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

Purpose

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.

Conditions

  • Diabetes Mellitus, Type 2
  • Impaired Glucose Tolerance (IGT)
  • Impaired Fasting Glucose (IFG)

Eligibility

Eligible Ages
Between 18 Years and 65 Years
Eligible Genders
All
Accepts Healthy Volunteers
Yes

Inclusion Criteria

  • NGT subjects will serve as controls and will be matched in age, gender, ethnicity, and BMI to IGT and IFG subjects
  • Male or female subjects between the ages of 18 and 65 years of age, inclusive, at Screening.
  • FPG < 100 mg/dl and 2-h PG < 140 mg/dl
  • BMI = 24-40 kg/m2;
  • Stable body weight (±4lbs) over the preceding 3 months
  • Subjects with no evidence of major organ system disease as determined by physical exam, history, and screening laboratory data
  • 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.
  • Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
  • 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 Design

Phase
N/A
Study Type
Interventional
Allocation
Randomized
Intervention Model
Crossover Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
No Intervention
(i) 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
ii) healthy subjects with isolated IGT
(ii) healthy subjects with isolated IGT (FPG < 100; 2-h PG = 140-199) will receive one of the following four treatments: (1) Dapagliflozin, 10 mg/day, (2) Saxagliptin, 5 mg/day (3) Pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two; (4) Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.
  • Drug: Dapagliflozin
    10mg/day
    Other names:
    • farxiga
  • Drug: Saxagliptin
    5mg/day
    Other names:
    • onglyza
  • Drug: Pioglitazone
    the dose will increase from 15 mg/day to 30 mg/day at month two
    Other names:
    • actos
  • Drug: Metformin
    starting at 1000 mg/day and increased to 2000 mg/day at month 2.
    Other names:
    • glucophage
Active Comparator
(iii) healthy subjects with isolated IFG
(iii) healthy subjects with isolated IFG (FPG = 100-125; 2-h PG < 140) will receive one of the following four treatments: (1) Dapagliflozin, 10 mg/day, (2) Saxagliptin, 5 mg/day (3) Pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two; (4) Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.
  • Drug: Dapagliflozin
    10mg/day
    Other names:
    • farxiga
  • Drug: Saxagliptin
    5mg/day
    Other names:
    • onglyza
  • Drug: Pioglitazone
    the dose will increase from 15 mg/day to 30 mg/day at month two
    Other names:
    • actos
  • Drug: Metformin
    starting at 1000 mg/day and increased to 2000 mg/day at month 2.
    Other names:
    • glucophage
Active Comparator
(iv) healthy subjects with IGT plus IFG
(iv) healthy subjects with IGT plus IFG will receive one of the following four treatments: (1) Dapagliflozin, 10 mg/day, (2) Saxagliptin, 5 mg/day (3) Pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two; (4) Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.
  • Drug: Dapagliflozin
    10mg/day
    Other names:
    • farxiga
  • Drug: Saxagliptin
    5mg/day
    Other names:
    • onglyza
  • Drug: Pioglitazone
    the dose will increase from 15 mg/day to 30 mg/day at month two
    Other names:
    • actos
  • Drug: Metformin
    starting at 1000 mg/day and increased to 2000 mg/day at month 2.
    Other names:
    • glucophage

Recruiting Locations

The University of Texas Health Science Center at San Antonio
San Antonio, Texas 78229
Contact:
Ralph A DeFronzo, MD
210-567-6691
defronzo@uthscsa.edu

More Details

NCT ID
NCT02969798
Status
Recruiting
Sponsor
The University of Texas Health Science Center at San Antonio

Study Contact

Ralph A DeFronzo, MD
210-567-6691
defronzo@uthscsa.edu

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.