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SGLT2 Inhibition in Older Obese Adults With Pre-diabetes (SGLT2i)

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ClinicalTrials.gov Identifier: NCT04401904
Recruitment Status : Recruiting
First Posted : May 26, 2020
Last Update Posted : December 27, 2021
Sponsor:
Information provided by (Responsible Party):
The University of Texas Health Science Center at San Antonio

Tracking Information
First Submitted Date  ICMJE April 22, 2020
First Posted Date  ICMJE May 26, 2020
Last Update Posted Date December 27, 2021
Actual Study Start Date  ICMJE June 25, 2020
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 20, 2020)
AGE-RAGE measurement in urine [ Time Frame: Baseline to 12 weeks ]
Change in AGE-RAGE measured by enzyme-linked immunosorbent assay (ELISA).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 20, 2020)
  • Mitochondrial Function [ Time Frame: Baseline to 12 weeks ]
    Change % on muscle mitochondrial respiration measured in muscle tissue with Oroboros in O2 Flux per mg tissue.
  • Insulin Sensitivity [ Time Frame: Baseline to 12 weeks ]
    Percentage of change in insulin sensitivity using the Matsuda index derived from the Oral GlucoseTolerance test.
  • Oxidative Stress [ Time Frame: Baseline to 12 weeks ]
    Change in reactive oxygen species (ROS) production using the Oxygraph instrument.
  • Cellular Senescence [ Time Frame: Baseline to 12 weeks ]
    Change in senescence cell markers (p16, p21, beta gal) measure by Reverse transcription polymerase chain reaction (RT PCR) (Australia (AU)).
  • DNA methylation [ Time Frame: Baseline to 12 weeks ]
    Change in DNA methylation and epigenetic clock.
  • Grip Strength [ Time Frame: Baseline to 12 weeks ]
    Change in grip strength measured using a hand-held dynamometer in Newton meters (Nm)
  • Isometric knee extension [ Time Frame: Baseline to 12 weeks ]
    Change in isometric torque using a Biodex dynamometer (Nm)
  • 6 minute walking distance [ Time Frame: Baseline to 12 weeks ]
    Change in walking distance in the 6 minute walking test.
  • Volumes of maximal oxygen uptake (VO2 max) [ Time Frame: Baseline to 12 weeks ]
    Change % in VO2 max measured by cardiopulmonary exercise testing (CPET)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE SGLT2 Inhibition in Older Obese Adults With Pre-diabetes
Official Title  ICMJE Effect of SGLT2 Inhibition on Aging-related Biomarkers in Older Obese Adults With Pre-diabetes
Brief Summary Inhibitors of the sodium-glucose co-transporter (SGLT2) are FDA-approved for the treatment of type 2 diabetes (T2DM). Their mechanism of action involves lowering of blood glucose concentration secondary to increased glucose excretion of glucose by the kidney. These drugs also improve body weight, blood pressure, and cardiac function. Based on these pleiotropic effects, including its calorie restriction-mimetic properties, the study team hypothesize that SGLT2 drugs will impact several basic aging-related processes, including reductions in oxidative damage to DNA and proteins, advanced glycation end products (AGE) and receptor for AGE (RAGE), cellular senescence, and mitochondrial function.
Detailed Description

Investigations into the aging process have identified major cellular dysfunctions that contribute to aging, including but not limited to increased burden of damaged DNA and protein, reduction in mitochondrial respiration, and the development of pro-inflammatory senescent cells. Developing and testing interventions that interact with multiple points of this spectrum may delay the aging process. Based on prior investigations, the study team believe the SGLT2 inhibitor class of drugs may target these basic mechanisms involved in the aging process and propose testing in a high-risk human population to evaluate their effectiveness in ameliorating aging-associated dysfunctions. Specifically, the investigators hypothesize that SGLT2i drugs will lead to reductions in oxidative damage to DNA and proteins, AGE-RAGE, and cellular senescence, which will be accompanied by improvements in mitochondrial function. If the hypothesis is correct, these findings could lead to the development of new approaches to increase both health-span and lifespan.

