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

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

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.

Study Overview

• Status: Completed
• Conditions: Aging
• Intervention / Treatment: Drug: Dapagliflozin 10 mg; Behavioral: Nutritional counseling

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: Interventional
• Enrollment (Actual): 20
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
    • San Antonio, Texas, United States, 78207
      • Texas Diabetes Institute - University Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dapagliflozin; 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; 10 participants randomized to receive 12 weeks of daily dapagliflozin 10mg by mouth; Other Names: Farxiga
Other: Nutritional Counseling; 10 participants with pre-diabetes will be randomized to receive nutritional counseling weekly for 12 weeks	Behavioral: Nutritional counseling; 10 participants randomized to receive 12 weeks of weekly counseling on nutrition

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Grip Strength	Change in grip strength measured using a hand-held dynamometer in Newton meters (Nm)	Baseline to 12 weeks
6 Minute Walking Distance	Change in walking distance in the 6 minute walking test.	Baseline to 12 weeks

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute on Aging (NIA)
• Investigators: Principal Investigator: Carolina Solis-Herrera, University of Texas Health at San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): June 25, 2020
• Primary Completion (Actual): September 14, 2022
• Study Completion (Actual): September 14, 2022

Study Registration Dates

• First Submitted: April 22, 2020
• First Submitted That Met QC Criteria: May 20, 2020
• First Posted (Actual): May 26, 2020

Study Record Updates

• Last Update Posted (Actual): January 5, 2024
• Last Update Submitted That Met QC Criteria: January 4, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: aging; glucose metabolism; pre-diabetes; borderline diabetes
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Hyperglycemia; Prediabetic State; Glucose Intolerance; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Sodium-Glucose Transporter 2 Inhibitors; Dapagliflozin
• Other Study ID Numbers: HSC20190766H; 2P30AG044271 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD 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
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP

Drug and device information, study documents

• 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