Data from several clinical trials and meta-analyses have demonstrated a beneficial effect of SGLT2i on HF cardiac complications that goes beyond its glycemic effects (Table 2).
SGLT2i in Patients with HFrEF, with and without T2D
In 2019, the DAPA-HF study confirmed, for the first time, a significant reduction in the risk of worsening HF or death from cardiovascular causes among patients with HFrEF, in patients with and without T2D treated with this class of drugs . With a population of 4744 patients, this study analyzed whether, compared with placebo, a once-daily dose of dapagliflozin 10 mg improves morbidity, mortality, and quality of life (QoL) in symptomatic patients with HF and a LVEF ≤ 40%. The direct result of cardiovascular death or worsening HF (defined as HF hospitalization or urgent hospital visit for HF treatment) was significantly reduced (HR 0.74, 95% CI 0.65–0.85, P < 0.001) with a sustained statistically significant benefit by 28 days after randomization (HR 0.51, 95% CI 0.28–0.94, P = 0.03) .
The number needed to treat (NNT) to prevent one event was 21 over the median follow-up of 18.2 months. A decrease in the risk of other outcomes was also detected, including cardiovascular mortality (HR 0.82, 95% CI 0.69–0.98), all-cause mortality (HR 0.83; 95% CI 0.71–0.97), and HF hospitalization (HR 0.70, 95% CI 0.59–0.83). Furthermore, patients undergoing dapagliflozin treatment were more likely to show a clinically relevant improvement in their QoL after 8 months of treatment, and there was no difference in prespecified adverse severe events between the dapagliflozin and placebo groups. More importantly, there was no evidence of heterogeneity in the efficacy of dapagliflozin in any of the prespecified subgroups, including those with lower LVEF or higher N-terminal-pro B-type natriuretic peptide (NT-proBNP) levels, or in patients with more advanced age or renal insufficiency, which indicates that dapagliflozin may be just as effective in patients with more severe HF . In 2020, a published exploratory analysis of DAPA-HF showed that dapagliflozin’s efficacy was comparable over the whole range of glycosylated hemoglobin values, in both nondiabetic and diabetic populations. These results suggest that the SGLT2 inhibition with dapagliflozin has beneficial effects in HFrEF regardless of T2D status and that the mechanism of action of dapagliflozin in HFrEF extends beyond a simple glucose-lowering effect .
Furthermore, another post-hoc analysis of the DAPA-HF trial showed comparable risk reductions in HF hospitalization and mortality with dapagliflozin, regardless of previous HF therapy. These results indicate a complementary value of dapagliflozin in addition to the established combined therapy for HF and further evidence for its use in ambulatory patients with HFrEF to improve clinical outcomes . Finally, an exploratory analysis on the effect of dapagliflozin on incident T2D in the cohort without diabetes enrolled in the trial showed that treatment with dapagliflozin reduced the incidence of new diabetes  and therefore could be exerting a protective effect in these patients with HF where the risk of developing diabetes is elevated.
A beneficial independent glucose-lowering effect of SGLT2i on morbidity and mortality in patients with HFrEF, with and without T2D, was confirmed in the EMPEROR-Reduced study. In the EMPEROR-Reduced study, 3730 patients with HFrEF on recommended therapy were randomized to receive a 10 mg once-daily dose of empagliflozin or placebo. The main outcome (cardiovascular death or hospitalization for heart failure) event was significantly reduced in the empagliflozin (19.4%) group compared with the placebo (24.7%) group (HR 0.75, 95% CI 0.65–0.86, P < 0.001; NNT 19), and this reduction was consistent in patients regardless of their diabetes status. In this study, the total number of hospitalizations for HF was also lower in the empagliflozin group than in the placebo group (HR 0.70, 95% CI 0.58–0.85, P < 0.001). It is noteworthy to mention that the annual rate of decline in the estimated glomerular filtration rate (eGFR) was less in the empagliflozin group than in the placebo group (−0.55 versus −2.28 ml/min per 1.73 m2 of body-surface area per year, P < 0.001), and patients treated with empagliflozin had a decreased risk of serious renal outcomes . In patients with prediabetes or normoglycemia, empagliflozin did not lower HbA1c, and there was no increased risk of hypoglycemia, but the effects of the drug over the endpoints analyzed did not differ. When evaluated as a regular variable, baseline HbA1c did not significantly alter the advantages of empagliflozin on the primary outcome (P-interaction = 0.40), suggesting an independent glucose-lowering effect .
