The Effect of SGLT2 Inhibition on Adipose Inflammation and Endothelial Function

Inclusion criteria

• Age 18+ 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 1 month
• 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 90-270 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