INTRODUCTION

Over the past decade, the conceptual framework of cardiovascular disease has expanded beyond viewing the heart as an isolated organ system to an integrated cardiovascular-kidney-metabolic (CKM) paradigm that recognizes bidirectional and mutually amplifying interactions among metabolic dysregulation, renal dysfunction, vascular injury, and myocardial remodeling [1]. This broader construct has been formally articulated in recent scientific statements from the American Heart Association, which emphasize that obesity, insulin resistance, type 2 diabetes, hypertension, and chronic kidney disease are not parallel comorbidities but interconnected biological drivers that accelerate cardiovascular injury along a continuous trajectory [2]. Within this CKM continuum, systemic inflammation, endothelial dysfunction, oxidative stress, neurohormonal activation, and microvascular rarefaction act synergistically to promote adverse cardiac remodeling well before the onset of overt heart failure (HF) [3]. HF with preserved ejection fraction (HFpEF) represents a prototypical manifestation of this multisystem interaction. Rather than reflecting isolated diastolic dysfunction, HFpEF is now understood as the downstream consequence of complex interactions among chronic metabolic stress, cardiorenal crosstalk, vascular stiffening, and progressive atrial and ventricular remodeling. Obesity-driven systemic inflammation, insulin resistance–mediated myocardial energetic inefficiency, hypertensive arterial stiffening, and chronic kidney disease (CKD)-related volume expansion and uremic toxicity collectively increase left ventricular (LV) stiffness, impair diastolic reserve, and disrupt ventricular-arterial coupling and right ventricular (RV)–pulmonary vascular coupling [4]. Importantly, these CKM components function not only as risk factors for HFpEF development but also as key determinants of disease progression and clinical instability after HFpEF is established. Recurrent congestion, worsening renal function, and escalating systemic inflammation perpetuate a self-reinforcing cycle that promotes myocardial fibrosis, atrial myopathy, pulmonary vascular remodeling, and RV dysfunction [5]. Accordingly, HFpEF should be understood less as a discrete cardiac entity and more as a systemic syndrome arising from the convergence of metabolic, renal, vascular, and myocardial stressors within the CKM axis. This evolving perspective underscores the need for preventive strategies that target upstream pathophysiologic pathways within the CKM continuum before irreversible structural remodeling and symptomatic HF development.

CARDIOMETABOLIC STRESS AND STRUCTURAL REMODELING IN HFpEF

HFpEF is increasingly recognized as the structural and functional culmination of chronic cardiometabolic stress rather than an isolated abnormality of relaxation. Excess adiposity and insulin resistance initiate a cascade of hemodynamic and metabolic perturbations that progressively remodel the myocardium [6]. Obesity is characterized by expanded plasma volume, increased sympathetic tone, and activation of the renin-angiotensin-aldosterone system, which collectively increase preload and afterload [7]. Concurrently, arterial stiffening and impaired vasodilatory reserve increase pulsatile load, promoting concentric LV hypertrophy as an adaptive response to sustained pressure overload. At the cellular level, hyperinsulinemia and glucotoxicity impair myocardial substrate flexibility, shifting energy utilization toward less efficient fatty acid oxidation, increasing oxidative stress, and reducing nitric oxide bioavailability [8]. These metabolic disturbances promote interstitial fibrosis and increased cardiomyocyte stiffness, thereby elevating LV diastolic stiffness independent of overt systolic dysfunction. Chronic kidney dysfunction further amplifies these processes through sodium retention, volume expansion, endothelial dysfunction, and low-grade inflammation, thereby increasing wall stress and promoting myocardial fibrosis [9]. As LV compliance declines, left atrial (LA) pressure increases to maintain ventricular filling, leading to progressive LA remodeling, atrial myopathy, and chamber dilation [10]. Elevated LA pressure is transmitted to the pulmonary circulation, contributing to pulmonary vascular remodeling and eventual right ventricular–pulmonary arterial uncoupling [11]. Thus, obesity, diabetes, hypertension, and renal dysfunction collectively drive a continuum characterized by concentric hypertrophy, diastolic stiffening, impaired relaxation, LA enlargement, and chronically elevated filling pressures. HFpEF emerges when these hemodynamic and metabolic stress pathways converge, producing a heart that preserves ejection fraction at rest yet exhibits impaired diastolic reserve, chronotropic incompetence, and abnormal ventricular-vascular coupling during physiological stress.

INTEGRATED CARDIORENAL AND METABOLIC MECHANISMS OF SGLT2 INHIBITION

Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a broad range of biological effects that extend well beyond glycemic lowering and directly target key nodes within the CKM axis [12]. By inhibiting sodium-glucose cotransport in the proximal tubule, these agents promote glycosuria and natriuresis, restore tubuloglomerular feedback, and reduce intraglomerular hypertension—mechanisms central to renal protection and the attenuation of maladaptive cardiorenal signaling [13]. The resulting osmotic diuresis preferentially reduces interstitial rather than intravascular volume, thereby alleviating myocardial wall stress and lowering LV filling pressures without provoking substantial neurohormonal activation [14]. Concurrent reductions in blood pressure, arterial stiffness, and plasma volume may improve ventricular-arterial coupling and decrease pulsatile afterload, thereby attenuating concentric hypertrophic remodeling [14]. At the metabolic level, SGLT2 inhibition enhances systemic insulin sensitivity, promotes mild ketosis with increased availability of β-hydroxybutyrate as an energetically efficient myocardial substrate, and improves mitochondrial function, collectively contributing to greater myocardial energetic flexibility [15]. These metabolic shifts are accompanied by reductions in oxidative stress, systemic inflammation, epicardial adipose tissue activity, and profibrotic signaling pathways, leading to less interstitial fibrosis and improved diastolic compliance. Experimental and translational data further suggest favorable effects on endothelial function, nitric oxide bioavailability, and microvascular integrity, all of which are central to HFpEF pathophysiology. Importantly, SGLT2 inhibitors also appear to modulate sympathetic tone and renin-angiotensin-aldosterone system activity indirectly through their effects on volume status and renal hemodynamics, thereby interrupting the cycle of neurohormonal activation and progressive remodeling that characterizes CKM progression [16]. Through these integrated hemodynamic, metabolic, renal, and anti-inflammatory effects, SGLT2 inhibition provides a biologically coherent strategy for attenuating the structural and functional evolution toward HFpEF (Fig. 1).

CLINICAL EVIDENCE FOR HF PREVENTION WITH SGLT2 INHIBITORS

Table 1 summarizes the major trials that have evaluated the effects of SGLT2 inhibitors on HF outcomes [17–21]. The clinical relevance of the mechanistic effects of SGLT2 inhibition has been consistently substantiated in large-scale cardiovascular and dedicated HF outcome trials, which have reproducibly demonstrated reductions in incident HF and HF hospitalization. Among patients with type 2 diabetes at high cardiovascular risk, the EMPA-REG OUTCOME trial first demonstrated a marked reduction in HF hospitalization with empagliflozin [17]. Notably, the event curves separated early, and this effect was disproportionate to the modest changes in glycemic control, suggesting mechanisms beyond glucose reduction alone. These findings were corroborated in the CANVAS Program, which enrolled a broad population of patients with type 2 diabetes, most of whom had established atherosclerotic cardiovascular disease or were at high cardiovascular risk. In this integrated analysis, canagliflozin significantly reduced the composite of major adverse cardiovascular events and was also associated with a meaningful reduction in HF hospitalization [18]. The consistency of HF risk reduction across subgroups further supported a class effect and strengthened the emerging concept that SGLT2 inhibition confers cardioprotective benefits independent of glycemic control. This concept was subsequently reinforced in DECLARE–TIMI 58 trial, which included a large proportion of patients without established atherosclerotic disease. In that trial, dapagliflozin significantly reduced HF hospitalization, primarily through a reduction in HF admissions, despite a neutral effect on major adverse atherosclerotic events in the overall study population [19]. Importantly, reductions in HF events observed in these trials should not be interpreted as direct evidence of HFpEF prevention, because most studies did not prespecify HF subtype classification or evaluate incident HFpEF as a primary endpoint. Taken together, these cardiovascular outcome trials established a consistent and reproducible reduction in HF hospitalization across diverse risk profiles, thereby laying the foundation for subsequent dedicated HF trials.

