Sodium–Glucose Cotransporter 2 Inhibitors in Valvular Heart Disease: Cardiovascular Benefit, Valve-Specific Effects, and Evidence Gaps—A Structured Narrative Review

Figures

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  Figure 1. Mechanistic evidence hierarchy for SGLT2 inhibition in valvular heart disease. Level 1 comprises direct SGLT2i-specific ex vivo human valve evidence [12]; Level 2 comprises experimental valve and VIC models [7,8,12,25,26,27,28,29,30,31]; and Level 3 comprises mechanisms extrapolated from vascular and myocardial biology [10,11,32,33]. Functional MR improvement may result from ventricular/atrial unloading and reverse remodeling, whereas post-TAVI benefit is best interpreted as post-interventional cardiorenal and HF protection. None of these levels establishes in vivo modification of an untreated native human valve lesion. ALP, alkaline phosphatase; AMPK, AMP-activated protein kinase; ER, endoplasmic reticulum; HF, heart failure; LA, left atrial; LV, left ventricular; MR, mitral regurgitation; NRF2, nuclear factor erythroid 2-related factor 2; ROS, reactive oxygen species; RUNX2, runt-related transcription factor 2; TAVI, transcatheter aortic valve implantation; TXNDC5, thioredoxin domain-containing protein 5; VIC, valvular interstitial cell.

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  Figure 2. Clinical evidence hierarchy and practical pathway across valvular phenotypes. Functional/secondary MR provides the strongest valve-related randomized signal, whereas DapaTAVI provides the strongest hard-outcome evidence after the mechanical correction of aortic stenosis [13,14,16]. Large amounts of SHEBAHEART registry data place functional TR in a promising observational tier, with randomized confirmation awaited from EVENT [24,34]. Native AS remains an emerging, unconfirmed disease-modification hypothesis [15,19], while native aortic regurgitation lacks dedicated clinical evidence. The lower pathway summarizes the contemporary sequence for secondary MR: optimize HF GDMT (including SGLT2is when indicated and CRT when appropriate), reassess MR and remodeling, then consider TEER or surgery for persistent significant MR [35,36]. AS, aortic stenosis; GDMT, guideline-directed medical therapy; HF, heart failure; MR, mitral regurgitation; TAVI, transcatheter aortic valve implantation; TEER, transcatheter edge-to-edge repair; TR, tricuspid regurgitation.