The EMPEROR-Preserved trial was the first clinical trial to show a clear benefit in a composite outcome of cardiovascular mortality and HF hospitalization in patients with HFpEF. This trial analyzed the effect of empagliflozin versus placebo in a group of 5988 patients with symptomatic HF and LVEF $>$40%. There was a 21% relative risk reduction for the composite primary outcome (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.69–0.90), largely due to a 29% lower relative risk of HF hospitalization (HR 0.71; 95% CI 0.60–0.83). This effect was found to be strongest for the subgroup of patients with LVEF 50% (i.e., the mildly reduced HF [HFmrEF] subgroup), who comprised approximately one-third of the trial population (HR 0.71; 95% CI 0.57–0.88) [18]. Empagliflozin also showed a clinical benefit independent of baseline N-terminal pro-B type natriuretic peptide (NT-proBNP) or high-sensitivity cardiac troponin T levels [22]. A pooled meta-analysis of data from both EMPEROR trials found that the benefit of empagliflozin was consistent in patients with reduced and preserved LVEF, although the authors found a potential attenuation of effect in a sub-group of patients with LVEF $\ge$65% [23]. When considering potential interactions with other HF medications, the effect of empagliflozin in reducing first and total HF hospitalizations persisted regardless of concomitant treatment with mineralocorticoid antagonists [24].

More recently, the DELIVER trial, a phase III randomized clinical trial studying the effect of dapagliflozin on patients with preserved or mildly reduced LVEF (LVEF $>$40%), showed similar results [19]. DELIVER was a multicenter, event-driven, double-blind, randomized controlled trial that randomized 6263 patients to treatment with dapagliflozin 10 mg once daily or placebo. Eligible patients were at least 40 years of age, had stabilized HF with LVEF $>$40% (including patients with improved LVEF from $\le$40%), and had evidence of structural heart disease and elevated natriuretic peptides. Patients could be enrolled as outpatients or during hospitalization for HF (after stabilization). The trial found a statistically significant risk reduction of 18% in the primary composite endpoint of time to cardiovascular death or worsening HF with dapagliflozin (HR 0.82; 95% CI 0.73–0.92), mostly driven by a reduction in worsening HF events with no effect on cardiovascular mortality [19]. This effect was found to be consistent in a subgroup analysis comparing patients with LVEF $\ge$60% and LVEF 60%, showing no attenuation of benefit in patients with higher LVEF [25]. Similarly, this benefit was also found to be maintained in the subgroup of patients with improved LVEF from $\le$40% [19]. Patients with atrial fibrillation (particularly paroxysmal atrial fibrillation) were found to be at greater risk of suffering the primary endpoint (mostly due to HF hospitalizations), however, treatment with dapagliflozin (as compared to placebo) was found to be consistent regardless of the presence or absence of atrial fibrillation [26]. Benefit of dapagliflozin treatment was also found to be consistent and irrespective of frailty class [27], age [28], body mass index [29]or New York Heart Association (NYHA) functional class [30].

In the VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial) trial, which studied the effect of ertugliflozin versus placebo in a group of 8246 patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease, ertugliflozin was found to reduce the risk of first and total HF hospitalization (HR 0.70; 95% CI 0.54–0.90) [14]. The effects of ertugliflozin were similar in patients with known HFrEF and HFpEF, although it must be noted that only 23.7% of patients included in the trial had HF, 68% of whom had HFpEF (defined as LVEF $>$45%) [31].

Sotagliflozin is a dual SGLT-2 and SGLT-1 inhibitor, developed for the treatment of type 1 and type 2 diabetes mellitus. Due to its effects on SGLT-1 inhibition, sotagliflozin has an additional glucose-lowering mechanism by delaying the gastrointestinal absorption of glucose [32]. In the SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) trial, 10,584 patients with chronic kidney disease and type 2 diabetes mellitus were randomized to treatment with sotagliflozin or placebo. In this trial, 31% of the patients randomized had a previous history of HF, with a median LVEF of 60%. Approximately 21% of the patients randomized had an LVEF of greater than 40%, while 19.9% of the patients presented an LVEF of less than 40% or had been hospitalized for HF within the previous two years. Patients randomized to sotagliflozin presented a lower risk of suffering the primary endpoint of total cardiovascular deaths, HF hospitalizations or urgent HF visits (HR 0.74; 95% CI 0.63–0.88) [33].