Building on the reductions in HF hospitalization observed in cardiovascular outcome trials, subsequent studies specifically designed for HF populations produced transformative results and substantially influenced contemporary HF treatment guidelines. In the DAPA-HF trial [22] and the EMPEROR-Reduced trial [23], significant reductions in worsening HF and cardiovascular death were observed in patients with HF with reduced ejection fraction, irrespective of diabetes status. The therapeutic paradigm shifted further with the EMPEROR-Preserved trial [24] and the DELIVER trial [25], both of which demonstrated significant reductions in the composite endpoint of cardiovascular death or HF hospitalization among patients with preserved or mildly reduced ejection fraction, and these findings have been incorporated into multiple clinical guidelines (Table 2) [26–29]. These findings confirmed efficacy across the full spectrum of LV ejection fraction, including HFpEF, a population in which prior disease-modifying therapies had largely failed. Collectively, these landmark trials demonstrated a consistent early separation of HF event curves, suggesting that the observed benefits are unlikely to be attributable solely to long-term reverse structural remodeling. Instead, they likely reflect rapid hemodynamic optimization through natriuresis, plasma volume reduction, and improved ventricular loading conditions, coupled with sustained modification of myocardial and renal pathophysiologic pathways. The convergence of mechanistic plausibility and reproducible clinical benefit positions SGLT2 inhibitors as foundational agents not only for the treatment of established HF but also for the prevention of HF development across the CKM spectrum.

Parallel renal outcome trials further strengthened the concept that SGLT2 inhibitors provide integrated cardiorenal-metabolic protection. In the DAPA-CKD trial, dapagliflozin significantly reduced kidney disease progression while also lowering the risk of HF hospitalization, reinforcing the interconnected nature of cardiovascular, kidney, and metabolic disease within the CKM continuum [20]. Additional supportive evidence comes from the SCORED trial, which specifically enrolled patients with type 2 diabetes and CKD, many of whom had not yet developed overt HF at baseline. The SCORED trial evaluated sotagliflozin, a dual SGLT1/SGLT2 inhibitor, and demonstrated a significant reduction in the composite endpoint of cardiovascular death, HF hospitalization, or urgent HF visit compared with placebo [21]. Importantly, the benefit was largely driven by reductions in HF events, and the event curves separated early after treatment initiation. Although the trial was terminated prematurely because of funding issues, thereby limiting statistical power for certain endpoints, the consistency of HF risk reduction in this high-risk CKD population provides additional evidence that SGLT2 pathway inhibition exerts preventive effects on HF development before clinical HF becomes established.

According to pooled analyses and meta-analyses of these trials, SGLT2 inhibitors not only significantly reduced major adverse cardiovascular events in patients with established HF but also significantly lowered the risk of HF hospitalization and cardiovascular death in individuals without preexisting HF [30]. These findings provide supportive, albeit indirect, evidence that SGLT2 inhibitors may exert a primary preventive effect against HF development in patients with type 2 diabetes.

Importantly, the robust clinical benefits of SGLT2 inhibitors demonstrated in trials such as EMPEROR-Preserved and DELIVER were observed in populations with established HF, including HFpEF, and therefore reflect treatment effects rather than primary prevention. Although these findings strongly support the ability of SGLT2 inhibition to favorably modify key pathophysiologic pathways relevant to HFpEF, extrapolation to prevention in individuals without established HF requires caution. Evidence supporting a preventive role is currently indirect and is derived primarily from cardiovascular and renal outcome trials conducted in high-risk populations within the CKM continuum, in which reductions in incident HF events have been consistently observed. Accordingly, although mechanistic plausibility and cross-trial consistency suggest a potential role in modifying disease trajectory, definitive evidence for the primary prevention of HFpEF has yet to be established.

