The Role of SGLT2i in Management of Moderate AS

Background:

Aortic stenosis represents one of the commonest valvular heart diseases in the Western World. Studies have shown that as the valvular narrowing progresses, pathological left ventricular (LV) hypertrophy and fibrosis develop. This maladaptive left ventricular remodelling is associated with adverse events and worse long-term prognosis. Currently, there is no available medication to slow down or prevent these pathological processes occurring in aortic stenosis. Evidence from recent large randomised controlled trials have demonstrated that SGLT2 inhibitors have a significant positive impact on quality of life and cardiovascular outcomes of patients with heart failure. This is a result of complex mechanisms such as attenuation of cardiac myofibroblast activity and collagen remodelling. These could be proved to be very beneficial for patients with aortic stenosis since the left ventricular pathological changes occurring in aortic stenosis share similar pathways and mechanisms with heart failure.

Study aims and objectives:

The aims of this study are to assess if:

• SGLT2 inhibitors can prevent or decelerate adverse myocardial remodelling and fibrosis.
• SGLT2 inhibitors can improve the exercise tolerance and functional capacity of patients with aortic stenosis.

Methods:

Given that the use of SGLT2 inhibitors in aortic stenosis has not been investigated before, we aim to investigate the hypotheses with an early stage randomised controlled trial. For this, patients with moderate aortic stenosis identified in the outpatient cardiology clinic will be invited to participate. Management of moderate aortic stenosis is conservative with a 'watchful waiting' approach. The participants will be randomised either to usual conservative management or to the intervention group (use of SGLT2 inhibitor on top of regular medications). They will be assessed at baseline and at 6-months following initiation of the medication. Both appointments will include evaluation of symptoms (with the use of validated questionnaire) and functional capacity (cardiopulmonary exercise test), electrocardiogram and blood tests. An echocardiogram, a scan performed routinely on a yearly basis for all patients with moderate aortic stenosis, will also be performed at baseline and at completion of the 6 months' follow-up period to evaluate for myocardial hypertrophy and remodelling. Additionally, a cardiopulmonary exercise test and a cardiac magnetic resonance scan will be performed in these two timepoints to assess for myocardial remodelling and fibrosis.

Inclusion criteria

• Moderate aortic stenosis (aortic valve peak velocity ≥ 3m/s or mean gradient 20-40mmHg, or Aortic valve area 1.0-1.5cm2)
• Age over 18 years

Exclusion criteria

• Severe aortic stenosis (aortic valve peak velocity ≥ 4m/s or mean > 40mmHg or Aortic valve area < 1.0cm2) or planned cardiac surgery or likely need for surgery within 6 months.
• Previous valve replacement
• Severe hypertension (systolic >180mmHg or diastolic >100mmHg)
• Acute pulmonary oedema or cardiogenic shock
• Coexisting other valvular lesion of more than moderate severit.
• Coexisting hypertrophic cardiomyopathy or amyloidosis with cardiac involvement
• Any contraindications to MRI scanning including eGFR <30ml/min/1.73m2
• Pregnancy or breast-feeding
• Concomitant SGLT2 inhibitor therapy
• Inability to receive SGLT2 inhibitor therapy
• History of diabetes type 1 or 2
• Severe peripheral vascular disease or non-healed leg ulcers
• Severe liver disease
• Rare hereditary problems of galactose intolerance, total lactase deficiency, or glucose-galactose malabsorption