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

• 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 ]

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.

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.

• Pre-diabetes
• Type 2 Diabetes

• 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
• Drug: Sitagliptin
  Sitagliptin (Januvia®)100 mg by mouth every morning
• 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

• 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
  Intervention: Drug: Exenatide
• Experimental: Sitagliptin
  Sitagliptin (Januvia®)—100 mg by mouth every morning
  Intervention: Drug: Sitagliptin
• 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
  Intervention: Drug: Glimepiride

• King H, Aubert RE, Herman WH. Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections. Diabetes Care. 1998 Sep;21(9):1414-31.
• U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995 Nov;44(11):1249-58. Erratum in: Diabetes 1996 Nov;45(11):1655.
• Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003 Jan;52(1):102-10.
• Ritzel RA, Butler AE, Rizza RA, Veldhuis JD, Butler PC. Relationship between beta-cell mass and fasting blood glucose concentration in humans. Diabetes Care. 2006 Mar;29(3):717-8.
• Kahn SE. Clinical review 135: The importance of beta-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001 Sep;86(9):4047-58. Review.
• Godsland IF, Jeffs JA, Johnston DG. Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia. 2004 Jul;47(7):1157-66. Epub 2004 Jul 13.
• Ward WK, Bolgiano DC, McKnight B, Halter JB, Porte D Jr. Diminished B cell secretory capacity in patients with noninsulin-dependent diabetes mellitus. J Clin Invest. 1984 Oct;74(4):1318-28.

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