Mechanistic Insights to Weight Loss Maintenance Through SGLT2 Inhibitors

Study Overview
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Brief Summary
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Obesity increases the risk of cardiometabolic diseases such as hypertension and diabetes. Weight loss interventions such as low-calorie diet and physical activity are effective for weight loss in the short term, but weight loss maintenance (WLM) with low-calorie diet and physical activity is challenging. Weight loss is associated with a reduction in the amount of calories needed to maintain the body at rest, called the resting energy expenditure (REE), which may be a probable mechanism for this lack of WLM. Most individuals are unable to adequately change their diet and increase their physical activity levels to overcome this decrease in REE which prevents WLM. Therefore, techniques that increase REE may promote WLM in these individuals. Pre-clinical studies for Empagliflozin - Sodium-glucose Cotransporter-2 (SGLT2) inhibitor have shown an increase in REE. Thus, in addition to reducing the cardiovascular risk, SGLT2 inhibitor may promote WLM by increasing REE. This study aims to promote WLM in obese individuals by increasing the REE using SGLT2 inhibitor therapy.

Official Title
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Mechanistic Insights to Weight Loss Maintenance Through SGLT2 Inhibitors

Conditions
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Obesity, Weight Loss

Intervention / Treatment
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* Drug: Empagliflozin Arm
* Other: Control Arm
* Other: Exercise capacity VO2 maximum determination
* Other: Exercise Challenge


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age more than or equal to 18 years Body mass index more than or equal to 30 kg/m2 who have lost ≥5% of body weight within the past 6 months without taking any pharmacotherapy for weight loss Exclusion Criteria: Age less than 18 years at screening. Untreated systolic BP <100 or >160 mmHg at baseline, or diastolic BP <80 or >100 mmHg at baseline Women who are pregnant or breastfeeding or who can become pregnant and not practicing an acceptable method of birth control during the study (including abstinence) Taking pharmacotherapy indicated for weight loss, such as GLP-1 agonists or with weight loss as an adverse event History of Type I Diabetes History of lung disease Have any past or present illness of cardiovascular disease, including myocardial infarction, angina, cardiac arrhythmia, diabetes, stroke, TIA, or seizure Current or past (<12 months) history of smoking Estimated glomerular filtration rate (GFR) < 60 ml/min/1.73 m2 (CKD-EPI equation) urine albumin creatinine ratio ≥30 mg/g Hepatic Transaminase (AST and ALT) levels >3x the upper limit of normal Significant psychiatric illness Anemia (men, Hct < 38%; women, Hct <36%) Inability to exercise on a treadmill Consumption of more than 2 alcoholic drinks daily Any contraindications to empagliflozin

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Empagliflozin Arm<br>Investigator will enroll 12 obese participants who have intentionally lost greater than or equal to 5% of body weight through a non-pharmacological structured weight loss program based on diet and exercise within the last 6 months. The participants will take empagliflozin 25mg/day orally for 12 months. | Drug: Empagliflozin Arm<br>* The subject will be randomized, in a double-blind manner to Empagliflozin 25mg once daily for a period of 12 months<br>Other: Exercise capacity VO2 maximum determination<br>* Each participant's maximal oxygen capacity will be determined using a modified Bruce treadmill protocol and will also undergo a DEXA scan to determine the body mass.<br>Other: Exercise Challenge<br>* Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill and will also undergo a resting energy expenditure test.<br>|
| Placebo Comparator: Placebo Arm<br>Investigator will enroll 12 obese participants who have intentionally lost greater than or equal to 5% of body weight through a non-pharmacological structured weight loss program based on diet and exercise within the last 6 months. The participants will take a placebo pill orally once a day for 12 months. | Other: Control Arm<br>* The subject will be randomized, in a double-blind manner to receive placebo once daily for a period of 12 months<br>Other: Exercise capacity VO2 maximum determination<br>* Each participant's maximal oxygen capacity will be determined using a modified Bruce treadmill protocol and will also undergo a DEXA scan to determine the body mass.<br>Other: Exercise Challenge<br>* Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill and will also undergo a resting energy expenditure test.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Resting Energy Expenditure | Change in Resting Energy Expenditure between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight | Change in Body Weight between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in Body Mass Index | Change in Body Mass Index between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in Waist Circumference | Change in Waist Circumference between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in HbA1C levels | Change in HbA1C levels between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in lipid profile | Change in Lipid profile between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in HOMA-IR | Change in HOMA-IR between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in ESR | Change in ESR between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in CRP | Change in CRP between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in IL-6 | Change in IL-6 between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in TNF-α | Change in TNF-α between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in glucagon-like peptide-1 (GLP-1) | Change in glucagon-like peptide-1 (GLP-1) between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in peptide YY (PYY) | Change in peptide YY (PYY) between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in ghrelin | Change in ghrelin between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in glucose-dependent insulinotropic polypeptide (GIP) | Change in glucose-dependent insulinotropic polypeptide (GIP) between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months | 
| Change in glucagon | Change in glucagon between the two arms (Empagliflozin v/s Placebo) from baseline and after 12 months of intervention | 12 months |