TRANSLATING SGLT2 INHIBITION INTO HFpEF DISEASE MODIFICATION

The mechanistic profile of SGLT2 inhibitors can be mapped directly onto the core pathophysiologic abnormalities that define HFpEF, providing a biologically coherent framework for disease modification rather than symptomatic relief alone. LV diastolic dysfunction in HFpEF results from concentric hypertrophy, interstitial fibrosis, and impaired myocardial energetics; SGLT2 inhibition may attenuate these processes through reductions in wall stress, improvement in myocardial substrate efficiency, suppression of profibrotic signaling, and mitigation of oxidative stress, collectively enhancing myocardial compliance [14]. By lowering interstitial volume and LV filling pressures, these agents reduce LA afterload and may thereby slow LA remodeling and atrial myopathy while decreasing mean LA pressure, an upstream determinant of pulmonary venous hypertension [31]. Reduced transmission of LA pressure to the pulmonary circulation may in turn alleviate pulmonary vascular load, thereby limiting passive pulmonary hypertension and attenuating secondary pulmonary vascular remodeling. Improvements in pulmonary pressures and arterial stiffness may also favorably influence RV–pulmonary arterial (PA) coupling, reducing RV afterload and preserving right-sided systolic performance, a critical determinant of outcomes in HFpEF [32]. Importantly, the benefits of SGLT2 inhibition extend beyond resting hemodynamics: by improving ventricular-arterial coupling, optimizing preload without excessive neurohormonal activation, and enhancing myocardial energetic flexibility, these agents may preserve diastolic reserve during exertion [33]. Taken together, the convergence of effects on LV stiffness, LA pressure, pulmonary vascular load, and RV-PA interaction positions SGLT2 inhibition as a mechanistically plausible strategy for interrupting the progressive cascade from subclinical diastolic dysfunction to overt, hemodynamically unstable HFpEF.

LIMITED AND EVOLVING CLINICAL EVIDENCE FOR HFpEF PREVENTION WITH SGLT2 INHIBITORS

Despite the compelling mechanistic rationale and the consistent reduction in HF events observed across large cardiovascular and renal outcome trials, direct evidence supporting SGLT2 inhibitors for the primary prevention of HFpEF remains limited. To date, no randomized controlled trial has been specifically designed to enroll individuals without HF and evaluate incident HFpEF as a prespecified primary endpoint. Although studies such as the EMPA-REG OUTCOME trial and the CANVAS Program demonstrated significant reductions in HF hospitalization among patients with type 2 diabetes, these analyses did not distinguish HF phenotypes and were not designed to assess HFpEF prevention specifically. Similarly, dedicated HFpEF trials, including EMPEROR-Preserved and DELIVER, established therapeutic benefit in patients with existing disease but did not provide evidence regarding the prevention of HFpEF onset. Observational studies and secondary analyses suggest a reduction in incident HF events in high-risk populations; however, these findings are hypothesis-generating and insufficient to support the routine use of SGLT2 inhibitors solely for HFpEF prevention in individuals without HF [30]. Accordingly, although SGLT2 inhibition is biologically plausible as an upstream disease-modifying strategy within the CKM continuum, its role as a preventive therapy for HFpEF remains inferential rather than definitively established.

As HF research has expanded in recent years, interest has grown in the potential cardiometabolic benefits of combining SGLT2 inhibitors with glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) [34]. These two therapeutic classes exert distinct yet complementary effects: SGLT2 inhibitors primarily improve hemodynamic loading conditions through natriuresis, osmotic diuresis, and modulation of cardiorenal signaling, whereas GLP-1 RAs predominantly target metabolic dysfunction by promoting weight loss, improving insulin sensitivity, and reducing systemic inflammation. Given that obesity-driven inflammation and metabolic dysregulation are central to the pathophysiology of HFpEF, particularly in cardiometabolic phenotypes, this combination may provide additive or even synergistic benefits in modifying disease trajectory. Recent trials, including the STEP-HFpEF program, have demonstrated that GLP-1 RA–based therapy improves symptoms, exercise capacity, and weight reduction in patients with obesity-related HFpEF, supporting the relevance of targeting metabolic pathways in this population [4]. However, direct evidence evaluating combination therapy remains limited, and its role in preventing HFpEF has not yet been established. Accordingly, the integration of complementary hemodynamic and metabolic effects represents a promising strategy for more comprehensive intervention across the CKM spectrum and highlights an important area for future investigation.

Future prospective trials specifically targeting high-risk CKM phenotypes and incorporating mechanistic phenotyping, longitudinal imaging, and exercise hemodynamics will be essential to determine whether early initiation of SGLT2 inhibitors can truly alter the natural history of HFpEF development. From a clinical perspective, early initiation of SGLT2 inhibitors is most likely to benefit patients at high cardiometabolic risk, particularly those with type 2 diabetes or CKD, in whom consistent reductions in HF events have been demonstrated. Patients with obesity-related cardiometabolic phenotypes may derive additional benefit given the combined effects of volume reduction and metabolic modulation. Furthermore, individuals with early cardiac structural or functional abnormalities, such as LV diastolic dysfunction or LA enlargement, may represent a subgroup in whom preclinical intervention could help attenuate progression to overt HFpEF. However, these considerations remain hypothesis-generating and require confirmation in prospective studies.

