Key result
SGLT2i therapy in severe AS patients was associated with lower valvular SGLT2, SGLT1, NF-κB, and IL-6 expression (p<0.001) and modulation of 34 metabolites vs non-SGLT2i users.
Why the study?
Degenerative aortic stenosis lacks pharmacological therapy proven to slow its progression, and the role of SGLT2 inhibitors in valvular heart disease remains poorly defined.
Does SGLT2 inhibitor therapy alter valvular SGLT2 expression and molecular and metabolic signatures in patients with severe aortic stenosis undergoing surgical aortic valve replacement?
Observational (n=83)
Yes
Does SGLT2 inhibitor therapy alter valvular SGLT2 expression and molecular and metabolic signatures in patients with severe aortic stenosis undergoing surgical aortic valve replacement?
In patients with severe aortic stenosis undergoing surgical valve replacement, SGLT2 inhibitor use is associated with attenuated valvular inflammation, lower SGLT2/SGLT1 expression, and distinct metabolic reprogramming in explanted valve tissue.
Background Degenerative aortic stenosis (AS) is an active fibrocalcific disease with no pharmacological therapy proven to slow its progression.SGLT2 inhibitors exert pleiotropic effects, but their role in valvular heart disease remains poorly defined. Purpose To quantify SGLT2 expression in explanted human aortic valve leaflets and to compare molecular and metabolic signatures between SGLT2i users and those receiving other glucose-lowering therapies.Secondary objectives included associations with valvular and circulating biomarkers of inflammation, fibrosis, oxidative stress, and calcification. Methods In this international multicenter prospective study, consecutive patients with severe AS referred for SAVR were enrolled (Jul 2024-Aug 2025). Based on antidiabetic therapy at admission, patients were stratified into SGLT2i and non-SGLT2i users.Intraoperative peripheral venous blood samples and explanted aortic valve leaflets were collected.Valvular gene expression of metabolic, inflammatory, fibrotic, oxidative stress, and calcification-related markers were assessed by RT-PCR, while circulating biomarkers by ELISA.Global metabolomic profiling and MALDI-MSI were performed on explanted aortic valve to characterize metabolic signatures and their spatial distribution within the stenotic valve. Results The study population included 83 patients, of whom 21 (25.3%) were treated with SGLT2i. Clinical characteristics, surgical risk, echocardiographic parameters, and coronary artery disease burden were comparable between groups.SGLT2i users exhibited significantly lower valvular expression of SGLT2 and SGLT1 (p<0.001), GLUT4, and NHE (p<0.05) compared to non-SGLT2i users, while GLUT1 remained unchanged. Metabolic regulators showed increased PPARα (p<0.001) and reduced PPARγ expression (p<0.05).Inflammatory signaling was attenuated in SGLT2i users, with lower valvular NF-κB and IL-6 expression and reduced circulating IL-6 (p<0.001), alongside increased SOD2 expression (p<0.05).Fibrotic markers did not differ between groups; however, circulating Serpin-4 was higher (p<0.05), while MR-proADM, PINP, and NT-proBNP were lower (p<0.05) in SGLT2i users. MMP-9 and MMP-12 were significantly reduced in SGLT2i users (p<0.05).Global metabolomic profiling revealed a distinct metabolic segregation between groups. 34 metabolites within aminoacid, purine, phospholipid and glutathione pathways were differentially modulated.SGLT2i users exhibited enrichment of aminoacid and redox metabolites, while non-SGLT2i users showed elevated phospholipid derivatives.Altered purine intermediates indicated modified nucleotide turnover. Conclusions SGLT2i therapy is associated with distinct molecular and metabolic signatures in human calcific aortic valve tissue, suggesting therapy-related metabolic reprogramming of the valvular microenvironment and providing translational evidence supporting a potential role of SGLT2-related pathways in AS pathobiology.
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Belmonte et al. (2026) conducted an observational in Severe aortic stenosis (n=83). SGLT2 inhibitors vs. Other glucose-lowering therapies (non-SGLT2i users) was evaluated on Valvular SGLT2 expression and molecular/metabolic signatures in explanted human aortic valve leaflets (p=<0.001). SGLT2i therapy in severe AS patients was associated with lower valvular SGLT2, SGLT1, NF-κB, and IL-6 expression (p<0.001) and modulation of 34 metabolites vs non-SGLT2i users.
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