Inclusion Criteria:
- In order to be eligible to participate in this study, an individual must meet all the following criteria:
1. Provision of signed and dated informed consent form
2. Ability and stated willingness to comply with all study procedures and availability for the duration of the study
3. Ability to read and write in English
4. Male or female, aged 18 years or older, with group 1 PAH, idiopathic, heritable, associated with drugs and toxins, associated with connective tissue disease and with congenital heart disease (simple repaired or unrepaired defects) according to the current guidelines and adjudicated by the local PI
5. PAH confirmed by right heart catheterization in the last 5 years
6. RV dysfunction defined as FAC ≤ 40.0% on echocardiography performed during the screening visit. In PVDOMICS, FAC has a strong correlation with CMR RV ejection fraction; group 1 PAH patients with an FAC ≤ 40% (mean 27.0 ± 8.0%) had a mean RV ejection fraction of 35.5 ± 11.3% CMR RV ejection fraction ≤ 54% classifies PAH as intermediate (37-54%) or high (<37%) risk under current guidelines. However, to ensure we recruit patients with significantly impaired RV function, patients with RV FAC between 35.0-40.0% on the screening echocardiogram will have to meet at least one of the following additional criteria: a) TAPSE/sPAP ratio < 0.31 mm/mmHg; b) elevated right atrial pressure defined as inferior vena cava (IVC) > 2.1 cm in diameter and the IVC does not collapse with sniff/respiration; c) RV enlargement defined as RV basal diameter ≥ 4.1 cm; d) RV free wall longitudinal strain ≥ -22%; e) Interventricular septal flattening; and f) RV outflow tract mid or late systolic notching.
7. On FDA-approved PAH-targeted therapy (any combination including infused prostacyclin analogues and sotatercept) with stable doses for at least 8 weeks or 24 weeks for sotatercept prior to the screening visit and no clinical plans to change this therapy.
8. Diuretic doses stable for at least 4 weeks prior to screening. After screening, diuretic doses may be changed as directed by the site PIs and/or the treating physician.
9. Ability to take oral medication and willingness to adhere to the study drug regimen.
10. For females of reproductive potential: use of highly effective contraception for at least 4 weeks prior to screening and agreement to use such a method during study participation and for an additional 2 weeks after the end of study drug administration
11. Able to have baseline and week 24 CMR according to Imaging Core criteria, as adjudicated by the Site PI
Exclusion Criteria:
- An individual who meets any of the following criteria will be excluded from participation in this study:
1. Current use of insulin, insulin secretagogues (sulfonylureas and meglitinides), lithium or an SGLT2 inhibitor
2. Use of an SGLT2 inhibitor within the past 3 months prior to screening
3. Prior documented inability to tolerate an SGLT2 inhibitor
4. Volume depletion, as ascertained by the site PI, at screening or baseline
5. History of diabetic ketoacidosis or type 1 diabetes mellitus
6. Chronic alcohol or drug abuse
7. More than one bacterial or yeast genitourinary tract infection in the year prior to enrollment
8. Estimated glomerular filtration rate under 30 mL/minute/1.73m2 or on renal replacement therapy
9. Pregnancy or lactation
10. Known allergy or hypersensitivity to empagliflozin or another SGLT-2 inhibitor
11. Currently taking or has taken another investigational drug within the past 4 weeks
12. Enrollment in another randomized intervention trial. (Participants participating in observational trials will not be excluded).
13. Decompensated right heart failure, as adjudicated by the site PI.
14. Screening HbA1c >10% with symptoms such as polyuria and polydipsia