CONCLUSIONS

SGLT2 inhibitors exert broad cardiorenal and metabolic effects that mitigate many of the central pathophysiologic mechanisms driving HFpEF, including diastolic stiffening, LA remodeling, elevated filling pressures, and pulmonary vascular load. Together with the consistent reductions in HF events documented across outcome trials, these effects suggest a plausible role for SGLT2 inhibitors in modifying the trajectory of HF toward HFpEF. However, direct clinical evidence supporting their use for the primary prevention of HFpEF remains limited, because no trial has specifically evaluated incident HFpEF as a primary endpoint. Although SGLT2 inhibition represents a promising upstream strategy within the CKM continuum, prospective studies focused on high-risk populations are needed to determine whether early intervention can definitively prevent HFpEF development.

ARTICLE INFORMATION

Conflicts of interest

The author has no conflicts of interest to declare.

Funding

The author received no financial support for this study.

Fig. 1.

Modulating the heart failure with preserved ejection fraction (HFpEF) trajectory across the cardiovascular-kidney-metabolic (CKM) continuum. This schematic depicts the progression from CKM stress to overt HFpEF, with emphasis on upstream inflammatory mechanisms and the multilevel effects of sodium-glucose cotransporter 2 (SGLT2) inhibition. Within the CKM framework proposed by the American Heart Association, obesity, insulin resistance, and renal dysfunction promote chronic low-grade systemic inflammation. In parallel, inflammatory and neurohormonal activation drive interstitial fibrosis and extracellular matrix expansion, resulting in concentric remodeling, elevated filling pressures, and progression to clinical HFpEF. Thus, CKM-driven systemic inflammation serves as a key upstream driver of structural and functional cardiac deterioration. SGLT2 inhibitors are illustrated as multilevel modulators whose effects extend beyond simple natriuresis. Through hemodynamic unloading, restoration of cardiorenal signaling, attenuation of inflammatory and profibrotic pathways, and potential improvements in myocardial energetics, these agents may interrupt disease progression at several stages. The concept of “flattening the trajectory” reflects the potential of SGLT2 inhibition to attenuate or delay the transition from subclinical myocardial dysfunction to overt HFpEF, thereby shifting its role from symptomatic therapy toward a disease-modifying preventive role. LA, left atrium; LV, left ventricle; RAAS, renin-angiotensin-aldosterone system; IL-6, interleukin 6; TNF-α, tumor necrosis factor α.

