Effect of Exenatide, Sitagliptin or Glimepiride on Functional ß -Cell Mass

This study has been completed.
Sponsor:
Collaborator:
Pennsylvania Department of Health
Information provided by (Responsible Party):
University of Pennsylvania
ClinicalTrials.gov Identifier:
NCT00775684
First received: October 17, 2008
Last updated: January 31, 2013
Last verified: January 2013
  Purpose

This study evaluates exenatide, sitagliptin, and glimepiride for the treatment of high blood sugar in patients with impaired fasting glucose or early type 2 diabetes. The purpose of this study is to determine if exenatide and sitagliptin increase the amount of insulin made by the pancreas compared to glimepiride. It is hypothesized that exenatide or sitagliptin will sustain or increase the amount of insulin made by the pancreas in comparison to glimepiride.


Condition Intervention
Pre-diabetes
Type 2 Diabetes
Drug: Exenatide
Drug: Sitagliptin
Drug: Glimepiride

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Pharmacodynamics Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Randomized, Controlled Trial Comparing the Effect of Exenatide, Sitagliptin or Glimepiride on Functional ß -Cell Mass in Patients With Impaired Fasting Glucose or Early Type 2 Diabetes

Resource links provided by NLM:


Further study details as provided by University of Pennsylvania:

Primary Outcome Measures:
  • Effect on functional beta-cell mass as determined by change in ß-cell secretory capacity [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Change in acute insulin response to arginine [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Change in glucose-potentiation slope [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Change in insulin sensitivity [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Change in disposition index [ Time Frame: 6 months ] [ Designated as safety issue: No ]
  • Change in PG 50 (the plasma glucose level at which half-maximal insulin secretion is achieved during the glucose-potentiated arginine test) [ Time Frame: 6 months ] [ Designated as safety issue: No ]

Enrollment: 47
Study Start Date: October 2008
Study Completion Date: November 2012
Primary Completion Date: November 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Exenatide
Exenatide (Byetta®)—5 µg injected subcutaneously twice daily and increased after 1 month to 10 µg twice daily as tolerated by gastrointestinal effects
Drug: Exenatide
Exenatide (Byetta®)—5 µg injected subcutaneously twice daily and increased after 1 month to 10 µg twice daily as tolerated by gastrointestinal effects
Experimental: Sitagliptin
Sitagliptin (Januvia®)—100 mg by mouth every morning
Drug: Sitagliptin
Sitagliptin (Januvia®)100 mg by mouth every morning
Active Comparator: Glimepiride
Glimepiride (Amaryl®)—0.5 mg by mouth every morning and then increased by 0.5 - 1.0 mg at each monthly visit to achieve an average fasting glucose < 110mg/dl
Drug: Glimepiride
Glimepiride (Amaryl®)—0.5 mg by mouth every morning and then increased by 0.5 - 1.0 mg at each monthly visit to achieve an average fasting glucose < 110mg/dl

Detailed Description:

