Mechanistic Insights to Weight Loss Maintenance Through SGLT2 Inhibitors

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Obesity; Weight Loss
• Intervention / Treatment: Other: Exercise Challenge; Drug: Empagliflozin Arm; Other: Exercise capacity VO2 maximum determination; Other: Control Arm

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Nehal Vekariya, MS; Phone Number: 2059347173; Email: nvekariya@uabmc.edu
• Study Contact Backup: Name: Deborah Weber, BSN, RN; Phone Number: 205-975-9964; Email: dlowe@uabmc.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • University of Alabama at Birmingham
      • Contact: Nehal Vekariya; Phone Number: 205-934-7173; Email: nvekariya@uabmc.edu
      • Principal Investigator: Pankaj Arora, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Empagliflozin Arm; 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.	Other: Exercise Challenge; Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill and will also undergo a resting energy expenditure test.; Drug: Empagliflozin Arm; The subject will be randomized, in a double-blind manner to Empagliflozin 25mg once daily for a period of 12 months; Other: Exercise capacity VO2 maximum determination; 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.
Placebo Comparator: Placebo Arm; 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: Exercise Challenge; Each participant will walk at 70 % of his/her VO2max for 20 minutes on treadmill and will also undergo a resting energy expenditure test.; Other: Exercise capacity VO2 maximum determination; 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.; Other: Control Arm; The subject will be randomized, in a double-blind manner to receive placebo once daily for a period of 12 months

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Investigators: Principal Investigator: Pankaj Arora, MD, FAHA, University of Alabama at Birmingham

Study record dates

Study Major Dates

• Study Start (Estimated): January 30, 2025
• Primary Completion (Estimated): January 30, 2026
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: May 11, 2023
• First Submitted That Met QC Criteria: May 22, 2023
• First Posted (Actual): June 1, 2023

Study Record Updates

• Last Update Posted (Actual): January 19, 2024
• Last Update Submitted That Met QC Criteria: January 17, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Body Weight Changes; Weight Loss; Body Weight; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Empagliflozin
• Other Study ID Numbers: 300011125

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No