Effect of Exenatide, Sitagliptin or Glimepiride on Functional ß -Cell Mass
Condition: Pre-diabetes; Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2; Prediabetic State
Study type: Interventional

Summary: 
      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.
    

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 dipeptidyl peptidase 4 (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.
    

Intervention name(s): Exenatide; Sitagliptin; Glimepiride
Intervention type(s): Drug; Drug; Drug
Intervention description(s): Exenatide (Byetta®)-5 µg injected subcutaneously twice daily and increased after 1 month to 10 µg twice daily as tolerated by gastrointestinal effects; Sitagliptin (Januvia®)100 mg by mouth every morning; 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
Other intervention name(s): Byetta®; Januvia®; Amaryl®
Intervention MeSH terms: Sitagliptin Phosphate; Exenatide; Glimepiride
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Exenatide; Sitagliptin; Glimepiride; Glucagon-Like Peptide-1; Impaired Fasting Glucose; Type 2 Diabetes; Beta-cell Function; Beta-cell Secretory Capacity; Glucose-potentiated arginine