Sodium-glucose cotransporter-2 inhibitors (SGLT2i) may slow the progression of non-severe aortic stenosis (AS), according to a new retrospective observational study in more than 11,500 patients. The researchers — led by Tayyab Shah, MD, from The Hospital of the University of Pennsylvania — found that treatment with an SGLT2i drug was associated with an almost 40% lower hazard of progression to severe AS. The findings were published online in JACC: Cardiovascular Interventions. AS is the leading cause of valvular heart disease-related morbidity and mortality, Dr. Shah and the authors noted, with each stage of disease progression — from mild, to moderate then severe — associated with worsening risk of major adverse cardiovascular events (MACE), heart failure and death. More than 500,000 have severe AS in the US alone, they noted. However, there is still no effective medical treatment to slow the progression of non-severe AS or mitigate its associated adverse outcomes, with current standard of care revolving around "watchful surveillance" until the patient develops severe AS, "at which point surgical or transcatheter aortic valve replacement are indicated," the researchers said. While multiple trials have demonstrated cardioprotective effects associated with SGLT2i, they have not been specifically studied in patients with AS. The current study therefore set out to look into an associated slowing of AS disease progression in patients taking these drugs using retrospective electronic medical record data from the Yale New Haven Health System from January 2016 to September 2022. The study included 11,698 patients with native aortic valve sclerosis, a precursor to AS, or non-severe AS with at least 12 months of echocardiographic follow-up, 458 of which were prescribed SGLT2i (does for a median of 0.9 years) and 11,240 of whom were never prescribed an SGLT2i. Those with an estimated glomerular filtration rate <30 mL/min/1.72m2 or who had initiated an SGLT2i >1 year before the index echocardiogram were excluded. Patients given an SGLT2i were younger (71 years vs 75 years), had higher rates of diabetes (92.6% vs 37.7%) and chronic kidney disease (51.5% vs 32.6%) and were more likely to have left ventricular ejection fraction ≤40% (11.6% vs 4.3%). There were no significant differences between groups in baseline AS severity (66% sclerosis, 23% mild stenosis, and 11% moderate in the overall cohort; 66.8% sclerosis, 23.9% mild stenosis and 9.4% moderate stenosis in the SGLT2i cohort; and 65.7% sclerosis, 22.7% mild stenosis and 11.6% moderate stenosis in the no SGLT2i cohort; P = 0.34). The researchers found that the primary outcome of progression to severe AS was less likely to happen for patients prescribed SGLT2i (hazard ratio [HR]: 0.61; 95% confidence interval [CI]: 0.39-0.94; P = 0.03). There was also a progressively lower risk among patients on SGLT2i for more than 3, 6 and 12 months (HR: 0.54, 0.48 and 0.27, respectively; all P < 0.01). Disease-modifying potential “This retrospective, multicenter, observational study using target trial emulation methodology suggests that SGLT2i may substantially slow the progression of nonsevere AS,” the researchers said. They went on to call for randomized trials studying the effects of SGLT2i versus a control in patients with nonsevere aortic stenosis to assess the “potentially disease-modifying therapy.” In an accompanying editorial, Vanderbilt University Medical Center’s Brian R. Lindman, MD, MSC, and Bassim El-Sabawi, MD, highlighted the fact that SGLT2i users in the study also experienced slower rates of worsening in aortic valve function, demonstrated by less increase in aortic valve peak velocity and slower decline in aortic valve area. “Notably, the salutary effects of SGLT2i were more pronounced with longer use,” they said. “Most SGLT2i users had diabetes or chronic kidney disease — conditions known to accelerate AS progression — indicating that these patients were inherently at higher risk.” The editorialists added that the findings provide important evidence in support of the potential disease-modifying effects of SGLT2i in AS. However, the editorialists also pointed out several key limitations, including that echocardiographic assessments were not centrally reviewed in a core lab. “Quantitative measures of AS severity can be particularly noisy when there is aortic sclerosis or mild AS, which characterizes the majority of patients in this study,” they said. They also noted that a retrospective design “may not fully account for potential confounders,” and stressed that the study’s median duration of SGLT2i usage being below 1 year was “relatively short.” Nevertheless, the editorialists said that the findings may provide “another rationale” to prioritize SGLT2i in patients with non-severe AS who are already indicated for the drug, for instance dur to diabetes, chronic kidney disease or heart failure. “Beyond that, the findings point to an intriguing opportunity: a ‘2 for 1’ medical therapy trial in patients with earlier stage AS, namely one that targets both the valve and the myocardium,” they said. “The journey to identify an effective medical therapy for AS has been fruitless to date, but perhaps the solution is closer than we may realize and one that gets 2 targets with a single drug.” Sources: Shah T, Zhange Z, Shah H, et al. Effect of Sodium-Glucose Cotransporter-2 Inhibitors on the Progression of Aortic Stenosis. JACC: Cardiovasc Interv 2025; DOI: 10.1016/j.jcIN.2024.11.036. Lindman BR, El-Sabawi B. SGLT2 Inhibition in Aortic Stenosis: A Therapy for the Ventricle, the Valve, or Both? JACC: Cardiovasc Interv 2025; DOI: 10.1016/j.jcIN.2024.12.025. Image Credit: Andrii – stock.adobe.com