SGLT2 Inhibition as a Novel Therapeutic Strategy in Rheumatic Heart Disease

Until 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 ).

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. 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. RHD 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 The 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 Similarly, 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 In 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.

Although 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. SGLT2i and Valvular Heart Disease: Evidence from Clinical Studies 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. Emerging 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. In 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. The 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 Taken 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.

Contemporary 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. In 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 ).

RHD 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.

This 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.