Back to results

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

Primary Purpose

Aging

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Dapagliflozin 10 mg

Nutritional counseling

About this trial

This is an interventional basic science trial for Aging focused on measuring pre-diabetes, aging, glucose metabolism, borderline diabetes

Eligibility Criteria

60 Years - undefined (Adult, Older Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

Men or post-menopausal women.
Age= 60+ years.
All ethnic groups.
Body Mass index (BMI) between 30-38 kg/m2.
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).
Stable body weight (±3% for ≥3 months).
Willing to adhere to medication regimen for three months.
Montreal Cognitive Assessment score ≥21

Exclusion Criteria:

Diagnosis of diabetes based on American Diabetes Association (ADA) criteria
Impaired renal function with estimated Glomerular Filtration Rate (eGFR) < 45 mL/min/1.73m2 .
Impaired liver function with labs ≥3 times upper limits of normal range
Abnormal hematocrit with lower limits of ≤30%
Abnormal triglycerides with upper limits ≥600 mg/dL
Abnormal Thyroid stimulating hormone (TSH) values ≤0.3 and ≥10
Urinalysis results with ˃ 5-10 white blood cell count
Concomitant medications known to affect glucose and lipid homeostasis (anti-diabetes medications, glucocorticoids, atypical antipsychotics, anti-transplant rejection medications, anti-retrovirals).
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.
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
Poorly controlled blood pressure (systolic BP>180, diastolic BP>100 mmHg).
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)
Blood donation within 2 months prior to enrollment
History of frequent UTI

Sites / Locations

Texas Diabetes Institute - University Health System
University of Texas Health Science Center at San Antonio

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Other

Arm Label

Dapagliflozin

Nutritional Counseling

Arm Description

10 participants with pre-diabetes will be randomized to the experimental group to receive dapagliflozin 10mg by mouth daily for 12 weeks.

10 participants with pre-diabetes will be randomized to receive nutritional counseling weekly for 12 weeks

Outcomes

Primary Outcome Measures

AGE-RAGE measurement in urine

Change in AGE-RAGE measured by enzyme-linked immunosorbent assay (ELISA).

Secondary Outcome Measures

Mitochondrial Function

Change % on muscle mitochondrial respiration measured in muscle tissue with Oroboros in O2 Flux per mg tissue.

Insulin Sensitivity

Percentage of change in insulin sensitivity using the Matsuda index derived from the Oral GlucoseTolerance test.

Oxidative Stress

Change in reactive oxygen species (ROS) production using the Oxygraph instrument.

Cellular Senescence

Change in senescence cell markers (p16, p21, beta gal) measure by Reverse transcription polymerase chain reaction (RT PCR) (Australia (AU)).

DNA methylation

Change in DNA methylation and epigenetic clock.

Grip Strength

Change in grip strength measured using a hand-held dynamometer in Newton meters (Nm)

Isometric knee extension

Change in isometric torque using a Biodex dynamometer (Nm)

6 minute walking distance

Change in walking distance in the 6 minute walking test.

Volumes of maximal oxygen uptake (VO2 max)

Change % in VO2 max measured by cardiopulmonary exercise testing (CPET)

Full Information

NCT ID

NCT04401904

First Posted

April 22, 2020

Last Updated

July 25, 2023

Sponsor

The University of Texas Health Science Center at San Antonio

Collaborators

National Institute on Aging (NIA)

1. Study Identification

Unique Protocol Identification Number

NCT04401904

Brief Title

SGLT2 Inhibition in Older Obese Adults With Pre-diabetes

Acronym

SGLT2i

Official Title

Effect of SGLT2 Inhibition on Aging-related Biomarkers in Older Obese Adults With Pre-diabetes

Study Type

Interventional

2. Study Status

Record Verification Date

July 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

June 25, 2020 (Actual)

Primary Completion Date

September 14, 2022 (Actual)

Study Completion Date

August 31, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

The University of Texas Health Science Center at San Antonio

Collaborators

National Institute on Aging (NIA)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Aging

Keywords

pre-diabetes, aging, glucose metabolism, borderline diabetes

7. Study Design

Primary Purpose

Basic Science

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

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)

Allocation

Randomized

Enrollment

20 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Dapagliflozin

Arm Type

Experimental

Arm Description

10 participants with pre-diabetes will be randomized to the experimental group to receive dapagliflozin 10mg by mouth daily for 12 weeks.

