Metformin for Older Patients With Heart Failure With Preserved Ejection Fraction

Inclusion Criteria:

• Heart failure with preserved ejection fraction (HFpEF) will be defined in accordwith the American College of Cardiology/American Heart Association 2013 guidelinesstatement on Management of heart failure and as previously described. The 4 keyinclusion criteria for HFpEF include: 1) clinical signs and symptoms as scored byNational Health and Nutrition Examination Survey (NHANES)-HF Clinical Score ≥3 andthe Rich Criteria; 2) a normal left ventricular (LV) ejection fraction (≥50%) byechocardiography; 3) LV diastolic dysfunction > grade 1 (American Society ofEchocardiography Recommendations); 4) no evidence of significant ischemic, valvular,pulmonary or other medical disorder to account for their symptoms.

• Age ≥60

• Stable HF symptoms and medications for ≥3 weeks

• Final eligibility will be based upon all information available at the conclusion ofthe baseline visits tests, including review of hospital and outpatient records,history, physical examination, echocardiogram, and familiarization/screeningexercise test by a board-certified investigator cardiologist who have extensiveexperience in heart failure investigations in older persons with HFpEF

Exclusion Criteria:

• History of treatment with metformin or other anti-diabetic drug intended to treatdiabetes

• Body mass index (BMI) <25.0

• Uncontrolled dysrhythmia

• Uncontrolled hypertension (systolic blood pressure [SPB]>200 mmHg or diastolic bloodpressure [DBP]>100 mmHg at rest)

• Significant anemia (<9.5 g hemoglobin [Hb]) (eligibility will be determined bycomplete blood count)

• Significant renal insufficiency (estimated glomerular filtration rate [eGFR] <45ml/min/1.73 m2) (eligibility will be determined by comprehensive metabolic panel)

• Acute or chronic metabolic acidosis

• Type 2 diabetes, or HbA1c>6.5

• Low vitamin B12 (<232 pg/mL)

• Known valvular heart disease, infiltrative cardiomyopathy, or hypertrophicobstructive cardiomyopathy with active obstruction as the primary etiology of HF

• Evidence of significant chronic obstructive pulmonary disease (COPD) defined aseither: a. On continuous home oxygen therapy for COPD; b. Hospitalization for COPDin last 6 months

• Any condition that in the judgement of the investigator precludes participation instudy or study procedures such as significant dementia, mobility impairment,uncontrolled psychiatric disease, etc.

• Alcohol abuse (>14 drinks/week)

• Current or recent cancer, or chemotherapy/radiation treatment

• Pregnancy-women of child-bearing potential are excluded from participation in thisstudy.

• A treadmill exercise test revealing: a. Evidence of significant ischemia; b.Electrocardiogram: 1mm flat ST depression; c. Stopped exercising due to chest or legclaudication or any reason other than exhaustion/fatigue/dyspnea; d. Exercise SBP > 240 mmHg, DBP > 110 mmHg ; e. Unstable hemodynamics or rhythm; f. Unwilling orunable to complete adequate exercise test

• Exclusions for microbiome testing: a. Antibiotics use within last 30 days; b.Diarrhea and/or vomiting within last 30 days; c. Surgery related to gut in last 6months; d. Inflammatory bowel disease (such as Crohn's disease or ulcerativecolitis), or irritable bowel syndrome

• Plans to leave area within 1 year

• Currently participating in other investigational study

• Refuses informed consent