The Effect of SGLT2 Inhibition on Adipose Inflammation and Endothelial Function (SADIE2)

Inclusion Criteria: Age 18 to 70 years old Metabolic syndrome as defined by 3 or more of 5 criteria: Systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmg Hg or treatment with anti-hypertensive medications for minimum of 6 months Triglycerides ≥ 150 mg/dL or treatment with a triglyceride-targeted medication (fenofibrate, gemfibrozil, niacin, high dose omega-3 fatty acids) High-density lipoprotein (HDL) < 40 mg/dL in males or < 50 mg/dL in females Fasting blood glucose ≥ 100mg/dL or treatment with glucose-lowering medications Waist circumference ≥ 102 cm in males or ≥ 88cm in females BMI ≥ 35 kg/M2 Scheduled gastric bypass or gastric sleeve in approximately 90 days (range 90-150 days) The ability to provide informed consent Exclusion Criteria: Type 1 diabetes. Poorly controlled type 2 diabetes as defined by HbA1c ≥ 9%. Use of anti-diabetic medications other than stable dose of metformin or a sulfonylurea in the last 1 month. Treatment with a glucagon-like peptide-1 receptor agonist or co-agonist in the last 3 months. Treatment with an SGLT2 inhibitor in the last 3 months. Pregnancy or breast-feeding. Women of child-bearing potential will be required to have undergone surgical sterilization or to be using an intra-uterine device, hormonal contraceptive, or barrier methods of birth control. Cardiovascular disease such as myocardial infarction within six months prior to enrollment, presence of angina pectoris, significant arrhythmia, congestive heart failure (left ventricular hypertrophy acceptable), deep vein thrombosis, pulmonary embolism, -second- or third-degree heart block, mitral valve stenosis, aortic stenosis, or hypertrophic cardiomyopathy Presence of implanted cardiac defibrillator or pacemaker History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack History of pancreatitis or pancreatic surgery History or presence of immunological or hematological disorders Clinically significant gastrointestinal impairment that could interfere with drug absorption History of advanced liver disease with cirrhosis Individuals with an eGFR<45 mL/min/1.73 m2, where eGFR is determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine is expressed in mg/dL and age in years: eGFR (mL/min/1.73m2)=186 • Scr-1.154 • age-0.203 • (0.742 if female) Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month) Treatment with anticoagulants Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult History of alcohol abuse (>14 per week for men and >7 per week for women) or illicit drug use Treatment with any investigational drug in the one month preceding the study Previous randomization in this trial Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study Inability to comply with the protocol in the opinion of the principal investigator, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study Criteria Related to Known Adverse Effects of Drug: Uncircumcised men or men with history of balanitis History of urinary incontinence History of recurrent (>3) episodes of vulvovaginitis per year, or severe symptoms History of Fournier's gangrene History of recurrent (≥3) UTIs per year or pyelonephritis History of symptomatic hypotension or conditions predisposing to volume depletion Known peripheral vascular disease, neuropathy, history of foot ulcers or lower limb amputations Treatment with loop diuretics furosemide, torsemide, bumetanide, ethacrynic acid Known or suspected allergy to trial medications, excipients, or related products Contraindications to study medications, worded specifically as stated in the product's prescribing information