This is a single center, open-label, randomized controlled trial. The target enrollment for this pilot study is 20 completed subjects, split evenly between experimental and control groups. Each subject will be randomized to either the experimental group of dapagliflozin 10mg daily for 12 weeks or the control group of nutritional counseling for weight loss. Health-span and clinical evaluations will be taken at baseline and at weeks 10-12 of the study.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
20 completed subjects are planned. Each subject will be randomized to either the experimental group of dapagliflozin 10mg daily for 12 weeks or the control group of nutritional counseling for weight loss.
Masking: None (Open Label)
Primary Purpose: Basic Science
Condition  ICMJE Aging
Intervention  ICMJE
  • Drug: Dapagliflozin 10 mg
    10 participants randomized to receive 12 weeks of daily dapagliflozin 10mg by mouth
    Other Name: Farxiga
  • Behavioral: Nutritional counseling
    10 participants randomized to receive 12 weeks of weekly counseling on nutrition
Study Arms  ICMJE
  • Experimental: Dapagliflozin
    10 participants with pre-diabetes will be randomized to the experimental group to receive dapagliflozin 10mg by mouth daily for 12 weeks.
    Intervention: Drug: Dapagliflozin 10 mg
  • Nutritional Counseling
    10 participants with pre-diabetes will be randomized to receive nutritional counseling weekly for 12 weeks
    Intervention: Behavioral: Nutritional counseling
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 20, 2020)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2023
Estimated Primary Completion Date August 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Men or post-menopausal women.
  2. Age= 60+ years.
  3. All ethnic groups.
  4. Body Mass index (BMI) between 30-38 kg/m2.
  5. Diagnosis of pre-diabetes (HbA1c 5.7-6.4% and 2 hr. Oral Glucose Tolerance Test (OGTT) glucose between 140-199 mg/dL, evaluated at Visit 1 and 2).
  6. Stable body weight (±3% for ≥3 months).
  7. Willing to adhere to medication regimen for three months.
  8. Montreal Cognitive Assessment score ≥21

Exclusion Criteria:

  1. Diagnosis of diabetes based on American Diabetes Association (ADA) criteria
  2. Impaired renal function with estimated Glomerular Filtration Rate (eGFR) < 45 mL/min/1.73m2 .
  3. Impaired liver function with labs ≥3 times upper limits of normal range
  4. Abnormal hematocrit with lower limits of ≤30%
  5. Abnormal triglycerides with upper limits ≥600 mg/dL
  6. Abnormal Thyroid stimulating hormone (TSH) values ≤0.3 and ≥10
  7. Urinalysis results with ˃ 5-10 white blood cell count
  8. Concomitant medications known to affect glucose and lipid homeostasis (anti-diabetes medications, glucocorticoids, atypical antipsychotics, anti-transplant rejection medications, anti-retrovirals).
  9. Current treatment with anticoagulants (warfarin). Aspirin (up to 325 mg) and clopidogrel will be permitted if these can be held for seven days prior to the biopsies.
  10. History of recent cardiovascular event in the last 6 months or Heart Failure (New York Heart Classification greater than class III-IV; recent EKG changes that suggest active heart disease
  11. Poorly controlled blood pressure (systolic BP>180, diastolic BP>100 mmHg).
  12. Active inflammatory, autoimmune, infectious, hepatic, gastrointestinal, malignant, and uncontrolled psychiatric disease (Subjects with depression, anxiety, PTSD, etc. can enroll if controlled and on stable medication)
  13. Blood donation within 2 months prior to enrollment
  14. History of frequent UTI
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 60 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE
Contact: Carolina Solis-Herrera, MD 210-567-6691 solisherrera@uthscsa.edu
Contact: Antoinette Lewis 210-450-8023 lewisa@uthscsa.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04401904
Other Study ID Numbers  ICMJE HSC20190766H
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Protocol, Statistical Analysis Plan, Published data
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Time Frame: After study completion, upon publication of data and on ClinicalTrials.gov 1 year after primary completion date of study.
Access Criteria: Data will be analysed by a statistician for publication and by direct communication with the principal investigator
Current Responsible Party The University of Texas Health Science Center at San Antonio
Original Responsible Party Same as current
Current Study Sponsor  ICMJE The University of Texas Health Science Center at San Antonio
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Carolina Solis-Herrera University of Texas Health at San Antonio
PRS Account The University of Texas Health Science Center at San Antonio
Verification Date December 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP