Despite the current advancements in medical treatment of HF, this condition remains an important problem in terms of its socioeconomic significance because of the progressive nature of this disease and age-related changes in the population. There are various phenotypes of HF that have a different clinical presentation. Thus, heart failure with preserved ejection fraction (HFpEF) constitutes up to one half of all HF patients. The incidence of this phenotype increases due to population aging and the rising prevalence of obesity, hypertension, diabetes mellitus, chronic kidney disease, and atrial fibrillation. In contrast to heart failure with reduced ejection fraction (HFrEF), therapeutic advances in HFpEF have not been achieved previously. Until very recently, there has not been any pharmacological treatment that could reduce the incidence of cardiovascular mortality and HFpEF-related hospitalizations^1-2.

HFpEF is a complex and diverse disorder that is marked by the manifestation of features associated with HF, including preservation of left ventricular ejection fraction, which is usually above 50%. Besides, it is also associated with abnormal ventricular relaxation and stiffness, increased ventricular pressure, and different degrees of systemic inflammation and endothelial dysfunction³. There are various mechanisms of HFpEF beyond diastolic dysfunction, and this includes interactions between myocardial remodeling, microvascular dysfunction, neurohormonal activation, metabolic dysfunction, renal dysfunction, and non-cardiac diseases. This complexity has made HFpEF less responsive to many therapies used for traditional HF, including renin–angiotensin–aldosterone system inhibitors and neurohormonal agents⁴.

Initially, Sodium-Glucose Cotransporter-2 (SGLT2) inhibitors were discovered as glucose-lowering medications used to treat type 2 diabetes mellitus through the inhibition of glucose reabsorption in the proximal renal tubule, leading to glucosuria and natriuresis. Unexpectedly, the cardiovascular outcome studies showed that the use of these drugs has a significant effect on the cardiovascular system and kidneys without considering their action on glycemia. Randomized controlled trials have shown the effectiveness of SGLT2 inhibitors in HFrEF patients irrespective of whether they have diabetes or not, which led to research into their potential in HFpEF patients⁵.

The pathophysiological pathway by which SGLT2 inhibitors provide benefit for the heart seems to be complex. Pathways proposed include osmotic diuresis and natriuresis with selective loss of interstitial fluid, improved ventricular load conditions, decreased cardiac fibrosis and inflammation, improvement in myocardial energy metabolism by increasing ketone body uptake, decreased oxidative stress, prevention of renal damage, and alteration of sympathetic nerve activity. Overall, the various actions may help in improving ventricular compliance and decreasing filling pressures, which could help in delaying disease progression in HFpEF^3-4.

The paradigm shift in the treatment strategy of HFpEF was marked by the findings from the EMPEROR-Preserved trial where empagliflozin showed a statistically significant reduction in the composite endpoint of cardiovascular mortality or hospitalization for heart failure in patients with left ventricular ejection fraction greater than 40% mostly because of fewer HF hospitalizations⁶. These results were further corroborated by the findings from the DELIVER trial where dapagliflozin showed similar benefits in the cohort of patients with mildly reduced and preserved ejection fraction irrespective of the presence or absence of diabetes⁷. Pooled and subgroup analyses along with real-world studies have shown similar benefits regarding HF hospitalization, symptoms, function, and quality of life apart from renoprotection⁸.

While there have been several systematic reviews and meta-analyses that have attempted to investigate the efficacy of SGLT2 inhibitors for HFpEF, the growing body of evidence due to the follow-up data from studies, post-hoc analysis, and updates on clinical practices calls for a review of available literature. In addition, the current body of evidence poses some unresolved issues that require clarification including patient selection, comparative effectiveness of different SGLT2 inhibitors, safety in elderly patients, etc.

Therefore, this systematic review aims to comprehensively evaluate the current evidence regarding the effectiveness of SGLT2 inhibitors in patients with HFpEF. Specifically, this review synthesizes findings from randomized controlled trials, observational studies, and contemporary clinical evidence concerning cardiovascular outcomes, hospitalization for heart failure, mortality, quality of life, renal outcomes, and safety profiles, while highlighting current guideline recommendations, existing knowledge gaps, and future directions for research and clinical practice.

Study Design The current systematic review was undertaken with the aim of providing a thorough assessment of the efficacy of sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF). The process of conducting this systematic review adhered to the guidelines set out in the PRISMA 2020 Statement. A comprehensive electronic literature search was conducted across the following databases: PubMed, Google Scholar, Web of Science and Scopus. The search included studies published from January 2019 and January 2026, thereby capturing evidence generated after the emergence of major cardiovascular outcome trials evaluating SGLT2 inhibitors in HFpEF. Search Strategy Medical Subject Headings (MeSH) and free-text keywords were combined using Boolean operators (AND/OR). The search strategy included terms related to HFpEF and SGLT2 inhibitors. A representative PubMed search strategy is presented below: ("Heart Failure with Preserved Ejection Fraction" OR HFpEF OR "Diastolic Heart Failure") AND ("SGLT2 inhibitor*" OR "Sodium-Glucose Cotransporter 2 Inhibitor*" OR empagliflozin OR dapagliflozin OR canagliflozin OR ertugliflozin OR sotagliflozin) AND (randomized controlled trial OR clinical trial OR cohort study OR observational study). Eligibility Criteria Inclusion Criteria:  Adults of ≥18 years with diagnosis of HFpEF included.  At least one SGLT2 inhibitor evaluated.  Clinical outcomes such as cardiovascular mortality, heart failure hospitalization, all-cause mortality, renal outcomes, quality of life, functional capacity, or adverse events reported.  Randomized controlled trials, prospective/retrospective cohort study, registry data, post-hoc analysis, or real-world observational studies.  Peer-reviewed literature published.  English-language literature. Exclusion Criteria:  Commentaries, editorials, letters, conference abstracts without associated peer-reviewed full papers, case reports, and case series.  Studies based on animal or laboratory research.  Studies were conducted only in patients with heart failure with reduced or mild reduced ejection fraction, excluding cases where data from HFpEF were available.  Duplicate reports or studies with overlapping data sets, where in this case the most complete paper was selected. Study Selection All articles retrieved from the electronic database search were exported to reference manager software and duplicate references were eliminated. Titles and abstracts of articles were screened independently by considering the inclusion/exclusion criteria set up at the very beginning. The full texts of studies that might be eligible for inclusion were examined next. Disagreements about study eligibility were addressed by discussion and reaching consensus. The entire process of study selection is described in a PRISMA 2020 flow diagram (figure 4) Data Extraction A standardized data extraction form was developed before the review process. The following information was extracted from each included study: • First author • Year of publication • Country • Study design • Sample size • Patient characteristics • Mean age • Percentage of female participants • Type and dosage of SGLT2 inhibitor • Duration of follow-up • Primary and secondary outcomes • Key findings • Adverse events Data Analysis The studies included in the review were classified based on the themes. The themes include cardiovascular events, hospital admission due to heart failure, mortality, quality of life, renal outcomes, and safety. Consistencies and inconsistencies across the studies were critically analyzed especially with the key randomized clinical trials and sub-group analysis done after these trials. This is important to ascertain the quality and consistency of evidence currently available and areas that require more research. Quality Assessment of included studies The methodological quality of the studies that were included in the review was analyzed based on their study design. Randomized controlled trials were analyzed using the revised version of Cochrane Risk of Bias 2 (RoB 2), whereas observational studies were analyzed using the Newcastle-Ottawa Scale (NOS). Some of the domains analyzed include randomization, deviation from interventions, outcome data, outcome measurement, selective reporting, selection of participants, comparability, and ascertainment of outcome. Risk of bias assessment The methodological quality of each study was analyzed based on the type of study design. Randomized clinical trials were assessed for their risk of bias using the Cochrane Risk of Bias 2 (RoB 2), while observational studies were rated for methodological quality using the Newcastle-Ottawa Scale (NOS). The majority of randomized clinical trials exhibited low overall risk of bias due to appropriate randomization and allocation concealment, blinding of outcome measurement, and low levels of missing outcome data. A few trials, especially those that included post-hoc analysis and subgroup analysis, were considered to have some concern for selective reporting or limitations in secondary analysis. The methodological quality of most observational studies ranged from 7-9 stars on the Newcastle-Ottawa Scale. Details are given in table 1. Table 1: Risk of Bias Assessment of Included Studies Study Design Tool Overall Quality Key Findings Anker et al., 2021 RCT RoB 2 Low risk Low risk across all domains Solomon et al., 2022 RCT RoB 2 Low risk Low risk across all domains Nassif et al., 2021 RCT RoB 2 Low risk Some concerns for reporting bias only Abraham et al., 2021 RCT RoB 2 Some concerns Small sample size but otherwise low risk Bhatt et al., 2021 Prespecified subgroup of RCT RoB 2 Some concerns Subgroup analysis; otherwise low risk EMPERIAL-Preserved RCT RoB 2 Low risk Low overall bias Remaining observational studies Cohort Newcastle-Ottawa Scale 7–9/9 stars Moderate to high quality

Study Selection

The initial search for relevant studies using the electronic database resulted in the identification of papers published in PubMed, Scopus, Google Scholar and Web of Science. After excluding duplicate records, titles and abstracts were then scrutinized for their relevance. The full texts of potentially eligible studies were evaluated based on the previously established inclusion and exclusion criteria. Articles that were review articles, meta-analyses, abstracts of conferences, editorials, and case reports, or those which did not focus on assessing the efficacy of sodium-glucose cotransporter-2 (SGLT2) inhibitors in HFpEF patients were excluded from this study. This systematic review included primary studies that conducted randomized controlled trials, post-hoc analyses, and observational studies on the efficacy and safety of SGLT2 inhibitors in HFpEF. The PRISMA flow diagram is shown in figure 4 and also below.

Characteristics of Included Studies

The papers used in this paper were published between 2021 and 2025 and had mainly been conducted through randomized controlled trials across multiple sites, in addition to using post hoc analysis and observational studies. In the vast majority of the experiments, adults with HFpEF symptoms that entailed a left ventricular ejection fraction (LVEF) above 40% or 50% had been used.

Agents like empagliflozin and dapagliflozin had been the drugs mostly used in this research. The control subjects had mainly been using placebo in addition to guideline-directed medical therapy. Follow-up periods had varied from several weeks in quality-of-life experiments to more than two years in cardiovascular outcome trials.

Overall, the papers involved had shown different categories of patients with HFpEF, which comprised older people, women, type 2 diabetes mellitus, chronic kidney disease, atrial fibrillation, obese, and hypertensive, among others.

Cardiovascular Outcomes

In all the included randomized controlled trials, the SGLT2 inhibitors showed positive results with regards to the composite outcome of either death due to cardiovascular reasons or admission due to heart failure. The most significant positive results were seen when it came to reduction of the incidence of both first-time and repeat hospital admissions for heart failure, while the impact on cardiovascular mortality was relatively small and not always statistically significant.

Landmark trials EMPEROR-Preserved and DELIVER proved the effectiveness of treatment with empagliflozin and dapagliflozin, respectively, showing that the use of these drugs as an add-on therapy to standard medical treatment reduced the risk of heart failure progression compared with the control group, regardless of whether the patient suffered from diabetes or not. In the EMPEROR-Preserved trial, empagliflozin reduced the composite of cardiovascular death or first hospitalization for heart failure by 21% compared with placebo (HR 0.79, 95% CI 0.69–0.90). Similarly, the DELIVER trial showed that dapagliflozin reduced the risk of worsening heart failure or cardiovascular death by 18% (HR 0.82, 95% CI 0.73–0.92). Improvements in health-related quality of life were observed in the PRESERVED-HF trial, with significant increases in Kansas City Cardiomyopathy Questionnaire (KCCQ) scores of approximately 4–6 points. Across the included studies, SGLT2 inhibitors also demonstrated favorable renal outcomes and were generally well tolerated, with low rates of serious adverse events and no consistent increase in treatment discontinuation compared with placebo^6,7,22,.

These results were seen in the same way in different patient groups, regardless of age, gender, and other factors such as the presence of chronic kidney disease.

Heart Failure Hospitalization

In the randomized controlled trials analyzed, SGLT2 inhibitors showed a beneficial impact on the combined outcome of CV death or hospitalization due to heart failure. The greatest efficacy of the drug was achieved by decreasing first and recurrent hospitalizations due to heart failure, although the influence on the incidence of mortality from CV causes was relatively small and statistically insignificant.

Decreasing the risk of heart failure hospitalization became the most significant result of the analyzed studies. In almost all randomized controlled trials, there was a significant decrease in the number of first and recurrent cases of hospitalization caused by heart failure in patients using SGLT2 inhibitors compared with placebo.

The observational studies and post hoc analysis also indicated the lower rate of re-hospitalization and better control of heart failure after starting the treatment with SGLT2 inhibitors. These results may be used as an additional reason to include SGLT2 inhibitors in the routine HFpEF therapy.

Mortality Outcomes

Whereas reductions in the rates of hospitalizations have been consistently seen, the influence of SGLT2 inhibitors on cardiovascular mortality and all-cause mortality appears to be less robust. Most studies showed neutral or insignificant effects on mortality outcomes, without any consistent statistically significant benefits seen in any of the individual trials.

However, the pooled results of subgroup analyses and the data of real-world populations suggest that the use of SGLT2 inhibitors for an extended period may positively affect prognosis.

Renal Outcomes

Renal endpoints were assessed in some studies. The use of SGLT2 inhibitors is linked to less eGFR decline, no progression of chronic kidney disease, and renal function maintenance during the follow-up period. These effects on kidneys were independent of diabetic status and regarded as valuable additional advantages in patients with HFpEF, as many of them suffer from concomitant renal impairment.

Safety Profile of SGLT2 Inhibitors

Generally, the SGLT2 inhibitors were found to be well tolerated in all the studies included in the review, having similar safety profiles as compared to placebo. Most common adverse effects were mild genital mycotic infection and, in some cases, urinary tract infection. Diabetic ketoacidosis was very rarely seen among patients; however, it was mostly seen among those patients who had diabetes. Hypotension, dehydration and volume depletion was also seen in some cases; however, this happened in older patients and in those who were taking diuretics along with SGLT2 inhibitors, highlighting the need for proper patient selection. Though there was a temporary reduction in eGFR after starting treatment, long-term outcomes were better in terms of kidney function, showing slower progression of renal dysfunction as compared to placebo. Interestingly, older patients saw similar cardiovascular and renal benefits as young patients and there was no significant difference in the number of adverse events^21-22.

Risk of Bias assessment

The quality of literature review among the randomized controlled trials included was good. Bias was not an issue for many of these clinical trials, especially those relating to randomization, allocation concealment, assessment of outcomes, and completion of follow-up. The observational studies had moderate to high quality methodology as assessed by standard evaluation instruments. The evidence was rated strong because it was from large multicenter randomized controlled trials.

Summary of Findings

In summary, there is sufficient evidence to conclude that SGLT2 inhibitors can be considered a valid treatment strategy for HFpEF. It was shown that such drugs effectively reduce the risk of heart failure hospitalizations along with improving quality of life and renal function of patients. Even though the impact of SGLT2 inhibitors on mortality is less evident, it seems safe to assume that they are an essential element of modern HFpEF treatment due to their positive efficacy and safety. A summarized table of the "Selected Key Trials" is shown in table 2.

Table 2: A summarized table of the "Selected Key Trials".

Table 3: Current Guideline Recommendations for SGLT2 Inhibitors in Heart Failure with Preserved Ejection Fraction (HFpEF)^23-24

Abbreviations: ACC, American College of Cardiology; ADA, American Diabetes Association; AHA, American Heart Association; ESC, European Society of Cardiology; HFpEF, heart failure with preserved ejection fraction; HFSA, Heart Failure Society of America.

Figure 1 and 2: Proposed mechanisms of action of SGLT2 inhibitors in heart failure with preserved ejection fraction (HFpEF)

Figure 3: Clinical benefits of SGLT2 inhibitors in heart failure with preserved ejection fraction (HFpEF)

Figure 4: Prisma Flow Diagram

This systematic review shows that SGLT2 inhibitors have been found to be effective in treating heart failure with preserved ejection fraction (HFpEF) patients, especially in reducing hospitalization due to heart failure (HF). Empagliflozin and Dapagliflozin were found to significantly reduce the composite endpoint of cardiovascular death and HF in the EMPEROR-Preserved and DELIVER trials. Several pooled analyses and real-life data have shown that such effects persist in various subgroups of patients regardless of diabetes, age, gender, renal function, or left ventricular ejection fraction13. While both EMPEROR-Preserved and DELIVER showed significant decreases in the composite outcome of worsening heart failure or cardiovascular mortality, some key differences must be noted. In EMPEROR-Preserved, patients had a left ventricular ejection fraction (LVEF) greater than 40%. In contrast, DELIVER included patients who had mild reduction or preserved ejection fraction and also those who had a previously reduced LVEF that improved. Both EMPEROR-Preserved and DELIVER saw their primary benefit in decreased heart failure hospitalizations but not in cardiovascular mortality. While DELIVER showed a more consistent effect throughout the range of ejection fraction, EMPEROR-Preserved found less benefits at higher ejection fraction values. However, despite such differences, both EMPEROR-Preserved and DELIVER consistently demonstrated the beneficial role of SGLT2 inhibitors regardless of diabetes status and introduced empagliflozin and dapagliflozin as critical drugs for HFpEF6,7,21. Table 4 below further illustrates the comparison. Characteristic EMPEROR-Preserved DELIVER Publication 2021 2022 Drug Empagliflozin Dapagliflozin Sample size 5,988 6,263 LVEF eligibility >40% >40% (including improved EF) Primary outcome CV death or first HF hospitalization Worsening HF or CV death Main benefit Reduced HF hospitalization Reduced HF hospitalization Mortality benefit Neutral Neutral Diabetes required No No While SGLT2 inhibitors reliably decreased HF hospitalizations, there was less consensus regarding their impact on both cardiovascular and all-cause mortality. In general, most clinical trials reported mild or neutral effects on mortality, indicating that the primary therapeutic benefits of SGLT2 inhibitors in HFpEF were in delaying disease progression and recurrence of hospitalizations rather than in decreasing mortality. Recent literature analysis have also shown that there is more reliable evidence for the reduction of HF hospitalization than for mortality14-15. Despite the fact that SGLT2 inhibitors decreased heart failure hospitalization rates significantly, their impact on the risk of cardiovascular and overall mortality appeared not to be so evident. The reasons for that may include, among others, the low statistical power of HFpEF trials in order to demonstrate mortality outcomes, the heterogeneity of HFpEF population, the low event rate and non-cardiovascular mortality in elderly patients, and the short follow-up period of the available researches16-17. One common result in all the included studies is the improvement in quality of life related to health. Patient trials that used outcomes measures were seen to have significantly increased KCCQ scores. Furthermore, some studies showed preserved renal function as well as decreased deterioration in glomerular filtration rate, which demonstrates the increasing appreciation of the cardiorenal benefits associated with the use of SGLT2 inhibitors. These effects have been shown to occur through various pathways, such as natriuresis, osmotic diuresis, myocardial energetics, inflammation reduction, and inhibition of cardiac fibrosis18-19. The conclusions drawn from this review have significant clinical implications. It is now clear that the use of SGLT2 inhibitors should be considered a fundamental therapy for patients with HFpEF, in addition to guideline-directed medical therapy as shown in table 2. This is owing to their excellent safety profile as well as consistent benefits on reducing hospitalizations related to heart failure and improving quality of life20-22. While the promising results have been found, the existing evidence faces some drawbacks. Firstly, most of the data has been generated in two major randomized clinical trials along with their subgroup and post hoc analysis, whereas independent research on various SGLT2 inhibitors in HFpEF is scarce. Moreover, the heterogeneity of the population studied, definitions of HFpEF, and follow-up period makes direct comparison of the results difficult, whereas long-term evidence from practice is not abundant. Further studies are needed to establish the role of SGLT2 inhibitors in HFpEF6,7,14. There are several shortcomings to this review. For one, the data available mostly comes from only two randomized controlled trials along with their subgroup analyses, whereas there is less literature on real-life, long-term data. In addition, due to differences in the definition of HFpEF, patients enrolled in the study, and length of follow-up, direct comparison of the results between various studies was not possible. In general, it seems that the existing scientific data proves that the SGLT2 inhibitors are a significant treatment breakthrough for HFpEF. Although further research is required in order to define their impact on mortality and find phenotypes which will benefit the most from the treatment, there is strong scientific evidence confirming the usefulness of their regular use in HFpEF patients to avoid HF admissions. How Should Clinicians Use SGLT2 Inhibitors in HFpEF? Current evidence supports the early use of SGLT2 inhibitors, particularly empagliflozin and dapagliflozin, as part of guideline-directed medical therapy for eligible patients with HFpEF, regardless of diabetes status. These agents reduce heart failure hospitalizations, improve quality of life, and provide renal protection. Before initiation, clinicians should assess renal function, volume status, and concomitant diuretic therapy, with periodic monitoring during treatment. Patients should be informed about the potential risk of genital infections and the rare occurrence of diabetic ketoacidosis. Overall, the favorable efficacy and safety profile of SGLT2 inhibitors supports their routine incorporation into the management of HFpEF in accordance with current international guidelines.

The current review demonstrates the solid body of scientific evidence showing that SGLT2 inhibitors are the first class of pharmacological agents found to be effective in improving functional capacity and decreasing hospital admissions in patients with HFpEF – a disorder traditionally suffering from therapeutic inertia. The success achieved by empagliflozin and dapagliflozin owing to the consistently positive results obtained regardless of the age of the subjects involved, coexisting medical disorders, and initial levels of functional capacity makes the above-mentioned drugs an essential part of treatment addressing HFpEF in its full scope.

ACKNOWLEDGMENT:

Grammarly for grammar check and turnitin for plagiarism.

DECLARATION OF PATIENT’S INTEREST:

Patients’ consent was not required as patients were not physically enrolled in this study.

FINANCIAL SUPPORT AND SPONSORSHIP:

None. The whole project was self-funded by the authors. 

CONFLICTS OF INTEREST:

There are no conflicts of interest.

USE OF ARTIFICIAL INTELLIGENCE (AI)-ASSISTED TECHNOLOGY FOR MANUSCRIPT PREPARATION:

The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.

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