The effects of SGLT2 inhibitors in patients hospitalized with acute HF has been studied in populations including both HFrEF and HFpEF patients. The SOLOIST-WHF (Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure) trial was a randomized, double-blind trial in which 1222 patients with type 2 diabetes mellitus who were recently hospitalized for acute decompensated HF were randomized to treatment with sotagliflozin or placebo. Approximately 20% of the patients included had HFpEF (LVEF $\ge$50%). Although the trial was stopped early due to loss of funding, sotagliflozin led to a reduction in the rate of the primary composite endpoint of total cardiovascular deaths, HF hospitalizations and urgent HF visits (HR 0.67; 95% CI 0.52–0.85) over a median of nine months follow-up [13]. The EMPULSE trial included 530 patients hospitalized for acute HF, who were randomized as soon as possible after stabilization (before hospital discharge) to treatment with empagliflozin or placebo and followed for up to 90 days. Approximately 32% of the patients included presented an LVEF $>$40%. The primary outcome was clinical benefit assessed using a win-ratio analysis, which included a composite of death from any cause, number of HF events, time to first HF event, or a change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Total Symptom Score of $\ge$5 points. In this trial, more patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio 1.36; 95% CI 1.09–1.6), an effect which was observed regardless of ejection fraction. Finally, the DELIVER trial showed that in the 654 patients included who were recently hospitalized (post-stabilization or within 30 days after discharge), dapagliflozin was also found to be effective with a 22% reduction in the primary outcome (HR 0.78; 95% CI 0.60–1.03), without an increase in adverse events [34].

In a pooled analysis of the SOLOIST-WHF and SCORED trials including 11,784 patients, sotagliflozin showed a benefit in cardiovascular outcomes across the spectrum of ejection fractions, including HFpEF [35, 36]. However, these initial data were limited as patients with HFpEF comprised a very small subgroup of both the SOLOIST-WHF and SCORED trials, making it difficult to draw firm conclusions about the effects of SGLT-2 inhibition in HFpEF from these trials [13].

Recent meta-analyses have helped to demonstrate the benefits of SGLT2 inhibition in HFpEF, mainly due to a reduced incidence of HF hospitalization as well as in the composite outcome of cardiovascular death or HF hospitalization with the use of SGLT2 inhibitors [37, 38, 39]. These meta-analyses also showed evidence for a reduced incidence of first HF hospitalization with SGLT2 inhibitors [38] and persistent benefit in a subgroup of patients with stage 3–4 chronic kidney disease and HFpEF [40].

Contrary to the results regarding HF hospitalizations, SGLT2 inhibitors have not shown a significant decrease in cardiovascular death in any of the major randomized clinical trials studying HFpEF patients [14, 18, 19, 36].

However, along with the results from the DELIVER trial, a patient-level pooled meta-analysis was published using results from two trials (DELIVER and DAPA-HF [Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure]) testing the use of dapagliflozin in patients with HF and across the range of left ventricular function (namely LVEF $>$40% and $\le$40%). This meta-analysis pooled results from 11,007 participants who were randomized to treatment with dapagliflozin or placebo, and found that dapagliflozin reduced the risk of death from cardiovascular causes, death from any cause and total HF hospitalizations, irrespective of LVEF [25]. When considering the primary composite endpoint of the DAPA-HF and DELIVER trials (that is, time to HF hospitalization or death from cardiovascular causes), dapagliflozin was found to reduce the risk of the primary outcome by 22% [25]. These results seem to be contrary to the results of the pooled EMPEROR trials, a post hoc analysis which found that treatment with empagliflozin appeared to be attenuated in patients with LVEF $\ge$65% [23]. This subgroup, however, comprised only 10% of the total trial population, and as such these results may be imprecise for patients with higher LVEF. Notwithstanding, the recent results from the dapagliflozin trials, comprising data from a larger population base, may serve to assuage the concerns from the pooled EMPEROR trials regarding the efficacy of SGLT2 inhibitors in patients with supra-normal LVEF ($\ge$65%).

