SGLT2 Inhibitors for Diabetes May Suppress Aortic Valve Calcification by Regulating SIRT1
Background
Aortic stenosis (AS) is a cardiovascular disease in which calcium deposition and fibrosis progress in the valve due to aging, restricting blood flow. It affects approximately 3% of the population aged 65 and older, with numbers rising rapidly due to an aging population. As stenosis worsens, it causes chest pain, dyspnea, and heart failure, eventually leading to fatal outcomes. The problem is the total lack of medical treatments that fundamentally slow or stop disease progression. While once considered a degenerative disease due to simple mechanical wear, recent pathological research has identified it as an active biological process involving chronic inflammation, oxidative stress, and extracellular matrix remodeling.
Past attempts to apply statins or osteoporosis treatments to valve disease failed to prove efficacy in large-scale clinical trials. Currently, clinical practice remains limited to symptomatic intervention, where regular ultrasound follow-up is conducted until symptoms worsen, followed by surgical aortic valve replacement (SAVR) or transcatheter aortic valve implantation (TAVR) once valve function reaches its limit. For elderly patients at high surgical risk, physical procedures impose a significant physical burden, and there is an urgent need to secure standard treatments that can inhibit disease progression in the early stages.
Key Findings
Researchers focused on Sirtuin 1 (SIRT1), a protein deacetylase, as an upstream regulator controlling the entire fibro-calcification pathway of valve tissue. Analyzing RNA-seq data from human aortic valve tissue extracted from the ARChS4 transcriptome database, they found that the SIRT1 signaling pathway is suppressed in AS patient tissues and is closely linked to oxidative stress and matrix modification pathways.
To validate the molecular mechanism, we established a control group by creating SIRT1 knockdown (SIRT1 KD) and overexpression (SIRT1 Over) cell lines of human valve interstitial cells (VICs) using CRISPR/Cas9 technology to inhibit SIRT1 expression. This was followed by results from real-time polymerase chain reaction (RT-PCR), immunofluorescence staining, and quantitative calcium assessment. In SIRT1-deficient cells, matrix calcification increased sharply along with the activation of osteogenic transcription factors. Conversely, in cells overexpressing SIRT1, calcification deposition was markedly suppressed compared to wild-type cells. This indicates that SIRT1 prevents the osteoblast-like differentiation of valvular cells by regulating antioxidant defense mechanisms and matrix homeostasis.
The pharmacological action of Sodium-Glucose co-Transporter 2 inhibitors (SGLT2i) was also clearly demonstrated through cell-to-cell interaction experiments. When valve interstitial cells were cultured in conditioned medium obtained after treating vascular endothelial cells with SGLT2 inhibitors, calcification formation significantly decreased. It was confirmed that nitric oxide (NO) secreted from endothelial cells acts as a key mediator in inhibiting the osteogenic differentiation of valve interstitial cells.
Consistent results were also derived from actual patient cohort data. Based on the Lombardy regional healthcare database in Italy, we completed 1:1 propensity score matching for patients taking SGLT2 inhibitors and those taking sulphonylureas (SU), which do not affect the SIRT1 pathway, by age, sex, and comorbidity index. The cumulative incidence of hospitalization for non-rheumatic aortic valve disease was precisely tracked using Kaplan-Meier and Fine-Gray competing risk models. Multivariate Cox proportional hazards model analysis revealed that the SGLT2 inhibitor group had a 40% lower risk of hospitalization related to aortic valve disease compared to the sulfonylurea group (Hazard Ratio 0.60, 95% CI 0.41-0.85).
Significance and Outlook
This study opens a specific pathway for drug repurposing in the field of aortic valve stenosis, which previously relied solely on invasive surgery due to the absence of therapeutic drugs. It demonstrated through molecular biological experiments and large-scale real-world data (RWD) that SGLT2 inhibitors, already established as safe for the treatment of type 2 diabetes and heart failure, can control calcification of heart valves. In particular, identifying that SIRT1 activation is a key axis in preventing valve sclerosis through the interaction between endothelial and interstitial cells is a major advancement in target discovery.
Challenges remain before clinical application can be fully realized. Since this human data is based on a retrospective observational cohort, direct causality must be proven through randomized controlled trials (RCT). It is essential to verify whether the same valve-protective effect occurs in patients with non-diabetic aortic stenosis. Follow-up clinical trials to establish the timing of administration—specifically how much disease progression can be slowed in the early and moderate stages compared to the late stage where calcification has hardened—are considered the watershed for commercialization.
BACKGROUND: Calcific aortic valve stenosis (AS) affects 3% of older adults and lacks medical treatment. The deacetylase Sirtuin 1 (SIRT1) could be involved in many pathways linked to AS progression. Sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucose-lowering agents, have been shown to reduce cardiovascular events (likely via SIRT1), but their possible benefits in AS are unknown. Our study aims to uncover the role of SIRT1 in AS progression and assess the benefit of SGLT2i to slow down the aortic valve fibro-calcification processes. METHODS: RNA-seq data of human aortic valve specimens were collected from the ARChS4 database. SIRT1 knockdown (SIRT1 KD) and overexpressing (SIRT1 Over) valve interstitial cells (VIC) were generated by CRISPR/Cas9. Real-time PCR, immunofluorescence, and calcification assays were used to characterise mutant VICs. Conditioned medium experiments were implemented to evaluate SGLT2i effect on cellular cross-talk and calcification. Diabetic patients' data from the Lombardy regional healthcare database, treated with sulphonylureas (SU; no effect on SIRT1) and SGLT2i (acting on SIRT1), were selected and matched 1:1 by age, sex, and multisource comorbidity score. Cumulative incidence of hospitalisation for non-rheumatic aortic valve disease was assessed by Kaplan-Meier, and Fine and Gray models were used to estimate subdistribution hazard ratios. RESULTS: RNA-seq showed that SIRT1 could be an upstream regulator of multiple AS-related pathways. Functional studies on mutant VICs revealed that SIRT1 directly regulates antioxidant processes, extracellular-matrix remodelling, and calcification by modulating key transcription factors. Moreover, calcification assays further support this role, revealing increased calcification in SIRT1 KD VICs and a concomitant decrease in VICs with SIRT1 overexpression compared to wild type. Then, exploring SGLT2i impact on calcification, we showed that VICs cultured in SGLT2i-treated-endothelial medium exhibited reduced calcification.
This research presents a turning point in the management of aortic stenosis, which previously involved merely observing patients passively from early diagnosis until surgery. It enables the establishment of clinical guidelines to preemptively block valve fibrosis by early administration of SGLT2 inhibitors to high-risk patients with diabetes or cardiovascular disease who have been confirmed to have mild valve calcification via echocardiography. We can expect clinical strategies to delay the progression to severe stenosis by several years, thereby postponing the timing of invasive valve replacement surgery or reducing the need for surgery altogether. The pharmaceutical industry is also expected to accelerate investment in new clinical development to expand the indications of existing cardiovascular and metabolic blockbuster drugs to intractable valve diseases.