects on endpoints for both drugs [
7,
8] were not different in patients with or without DM. There was also no difference in the treatment effect of empagliflozin or dapagliflozin across the spectrum of HbA1C levels [
7,
8]. Additionally, the marked reduction of CV death and HF hospitalizations and the renal end point (slope of the change in eGFR) was similar in patients with and without ARNI treatment at baseline [
9]. Furthermore, in HF, low blood pressure is a problem that often discourages physicians from prescribing guideline-guided therapies. This is related to a fear of adverse drug effects as most of effective HF agents and to the fact that low blood pressure associates with poor prognosis [
10‐
12]. Since SGLT2 inhibitors also lower blood pressure in hypertensive patients [
13], there was concern that SGLT2 inhibitors also lower blood pressure in HF to a range that leads to intolerance [
14]. However, DAPA-HF trial showed only a small drop (1–2 mmHg) in blood pressure, which was negligible in patients with low baseline blood pressure (< 110 mmHg). At follow-up, blood pressure values rose again [
15]. Correspondingly, there were no significant differences in side effects in the individual blood pressure groups and no increased discontinuation rates due to low blood pressure [
15]. Taking together, this therapy appears to be cost-effective [
16], and so far, no subgroup showed more or less therapeutic effects in both trials. For the SGLT1/2 inhibitor, sotagliflozin, the SCORED trial including patients with DM with and without HF [
17] and SOLOIST (HF trial with inclusion of patients immediately after decompensation in patients with DM) [
18] were conducted. The endpoint of reduction of CV death and HF hospitalizations was also shown. These trials were stopped early due to the COVID-19 pandemic and loss of sponsoring and recruited less than half of the planned number of patients. Nevertheless, the results were striking enough to confirm the data from the DAPA-HF [
3] and EMPEROR-Reduced trials [
4].