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

Official title

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

Overview

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.

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.

Interventions

• Drug Dapagliflozin
  10mg/day
• Drug Saxagliptin
  5mg/day
• Drug Pioglitazone
  the dose will increase from 15 mg/day to 30 mg/day at month two
• Drug Metformin
  starting at 1000 mg/day and increased to 2000 mg/day at month 2.

Primary outcome measures

• Beta cell function [Time frame: 24 months after treatment phase begins]
• Insulin sensitivity [Time frame: 24 months after treatment phase begins]
• Glucose tolerance status [Time frame: 24 months after treatment phase begins]

Eligibility criteria

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

• 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.
• Subjects with a family history of diabetes in a first degree relative
• BMI of less than 24 or greater than 40 kg/m2
• Unstable body weight (change of greater than ±4lbs over the preceding 3 months
• Subjects participating in an excessively heavy exercise program
• Subject with a feeding/sleeping schedule different from a daytime feeding/night time sleeping schedule
• Subjects taking medications known to alter glucose metabolism (with the exception of metformin and/or pioglitazone) or which effect brain neurosynaptic function are excluded.
• Subjects with evidence of major organ system disease as determined by physical exam, history, and screening laboratory data
• Pregnant subjects or subjects unwilling to use birth control during their study enrollment
• Blood donation of approximately 1 pint (500 mL) within 8 weeks prior to Screening.
• 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
• Subjects with hematuria will be excluded.
• Subjects with evidence or prior history of heart failure will be excluded
• Subjects with family history of pancreatic, bladder, and breast cancer will be excluded.
• Subjects with history of pancreatitis will be excluded.
• Subjects with eGFR < 60 ±5 ml/min.1.73m2 will be excluded.
• Subjects with elevated serum creatinine (>1.5 mg/dl males/1.4 mg/dl females) will be excluded.
• Subjects with a history of orthostatic hypotension (>15/10 mmHg) will be excluded.
• Subjects with liver enzymes (ALT, AST) >3-fold above upper normal limit will be excluded.
• Subjects with a history of hypersensitivity to pioglitazone, dapagliflozin, or Saxagliptin will be excluded.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: Yes

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• The University of Texas Health Science Center at San Antonio — San Antonio

Identifiers

NCT: NCT02969798 · HSC20130414H · R01DK024092-34

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