Pre-diabetes in Subject With Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT)

Preservation of Beta Cell Function in Pre-diabetes in Subject With Impaired Fasting Glucose (IFG) and Impaired Glucose Tolerance (IGT)

HYPOTHESIS: Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) have distinct pathophysiologic etiologies. Therefore, therapeutic interventions designed to correct the specific underlying pathogenic abnormalities in IGT and IFG will be required to optimally prevent the progressive beta cell failure and development of overt type 2 diabetes.

Study Overview

• Status: Recruiting
• Conditions: Diabetes Mellitus, Type 2; Impaired Glucose Tolerance (IGT); Impaired Fasting Glucose (IFG)
• Intervention / Treatment: Drug: Dapagliflozin; Drug: Saxagliptin; Drug: Pioglitazone; Drug: Metformin

Detailed Description

SPECIFIC AIMS:

1. To examine the effect of the following pharmacologic interventions on beta cell function, insulin sensitivity, and glucose tolerance status in individuals with isolated impaired glucose tolerance (IGT): (i) treatment with the renal Sodium-glucose co-transporter 2 (SGLT2) inhibitor inhibitor, dapagliflozin; (ii) treatment with the inhibitors of dipeptidyl peptidase 4, also DPP4, saxagliptin ; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin.
2. To examine the effect of the following pharmacologic interventions on beta cell function, insulin sensitivity, and glucose tolerance status in individuals with isolated impaired fasting glucose (IFG): (i) treatment with the renal SGLT2 inhibitor, dapagliflozin; (ii) treatment with the DPP4 inhibitor, saxagliptin; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin.
3. To examine the effect of the following pharmacologic interventions on beta cell function, insulin sensitivity, and glucose tolerance status in individuals with combined impaired glucose tolerance (IGT) plus impaired fasting glucose (IFG): i) treatment with the renal SGLT2 inhibitor, dapagliflozin; (ii) treatment with the DPP4 inhibitor, saxagliptin; (iii) treatment with the thiazolidinedione, pioglitazone; (iv) treatment with the biguanide, metformin.

• Study Type: Interventional
• Enrollment (Estimated): 700
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Ralph A DeFronzo, MD; Phone Number: 210-567-6691; Email: defronzo@uthscsa.edu
• Study Contact Backup: Name: Monica Palomo, BS; Phone Number: 210-567-6710; Email: palomom@uthscsa.edu

Study Locations

• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • The University of Texas Health Science Center at San Antonio
      • Contact: Ralph A DeFronzo, MD; Phone Number: 210-567-6691; Email: defronzo@uthscsa.edu
      • Contact: Monica Palomo, BS; Phone Number: 210-567-6710; Email: palomom@uthscsa.edu
      • Principal Investigator: Ralph A DeFronzo, MD
      • Sub-Investigator: Eugenio Cersosimo, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• NGT subjects will serve as controls and will be matched in age, gender, ethnicity, and BMI to IGT and IFG subjects

  1. Male or female subjects between the ages of 18 and 65 years of age, inclusive, at Screening.
  2. FPG < 100 mg/dl and 2-h PG < 140 mg/dl
  3. BMI = 24-40 kg/m2;
  4. Stable body weight (±4lbs) over the preceding 3 months
  5. Subjects with no evidence of major organ system disease as determined by physical exam, history, and screening laboratory data

  6. Females of childbearing potential with a negative pregnancy test at Screening and Treatment visits, using one of the following forms of contraception for the duration of participation in the study (i.e., until Follow-up 7-14 days post last dose):

     • Oral contraceptive
     • Injectable progesterone
     • Subdermal implant
     • Spermicidal foam/gel/film/cream/suppository
     • Diaphragm with spermicide
     • Copper or hormonal containing IUD
     • Sterile male partner vasectomized > 6 month pre-dosing.
  7. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
  8. Subjects must be willing and able to comply with scheduled visits, treatment, laboratory tests and study procedures.

Exclusion Criteria:

1. Recent (i.e., within three (3) months prior to Screening) evidence or medical history of unstable concurrent disease such as: documented evidence or history of clinically significant hematological, endocrine, pulmonary, gastrointestinal, cardiovascular, hepatic, psychiatric, immunological, or clinically significant neurological disease.
2. Subjects with a family history of diabetes in a first degree relative
3. BMI of less than 24 or greater than 40 kg/m2
4. Unstable body weight (change of greater than ±4lbs over the preceding 3 months
5. Subjects participating in an excessively heavy exercise program
6. Subject with a feeding/sleeping schedule different from a daytime feeding/night time sleeping schedule
7. Subjects taking medications known to alter glucose metabolism (with the exception of metformin and/or pioglitazone) or which effect brain neurosynaptic function are excluded.
8. Subjects with evidence of major organ system disease as determined by physical exam, history, and screening laboratory data
9. Pregnant subjects or subjects unwilling to use birth control during their study enrollment
10. Blood donation of approximately 1 pint (500 mL) within 8 weeks prior to Screening.
11. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study
12. Subjects with hematuria will be excluded.
13. Subjects with evidence or prior history of heart failure will be excluded
14. Subjects with family history of pancreatic, bladder, and breast cancer will be excluded.
15. Subjects with history of pancreatitis will be excluded.
16. Subjects with eGFR < 60 ±5 ml/min.1.73m2 will be excluded.
17. Subjects with elevated serum creatinine (>1.5 mg/dl males/1.4 mg/dl females) will be excluded.
18. Subjects with a history of orthostatic hypotension (>15/10 mmHg) will be excluded.
19. Subjects with liver enzymes (ALT, AST) >3-fold above upper normal limit will be excluded.
20. Subjects with a history of hypersensitivity to pioglitazone, dapagliflozin, or Saxagliptin will be excluded.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