Arm Title

Nutritional Counseling

Arm Type

Other

Arm Description

10 participants with pre-diabetes will be randomized to receive nutritional counseling weekly for 12 weeks

Intervention Type

Drug

Intervention Name(s)

Dapagliflozin 10 mg

Other Intervention Name(s)

Farxiga

Intervention Description

10 participants randomized to receive 12 weeks of daily dapagliflozin 10mg by mouth

Intervention Type

Behavioral

Intervention Name(s)

Nutritional counseling

Intervention Description

10 participants randomized to receive 12 weeks of weekly counseling on nutrition

Primary Outcome Measure Information:

Title

AGE-RAGE measurement in urine

Description

Change in AGE-RAGE measured by enzyme-linked immunosorbent assay (ELISA).

Time Frame

Baseline to 12 weeks

Secondary Outcome Measure Information:

Title

Mitochondrial Function

Description

Change % on muscle mitochondrial respiration measured in muscle tissue with Oroboros in O2 Flux per mg tissue.

Time Frame

Baseline to 12 weeks

Title

Insulin Sensitivity

Description

Percentage of change in insulin sensitivity using the Matsuda index derived from the Oral GlucoseTolerance test.

Time Frame

Baseline to 12 weeks

Title

Oxidative Stress

Description

Change in reactive oxygen species (ROS) production using the Oxygraph instrument.

Time Frame

Baseline to 12 weeks

Title

Cellular Senescence

Description

Change in senescence cell markers (p16, p21, beta gal) measure by Reverse transcription polymerase chain reaction (RT PCR) (Australia (AU)).

Time Frame

Baseline to 12 weeks

Title

DNA methylation

Description

Change in DNA methylation and epigenetic clock.

Time Frame

Baseline to 12 weeks

Title

Grip Strength

Description

Change in grip strength measured using a hand-held dynamometer in Newton meters (Nm)

Time Frame

Baseline to 12 weeks

Title

Isometric knee extension

Description

Change in isometric torque using a Biodex dynamometer (Nm)

Time Frame

Baseline to 12 weeks

Title

6 minute walking distance

Description

Change in walking distance in the 6 minute walking test.

Time Frame

Baseline to 12 weeks

Title

Volumes of maximal oxygen uptake (VO2 max)

Description

Change % in VO2 max measured by cardiopulmonary exercise testing (CPET)

Time Frame

Baseline to 12 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

60 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Men or post-menopausal women. Age= 60+ years. All ethnic groups. Body Mass index (BMI) between 30-38 kg/m2. 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). Stable body weight (±3% for ≥3 months). Willing to adhere to medication regimen for three months. Montreal Cognitive Assessment score ≥21 Exclusion Criteria: Diagnosis of diabetes based on American Diabetes Association (ADA) criteria Impaired renal function with estimated Glomerular Filtration Rate (eGFR) < 45 mL/min/1.73m2 . Impaired liver function with labs ≥3 times upper limits of normal range Abnormal hematocrit with lower limits of ≤30% Abnormal triglycerides with upper limits ≥600 mg/dL Abnormal Thyroid stimulating hormone (TSH) values ≤0.3 and ≥10 Urinalysis results with ˃ 5-10 white blood cell count Concomitant medications known to affect glucose and lipid homeostasis (anti-diabetes medications, glucocorticoids, atypical antipsychotics, anti-transplant rejection medications, anti-retrovirals). 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. 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 Poorly controlled blood pressure (systolic BP>180, diastolic BP>100 mmHg). 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) Blood donation within 2 months prior to enrollment History of frequent UTI

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Carolina Solis-Herrera

Organizational Affiliation

University of Texas Health at San Antonio

Official's Role

Principal Investigator

Facility Information:

Facility Name

Texas Diabetes Institute - University Health System

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78207

Country

United States

Facility Name

University of Texas Health Science Center at San Antonio

City

San Antonio

State/Province

Texas

ZIP/Postal Code

78229

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing Plan Description

Protocol, Statistical Analysis Plan, Published data

IPD Sharing Time Frame

After study completion, upon publication of data and on ClinicalTrials.gov 1 year after primary completion date of study.

IPD Sharing Access Criteria

Data will be analysed by a statistician for publication and by direct communication with the principal investigator

Learn more about this trial

SGLT2 Inhibition in Older Obese Adults With Pre-diabetes

We'll reach out to this number within 24 hrs