{"paper_id":"a1f17f7c-3661-4b07-bbe9-81cab6ce7d79","body_text":"RHD remains the leading cause of acquired cardiovascular morbidity and mortality among individuals younger than 25 years. Globally, it affects approximately 54.7 million people and accounts for more than 370,000 deaths annually, 5  with Asia bearing a disproportionate burden, particularly in LMICs. 1  Although global prevalence has declined, projections suggest that by 2030 the burden of RHD will remain substantial, with prevalence estimates of 35.8 per 100,000 in high-income Asia–Pacific regions and as high as 300.8 per 100,000 in Southeast Asia, underscoring its persistent societal and economic impact. 1  Despite this burden, RHD continues to receive disproportionately limited attention from the global medical and research communities ( Central Illustration ). Central Illustration SGLT2 Inhibition as a Disease-Modifying Strategy in RHD The global burden, pathophysiology, therapeutic stagnation, and proposed innovation in rheumatic heart disease (RHD). RHD affects 54.7 million people worldwide, disproportionately impacting Asia and low- and middle-income countries (LMICs). Disease progression follows group A  Streptococcus  infection, leading to chronic immune activation, fibrosis, and calcification of predominantly left-sided valves. Current management relies on secondary prophylaxis and delayed valve intervention, without targeting immune-inflammatory injury. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are presented as candidate first disease-modifying therapies, with potential to attenuate inflammation, remodeling, and structural deterioration, addressing both unmet therapeutic and equity gaps in RHD care. CAD = coronary artery disease; HF = heart failure.\nSGLT2 Inhibition as a Disease-Modifying Strategy in RHD\nThe global burden, pathophysiology, therapeutic stagnation, and proposed innovation in rheumatic heart disease (RHD). RHD affects 54.7 million people worldwide, disproportionately impacting Asia and low- and middle-income countries (LMICs). Disease progression follows group A  Streptococcus  infection, leading to chronic immune activation, fibrosis, and calcification of predominantly left-sided valves. Current management relies on secondary prophylaxis and delayed valve intervention, without targeting immune-inflammatory injury. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are presented as candidate first disease-modifying therapies, with potential to attenuate inflammation, remodeling, and structural deterioration, addressing both unmet therapeutic and equity gaps in RHD care. CAD = coronary artery disease; HF = heart failure.\nRHD represents the long-term consequence of repeated episodes of acute rheumatic fever triggered by group A  Streptococcus  infection. The disease typically follows a silent and insidious course, evolving over decades before clinical presentation in adolescence or young adulthood. Its pathogenesis is multifactorial, involving systemic inflammation, endothelial dysfunction, sustained immune-cell infiltration, activation of valvular interstitial cells, extracellular matrix remodeling, and progressive mechanical stress — ultimately culminating in fibrosis and calcification, predominantly affecting the left-sided cardiac valves. 2\nThe contemporary burden of RHD in LMICs is starkly illustrated by the REMEDY (Global Rheumatic Heart Disease Registry) registry, a prospective observational study enrolling more than 3,400 patients across 25 hospitals in 14 countries, primarily in Africa, Yemen, and India. 6  Two-thirds of participants were female, with a median age of 28 years at enrollment. Despite their young age, the 2-year mortality rate was 16.9%, with a median age at death of only 28.7 years. Notably, only 10.3% of patients with severe symptomatic valvular disease underwent surgery or percutaneous intervention within 2 years. Access to intervention varied widely, ranging from 22% in a South African center to as low as 2.2% in parts of West Africa. 