Sodium Glucose Co-transporter (SGLT) Inhibitors in Nonobstructive Hypertrophic Cardiomyopathy

Inclusion criteria

• Age at least 18 years, both sexes
• Provision of signed and dated informed consent form
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Ability to take oral medication and be willing to adhere to the study intervention.
• For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation and for an additional 2 weeks after the end of administration of study drug.
• Diagnosis of HCM with NYHA Class II-III functional class or New York Heart Association (NYHA) Class I with peak VO2 < 90% on cardiopulmonary exercise stress testing performed at Visit 1.
• Left ventricular outflow tract gradient < 50 mmHg at rest, with valsalva, and with exercise.

• Left ventricular ejection fraction > 50% by echocardiogram or cardiac MRI based on the most recent assessment in the past year prior to screening and confirmed during Visit 1 echocardiogram.

• Stable medical therapy for at least 1 month prior to study enrollment.

Exclusion criteria

• Receiving therapy with an SGLT2 inhibitor within 8 weeks prior to enrollment or previous intolerance of an SGLT2 inhibitor
• Type 1 diabetes mellitus
• Age <18 years old
• Pregnant or lactating women: Women of childbearing potential will undergo a urine pregnancy test during the screening visit.
• Uncontrolled atrial fibrillation, as defined by a resting heart rate > 100 beats per minute at the time of the baseline assessment
• Paroxysmal atrial fibrillation (Afib) or flutter with plans to attempt to restore sinus rhythm (with drug therapy, ablation, or DC cardioversion) during the study period.
• Unable to attain a respiratory exchange ratio of at least 1.05 on cardiopulmonary exercise test (CPET) on the day of screening.
• Septal reduction therapy within the previous 3 months.
• Implantable cardio-defibrillator (ICD) implantation planned during the study period.
• Implantation of a cardiac resynchronization therapy (CRT) device within 12 weeks prior to enrollment or intent to implant a CRT device during the study period
• Hemoglobin < 10 g/dL
• Estimated glomerular filtration rate (eGFR) < 25 mL/min/1.73m^2, or unstable or rapidly progressing renal disease at the time of randomization
• Subject inability/unwillingness to exercise
• Greater than moderate left sided valvular disease (mitral regurgitation, aortic stenosis, aortic regurgitation), moderate or greater mitral stenosis, or severe right-sided valvular disease based on baseline echo at the time of enrollment
• Current angina due to clinically significant epicardial coronary disease, as per investigator judgment
• Acute coronary syndrome or coronary intervention within the past 2 months
• Primary pulmonary artery hypertension (WHO Group 1 Pulmonary Arterial Hypertension)
• Clinically significant lung disease as defined by: Chronic Obstructive Pulmonary Disease meeting Stage III or greater GOLD criteria (FEV1<50% predicted), treatment with oral steroids within the past 6 months for an exacerbation of obstructive lung disease, or current use of supplemental oxygen aside from nocturnal oxygen for the treatment of obstructive sleep apnea.
• Clinically-significant ischemia, as per investigator's judgement, on stress testing without either (1) subsequent revascularization, (2) an angiogram demonstrating the absence of clinically significant epicardial coronary artery disease, as per investigator judgment; (3) a follow-up 'negative' stress test, particularly when using a more specific technique (i.e., a negative perfusion imaging test following a 'positive' ECG stress test)
• Symptomatic bradycardia or second- or third-degree heart block, in the absence of a pacemaker
• Significant liver disease impacting synthetic function or volume control (ALT/AST > 3x ULN, Albumin < 3.0 g/dL)
• Severe right ventricular dysfunction on baseline echocardiogram
• Orthostatic blood pressure response to the transition from supine to standing (>20 mmHg reduction in systolic blood pressure 2-3 minutes after standing)
• Active participation in another study that utilizes an investigational agent (observational studies/registries allowed)
• Any condition that, in the opinion of the investigator, will interfere with the completion of the study. This may include comorbid or psychiatric conditions that may impede successful completion of the protocol, or logistical concerns (e.g. inability to travel to the exercise unit).