REFERENCES

• 1. Ndumele CE, Rangaswami J, Chow SL, Neeland IJ, Tuttle KR, Khan SS, et al. Cardiovascular-kidney-metabolic health: a presidential advisory from the American Heart Association. Circulation 2023;148:1606–35. ArticlePubMedPMC
• 2. Khan SS, Coresh J, Pencina MJ, Ndumele CE, Rangaswami J, Chow SL, et al. Novel prediction equations for absolute risk assessment of total cardiovascular disease incorporating cardiovascular-kidney-metabolic health: a scientific statement from the American Heart Association. Circulation 2023;148:1982–2004. Article
• 3. Delalat S, Sultana I, Osman H, Sieme M, Zhazykbayeva S, Herwig M, et al. Dysregulated inflammation, oxidative stress, and protein quality control in diabetic HFpEF: unraveling mechanisms and therapeutic targets. Cardiovasc Diabetol 2025;24:211.ArticlePubMedPMCPDF
• 4. Solomon SD, Ostrominski JW, Wang X, Shah SJ, Borlaug BA, Butler J, et al. Effect of semaglutide on cardiac structure and function in patients with obesity-related heart failure. J Am Coll Cardiol 2024;84:1587–602. Article
• 5. Paulus WJ, Tschöpe C. A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 2013;62:263–71. ArticlePubMed
• 6. Reddy YN, Frantz RP, Hemnes AR, Hassoun PM, Horn E, Leopold JA, et al. Disentangling the impact of adiposity from insulin resistance in heart failure with preserved ejection Fraction. J Am Coll Cardiol 2025;85:1774–88. ArticlePubMedPMC
• 7. Borlaug BA, Jensen MD, Kitzman DW, Lam CS, Obokata M, Rider OJ. Obesity and heart failure with preserved ejection fraction: new insights and pathophysiological targets. Cardiovasc Res 2023;118:3434–50. ArticlePubMedPMCPDF
• 8. Park JJ. Epidemiology, pathophysiology, diagnosis and treatment of heart failure in diabetes. Diabetes Metab J 2021;45:146–57. ArticlePubMedPMCPDF
• 9. Jankowski J, Floege J, Fliser D, Böhm M, Marx N. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 2021;143:1157–72. ArticlePubMedPMC
• 10. Nagueh SF, Sanborn DY, Oh JK, Anderson B, Billick K, Derumeaux G, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography and for heart failure with preserved ejection fraction diagnosis: an update from the American Society of Echocardiography. J Am Soc Echocardiogr 2025;38:537–69. ArticlePubMed
• 11. Humbert M, Kovacs G, Hoeper MM, Badagliacca R, Berger RM, Brida M, et al. 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension: developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Endorsed by the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG). Eur Heart J 2022;43:3618–731. ArticlePubMed
• 12. Guerrero-Mauvecin J, Villar-Gómez N, Miño-Izquierdo L, Povo-Retana A, Ramos AM, Ruiz-Hurtado G, et al. Antioxidant effects of SGLT2 inhibitors on cardiovascular-kidney-metabolic (CKM) syndrome. Antioxidants (Basel) 2025;14:701.ArticlePubMedPMC
• 13. Wanner C. EMPA-REG OUTCOME: the nephrologist's point of view. Am J Cardiol 2017;120(1S):S59–67. ArticlePubMed
• 14. Heerspink HJ, Kosiborod M, Inzucchi SE, Cherney DZ. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int 2018;94:26–39. ArticlePubMed
• 15. Tamargo J. Sodium-glucose cotransporter 2 inhibitors in heart failure: potential mechanisms of action, adverse effects and future developments. Eur Cardiol 2019;14:23–32. ArticlePubMedPMC
• 16. Vallon V, Verma S. Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annu Rev Physiol 2021;83:503–28. ArticlePubMedPMC
• 17. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–28. ArticlePubMedPMC
• 18. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644–57. ArticlePubMedPMC
• 19. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347–57. ArticlePubMedPMC
• 20. Heerspink HJ, Stefánsson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436–46. ArticlePubMedPMC
• 21. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021;384:129–39. ArticlePubMed
• 22. McMurray JJ, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995–2008. ArticlePubMed
• 23. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413–24. ArticlePubMed
• 24. Anker SD, Butler J, Filippatos G, Ferreira JP, Bocchi E, Böhm M, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021;385:1451–61. ArticlePubMed
• 25. Solomon SD, McMurray JJ, Claggett B, de Boer RA, DeMets D, Hernandez AF, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022;387:1089–98. ArticlePubMed
• 26. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. J Am Coll Cardiol 2022;79:e263–421. ArticlePubMed
• 27. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2023 Focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2023;44:3627–39. ArticlePubMed
• 28. Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2024 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int 2024;105(4S):S117–314. Article
• 29. American Diabetes Association Professional Practice Committee. Erratum. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes: 2024. Diabetes Care 2024;47(Suppl. 1):S158-S178. Diabetes Care 2024;47:1238.ArticlePubMedPMCPDF
• 30. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019;393:31–9. ArticlePubMedPMC
• 31. Huston JH, Shah SJ. Understanding the pathobiology of pulmonary hypertension due to left heart disease. Circ Res 2022;130:1382–403. ArticlePubMedPMC
• 32. Kim BJ, Thomas JD. Echocardiographic parameters of the right ventricle in patients with pulmonary hypertension: a review. Korean Circ J 2025;55:259–74. ArticlePubMedPMCPDF
• 33. Savarese G, Stolfo D, Sinagra G, Lund LH. Heart failure with mid-range or mildly reduced ejection fraction. Nat Rev Cardiol 2022;19:100–16. ArticlePubMedPMCPDF
• 34. Scheen AJ. GLP-1 receptor agonists and SGLT2 inhibitors in type 2 diabetes: pleiotropic cardiometabolic effects and add-on value of a combined therapy. Drugs 2024;84:1347–64. ArticlePubMedPDF

Figure & Data

References

Citations

Citations to this article as recorded by