This is a 26-week, open label, single-arm prospective evaluation of the effects of sodium glucose cotransporter 2 (SGLT2) inhibition on cardiac biomarkers, myocardial remodeling and patient reported outcomes in heart failure with both impaired and preserved left ventricular fraction.

The primary aims of this study are to evaluate whether SGLT2 inhibition in patients with heart failure effects changes in novel cardiac biomarkers. This is an exploratory evaluation of novel cardiac pathways which may serve to establish, as of yet unknown, therapeutic mechanisms of action of SGLT2 inhibition in heart failure. Secondary aims include evaluation of changes in standard of care biomarkers following SGLT2 inhibition and changes in markers of cardiac remodeling as identified on echocardiography. Further exploratory analysis will seek to correlate changes in quantitative and qualitative heart failure outcomes with changes in both novel and standard of care cardiac biomarkers.

Inclusion Criteria:

1. Provision of signed informed consent prior to any study specific procedures.

2. Male or female, between 40 and 90 years of age.

3. LVEF <50% on echocardiography or if >50%, co-existing structural markers of diastolic dysfunction must be present;

   • LA width (diameter) ≥3.8 cm or LA length ≥5.0 cm, or LA area ≥20 cm, or LA volume ≥55 mL or LA volume index ≥29 mL/m.
   • Left ventricular hypertrophy.
   • Markers of diastolic dysfunction as assessed by pulsed wave doppler echocardiography.
   • N-terminal pro-B-type natriuretic peptide (NT-proBNP) of at least 125pg per millilitre (or ≥365pg per millilitre if co-existing atrial fibrillation).

4. New York Heart Association (NYHA) class II, III, or IV symptoms.

5. On optimal tolerated evidence-based HF medications.

6. Patients may be ambulatory or recently hospitalized; however, must be >6 weeks post-discharge on stable diuretic therapy.

Exclusion Criteria:

1. Receiving therapy with an SGLT2 inhibitor > 6 weeks prior to enrolment or previous intolerance of an SGLT2 inhibitor.
2. Severe (eGFR <20 mL/min/1.73m2), unstable or rapidly progressing renal disease at the time of recruitment.
3. Type 1 diabetes mellitus
4. Recent hospitalisation < 1 month.
5. Symptomatic hypotension or systolic BP <95 mmHg at 2 out of 3 measurements
6. Symptomatic bradycardia or second or third-degree heart block without a pacemaker.
7. Previous cardiac transplantation or implantation of a ventricular assistance device or similar device, or implantation expected after recruitment.
8. Cardiomyopathy secondary to uncorrected primary valvular disease, infiltrative, arrhythmogenic or right ventricular dysplasia.
9. Significant comorbidity including; pulmonary lung disease requiring home oxygen or non-invasive ventilation, CTEPH or primary pulmonary hypertension.

Patients identified with heart failure (both reduced ejection fraction and preserved) who are on optimal standard therapy and are candidates for treatment with SGLT2 inhibition will be identified from local heart failure databases, and local heart failure clinics. Following signed, informed consent and screening, patients will be enrolled into the trial.