A meta-analysis using data from both previous studies confirms earlier findings on the reduction of HF hospitalization by SGLT2 inhibition and confirms that these agents also improve renal outcomes (composite renal endpoint HR 0.62, 95% CI 0.43–0.90, P = 0.013) and reduce all-cause death (pooled HR 0.87, 95% CI 0.77–0.98, P = 0.018) and cardiovascular death (pooled HR 0.86, 95% CI 0.76–0.98, P = 0.027) in patients with HFrEF. It is noteworthy to mention that the pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI, and baseline eGFR .
SGLT2i in Patients with HFpEF, with and without T2D
Although there is no universal conception of HFpEF, and the effects of SGLT2i are considered to be related to the studies’ design, SGLT2i are the only drugs that have shown efficacy in patients with HFpEF. Very recently, in the EMPEROR-Preserved Trial carried out in 5988 patients with HF and EF > 40%, empagliflozin was also demonstrated to reduce the combined risk of cardiovascular death or hospitalization for HF in patients with HFpEF (HR 0.79, 95% CI 0.69–0.90, P < 0.001), regardless of the presence or absence of diabetes, with an NNT of 31. This effect was mainly related to a lower risk of hospitalization for HF in the SGLT2 inhibitor (empagliflozin 10 mg) group . Recently, the US Food and Drug Administration (FDA) approved empagliflozin for the treatment of adults with HF regardless of the phenotype of the condition .
Taking into account these results, the unique mechanism of action of SGLT2i across the EF spectrum, and the collective experience from prior HFpEF trials showing that treatment effect with currently available therapies declined with increasing LVEF, the DELIVER trial has been designed to determine the efficacy and safety of the SGLT2 inhibitor dapagliflozin, added to conventional therapy, in patients with HF and preserved and mildly reduced EF. In this study, a total of 6263 patients with or without diabetes, with signs and symptoms of HF, an LVEF > 40%, elevation in NPs, and evidence of structural heart disease are eligible. The primary endpoint is time to first cardiovascular death or worsening HF event (HF hospitalization or urgent HF visit), and will be assessed in dual primary analyses—the full population and in those with LVEF < 60%. This study will provide complementary information to DAPA-HF, and the results of both studies will be pooled to assess the effects of dapagliflozin across the EF spectrum .
Finally, patients with HF and HFpEF have a high burden of symptoms and functional limitations, and have a poor quality of life. In this regard, a recent multicenter, randomized trial of patients with HFpEF (PRESERVED-HF) showed that 12 weeks of dapagliflozin treatment, by targeting cardiometabolic abnormalities, significantly improve patient-reported symptoms [improved KCCQ-CS 5.8 points (95% CI 2.3–9.2, P = 0.001)], physical limitations [improved 5.3 points (95% CI 0.7–10.0; P = 0.026)], and exercise function [improved 6MWT 20.1 m (95% CI 5.6–34.7, P = 0.007)] and was well tolerated in chronic HFpEF .
SGLT2i in Hospitalized Patients with T2D with Decompensated HF (HFrEF and HFpEF)
Another recent study, the SOLOIST-WHF trial (effect of sotagliflozin on cardiovascular events in patients with type 2 diabetes post worsening heart failure), focused on a different clinical scenario. This study analyzed the safety and efficacy of SGLT2i when initiated soon after an episode of decompensated HF. Patients with T2D recently hospitalized for worsening HF were randomly assigned to receive sotagliflozin or placebo and were followed up for an average of 9.0 months. In these patients with T2D with newly diagnosed, worsening heart failure, sotagliflozin therapy started before or shortly after discharge resulted in a significantly lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for HF than placebo (HR 0.67, 95% CI 0.52–0.85, P < 0.001). This result was consistent regardless of EF at study entry, including patients with EF > 50%. The percentage of patients with low blood pressure was comparable in both the sotagliflozin and placebo groups (6.0% and 4.6%, respectively), as was the percentage with acute kidney injury (4.1% and 4.4%, respectively). The benefits derived from sotagliflozin therapy were consistent in the prespecified subgroups of patients stratified according to the timing of the first dose .
Addressing the vulnerable period of hospital admission for worsening HF, a meta-analysis including SOLOIST and SCORED data found a reduction in the primary endpoint (total death, hospitalized HF, urgent HF visit) independent of the ejection function [HFrEF (< 40%), HFmrEF (40–50%) or HFp (> 50%)] and an NNT of 9 as well as the existence or not of a previous history. This highlights the benefits of SGLT2i across the cardiorenal continuum, with different molecules and in different clinical settings .