In a prespecified meta-analysis including results from the 12,251 patients included in the EMPEROR-Preserved and DELIVER trials, SGLT2 inhibitors reduced the primary composite outcome of cardiovascular death or first hospitalization for HF, without evidence of significant heterogeneity between trials. Both components of the primary outcome had consistent reductions with SGLT2 inhibitor use, with demonstrated reductions in cardiovascular death, first HF hospitalization and worsening HF events when each outcome was considered separately. No significant difference in all-cause death was found [41].

When including results from five outcome trials with SGLT2 inhibitors across the range of LVEF (DAPA-HF, EMPEROR-Reduced, DELIVER, EMPEROR-Preserved and SOLOIST), the use of SGLT2 inhibitors as compared with placebo showed a reduction in the risk of cardiovascular death or HF hospitalization over an average of 23 months of follow-up, independent of LVEF, with a number needed to treat of 25 [41].

Several trials aimed to provide insights into the effect of SGLT2 inhibitors on overall health status and exercise capacity in patients with HFpEF. Recent data from the EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials analyzed the effect of empagliflozin after twelve weeks of treatment on health status in both HFrEF and HFpEF patients, with and without type 2 diabetes, but no significant differences in health status outcomes were observed in either trial [42]. However, in the DELIVER trial, dapagliflozin was associated with a statistically significant improvement in the KCCQ Total Symptom Score, with a mean improvement of 2.4 points at eight months (95% CI 1.5–3.4), although the magnitude of this improvement was mild [19].

The effect of dapagliflozin on HF-related health status was also evaluated in a previous trial, PRESERVED-HF, in which 324 patients with symptomatic HF (NYHA II-IV), elevated natriuretic peptides and LVEF $\ge$45% were randomized to 12 weeks of treatment with dapagliflozin or placebo [43]. Change in the KCCQ Clinical Summary Score after treatment was evaluated as the primary endpoint. The authors found that treatment with dapagliflozin led to a 5.8 point improvement in the KCCQ Clinical Summary Score (95% CI 2.3–9.2), mainly due to improvements in the KCCQ total symptom scores and physical limitations scores. Dapagliflozin was also associated with an increase in six-minute walking distance (6MWD). These results may thereby show evidence for an early benefit in health status and physical function with SGLT2 inhibition [43].

Amidst the COVID19 pandemic, the CHIEF-HF investigators designed a novel type of clinical trial, conducted remotely, which studied the effect of canagliflozin on health status outcomes in patients with HF, regardless of LVEF or presence of type 2 diabetes [44]. Although the trial was stopped early due to shifting sponsor priorities, the primary outcome of change in the KCCQ total symptom score was met after 12 weeks of treatment, with a 4.3 point increase in the KCCQ score in the intervention arm (95% CI 0.8–7.8). A 4.5 point increase in the KCCQ score was shown in the HFpEF subgroup, although this value was not statistically significant (95% CI –0.3–9.4) [44].

A recent meta-analysis considering differences in exercise capacity with SGLT2 inhibitors in HFpEF found that treatment with this drug class did not lead to a difference in six-minute walking distance [39]. Although the currently available results only show a mild benefit with SGLT2 inhibitor use when considering quality of life outcomes, several major international randomized clinical trials are further studying the effect of treatment with dapagliflozin (NCT03877224 and NCT04730947) and empagliflozin (NCT03753087) on the exercise capacity of HFpEF patients.

The effects of SGLT2 inhibitors on diastolic function has been established as one of the potential mechanisms for cardiovascular benefit in this drug class, particularly in experimental models [45, 46, 47]. In the EMPA-REG-OUTCOME trial, treatment with empagliflozin was associated with decreased left ventricular mass index and improved diastolic function as measured by e’ [48]. In patients with stable HF, including HFpEF, dapagliflozin has been shown to decrease E/e’ ratios as well as improved global longitudinal strain [49, 50]. When considering HFpEF patients in particular, a study analyzing the effect of the SGLT2 inhibitors luseogliflozin, empagliflozin and tofogliflozin on left ventricular function in patients with type 2 diabetes and HFpEF showed that these drugs led to a significant decrease in E/A ratios and E/e’ ratios after treatment [51]. However, in another study including patients with type 2 diabetes and HFpEF (LVEF $\ge$50%), ipragliflozin was not found to have a significant effect on diastolic function when compared with conventional treatment [52]. Ongoing studies (NCT04739215 and NCT04475042) may help further clarify the effect of SGLT2 inhibition on diastolic function in HFpEF patients.

