Aging
Conditions
Keywords
pre-diabetes, aging, glucose metabolism, borderline 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.
Interventions
DRUGDapagliflozin 10 mg
10 participants randomized to receive 12 weeks of daily dapagliflozin 10mg by mouth
BEHAVIORALNutritional counseling
10 participants randomized to receive 12 weeks of weekly counseling on nutrition
Sponsors
National Institute on Aging (NIA)
The University of Texas Health Science Center at San Antonio
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
60 Years to No maximum
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AGE-RAGE Measurement in Plasma | Baseline to 12 weeks | Change in AGE-RAGE measured by enzyme-linked immunosorbent assay (ELISA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Grip Strength | Baseline to 12 weeks | Change in grip strength measured using a hand-held dynamometer in Newton meters (Nm) |
| 6 Minute Walking Distance | Baseline to 12 weeks | Change in walking distance in the 6 minute walking test. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dapagliflozin 10 participants with pre-diabetes will be randomized to the experimental group to receive dapagliflozin 10mg by mouth daily for 12 weeks.
Dapagliflozin 10 mg: 10 participants randomized to receive 12 weeks of daily dapagliflozin 10mg by mouth | 10 |
| Nutritional Counseling 10 participants with pre-diabetes will be randomized to receive nutritional counseling weekly for 12 weeks
Nutritional counseling: 10 participants randomized to receive 12 weeks of weekly counseling on nutrition | 10 |
| Total | 20 |
Baseline characteristics
| Characteristic | Dapagliflozin | Nutritional Counseling | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 8 Participants | 9 Participants | 17 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 10 Participants | 20 Participants |
| Region of Enrollment United States | 10 participants | 10 participants | 20 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
AGE-RAGE Measurement in Plasma
Change in AGE-RAGE measured by enzyme-linked immunosorbent assay (ELISA).
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | AGE-RAGE Measurement in Plasma | -172 pg/mL | Standard Error 121 |
| Nutritional Counseling | AGE-RAGE Measurement in Plasma | -86 pg/mL | Standard Error 112 |
Secondary
6 Minute Walking Distance
Change in walking distance in the 6 minute walking test.
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | 6 Minute Walking Distance | 6.6 m | Standard Error 7.6 |
| Nutritional Counseling | 6 Minute Walking Distance | 9.1 m | Standard Error 11.8 |
Secondary
Grip Strength
Change in grip strength measured using a hand-held dynamometer in Newton meters (Nm)
Time frame: Baseline to 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dapagliflozin | Grip Strength | -2 Nm | Standard Error 1.3 |
| Nutritional Counseling | Grip Strength | -1 Nm | Standard Error 1.2 |