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

The University of Texas System (UT)

Status: Enrolling

Conditions: Impaired Fasting Glucose (IFG); Impaired Glucose Tolerance (IGT); Diabetes Mellitus, Type 2

Treatments: Drug: Pioglitazone; Drug: Metformin; Drug: Saxagliptin; Drug: Dapagliflozin

Study type: Interventional

Funder types: Other; Industry; NIH

Identifiers

NCT02969798

R01DK024092-34 (U.S. NIH Grant/Contract)

HSC20130414H

Details and patient eligibility

About

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.

Full 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.

Enrollment: 700 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: Accepts Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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700 participants in 13 patient groups

Healthy normal glucose tolerance (NGT) subjects

No Intervention group

Description:

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

Isolated IGT with Dapagliflozin

Active Comparator group

Description:

Healthy subjects with isolated IGT (FPG \< 100; 2-h PG = 140-199) will receive dapagliflozin, 10 mg/day

Treatment:

Drug: Dapagliflozin

Isolated IGT with Saxagliptin

Active Comparator group

Description:

Healthy subjects with isolated IGT (FPG \< 100; 2-h PG = 140-199) will receive saxagliptin, 5 mg/day

Treatment:

Drug: Saxagliptin

Isolated IGT with Pioglitazone

Active Comparator group

Description:

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

Treatment:

Drug: Pioglitazone

Isolated IGT with Metformin

Active Comparator group

Description:

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.

Treatment:

Drug: Metformin

Isolated IFG with Dapagliflozin

Active Comparator group

Description:

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG \< 140) will receive dapagloflozin, 10mg/day

Treatment:

Drug: Dapagliflozin

Isolated IFG with Saxagliptin

Active Comparator group

Description:

Healthy subjects with isolated IFG (FPG = 100-125; 2-h PG \< 140) will receive saxagliptin, 10mg/day

Treatment:

Drug: Saxagliptin

Isolated IFG with Pioglitazone

Active Comparator group

Description:

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

Treatment:

Drug: Pioglitazone

Isolated IFG with Metformin

Active Comparator group

Description:

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.

Treatment:

Drug: Metformin

IGT plus IFG with Dapagliflozin

Active Comparator group

Description:

Healthy subjects with IGT plus IFG will receive dapagliflozin, 10mg/day

Treatment:

Drug: Dapagliflozin

IGT plus IFG with Saxagliptin

Active Comparator group

Description:

Healthy subjects with IGT plus IFG will receive saxagliptin, 10mg/day

Treatment:

Drug: Saxagliptin

IGT plus IFG with Pioglitazone

Active Comparator group

Description:

Healthy subjects with IGT plus IFG will receive pioglitazone, the dose will increase from 15 mg/day to 30 mg/day at month two

Treatment:

Drug: Pioglitazone

IGT plus IFG with Metformin

Active Comparator group

Description:

Healthy subjects with IGT plus IFG will receive Metformin, starting at 1000 mg/day and increased to 2000 mg/day at month 2.

Treatment:

Drug: Metformin