Aortic Stenosis Slowed by SGLT2 Inhibitors in Observational Study

Sodium-glucose cotransporter 2 (SGLT2) inhibition seems to reduce the progression of nonsevere aortic stenosis over 5 years, with a larger treatment effect seen in those who take the drugs the longest, observational data suggest.

With no available medical treatments or lifestyle interventions for the prevention of aortic stenosis, the promise for this class of drugs—which now has substantial evidence to support its cardiovascular benefit in patients with heart failure regardless of ejection fraction—is vast, say researchers.

“This is the first study to demonstrate the potential for a plausible medical therapy to prevent aortic stenosis,” senior author Alexandra J. Lansky, MD (Yale Cardiovascular Research Group, New Haven, CT), told TCTMD in an email. “If confirmed, these results will be groundbreaking.”

Jordan Miller, PhD (Mayo Clinic, Rochester, MN), who commented on the study for TCTMD, called the study findings exciting. “We know that clinicians are frustrated with the reality that once a patient is diagnosed with aortic stenosis, it’s just watchful waiting,” he said. “We try to mitigate risk factors [and] we try to identify emerging therapeutic opportunities for them, but really, there’s just a huge gap which results in a lot of feelings of patient and provider helplessness.”

The study, with first author Tayyab Shah, MD (The Hospital of the University of Pennsylvania, Philadelphia), was published online Wednesday in JACC: Cardiovascular Interventions.

Less Progression with SGLT2 Inhibition

For the analysis, the researchers retrospectively compared 458 patients with nonsevere aortic stenosis ever prescribed SGLT2 inhibitors and 11,240 patients who were never prescribed the drugs from electronic medical record data spanning January 2016 to September 2022. The study group took SGLT2 inhibitors for a median of 0.9 years and were younger and had more diabetes and chronic kidney disease compared with controls. Severity of aortic stenosis was well balanced between the groups, with 66%, 23%, and 11% overall having sclerosis, mild stenosis, and moderate stenosis, respectively.

Over 5 years, fewer patients who had ever received SGLT2 inhibitors progressed to severe aortic stenosis compared with those who were not prescribed these drugs (4.6% vs 10.9%; P < 0.001). This risk was significantly lower even after adjustment for a variety of factors (HR 0.61; 95% CI 0.39-0.94), with consistent results across a range of subgroup analyses.

We know that clinicians are frustrated with the reality that once a patient is diagnosed with aortic stenosis, it’s just watchful waiting. Jordan Miller

The risk of progressing to severe aortic stenosis was progressively lower as patients took SGLT2 inhibitors for longer: HR 0.54 for at least 3 months, HR 0.48 for at least 6 months, and HR 0.27 for at least 12 months.

Lansky said the mechanism at play is likely the result of several pathways, which will hopefully bear out in a prospective trial. “There are reports of overexpression of SGLT2 receptors on calcified aortic valve leaflets and it stands to reason that reducing inflammation and cellular calcium by inhibiting these receptors can reduce the rate of progression,” she said.

It’s too early to begin “advocating the use of SGLT2 inhibitors in the absence of other approved indications,” Lansky noted. “But in the meantime, this may serve as added incentive to use these agents when an indication exists and there is evidence of even mild aortic valve stenosis.”

Miller agreed. For a patient already indicated for SGLT2 inhibition with developing aortic stenosis, “I think you can say with some degree of confidence that it’s more likely than not that they’re going to be receiving some clinical benefit,” he said, noting that the data do not indicate that these drugs should be used in patients who might not meet all the current criteria for SGLT2 inhibition.

In the future, Miller continued, “if we can start to identify accelerated pathways for some of these novel therapies to be moving forward in a more expedited way towards rigorous testing, that’ll enable approval by the FDA. I think it’d be really transformative for how these patients are managed and their quality of life later on in life.”

A ‘2 for 1’ Medical Therapy

In an accompanying editorial, Brian R. Lindman, MD, MSC, and Bassim El-Sabawi, MD (both Vanderbilt University Medical Center, Nashville, TN), write that “these findings provide important evidence supporting the potential disease-modifying effects of SGLT2 inhibitors in aortic stenosis.”

However, they note several limitations of the study, including echocardiographic assessments that were not reviewed by a core lab, which potentially muddies the classification of aortic stenosis. “The investigators are to be commended for the rigor of their sensitivity analyses and efforts to address confounding, but a retrospective design may not fully account for potential confounders,” the editorialists add.

Lindman and El-Sabawi also note the “relatively short” duration of SGLT2 inhibition in the study patients and the inclusion of patients with mostly aortic sclerosis and mild aortic stenosis, which both limit the potential to draw conclusions within the study’s time frame.

Nonetheless, they write, “the results may serve as another rationale to prioritize SGLT2 inhibitors in patients with nonsevere aortic stenosis who already have an existing indication for the drug (eg, 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 aortic stenosis, namely one that targets both the valve and the myocardium.”

With safety and tolerability both established for SGLT2 inhibitors, the editorialists conclude, “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.”