Obesity, Pre-diabetes
Conditions
Brief summary
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 project 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.
Detailed description
This study will be expanded to include another 10 participants. Enrollment will begin July 1, 2023.
Interventions
DRUGEmpagliflozin 25 MG
Oral empagliflozin daily
Sponsors
Vanderbilt University Medical Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18 to 70 years old 2. Impaired glucose tolerance (two-hour plasma glucose 140-199 mg/dL) or impaired fasting glucose (100-125mg/dL) or HbA1c 5.7-6.4% 3. BMI ≥ 30 kg/M2 4. The ability to provide informed consent
Exclusion criteria
Criteria Related to Medical Diagnoses/Conditions/Treatments: 1. Diabetes type 1 or type 2, as defined by a fasting plasma glucose of 126 mg/dL or greater, a two-hour plasma glucose of 200 mg/dL or greater, HbA1c ≥6.5%, or the use of anti-diabetic medication 2. Pregnancy or breast-feeding. Women of child-bearing potential will be required to have undergone tubal ligation or to be using an oral contraceptive or barrier methods of birth control 3. 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 4. Presence of implanted cardiac defibrillator or pacemaker 5. History of serious neurologic disease such as cerebral hemorrhage, stroke, or transient ischemic attack 6. History of pancreatitis or pancreatic surgery 7. History or presence of immunological or hematological disorders 8. Clinically significant gastrointestinal impairment that could interfere with drug absorption 9. History of advanced liver disease with cirrhosis 10. 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) 11. Treatment with chronic systemic glucocorticoid therapy (more than 7 consecutive days in 1 month) 12. Treatment with anticoagulants 13. 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 14. History of alcohol abuse (\>14 per week for men and \>7 per week for women) or illicit drug use 15. Treatment with any investigational drug in the one month preceding the study 16. Previous randomization in this trial 17. Mental conditions rendering a subject unable to understand the nature, scope and possible consequences of the study 18. 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: 19. Uncircumcised men or men with history of balanitis 20. History of urinary incontinence 21. History of recurrent (\>3) episodes of vulvovaginitis per year, or severe symptoms 22. History of Fournier's gangrene 23. History of recurrent (≥3) UTIs per year or pyelonephritis 24. History of symptomatic hypotension or conditions predisposing to volume depletion 25. Known peripheral vascular disease, neuropathy, history of foot ulcers or lower limb amputations 26. Treatment with loop diuretics furosemide, torsemide, bumetanide, ethacrynic acid 27. Known or suspected allergy to trial medications, excipients, or related products 28. Contraindications to study medications, worded specifically as stated in the product's prescribing information
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Adipose Pro-inflammatory T Helper Type 1 Cell Percentages After 3 Months | Baseline to 12 weeks | Pro-inflammatory T helper type 1 cells are quantified using flow cytometry |
| Change in Flow-mediated Dilation After 3 Months | Baseline to 12 weeks | Endothelial function quantified using flow-mediated dilation by ultrasound, measuring percentage increase in artery diameter during hyperemia. |
| Change in Liver Steatosis at 3 Months | Baseline to 12 weeks | Liver steatosis assessment by transient elastography-controlled attenuation parameter imaging, reported as Controlled Attenuation Parameter (CAP) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Adipose Pro-inflammatory T Helper Type 1 Cell Percentages After 2 Weeks | Baseline to 2 weeks | Pro-inflammatory T cells are quantified using flow cytometry |
| Change in the Plasma Inflammatory Cytokine IL-6 After 3 Months | Baseline to 12 weeks | IL-6 is quantified in plasma samples. |
Countries
United States
Participant flow
Pre-assignment details
* 17 in the Original study + 21 in the Extension study signed consent for a total of 38. * 9 individuals in the Extension study did not perform screening procedures after consent and were not enrolled. In total 29 individuals enrolled. * 11 individuals in the Original study and 2 individuals in the Extension study did not meet inclusion/exclusion criteria after screening. * 6 individuals in the Original study and 10 individuals in the Extension study started and completed study days.
Participants by arm
| Arm | Count |
|---|---|
| Empagliflozin Individuals receive empagliflozin 25mg/day orally for 12 weeks
Empagliflozin 25 MG: Oral empagliflozin daily | 6 |
| Total | 6 |
Baseline characteristics
| Characteristic | Empagliflozin |
|---|---|
| Age, Continuous | 51.5 years STANDARD_DEVIATION 16.5 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Pro-inflammatory T helper type 1 cells in adipose tissue | 13.0 Percentage of CD3+ T cells STANDARD_DEVIATION 5.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 3 Participants |
| Region of Enrollment United States | 6 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 2 / 6 |
| serious Total, serious adverse events | 0 / 6 |
Outcome results
Primary
Change in Adipose Pro-inflammatory T Helper Type 1 Cell Percentages After 3 Months
Pro-inflammatory T helper type 1 cells are quantified using flow cytometry
Time frame: Baseline to 12 weeks
Population: One individual did not tolerate the liposuction technique and did not provide adipose tissue for the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin | Change in Adipose Pro-inflammatory T Helper Type 1 Cell Percentages After 3 Months | -1.6 Percentage of CD3+ T cells | Standard Deviation 1.8 |
Primary
Change in Flow-mediated Dilation After 3 Months
Endothelial function quantified using flow-mediated dilation by ultrasound, measuring percentage increase in artery diameter during hyperemia.
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin | Change in Flow-mediated Dilation After 3 Months | -2.33 Percentage change in diameter | Standard Deviation 7.72 |
Primary
Change in Liver Steatosis at 3 Months
Liver steatosis assessment by transient elastography-controlled attenuation parameter imaging, reported as Controlled Attenuation Parameter (CAP)
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin | Change in Liver Steatosis at 3 Months | 0.17 Decibels per meter | Standard Deviation 28.12 |
Secondary
Change in Adipose Pro-inflammatory T Helper Type 1 Cell Percentages After 2 Weeks
Pro-inflammatory T cells are quantified using flow cytometry
Time frame: Baseline to 2 weeks
Population: One individual did not tolerate the liposuction technique and did not provide adipose tissue for the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin | Change in Adipose Pro-inflammatory T Helper Type 1 Cell Percentages After 2 Weeks | -0.5 Percentage of CD3+ T cells | Standard Deviation 5 |
Secondary
Change in the Plasma Inflammatory Cytokine IL-6 After 3 Months
IL-6 is quantified in plasma samples.
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Empagliflozin | Change in the Plasma Inflammatory Cytokine IL-6 After 3 Months | 0.078 picogram per milliliter | Standard Deviation 0.717 |