6\nSimilarly, data from the large Indonesia multicenter registry (Ina-RHD) which included 3,431 patients show that most patients with RHD are women (64.4%) and commonly present with isolated mitral stenosis (39.6%). 7  Patients were frequently diagnosed at advanced stages, characterized by older age, a high prevalence of atrial fibrillation, pulmonary hypertension, and right heart involvement. Major challenges included suboptimal anticoagulation despite high rates of atrial fibrillation and underuse of secondary prophylaxis, which was implemented in only 37.3% of patients. Among patients with heart failure, adherence to guideline-directed medical therapy was poor, with particularly low prescription rates of SGLT2 inhibitors (8.3% to 24.7%). 8\nIn LMICs where RHD remains endemic, the annual demand for cardiac surgery is estimated at approximately 300 procedures per million population — far exceeding available surgical capacity. 1  Consequently, despite declining global prevalence, RHD continues to pose a major public health challenge in endemic regions, where late presentation remains the norm. These observations highlight the urgent need for earlier detection, 9  structured longitudinal care, and — critically — novel pharmacological strategies capable of modifying disease biology and delaying progression.\n\nContemporary treatment of RHD remains largely confined to secondary prophylaxis of streptococcal infections with intramuscular benzathine penicillin and delayed surgical or transcatheter interventions of the affected valves. The landmark GOAL (Gwoko Adunu pa Lutino) trial, led by Beaton et al 10  was a multicenter, randomized study that demonstrated the effectiveness of penicillin in halting disease progression in 818 Ugandan children and adolescents with RHD. However, there are no proven medical therapies that directly attenuate the chronic immune-inflammatory mechanisms driving ongoing valvular injury.\nIn sharp contrast to the remarkable advances in heart failure, coronary artery disease, arrhythmias, and structural heart interventions, progress in the management of RHD has been negligible, arguably because it most often affects young people in densely populated, underserved areas in LMICs. Despite its prevalence and high mortality, RHD attracts a fraction of the research funding, clinical innovation, and policy focus devoted to diseases more prevalent in high-income settings. This reality stands in opposition to the ethical imperative of equity in global cardiovascular care delivery ( Central Illustration ).\n\nSGLT2 inhibitors have shown broad cardiovascular and renal benefits that extend well beyond glucose lowering. 11 , 12  Their pleiotropic effects — including anti-inflammatory, antifibrotic, antithrombotic, and endothelial-stabilizing actions — closely align with the key mechanisms underlying RHD pathophysiology. 11  Although the expression of SGLT2 within the cardiovascular system has long been controversial, recent data have reported its presence in both the myocardium and cardiac valves, with low-grade inflammation acting as a potent inducer of SGLT2 expression. 3 , 13 , 14  Although direct clinical evidence in RHD remains limited, accumulating mechanistic, translational, and clinical data from other valvular disease models provide a compelling biological rationale for a potential disease-modifying role of SGLT2 inhibition in this population ( Figure 1 ). Figure 1 Mechanistic Effects of SGLT2 Inhibition in Rheumatic Heart Disease The proposed mechanisms by which sodium-glucose cotransporter 2 (SGLT2) inhibitors may modify disease progression in rheumatic heart disease. SGLT2 inhibition suppresses nuclear factor kappa B (NF-κB)/NOD-, LRR- and pyrin domain–containing protein 3 (NLRP3)–mediated inflammation, reduces tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), and promotes anti-inflammatory macrophage polarization. Endothelial function is improved through enhanced nitric oxide (NO) bioavailability and reduced vascular cell adhesion molecule 1 (VCAM-1) expression, limiting endothelial-to-mesenchymal transition. Downregulation of TGF-β and matrix metalloproteinase-9 (MMP-9) attenuates valvular interstitial cell activation, extracellular matrix (ECM) remodeling, fibrosis, and calcification. Additional effects include reduced thrombogenicity, hemodynamic unloading, improved myocardial energetics, attenuation of pulmonary vascular remodeling, and decreased arrhythmogenesis. Collectively, these pathways support a potential disease-modifying role of SGLT2 inhibition in rheumatic heart disease. miRNA = microRNA; miRNA-155 = microRNA 155; RV = right ventricle.\nMechanistic Effects of SGLT2 Inhibition in Rheumatic Heart Disease\nThe proposed mechanisms by which sodium-glucose cotransporter 2 (SGLT2) inhibitors may modify disease progression in rheumatic heart disease. SGLT2 inhibition suppresses nuclear factor kappa B (NF-κB)/NOD-, LRR- and pyrin domain–containing protein 3 (NLRP3)–mediated inflammation, reduces tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), and promotes anti-inflammatory macrophage polarization. Endothelial function is improved through enhanced nitric oxide (NO) bioavailability and reduced vascular cell adhesion molecule 1 (VCAM-1) expression, limiting endothelial-to-mesenchymal transition. Downregulation of TGF-β and matrix metalloproteinase-9 (MMP-9) attenuates valvular interstitial cell activation, extracellular matrix (ECM) remodeling, fibrosis, and calcification. Additional effects include reduced thrombogenicity, hemodynamic unloading, improved myocardial energetics, attenuation of pulmonary vascular remodeling, and decreased arrhythmogenesis. Collectively, these pathways support a potential disease-modifying role of SGLT2 inhibition in rheumatic heart disease. miRNA = microRNA; miRNA-155 = microRNA 155; RV = right ventricle.\nMechanistic studies in degenerative aortic valve disease have demonstrated upregulation of SGLT2 in calcified human valves and myocardium, colocalizing with markers of inflammation, oxidative stress, and fibrosis. 3  Pro-inflammatory cytokines 15  and extracellular vesicles derived from platelets and erythrocytes further amplify SGLT2 expression through AT1R/NADPH oxidase signaling, thereby promoting oxidative stress, immune activation, thrombogenicity, and maladaptive valvular remodeling. 3  Moreover, plasma from patients with aortic stenosis contains proinflammatory and prothrombotic mediators capable of inducing oxidative stress, SGLT2 expression, and endothelial dysfunction in aortic valvular endothelial cells — effects that can be effectively mitigated by empagliflozin 4  ( Table 1 ,  Figure 1 ). Table 1 Proposed Cardiovalvular Mechanisms of SGLT2 Inhibitors Relevant to Rheumatic Heart Disease Mechanistic Domain Key Effects of SGLT2 Inhibition Chronic inflammation Suppression of NLRP3 inflammasome and NF-κB signaling; reduction in pro-inflammatory cytokine release; promotion of anti-inflammatory macrophage polarization; reduction of monocyte adhesion to VECs 3 , 4 , 13 , 16 ,  17 ,  18 ,  19 ,  20 ,  21 ,  22 Valvular endothelial dysfunction Preservation of endothelial integrity; restoration of nitric oxide bioavailability; reduction of VCAM-1–mediated leukocyte adhesion; inhibition of endothelial-to-mesenchymal transition 3 , 4 , 23 ,  24 ,  25 Valvular fibrosis, remodeling and calcification Attenuation of TGF-β and MMP-9 signaling; prevention of valvular interstitial cell activation and osteogenic differentiation; reduction of extracellular matrix remodeling and calcification 4 , 26 ,  27 ,  28 miRNA Suppressed the expression of miRNA i155, involved in inflammatory processes and fibrosis 29 , 30 Mechanical stress responses Enhanced resistance of valvular endothelial cells to shear stress and turbulence-related mechano-inflammatory signalling 25 , 31 Valvular thrombogenicity Decreased platelet activation and thrombin generation; downregulation of tissue factor expression 3 , 4 Atrial remodeling and arrhythmogenesis Reduced atrial fibrillation susceptibility and burden; modulation of calcium-handling proteins and gap-junction signaling; attenuation of cellular stress and apoptosis 32 ,  33 ,  34 Hemodynamic unloading Reduction in preload and afterload