SGLT2 inhibitor prescription associated with slower progression of aortic stenosis

In a retrospective observational study among patients with nonsevere aortic stenosis (AS), use of SGLT2 inhibitors was associated with a lower risk of progression to severe AS than no SGLT2 inhibitor treatment.

This summary is based on the publication of Shah T, Zhang Z, Shah H, et al. - Effect of Sodium-Glucose Cotransporter-2 Inhibitors on the Progression of Aortic Stenosis. JACC Cardiovasc Interv. 2025 Mar 24;18(6):738-748. doi: 10.1016/j.jcin.2024.11.036.

Introduction and methods

Background

In aortic stenosis (AS), each stage is associated with a progressively increasing risks of MACE, HF, and death [1-3]. Currently, there are no proven medical therapies that slow AS progression or reduce the risk of related adverse outcomes [4-8]. Based on their cardioprotective, antifibrotic, antioxidative, and possible anti-inflammatory effects [9-12], SGLT2 inhibitors are a potential candidate to delay the progression of AS.

Aim of the study

The study aim was to determine whether the use of SGLT2 inhibitors is associated with slower progression of nonsevere AS.

Methods

In a multicenter, retrospective, observational study, data of 11,698 patients with aortic valve sclerosis, mild AS, or moderate AS on echocardiography were extracted from the Yale New Haven Health System for the period January 1, 2016–September 30, 2022. Exclusion criteria were, among others, severe AS, prior aortic valve replacement, eGFR <30 mL/min/1.73 m², echocardiographic follow-up <12 months, and initiation of SGLT2 inhibitor treatment >1 year before the index echocardiogram.

To estimate the causal effect of SGLT2 inhibitor use on the progression of nonsevere AS, the authors used the target trial emulation framework to mimic a hypothetical RCT [13]. They applied outcome regression to adjust for confounders and account for baseline differences between patients who were ever prescribed SGLT2 inhibitors and those who were not prescribed this medication during 5-year follow-up. The median duration of SGLT2 inhibitor use in the first group was 0.9 years (Q1–Q3: 0.3–2.1) after the index echocardiogram.

Outcomes

The prespecified primary endpoint was progression to severe AS (as interpreted by the reading cardiologist’s diagnosis in the original echocardiography report). Secondary endpoints included all-cause mortality and annual changes in aortic valve peak velocity, aortic valve area, and dimensionless index.

Main results

Study population

• Patients who were prescribed SGLT2 inhibitors were younger and more frequently had diabetes, CKD, coronary artery disease, or LVEF ≤40% compared with those not receiving SGLT2 inhibitor treatment (all P<0.001).
• At baseline, 66% of the patients had aortic sclerosis, 23% had mild AS, and 11% had moderate AS, with no significant difference in prevalences between the 2 treatment groups (P=0.34).

Primary and secondary endpoints

• Patients prescribed SGLT2 inhibitors (n=458) were less likely to progress to severe AS over 5 years than those not receiving SGLT2 inhibitors (n=11,240) (4.6% vs. 10.9%; adjusted HR: 0.61; 95%CI: 0.39–0.94; P=0.026).
• Patients on SGLT2 inhibitors showed lower rates of worsening of aortic valve peak velocity (0.029 vs. 0.052 m/s per year; adjusted mean difference: –0.037 m/s per year; 95%CI: –0.071 to –0.003; P=0.03) and decrease of aortic valve area (–0.061 vs. –0.077 cm²/year; adjusted mean difference: 0.027 cm²/year; 95%CI: 0.002–0.053; P=0.04) compared with patients not taking this medication.
• There were no significant differences in the change in dimensionless index (–0.018 vs. –0.021/year; adjusted mean difference: 0.0044/year; 95%CI: –0.0021 to 0.0110; P=0.19) and the incidence of all-cause mortality (9.0% vs. 13.0%; adjusted HR: 0.98; 95%CI: 0.71–1.37; P=0.912) between participants with and with no SGLT2 inhibitor treatment.
• Compared with patients not treated with SGLT2 inhibitors, those who were had a progressively lower risk of developing severe AS when taking SGLT2 inhibitors for a total of >3 months (HR: 0.54; 95%CI: 0.34–0.83; P=0.006), >6 months (HR: 0.48; 95%CI: 0.30–0.77; P=0.002), or >12 months (HR: 0.27; 95%CI:0.14–0.52; P<0.001).

Conclusion

This retrospective observational study using the target trial emulation methodology indicated that use of SGLT2 inhibitors among patients with nonsevere AS was associated with a decreased risk of progression to severe AS and lower rates of worsening of aortic valve peak velocity and decrease of aortic valve area, compared with no SGLT2 inhibitor treatment. The risk of progression to severe AS was progressively lower with longer SGLT2 inhibitor use.

Find this article online at JACC Cardiovasc Interv.

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