Empagliflozin and dapagliflozin both showed a consistent benefit in HF hospitalizations regardless of baseline natriuretic peptide levels [22, 53], with dapagliflozin also showing a greater absolute effect in patients with higher baseline NT-proBNP levels [53]. When regarding specific effects of SGLT2 inhibitors on cardiovascular biomarkers, in EMPEROR-Preserved, empagliflozin led to a modest reduction in NT-ProBNP levels by approximately 7% over 100 weeks of treatment. However, most trials did not find a significant reduction in natriuretic peptide levels with SGLT2 inhibitors [54, 55, 56, 57].

In a meta-analysis considering differences in echocardiographic parameters, biomarkers and adverse events between the SGLT2 inhibitor and placebo groups, SGLT2 inhibitors significantly reduced the E/e’ ratio and the incidence of adverse events in patients with HFpEF, but did not affect natriuretic peptide levels [39].

Real-world evidence for the cardiovascular outcomes of dapagliflozin and empagliflozin in HFpEF may still be scarce, but it is important to consider the generalizability of the results of these randomized clinical trials in a real-world population. The main eligibility criteria for the DELIVER, EMPEROR-Preserved and SOLOIST trials are summarized in Table 2.

One study used data from the Swedish HF registry (SwedeHF) to assess the eligibility of a real-world population for treatment with dapagliflozin or empagliflozin according to the selection criteria of the DELIVER or EMPEROR-Preserved trials respectively [58]. When applying strict trial criteria, 30% of HFpEF patients were eligible for treatment according to the DELIVER criteria and 32% were eligible according to the EMPEROR-Preserved criteria, mainly limited by HF duration and NT-proBNP levels. However, when considering the differences between eligible and non-eligible patients, the authors found that eligible patients were more likely to be older and to have more severe HF with higher NYHA functional class, higher NT-proBNP levels and longer HF duration than non-eligible patients [58]. Real-world evidence may not be as striking as the results from randomized clinical trials, perhaps because SGLT2 inhibitors may be more likely to benefit sicker patients.

Nevertheless, it must be remembered that patients with HFpEF often present several comorbidities, aside from type 2 diabetes, which may broaden the population eligible for SGLT2 inhibition according to strict trial criteria. One such comorbidity which has been gaining emphasis in recent trials is chronic kidney disease, due to favorable renal outcomes in several landmark trials [59, 60, 61]. The CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial included patients with type 2 diabetes, chronic kidney disease (with an estimated glomerular filtration rate [eGFR] between 30 and 90 mL/min/1.73 m${}^2$) and albuminuria, and showed a decreased risk of kidney failure and progression of kidney disease in the canagliflozin group [10]. More recently, the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial included 4094 patients, irrespective of diabetes status, who presented an eGFR between 25 and 75 mL/min/1.73 m${}^2$ (CKD-EPI formula) and a urinary albumin-to-creatinine ratio $\ge$200 mg/g. The trial was stopped early due to efficacy, with a significantly lower rate of the composite outcome of a sustained decline in the eGFR of at least 50%, end-stage kidney disease or death from renal causes in the dapagliflozin group [15]. Finally, the results of the EMPA-KIDNEY trial (NCT03594110), stopped early due to positive interim efficacy, have been highly anticipated. This trial included two groups of patients with evidence of chronic kidney disease, with or without proteinuria: one group including patients with an eGFR between 20 and 45 mL/min/1.73 m${}^2$ (CKD-EPI formula); and the other including patients with an eGFR between 45 and 90 mL/min/1.73 m${}^2$ as well as a urinary albumin-to-creatinine ratio $\ge$200 mg/g (or protein:creatinine ratio $\ge$300 mg/g) [62]. In this trial, empagliflozin reduced the risk of the primary outcome (a composite of kidney disease progression or death from cardiovascular causes) by 28% (HR 0.72, 95% CI 0.78–0.95), with consistent results between subgroups and greater risk reduction in patients with higher urinary albumin-to-creatinine ratios [63]. However, there were no significant differences between the empagliflozin and placebo groups with respect to HF hospitalizations or death from cardiovascular causes, likely due to a low number of cardiovascular events during the trial [63].

In this manner, patients with HFpEF may be eligible for cardioprotective treatment with SGLT2 inhibitors when considering the presence of nephropathy or their diabetes status, and not only according to HFpEF criteria.