through natriuresis and osmotic diuresis; lowering of intracardiac filling pressures and transmitral gradients 32 , 35 Pulmonary vascular damage and right heart dysfunction Reduction of pulmonary vascular damage and right heart dysfunction through antagonism effect of fibrosis and NLRP3 inflammasome-associated inflammatory pathway 34 Myocardial remodeling and fibrosis Limitation of adverse ventricular remodeling; reduction of myocardial fibrotic deposition via anti-inflammatory and antifibrotic pathway 14 , 36 Myocardial energetics and efficiency Improved myocardial energy efficiency through enhanced substrate utilization and mitochondrial function; reduction of oxidative stress–related energetic impairment 37 , 38 miR-155 = microRNA-155; miRNA = microRNA; MMP-9 = matrix metalloproteinase 9; NF-κB = nuclear factor kappa B; NLRP3 = NOD-, LRR-, and pyrin domain containing 3; NLRP3 = NOD-like receptor family, pyrin domain–containing 3; SGLT2 = sodium-glucose cotransporter 2; TGF-β = transforming growth factor beta; VCAM-1 = vascular cell adhesion molecule 1; VECs = valvular endothelial cells.\nProposed Cardiovalvular Mechanisms of SGLT2 Inhibitors Relevant to Rheumatic Heart Disease\nmiR-155 = microRNA-155; miRNA = microRNA; MMP-9 = matrix metalloproteinase 9; NF-κB = nuclear factor kappa B; NLRP3 = NOD-, LRR-, and pyrin domain containing 3; NLRP3 = NOD-like receptor family, pyrin domain–containing 3; SGLT2 = sodium-glucose cotransporter 2; TGF-β = transforming growth factor beta; VCAM-1 = vascular cell adhesion molecule 1; VECs = valvular endothelial cells.\nPreclinical data further support this concept. In animal models of mitral regurgitation, SGLT2 inhibition attenuates valvular inflammation and injury, improves cardiac hemodynamics, and reduces arrhythmogenesis. 32  At the molecular level, SGLT2 inhibitors suppress activation of nuclear factor kappa B and the NOD-, LRR- and pyrin domain containing protein 3 inflammasome, downregulate vascular cell adhesion molecule 1 expression, promote macrophage polarization toward anti-inflammatory phenotypes, and attenuate transforming growth factor beta– and matrix metalloproteinase-9–mediated fibrotic remodeling — processes central to the chronic immune-inflammatory cascade driving RHD progression. 3 , 4 , 16 , 32  Dapagliflozin and empagliflozin also inhibit the accumulation of T and B lymphocytes and reduce levels of key proinflammatory cytokines, including tumor necrosis factor-α and interleukin-6. 17 , 18  Consistent with these immunomodulatory effects, a clinical trial in patients with type 2 diabetes has shown that 6 months of empagliflozin therapy suppressed T-cell proliferation and interleukin-17 production 19  — pathways implicated in endothelial-to-mesenchymal transition and macrophage polarization, which contribute to progressive valvular fibrosis. Supporting a clinically relevant anti-inflammatory effect, a large retrospective cohort study further showed an 11% reduction in autoimmune rheumatic disease incidence among SGLT2 inhibitor users. 39\nEmerging evidence also implicates noncoding RNAs, particularly microRNA-155 (miR-155), as key regulators of immune activation, endothelial-to-mesenchymal transition, inflammation and fibrotic remodeling in RHD. 29 , 40  Modulation of inflammatory signaling pathways linked to miR-155 by SGLT2 inhibitors represents a novel mechanistic axis through which these agents may attenuate immune-mediated valvular injury. 30\n\nAlthough outcome data on SGLT2 inhibitors in RHD remain limited, early clinical signals suggest potential benefit across valvular disease phenotypes ( Table 2 ). In RHD, preliminary clinical observations indicate that dapagliflozin may reduce mean transmitral gradients, lower natriuretic peptide levels, and improve atrioventricular compliance. 35  In degenerative aortic stenosis, a post hoc analysis including 458 patients treated with SGLT2 inhibitors and 11,240 untreated patients demonstrated that, after adjustment for time-varying exposure, relevant covariates, and competing risks, SGLT2 inhibitor use was associated with a significantly lower risk of progression from nonsevere to severe aortic stenosis over a median follow-up of 3.4 years. Notably, longer treatment duration was associated with progressively slower disease progression (HRs of 0.54, 0.48, and 0.27 for 3-, 6-, and 12-month exposure, respectively). 41  In a large retrospective cohort study conducted by our group using a federated electronic medical record network, SGLT2 inhibitor use in 10,912 propensity-matched patients per group with non-rheumatic aortic stenosis was independently associated with significantly lower all-cause mortality and a reduced need for both transcatheter and surgical aortic valve replacement. 42 Table 2 SGLT2i and Valvular Heart Disease: Evidence from Clinical Studies Clinical Setting Study Design Number of Patients Main Effects of SGLT2 Inhibitors RHD, mitral stenosis Open-label randomized trial 17 dapagliflozin, 16 controls Improved atrioventricular compliance, reduced mitral valve pressure gradient, and reduced NT-proBNP levels 35 Degenerative AS Retrospective, propensity score matching 458 SGLT2i users, 11,240 controls Lower progression to severe AS (HR: 0.61; 95% CI: 0.39-0.94;  P  = 0.026) 41 Degenerative AS Retrospective, propensity score matching 10,912 per group Reduced all-cause mortality (HR: 0.59; 95% CI: 0.55-0.64;  P  < 0.001), TAVR (HR: 0.83; 95% CI: 0.74-0.93;  P  = 0.002), SAVR (HR: 0.51; 95% CI: 0.44-0.60;  P  < 0.001), cardiac arrest (HR: 0.71; 95% CI: 0.58-0.87;  P  < 0.001), and end-stage kidney disease (HR: 0.29; 95% CI: 0.22-0.38;  P  < 0.001) 42 TAVR; diabetic patients with LVEF <50% and extravalvular cardiac damage Multicenter international registry, observational 74 SGLT2i users, 237 nonusers Reduced MACE (HR: 0.45; 95% CI: 0.17-0.75;  P  < 0.001), all-cause mortality (HR: 0.51; 95% CI: 0.25-0.98;  P  < 0.001), and HF hospitalization (HR: 0.40; 95% CI: 0.27-0.62;  P  = 0.009) 43 TAVR Randomized clinical trial 620 dapagliflozin vs 637 controls Reduced primary outcome (all-cause death or worsening HF) at 1 year (HR: 0.72; 95% CI: 0.55-0.95;  P  = 0.02). Higher rates of genital infections and hypotension with dapagliflozin 44 TAVR Multicenter international registry, observational No CKD: 226 (43 SGLT2i users, 183 nonusers); CKD: 288 (71 SGLT2i users, 217 nonusers) Lower incidence of AKI in CKD patients (OR: 0.70; 95% CI: 0.42-0.91;  P  = 0.014) 45 TAVR Retrospective, propensity score matching 2,039 per group Nonsignificant reduction in composite outcome (AMI, stroke, all-cause mortality, acute HF; HR: 0.79; 95% CI: 0.61-1.02;  P  = 0.067); lower risk of AMI (HR: 0.69;  P  = 0.043) and all-cause hospitalization/ER visits (HR: 0.69;  P  < 0.001) 46 TAVR Retrospective, propensity score matching 3,022 per group Lower mortality at 12 months (7.3% vs 10.5%; HR: 0.71) and 5 years (10.7% vs 20.6%; HR: 0.59; all  P  < 0.01); lower 5-year MI incidence (12.0% vs 14.4%; OR: 0.81;  P  = 0.007) 47 TAVR Retrospective, propensity score matching 2,297 per group Lower all-cause mortality (HR: 0.83; 95% CI: 0.71-0.97;  P  = 0.02) and bioprosthetic valve failure (HR: 0.62; 95% CI: 0.39-0.99;  P  = 0.04) 48 Bioprosthetic valve replacement (TAVR or SAVR) Retrospective, propensity score matching 83 SGLT2i users, 332 controls Lower incidence of structural valve dysfunction (HR: 0.37; 95% CI: 0.18-0.78;  P  = 0.008) 49 FMR Randomized controlled trial 52 under dapagliflozin, 52 under GDMT EROA reduction of FMR, RV reduction, decreased E/e’ ratio, LVEF improvement. No significant reduction in HF hospitalization and cardiovascular mortality 50 Pulmonary hypertension Retrospective, propensity score matching 58,302 per group Reduction of all-cause mortality, RHF, hospital admissions (HR: 0.71; 95% CI: 0.70-0.72) 51 AKI = acute kidney injury; AMI = acute myocardial infarction; AS = aortic stenosis; CKD = chronic kidney disease; ER = emergency room; EROA = effective regurgitant orifice area; FMR = functional mitral regurgitation; GDMT = guideline-directed medical therapy; HF = heart failure; LVEF = left ventricular ejection fraction; MACE = major adverse cardiac events; MI = myocardial infarction; NT-proBNP = N-terminal pro–B-type natriuretic peptide; OR = odds ratio; RHD = rheumatic heart disease; RHF = right heart failure; RV = regurgitant volume; SAVR = surgical aortic valve replacement; SGLT2i = sodium–glucose cotransporter 2 inhibitor; TAVR = transcatheter aortic valve replacement.