SGLT2 Inhibition in Older Obese Adults With Pre-diabetes

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Aging

Intervention / Treatment
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* Drug: Dapagliflozin 10 mg
* Behavioral: Nutritional counseling


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 60 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
Interventional 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)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dapagliflozin<br>10 participants with pre-diabetes will be randomized to the experimental group to receive dapagliflozin 10mg by mouth daily for 12 weeks. | Drug: Dapagliflozin 10 mg<br>* 10 participants randomized to receive 12 weeks of daily dapagliflozin 10mg by mouth<br>* Other names: Farxiga;|
| Other: Nutritional Counseling<br>10 participants with pre-diabetes will be randomized to receive nutritional counseling weekly for 12 weeks | Behavioral: Nutritional counseling<br>* 10 participants randomized to receive 12 weeks of weekly counseling on nutrition<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| AGE-RAGE measurement in urine | Change in AGE-RAGE measured by enzyme-linked immunosorbent assay (ELISA). | Baseline to 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mitochondrial Function | Change % on muscle mitochondrial respiration measured in muscle tissue with Oroboros in O2 Flux per mg tissue. | Baseline to 12 weeks | 
| Insulin Sensitivity | Percentage of change in insulin sensitivity using the Matsuda index derived from the Oral GlucoseTolerance test. | Baseline to 12 weeks | 
| Oxidative Stress | Change in reactive oxygen species (ROS) production using the Oxygraph instrument. | Baseline to 12 weeks | 
| Cellular Senescence | Change in senescence cell markers (p16, p21, beta gal) measure by Reverse transcription polymerase chain reaction (RT PCR) (Australia (AU)). | Baseline to 12 weeks | 
| DNA methylation | Change in DNA methylation and epigenetic clock. | Baseline to 12 weeks | 
| Grip Strength | Change in grip strength measured using a hand-held dynamometer in Newton meters (Nm) | Baseline to 12 weeks | 
| Isometric knee extension | Change in isometric torque using a Biodex dynamometer (Nm) | Baseline to 12 weeks | 
| 6 minute walking distance | Change in walking distance in the 6 minute walking test. | Baseline to 12 weeks | 
| Volumes of maximal oxygen uptake (VO2 max) | Change % in VO2 max measured by cardiopulmonary exercise testing (CPET) | Baseline to 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pre-diabetes, aging, glucose metabolism, borderline diabetes