SGLT2 inhibitors block SGLT2 cotransporters in the proximal tubules of the kidney, thereby inhibiting renal glucose reabsorption and causing glycosuria, leading to a reduction in blood glucose levels and a reduction in HbA1c of about 0.5–1.0% in patients with diabetes, while these effects are attenuated in non-diabetic patients [64]. Aside from glycosuria, SGLT2 inhibitors were also thought to increase the excretion of urinary sodium by decreasing the reabsorption of approximately 40% of urinary sodium in the proximal tubule as well as by a mild osmotic effect [65]. However, this diuretic effect is not sustained, mainly due to the activation of adaptive renal mechanisms to reduce free water clearance, and as such may not lead to a significant change in urinary sodium concentrations [66].

A recent study which evaluated the diuretic effects of empagliflozin found that SGLT2 inhibition had a modest natriuretic effect with a synergistic natriuretic effect when combined with loop diuretics [67]. This natriuretic effect, contrary to traditional diuretics, occurs without the activation of the neurohormonal or renin–angiotensin–aldosterone systems and without increased excretion of potassium or magnesium [67]. Unlike loop diuretics, SGLT2 inhibitors do not inhibit intravascular volume sensing by the macula densa, and so do not lead to a compensatory increase in renin secretion or intraglomerular pressures [65]. This signifies that SGLT2 inhibitors do not lead to the braking phenomenon often seen with loop diuretics, where the chronic use of loop diuretics leads to the increased reabsorption of sodium by the distal nephron with a secondary decrease in natriuresis [68]. Furthermore, SGLT2 inhibitors also interact with sodium-hydrogen exchangers in the kidneys by inhibiting their action [69]. This is significant as sodium-hydrogen exchanger activity is increased in patients with HF and may be responsible in part for increased diuretic resistance in HF [70]. As such, SGLT2 inhibitors may offer a significant advantage to loop diuretics in the management of volume status in HF patients, as also suggested in studies in acute HF [71].

Additionally, increased renal sympathetic activity appears to be an important mechanism in the progression of HF due to increased activation of the renin-angiotensin system [72, 73]. Common comorbidities in HF such as diabetes and obesity are associated with chronic activation of the sympathetic nervous system [74]. In an experimental model, SGLT2 inhibition with dapagliflozin was shown to lead to decreased renal sympathetic activity in hypertensive mice, with lowered blood pressure, reduced weight gain, lower levels of inflammatory cytokines and improved endothelial function [75]. Therefore, SGLT2 inhibitors may counteract renal sympathetic overactivity in a manner which is functionally similar to renal denervation [76].

SGLT2 inhibitors may help to treat many of the comorbidities associated with HFpEF through increased natriuresis, glycosuria, and osmotic diuresis, leading to consequent reductions in body weight, blood pressure, blood glucose levels, uric acid levels and lipid profiles [69, 77, 78, 79].

A recent meta-analysis showed that SGLT2 inhibitors led to a significant reduction in body weight and body mass index in non-diabetic overweight or obese patients [80]. This weight loss appears to be induced by the glycosuric effects of SGLT2 inhibitors [81], and the resulting decrease in adiposity may lead to a reduction in the low-grade inflammation associated with fat deposition. For instance, in mice, empagliflozin has been shown to promote the utilization of fat by increasing the browning of adipose tissue. The increase in brown fat was associated with an increase in energy expenditure and was also found to induce the alternate activation of anti-inflammatory macrophages in adipose tissues [82, 83]. Additionally, SGLT2 inhibitors have been found to reduce epicardial adipose tissue [84, 85], which is an independent marker of cardiovascular risk, particularly in patients with HFpEF [86, 87]. Results from the EMPA-TROPISM study suggest that the reduction in epicardial adipose fat seen with empagliflozin may lead to a reduction in proinflammatory adipokines, which may in turn be associated with decreased aortic stiffness and decreased interstitial myocardial fibrosis in nondiabetic HFrEF patients [87, 88].

The cardiovascular benefits of SGLT2 inhibitors are preserved across the spectrum of renal function, even though the efficacy of glucose reduction is diminished at lower glomerular filtration rates [17, 89, 90]. In this manner, the favorable effects of SGLT2 inhibitors in HFpEF are not fully explained by the control of the metabolic comorbidities associated with the HFpEF syndrome and appear to be consistent across cholesterol levels [91] and independent of blood pressure reduction [90, 92, 93, 94].