The incidence of type 2 diabetes (T2D) has reached epidemic proportions throughout the world. In the United States more than 1.5 million new cases of diabetes were diagnosed in 2005, and the estimated prevalence of the disease was over 20 million. Another 54 million Americans are believed to have impaired fasting glucose, which represents a "pre-diabetic" state at increased risk for progression to overt diabetes. T2D ultimately results from an inadequate mass of functional beta-cells, where insufficient beta-cell compensation for insulin resistance leads to the development of impaired glucose tolerance and eventually diabetes. Autopsy studies have demonstrated a decreased beta-cell mass occurring with fasting glucose > 110 mg/dl, consistent with functional studies that demonstrate decreased beta-cell (insulin) secretory capacity beginning in the range of impaired fasting glucose. Strategies that might preserve or expand functional beta-cell mass in vivo would be expected to reverse the progressive deterioration in blood glucose control seen with diabetes. One such strategy involves the incretin hormone glucagon-like peptide-1 (GLP-1), which is trophic for islet beta-cells, having both pro-proliferative and anti-apoptotic effects. However, it is not known whether increasing GLP-1 effects can preserve or enhance functional beta-cell mass in humans. This proposal will determine the effect of increasing GLP-1 levels on functional beta-cell mass in human subjects with impaired fasting glucose (fasting glucose 110 - 126 mg/dl) or early T2D (fasting glucose 127 - 149 mg/dl) where a critical window exists for reversing further beta-cell deterioration. GLP-1 effects will be promoted by administration of either the GLP-1 analog, exenatide, or by increasing endogenous GLP-1 levels through administration of the oral DPP4 inhibitor sitagliptin for a 6-month period. To control for the effect of exenatide and sitagliptin on normalization of blood glucose, subjects will be randomized to receive exenatide, sitagliptin or the sulfonylurea glimepiride, the latter being a first-line anti-diabetogenic agent that will serve as an active comparator.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Male and female patients age 18 to 70 years.
  2. Ability to provide written informed consent
  3. Mentally stable and able to comply with the procedures of the study protocol
  4. Clinical history compatible with impaired fasting glucose or early T2D as defined by a plasma glucose concentration between 110-159 mg/dl following a 12 hour overnight fast performed off any anti-diabetogenic agent for at least 2 weeks (6 weeks for thiazolidinediones)
  5. Stable body weight (+ 5%) for at least 2 weeks
  6. Female Patients: Agree to use adequate contraception if reproductively capable. Adequate contraception includes either a hormonal or barrier method, or surgical sterilization.

Exclusion Criteria:

  1. Diagnosis of type 1 diabetes
  2. Receiving insulin, exenatide (Byetta®), or sitagliptin (Januvia®) treatment or taking > 2 oral anti-diabetogenic agents for the treatment of diabetes
  3. BMI > 44 kg/m2
  4. Allergy to any sulfa-containing compounds
  5. Uncontrolled hypertension (SBP >160 or DBP > 100 mmHg)
  6. Uncontrolled hyperlipidemia (triglycerides > 500 or LDL > 160 mg/dl)
  7. Elevation of liver function tests > 2 times the upper limit of normal
  8. Estimated GFR < 55 ml/min/1.73m2 (46)
  9. Hyperkalemia (serum potassium > 5.5 mmol/L)
  10. Moderate anemia (hemoglobin concentration < 12 g/dl in men and < 11 g/dl in women)
  11. Female patients: pregnant or lactating
  12. Hepatic cirrhosis
  13. Known active alcohol or substance abuse
  14. Active cardiovascular disease
  15. Use of any investigational agent within 6 weeks of the baseline visit
  16. Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00775684

Locations
United States, Pennsylvania
Rodebaugh Diabetes Center, Hospital of the University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Clinical and Translational Research Center, Hospital of University of Pennsylvania
Philadelphia, Pennsylvania, United States, 19104
Pennsylvania Hospital
Philadelphia, Pennsylvania, United States, 19107
Sponsors and Collaborators
University of Pennsylvania
Pennsylvania Department of Health
Investigators
Principal Investigator: Michael Rickels, M.D., M.S. University of Pennsylvania, Division of Endocrinology, Diabetes & Metabolism
  More Information

Additional Information:
Publications:
Responsible Party: University of Pennsylvania
ClinicalTrials.gov Identifier: NCT00775684     History of Changes
Other Study ID Numbers: 808425
Study First Received: October 17, 2008
Last Updated: January 31, 2013
Health Authority: United States: Institutional Review Board

Keywords provided by University of Pennsylvania:
Exenatide
Sitagliptin
Glimepiride
Glucagon-Like Peptide-1
Impaired Fasting Glucose
Type 2 Diabetes
Beta-cell Function
Beta-cell Secretory Capacity
Glucose-potentiated arginine

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Intolerance
Prediabetic State
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Hyperglycemia
Glimepiride
Exenatide
Sitagliptin
Anti-Arrhythmia Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Hypoglycemic Agents
Physiological Effects of Drugs
Immunosuppressive Agents
Immunologic Factors
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on August 21, 2014