SGLT2 Inhibitors May Slow Nonsevere Aortic Stenosis Progression

For the first time, researchers said SGLT2 inhibitors may have some disease-modifying potential for nonsevere aortic stenosis (AS).

In this retrospective observational study, 4.6% of patients who received SGLT2 inhibitors progressed to severe AS over 5 years compared with 10.9% of those who did not receive these drugs (P<0.001), reported Alexandra Lansky, MD, of the Yale Cardiovascular Research Group in New Haven, Connecticut, and colleagues.

After adjusting for time-varying SGLT2 inhibitor use, covariates, and the competing risk of death, patients on SGLT2 inhibitors had a significantly reduced risk of progression to severe AS (HR 0.61, 95% CI 0.39-0.94), they wrote in JACC: Cardiovascular Interventions.

This was backed by echocardiographic valve deterioration data, as SGLT2 inhibitor recipients also showed slower annualized rates of worsening in aortic valve peak velocity and aortic valve area over follow-up, Lansky and team noted.

“Altogether, this target trial emulation strongly suggests that SGLT2 inhibitors prevent the progression of AS, and prospective randomized controlled trials evaluating the effect of SGLT2 inhibitors on progression of AS are warranted, given the substantial burden AS puts on patients, society, and the healthcare system,” they concluded.

This study provides hope when no other therapies or lifestyle changes have been proven to slow the progression of AS.

Without an effective medical therapy, watchful waiting is standard practice. Nonsevere AS often worsens over time (due to inflammation, fibrosis, and calcification of the aortic valve) to the point that patients require a surgical or transcatheter aortic valve replacement (AVR) — an operation not without risks.

“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,” wrote Brian Lindman, MD, MSc, and Bassim El-Sabawi, MD, both of Vanderbilt University Medical Center in Nashville, Tennessee, in an accompanying editorial.

“Medical therapy targeting the ventricle in patients with mild-moderate AS has never been a focus of attention nor rigorously tested, but there are numerous reasons why SGLT2 inhibitors would make sense to prevent or mitigate maladaptive hypertrophic remodeling/dysfunction in the heart experiencing pressure overload from AS,” they added. “Now, [the study authors] provide data suggesting that SGLT2 inhibitors may also be effective in targeting the valve to slow progressive valve obstruction.”

Originally developed as diabetes drugs, SGLT2 inhibitors have since gained approvals for cardiovascular and renal protection based on several randomized trials.

Lansky and colleagues hypothesized that these agents — such as empagliflozin (Jardiance), dapagliflozin (Farxiga), and canagliflozin (Invokana) — may also help slow the progressive valve obstruction in AS given their antifibrotic, antioxidative, and potential anti-inflammatory effects.

“Given the established safety and tolerability of SGLT2 inhibitors, this appears to be a particularly promising avenue of investigation to pursue; now that these drugs are coming off patent, it could also be a particularly cost-effective treatment path,” Lindman and El-Sabawi wrote.

For this study, Lansky and colleagues conducted a retrospective review of electronic medical record (EMR) data from the Yale New Haven Health System from January 2016 to September 2022. They included patients with native aortic valve sclerosis or nonsevere AS with at least 12 months of echocardiographic follow-up.

Patients were excluded from the study if they had an estimated glomerular filtration rate <30 mL/min/1.73 m², underwent AVR during follow-up for an indication other than severe AS, or had initiated an SGLT2 inhibitor over a year before the index echocardiogram.

The resulting cohort included 458 patients prescribed SGLT2 inhibitors and 11,240 controls who were never prescribed them.

These two study arms shared comparable baseline AS severity (66% sclerosis, 23% mild stenosis, 11% moderate stenosis). However, the SGLT2 inhibitor group was younger (median 71 vs 75 years at first echo), had higher rates of diabetes (92.6% vs 37.7%) and chronic kidney disease (51.5% vs 32.6%), and was more likely to have ejection fractions of 40% or less (11.6% vs 4.3%). These patients also underwent more echocardiograms and reached longer follow-ups.

After adjustment, the benefits of SGLT2 inhibitors appeared exposure-dependent, with more benefits after more months spent on therapy. Lansky’s team acknowledged that this analysis was limited by a relatively short duration of use of SGLT2 inhibitors (the median being just 0.9 years).

On top of that, the focus on patients in the earliest stages of disease “raises some question regarding the observations and their implications,” the editorialists noted. “However, the findings remained consistent when patients with less-significant AS were excluded.”

Other limitations of the study included its retrospective design, lack of verification of echocardiographic data by an independent core lab, and the assumption that patients complied with their prescribed SGLT2 inhibitor.

The study authors also reported that they could not find a survival benefit with SGLT2 inhibitors in the AS setting, but they cautioned that the study was underpowered for this.

“Despite these limitations, the results may serve as another rationale to prioritize SGLT2 inhibitors in patients with nonsevere AS who already have an existing indication for the drug (e.g., diabetes, chronic kidney disease, or heart failure),” wrote Lindman and El-Sabawi. “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.”

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