Metformin for PH+HFpEF

This is a 12-week blinded cross over trial of metformin in PH-HFpEF to improve exercise
hemodynamics, functional capacity, and glucose metabolism. This phase II clinical trial will
provide detailed phenotyping, physiological and mechanistic data on PH-HFpEF.

Inclusion Criteria:

2. PH-HFpEF Confirmed diagnosis by RHC within the past 6 months:

Mean Pulmonary Arterial Pressure (mPAP) ≥ 25 mm Hg AND Pulmonary artery wedge pressure
(PAWP) ≥ 15 mm Hg AND Transpulmonary Gradient (TPG) ≥ 12 mm Hg

OR Exercise measurements

Mean Pulmonary Arterial Pressure (mPAP) ≥ 30 mm Hg AND Pulmonary artery wedge pressure
(PAWP) ≥ 20 mm Hg AND PA calculation (change in mPAP/change in cardiac output) = ≥3
mmHg/L/min

3. Three or more features of metabolic syndrome defined as:

Body Mass Index (BMI) ≥ 30 kg/m² Systolic blood pressure (BP) ≥ 130 mm Hg and/or diastolic
BP ≥ 85 mm Hg Elevated waist circumference > 102 cm in men and > 88 cm in women Fasting
triglyceride (TG) level over 150 mg/dl High-density lipoprotein <40 mg/dL in men or < 50
mg/dL in women

Exclusion Criteria:

1. Age less than 18 years;

2. Uncontrolled systemic hypertension based on repeated measurement of sitting systolic
blood pressure >170 mm Hg or sitting diastolic blood pressure >95 mm Hg at Screening;

3. Systemic sitting blood pressure < 110 mmHg systolic or < 60 mm Hg diastolic at
Screening;

4. Hemoglobin A1C > 10;

5. Currently taking metformin or history of intolerance to metformin or contraindication
to taking metformin;

6. Known type 1 diabetes

7. Positive urine pregnancy test or breastfeeding

8. Ejection Fraction < 50%

9. Dementia;

11. End-stage malignancy; 12. Major cardiovascular event or procedure within 6 weeks prior
to enrollment; 13. Severe valvular disease; 14. Other severe acute or chronic medical,
psychiatric or laboratory abnormality that may increase the risk associated with study
participation or investigational product administration or may interfere with the
interpretation of study results and, in the judgment of the investigator, would make the
subject inappropriate for entry into this study or would prevent completion of the study;
15. Current Smoker; 16. Hemoglobin <9 g/dL; 17. Estimated glomerular filtration rate (eGFR)
<30 mL/min/1.73 m2; 18. Receipt of an investigational product or device, or participation
in a drug research study within a period of 15 days 19. <3 months of stable dose of PDE5i