JACC: CARDIOVASCULAR INTERVENTIONS VOL. -, NO.

-, 2025
ª 2025 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

EDITORIAL COMMENT

SGLT2 Inhibition in Aortic Stenosis

A Therapy for the Ventricle, the Valve, or Both?

Brian R. Lindman, MD, MSC,a,b Bassim El-Sabawi, MDa

A ortic stenosis (AS) represents a significant

global health challenge, accounting
approximately 125,000 deaths and 350,000
aortic valve replacements (AVRs) annually, along
for
also a compelling rationale to target the myocardium
before AVR (to protect the heart and prevent/mitigate
maladaptive remodeling) and after AVR (to augment
myocardial reverse remodeling and recovery). 2
with the loss of 1.8 million disability-adjusted life- Recent advances in understanding the pathobi-
years each year.1 Despite considerable advancements ology of AS have identified key mechanisms of dis-
in AVR techniques, including transcatheter ap- ease progression that highlight potential therapeutic
proaches with low procedural risks, the residual targets.4 AS progresses in 2 phases: an initiation
burden of heart failure after successful valve replace- phase involving lipoprotein accumulation, oxidation,
ment remains high.2 These challenges have spurred inflammation, and endothelial injury, followed by a
interest in exploring whether earlier intervention— progression phase marked by leaflet fibrosis, calcifi-
before symptom onset or before AS is severe—might cation, and disruptions in mineral metabolism. When
improve patient outcomes. However, although these one considers the potential therapeutic benefit of
strategies hold promise, they still focus on the same sodium-glucose cotransporter-2 inhibitors (SGLT2i) in
tool (AVR) and the optimal timing of it to treat AS. patients with AS, their favorable effect on myocardial
By contrast, medical therapy targeting the valve structure/function is what initially comes to mind. 6
and/or myocardium offers a fundamentally different Although this is a very plausible hypothesis and
approach to management. Given that AS is a valve warrants testing (since patients with significant AS or
disease, targeting the active pathobiology in the valve those recently treated with AVR were typically
to slow progressive obstruction is the primary goal of excluded from trials testing SGLT2i7), emerging bio-
medical therapy. To date, no drug has effectively logical insights suggest that SGLT2i may also have a
slowed progressive narrowing of the valve, but pre- favorable effect on valvular pathobiology. These
clinical and genetic data support a number of prom- include improvements in endothelial function,
ising targets and emerging tools may allow for more reductions in endothelial permeability, and anti-
efficient clinical trials to test pharmacologic strate- inflammatory actions, such as modulation of
gies. 3-5 Although targeting the valve may be the macrophage activity and inhibition of the NLRP3
priority, maladaptive myocardial remodeling/ inflammasome (a pathway implicated in aortic valve
dysfunction that develops in response to pressure calcification). 8,9
overload from AS often does not reverse and recover In this issue of JACC: Cardiovascular Interventions,
after AVR or does so incompletely, and this has been Shah et al10 provide preliminary evidence of the po-
linked to residual risk after AVR. Accordingly, there is tential disease-modifying effects of SGLT2i in calcific
AS. This retrospective, multicenter observational
study included 11,698 patients with aortic valve
sclerosis, mild AS, or moderate AS, with a median
From the aDepartment of Medicine, Division of Cardiovascular Medicine,
Vanderbilt University Medical Center, Nashville, Tennessee, USA; and the
echocardiographic follow-up of approximately 3
b
Structural Heart and Valve Center, Vanderbilt University Medical Center, years. Patients on SGLT2i (n ¼ 448) had a significantly
Nashville, Tennessee, USA. lower risk of progression to severe AS compared with
The authors attest they are in compliance with human studies commit-
those not on SGLT2i (HR: 0.61) after adjusting for
tees and animal welfare regulations of the authors’ institutions and Food
and Drug Administration guidelines, including patient consent where covariates, time-varying SGLT2i use, and competing
appropriate. For more information, visit the Author Center. risks. SGLT2i users also experienced slower rates of