Anemia is a common comorbidity in HFpEF and is frequently associated with poorer outcomes [95, 96]. In a mediation analysis of the EMPA-REG OUTCOME trial, investigators found that changes in hemoglobin and hematocrit levels mediated the effect of empagliflozin on cardiovascular mortality [97]. Smaller mediation effects were also noted with reduced uric acid levels and improved glucose metabolism in the empagliflozin group [97]. In a substudy of the EMPA-HEART (Effects of Empagliflozin on Cardiac Structure in Patients With Type 2 Diabetes) CardioLink-6 randomized clinical trial, empagliflozin treatment over six months led to an increase in plasma erythropoietin levels, increased hematocrit and reduced ferritin levels in patients with type 2 diabetes and coronary disease [98].

The use of SGLT2 inhibitors has a clear impact on cardiovascular outcomes, in particular when considering their impact on HF hospitalizations. Recent evidence supports a pleiotropic and multifaceted effect of SGLT2 inhibition, with several studies showcasing positive effects on diastolic function and cellular metabolism as further detailed below [99].

Overnutrition disease states such as type 2 diabetes and obesity are common comorbidities in HFpEF and are associated with a chronic inflammatory state [1, 3, 100, 146]. Studies have shown that autophagy, a cellular mechanism that mediates the degradation of damaged cellular components through a lysosome-dependent pathway, is impaired in overnutrition states, resulting in cellular and organ injury [147, 148, 149, 150]. Autophagy maintains cellular homeostasis through a complex mechanism dependent on multiple signaling pathways, culminating in the degradation of damaged organelles and denatured proteins through the lysosome [147, 150]. Nutrient deprivation states activate pathways that promote energy utilization and decrease energy storage, including fatty acid oxidation and resulting ketogenesis [151]. Low-energy states stimulate cellular housekeeping through autophagic flux, which reduces intracellular toxicity through the removal of lipid and glucose intermediates as well as damaged organelles [151].

SGLT2 inhibitors potentially simulate a fasting state through increased glycosuria [150]. Treatment with SGLT2 inhibitors is characterized by ketogenesis and erythrocytosis, both of which are typical responses to nutrient and oxygen deprivation [151]. It is also noteworthy that in statistical mediation analyses of large clinical trials, erythrocytosis has been identified as a consistent mediator of cardiovascular benefit with SGLT2 inhibition [97, 152]. SGLT2 inhibitors have also been shown to promote the signaling pathways associated with nutrient deprivation and hypoxia, which in turn stimulate ketogenesis, erythrocytosis and decreases in intracellular sodium [151]. The upregulation of these low-energy signaling pathways with SGLT2 inhibition also promotes autophagic flux in the heart and kidney which reduces oxidative stress, enhances mitochondrial function, suppresses proinflammatory pathways and helps to preserve cellular function and integrity [76, 150, 151]. In this way, the nutrient deprivation hypothesis may provide a unifying theory for the cardioprotective and renoprotective mechanisms behind SGLT2 inhibition [151].

Fig. 1 shows the potential mechanisms of cardiovascular benefit with SGLT2 inhibitors in patients with HFpEF. In summary, the cardioprotective mechanisms behind SGLT2 inhibition in HFpEF could be related to better control of comorbidities such as diabetes mellitus, obesity and hypertension, improved mechanism of natriuresis as compared to loop diuretics, increased ketone bodies leading to more efficient energy metabolism by cardiomyocytes, reduction of cellular stress through autophagy, amelioration of endothelial function by reducing oxidative stress and systemic inflammation and cardio-specific molecular mechanisms that may improve myocardial contractility and potentially reduce the burden of arrythmias in HFpEF.

Fig. 1.

Potential cardioprotective mechanisms of sodium-glucose cotransporter-2 inhibition in heart failure with preserved ejection fraction. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have increasingly been demonstrated to have various beneficial effects on the cardiovascular system and have recently been shown to improve outcomes in heart failure with preserved ejection fraction (HFpEF). This may be due to pleiotropic effects of SGLT2 inhibitors, well beyond their effect on glycemic control.

Considering that these benefits go beyond the effects of SGLT-2 inhibition, we agree that the more appropriate term to designate this new class of drugs would be gliflozins [153].