\nSGLT2i and Valvular Heart Disease: Evidence from Clinical Studies\nAKI = acute kidney injury; AMI = acute myocardial infarction; AS = aortic stenosis; CKD = chronic kidney disease; ER = emergency room; EROA = effective regurgitant orifice area; FMR = functional mitral regurgitation; GDMT = guideline-directed medical therapy; HF = heart failure; LVEF = left ventricular ejection fraction; MACE = major adverse cardiac events; MI = myocardial infarction; NT-proBNP = N-terminal pro–B-type natriuretic peptide; OR = odds ratio; RHD = rheumatic heart disease; RHF = right heart failure; RV = regurgitant volume; SAVR = surgical aortic valve replacement; SGLT2i = sodium–glucose cotransporter 2 inhibitor; TAVR = transcatheter aortic valve replacement.\nEmerging evidence also supports a role for SGLT2 inhibitors in patients undergoing transcatheter aortic valve replacement (TAVR). In diabetic patients with reduced left ventricular ejection fraction (<50%) and extravalvular cardiac damage, observational registry data demonstrated that SGLT2 inhibitor therapy was associated with substantial reductions in major adverse cardiovascular events, all-cause mortality, and heart failure hospitalizations. 43  Randomized trial data further showed that dapagliflozin reduced the composite endpoint of all-cause death or worsening heart failure at 1 year, albeit with higher rates of genital infections and hypotension. 44  Additional registry and retrospective analyses indicate that SGLT2 inhibitor use is associated with a lower incidence of acute kidney injury in patients with chronic kidney disease, reduced all-cause mortality at 12 months and 5 years, decreased myocardial infarction incidence, and lower rates of bioprosthetic valve failure. 47 , 48  Notably, among patients undergoing bioprosthetic valve replacement (TAVR or surgical aortic valve replacement), SGLT2 inhibitor therapy was associated with a reduced risk of structural valve dysfunction. 49  Collectively, these findings suggest a potential role for SGLT2 inhibitors in improving both short- and long-term clinical outcomes, including valve durability following TAVR.\nIn the recent DEFORM randomized controlled trial including 104 patients with moderate-to-severe functional mitral regurgitation, dapagliflozin added to guideline-directed medical therapy significantly reduced effective regurgitant orifice area and regurgitant volume over 3 months while improving left ventricular ejection fraction, E/e′ ratio, and left atrial volume index. 50  Although differences in hard clinical endpoints were not statistically significant over short-term follow-up, these findings demonstrate that SGLT2 inhibition can favorably modulate mitral regurgitation severity and myocardial remodeling. Such mechanistic and hemodynamic improvements in functional mitral regurgitation provide supportive clinical proof-of-concept that SGLT2 inhibitors may also exert beneficial valvular and remodeling effects in RHD, where chronic inflammation and structural distortion drive progressive mitral dysfunction.\nThe effects of SGLT2 inhibitors have also been examined in pulmonary hypertension and atrial fibrillation, 2 key features of advanced RHD. In a large multicenter cohort of more than 770,000 patients with pulmonary hypertension, SGLT2 inhibitor use was associated with lower rates of all-cause mortality, right heart failure, and hospitalization at 1 year, with consistent associations across pulmonary hypertension phenotypes. 51  In a large nationwide cohort of patients with type 2 diabetes, SGLT2 inhibitor use was also associated with a lower risk of incident atrial fibrillation compared with other second-line glucose-lowering therapies. 