ISSN 1936-8798/$36.00 https://doi.org/10.1016/j.jcin.2024.12.025

2 Lindman and El-Sabawi JACC: CARDIOVASCULAR INTERVENTIONS VOL. -, NO. -, 2025
SGLT2 Inhibition for Aortic Stenosis - 2025:-–-

worsening in aortic valve function, demonstrated by follow-up—raises some question regarding the ob-
less increase in aortic valve peak velocity and slower servations and their implications. However, the
decline in aortic valve area. Notably, the salutary ef- findings remained consistent when patients with
fects of SGLT2i were more pronounced with longer less-significant AS were excluded. The number of
use (>3, 6, and 12 months; HR: 0.54, HR: 0.48, and events (patients progressing to severe AS) was
HR: 0.27, respectively), which reinforces the findings. particularly low in the SGLT2i group (n ¼ 21), making
Most SGLT2i users had diabetes or chronic kidney the finding vulnerable to chance.
disease—conditions known to accelerate AS progres- Despite these limitations, the results may serve as
sion—indicating that these patients were inherently another rationale to prioritize SGLT2i in patients with
at higher risk. If not fully accounted for, this would nonsevere AS who already have an existing indication
likely underestimate rather than overestimate the for the drug (eg, diabetes, chronic kidney disease, or
observed benefits. Relevant to this, even when heart failure). Beyond that, the findings point to an
compared with another second-line diabetes medi- intriguing opportunity: a “2 for 1” medical therapy
cation (DPP4 inhibitors), SGLT2i was associated with trial in patients with earlier stage AS, namely one that
slower AS progression. Sensitivity analyses demon- targets both the valve and the myocardium. Medical
strated the robustness of the findings across patient therapy targeting the ventricle in patients with mild-
subgroups, including those with varying kidney moderate AS has never been a focus of attention nor
function, diabetes control, ejection fraction, and AS rigorously tested, but there are numerous reasons
severity. Although angiotensin-converting enzyme why SGLT2i would make sense to prevent or mitigate
inhibitor/angiotensin receptor blocker/angiotensin maladaptive hypertrophic remodeling/dysfunction in
receptor-neprilysin inhibitor use was also associated the heart experiencing pressure overload from AS.11,12
with a lower risk of progression to severe AS, SGLT2i Now, Shah et al10 provide data suggesting that SGLT2i
uniquely slowed functional valve deterioration may also be effective in targeting the valve to slow
measured by annualized changes in aortic valvular progressive valve obstruction. Given the established
peak velocity and valve area. No other medication safety and tolerability of SGLT2i, this appears to be a
analyzed in this study was consistently associated particularly promising avenue of investigation to
with slower AS progression. pursue; now that these drugs are coming off patent, it
These findings provide important evidence sup- could also be a particularly cost-effective treatment
porting the potential disease-modifying effects of path. The journey to identify an effective medical
SGLT2i in AS, though several limitations in study therapy for AS has been fruitless to date, but perhaps
design warrant consideration. Echocardiographic as- the solution is closer than we may realize and one
sessments were not centrally reviewed in a core lab that gets 2 targets with a single drug.
and quantitative measures of AS severity can be
particularly noisy when there is aortic sclerosis or FUNDING SUPPORT AND AUTHOR DISCLOSURES
mild AS, which characterizes the majority of patients
Dr Lindman has received investigator-initiated research grants from
in this study. The investigators are to be commended
Edwards Lifesciences; and has been a consultant for Edwards Life-
for the rigor of their sensitivity analyses and efforts to sciences, Medtronic, Anteris, and AstraZeneca. Dr El-Sabawi has re-
address confounding, but a retrospective design may ported that he has no relationships relevant to the contents of this
not fully account for potential confounders. The paper to disclose.

study’s median duration of SGLT2i usage was rela-

tively short (<1 year), raising questions about the ADDRESS FOR CORRESPONDENCE: Dr Brian R.
plausibility of the observed effects on AS progression. Lindman, Structural Heart and Valve Center, Van-
The inclusion of patients primarily with aortic scle- derbilt University Medical Center, 2525 West End
rosis (66%) and mild AS (23%)—stages usually un- Avenue, Suite 300-A, Nashville, Tennessee 37203,
likely to progress to severe AS within the study’s USA. E-mail: [email protected].

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