Obesity is associated with increased cardiometabolic disease risk due, in part, to heightened chronic inflammation arising from adipose tissue. There are no current targeted therapies to prevent or reverse the chronic inflammation of obesity, and a better understanding of these inflammatory pathways in humans is key to future therapeutic interventions. This trial will determine both the anti-inflammatory potential of the SGLT2 inhibitor empagliflozin, and the contribution of adipose inflammation to surrogate measures of cardiovascular disease in a randomized controlled trial of obese patients.

Inclusion Criteria:

1. Age 18+ years old

2. Metabolic syndrome as defined by 3 or more of 5 criteria:

   1. Systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥ 85 mmg Hg or treatment with anti-hypertensive medications for minimum of 1 month
   2. Triglycerides ≥ 150 mg/dL or treatment with a triglyceride-targeted medication (fenofibrate, gemfibrozil, niacin, high dose omega-3 fatty acids)
   3. High-density lipoprotein (HDL) < 40 mg/dL in males or < 50 mg/dL in females
   4. Fasting blood glucose ≥ 100mg/dL or treatment with glucose-lowering medications
   5. Waist circumference ≥ 102 cm in males or ≥ 88cm in females

3. BMI ≥ 35 kg/M2

4. Scheduled gastric bypass or gastric sleeve in approximately 90 days (range 90-270 days)

5. The ability to provide informed consent

   Exclusion Criteria:

6. Type 1 diabetes.

7. Poorly controlled type 2 diabetes as defined by HbA1c ≥ 9%.

8. Use of anti-diabetic medications other than stable dose of metformin or a sulfonylurea in the last 1 month.

9. Treatment with a glucagon-like peptide-1 receptor agonist or co-agonist in the last 3 months.

10. Treatment with an SGLT2 inhibitor in the last 3 months.

11. 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.

12. 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

13. Presence of implanted cardiac defibrillator or pacemaker

14. History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack

15. History of pancreatitis or pancreatic surgery

16. History or presence of immunological or hematological disorders

17. Clinically significant gastrointestinal impairment that could interfere with drug absorption

18. History of advanced liver disease with cirrhosis

19. 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)

20. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month)

21. Treatment with anticoagulants

22. 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

23. History of alcohol abuse (>14 per week for men and >7 per week for women) or illicit drug use

24. Treatment with any investigational drug in the one month preceding the study

25. Previous randomization in this trial

26. Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study

27. 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:

28. Uncircumcised men or men with history of balanitis

29. History of urinary incontinence

30. History of recurrent (>3) episodes of vulvovaginitis per year, or severe symptoms

31. History of Fournier's gangrene

32. History of recurrent (≥3) UTIs per year or pyelonephritis

33. History of symptomatic hypotension or conditions predisposing to volume depletion

34. Known peripheral vascular disease, neuropathy, history of foot ulcers or lower limb amputations

35. Treatment with loop diuretics furosemide, torsemide, bumetanide, ethacrynic acid

36. Known or suspected allergy to trial medications, excipients, or related products

37. Contraindications to study medications, worded specifically as stated in the product's prescribing information

No plan to share IPD outside of VUMC study team.

Placebo consists of gelatin capsules. To ensure blinding, empagliflozin will be over-encapsulated in identical gelatin capsules as placebo.