33  Given the substantial burden of pulmonary hypertension and atrial fibrillation in RHD, these observational data provide indirect support for further investigation of the potential effects of SGLT2 inhibitors on pulmonary vascular pathology and arrhythmic outcomes in this population. 52\nTaken together, the convergence of mechanistic, translational, and emerging clinical evidence positions SGLT2 inhibition as a promising disease-modifying strategy in RHD, uniquely targeting the immune-inflammatory, endothelial, and fibrotic drivers of progressive valve damage ( Figure 1 ). Given the prolonged subclinical phase of RHD and the absence of effective medical therapies beyond antibiotic prophylaxis, SGLT2 inhibitors warrant prioritization in dedicated experimental models and early-phase clinical trials aimed at altering the natural history of rheumatic valve disease.\n\nUntil recently, no randomized controlled trial had specifically evaluated SGLT2 inhibitors in RHD. This landscape is beginning to evolve with ongoing clinical studies such as Dapa-Rhemis (Dapagliflozin Effect on Rheumatic Mitral Stenosis;  NCT05618223 ), assessing dapagliflozin in patients with rheumatic mitral stenosis, and Gliflozins on HF in Regurgitant Rheumatic Heart ( NCT06097585 ), investigating SGLT2 inhibitors in heart failure associated with regurgitant rheumatic valve disease. Although these trials primarily explore hemodynamic, functional, and biomarker outcomes, definitive evidence regarding hard cardiovascular endpoints and long-term disease modification remains lacking. Given their once-daily oral administration, well-established safety profile, broad cardiometabolic benefits, and relatively low cost — approximately 1 USD per day — SGLT2 inhibitors represent a promising and potentially cost-effective strategy, particularly in LMICs. We hypothesize that SGLT2 inhibition, by attenuating chronic inflammation and valvular fibrosis, can improve clinical outcomes and emerge as the first disease-modifying pharmacotherapy in RHD. With coordinated support from global foundations, industry partners, and the scientific community, a landmark outcomes trial targeting major adverse cardiovascular events in RHD is now both timely and achievable ( Central Illustration ).\n\nRHD remains a major yet under-recognized cause of cardiovascular morbidity and premature mortality across Asia, disproportionately affecting young populations in LMICs. Despite its substantial and persistent burden, therapeutic progress has been limited, with current strategies focused largely on infection prevention and late-stage valve intervention rather than disease modification. This gap reflects a broader inequity in cardiovascular innovation and care. Emerging mechanistic, translational, and observational evidence suggests that SGLT2 inhibitors may directly target the immune-inflammatory, endothelial, and fibrotic pathways central to RHD progression. Their favorable safety profile, oral administration, and low cost make them particularly attractive for large-scale implementation in resource-limited settings. Although randomized data in RHD are lacking, the convergence of biological plausibility and early clinical signals strongly supports prioritizing SGLT2 inhibitors for dedicated trials. Advancing such studies represents a timely and pragmatic opportunity to transform the management of RHD in Asia and to redefine the future of care for a long-neglected disease.\n\nThis study has been supported by GERCA, Ambassade de France à Hanoi, and Bourse d'excellence (excellence award) granted to Dr Anh Trung Mai. Dr Morel has received grants in support of investigator and investigator-initiated studies from AstraZeneca, Medtronic, and Boehringer Ingelheim; and has been awarded grants by “Fondation Cœur et Recherche” and “Endofrance,” two reputable charities in France committed to advancing research initiatives in cardiovascular disease in endometriosis. Dr Roffi has received institutional grants from Terumo, Boston Scientific, Cordis, Vascular Medical, and Biotronik. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.","source_license":"public-domain-us","license_restricted":false}