13

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
No Intervention: Healthy normal glucose tolerance (NGT) subjects; Subjects (Fasting Plasma Glucose or FPG < 100 mg/dl and 2-h PG < 140 mg/dl) without FH (family history) of diabetes in a first degree relative
Active Comparator: Isolated IGT with Dapagliflozin; Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive dapagliflozin, 10 mg/day	Drug: Dapagliflozin; 10mg/day; Other Names: farxiga
Active Comparator: Isolated IGT with Saxagliptin; Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive saxagliptin, 5 mg/day	Drug: Saxagliptin; 5mg/day; Other Names: onglyza
Active Comparator: Isolated IGT with Pioglitazone; Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two	Drug: Pioglitazone; the dose will increase from 15 mg/day to 30 mg/day at month two; Other Names: actos
Active Comparator: Isolated IGT with Metformin; Healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.	Drug: Metformin; starting at 1000 mg/day and increased to 2000 mg/day at month 2.; Other Names: glucophage
Active Comparator: Isolated IFG with Dapagliflozin; Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive dapagloflozin, 10mg/day	Drug: Dapagliflozin; 10mg/day; Other Names: farxiga
Active Comparator: Isolated IFG with Saxagliptin; Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive saxagliptin, 10mg/day	Drug: Saxagliptin; 5mg/day; Other Names: onglyza
Active Comparator: Isolated IFG with Pioglitazone; Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two	Drug: Pioglitazone; the dose will increase from 15 mg/day to 30 mg/day at month two; Other Names: actos
Active Comparator: Isolated IFG with Metformin; Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.	Drug: Metformin; starting at 1000 mg/day and increased to 2000 mg/day at month 2.; Other Names: glucophage
Active Comparator: IGT plus IFG with Dapagliflozin; Healthy subjects with IGT plus IFG will receive dapagliflozin, 10mg/day	Drug: Dapagliflozin; 10mg/day; Other Names: farxiga
Active Comparator: IGT plus IFG with Saxagliptin; Healthy subjects with IGT plus IFG will receive saxagliptin, 10mg/day	Drug: Saxagliptin; 5mg/day; Other Names: onglyza
Active Comparator: IGT plus IFG with Pioglitazone; Healthy subjects with IGT plus IFG will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two	Drug: Pioglitazone; the dose will increase from 15 mg/day to 30 mg/day at month two; Other Names: actos
Active Comparator: IGT plus IFG with Metformin; Healthy subjects with IGT plus IFG will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.	Drug: Metformin; starting at 1000 mg/day and increased to 2000 mg/day at month 2.; Other Names: glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Beta cell function	Beta cell function will be measured as insulin secretion during the hyperglycemic clamp (mean plasma insulin concentration in uU/ml) multiplied by insulin sensitivity measured with the euglycemic insulin clamp (mg/kg.min).	24 months after treatment phase begins
Insulin sensitivity	Insulin sensitivity will be measured with the euglycemic insulin clamp and expressed as mg/kg.min.	24 months after treatment phase begins
Glucose tolerance status	Glucose tolerance status will be evaluated by measuring the HbA1c which is a measure of the average of the amount of glucose attached to hemoglobin over the past 3 months, expressed as a percentage.	24 months after treatment phase begins

Collaborators and Investigators

• Sponsor: The University of Texas Health Science Center at San Antonio
• Collaborators: National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); AstraZeneca; American Diabetes Association
• Investigators: Principal Investigator: Ralph A DeFronzo, MD, The University of Texas Health Science Center at San Antonio

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2014
• Primary Completion (Estimated): December 1, 2024
• Study Completion (Estimated): July 1, 2025

Study Registration Dates

• First Submitted: March 16, 2016
• First Submitted That Met QC Criteria: November 16, 2016
• First Posted (Estimated): November 21, 2016

Study Record Updates

• Last Update Posted (Actual): August 3, 2023
• Last Update Submitted That Met QC Criteria: August 2, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperglycemia; Diabetes Mellitus; Diabetes Mellitus, Type 2; Prediabetic State; Glucose Intolerance; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Protease Inhibitors; Incretins; Sodium-Glucose Transporter 2 Inhibitors; Dipeptidyl-Peptidase IV Inhibitors; Dapagliflozin; Metformin; Pioglitazone; Saxagliptin
• Other Study ID Numbers: HSC20130414H; R01DK024092-34 (U.S. NIH Grant/Contract)