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

Tracking Information
First Submitted Date ICMJE	October 17, 2008
First Posted Date ICMJE	October 20, 2008
Results First Submitted Date	September 22, 2016
Results First Posted Date	December 6, 2017
Last Update Posted Date	January 4, 2018
Study Start Date ICMJE	October 2008
Actual Primary Completion Date	November 2012 (Final data collection date for primary outcome measure)
Current Primary Outcome Measures ICMJE; (submitted: October 31, 2017)	Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (μU/ml) [ Time Frame: Baseline and 6 months ]The acute insulin response to arginine (AIRarg) performed during the 340mg/dl glucose clamp allows for estimation of the the beta-cell secretory capacity (AIRmax) or functional beta-cell mass. Changes from baseline to 6 months of AIRmax were compared across groups; Effect on Functional Beta-cell Mass as Determined by Change in ß-cell Secretory Capacity at 6 Months (pg/mL) [ Time Frame: Baseline and 6 months ]AGRmin is performed during the 340mg/dl glucose clamp allows for estimation of the minimum alpha-cell glucagon secretion. Changes from baseline to 6 months of AGRmin were compared across groups.
Original Primary Outcome Measures ICMJE; (submitted: October 17, 2008)	Effect on functional beta-cell mass as determined by change in ß-cell secretory capacity [ Time Frame: 6 months ]
Change History	Complete list of historical versions of study NCT00775684 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures ICMJE; (submitted: October 31, 2017)	Change in Acute Insulin Response to Arginine. (AIRarg) [ Time Frame: Baseline and 6 months ]The changes in B-cell insulin secretion, Acute Insulin Response to arginine (AIRarg) after 6 months were compared to baseline AIRarg for each group. Listed below are AIRarg at baseline and 6 months for each group.; Insulin Sensitivity at Baseline and 6 Months [ Time Frame: Baseline and 6 months ]Insulin sensitivity (M/I) was determined by dividing the mean glucose infusion rate required during the 230 mg/dL glucose clamp (M) by the mean prestimulus insulin level (I) between 40 and 45 min of the glucose infusion The mean difference after 6 months in insulin sensitivity (M/I) were compared; PG 50 (the Plasma Glucose Level at Which Half-maximal Insulin Secretion is Achieved During the Glucose-potentiated Arginine Test) at Baseline and 6 Months [ Time Frame: Baseline and 6 months ]Between ∼60 and 250 mg/dL, the magnitude of AIRarg is a linear function of the plasma glucose level, so the difference in AIRarg at fasting and 230 mg/dL glucose levels divided by the difference in plasma glucose (ΔAIRarg/ΔPG) gives the glucose-potentiation slope (GPS) (8,24-26). Using the y-intercept (b) from the line created by these two points, the plasma glucose level at which half-maximal insulin secretion is achieved (PG50) is derived from solving the equation 1/2 (AIRmax) = (GPS · PG50) + b, and provides a measure of β-cell sensitivity to glucose The mean difference after 6 months in PG 50 were compared. Listed below are the PG50 values at baseline and 6 months.
Original Secondary Outcome Measures ICMJE; (submitted: October 17, 2008)	Change in acute insulin response to arginine [ Time Frame: 6 months ]; Change in glucose-potentiation slope [ Time Frame: 6 months ]; Change in insulin sensitivity [ Time Frame: 6 months ]; Change in disposition index [ Time Frame: 6 months ]; 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 ]
Current Other Outcome Measures ICMJE	Not Provided
Original Other Outcome Measures ICMJE	Not Provided
Descriptive Information
Brief Title ICMJE	Effect of Exenatide, Sitagliptin or Glimepiride on Functional ß -Cell Mass
Official Title ICMJE	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
Brief 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.
Study Type ICMJE	Interventional
Study Phase	Not Applicable
Study Design ICMJE	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
Condition ICMJE	Pre-diabetes; Type 2 Diabetes
Intervention ICMJE	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 Other Name: Byetta®; Drug: Sitagliptin Sitagliptin (Januvia®)100 mg by mouth every morning Other Name: Januvia®; 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 Other Name: Amaryl®
Study Arms	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
Publications *	National Diabetes Statistics http://diabetes.niddk.nih.gov/dm/pubs/statistics/index.htm 2005. 2-16-2007 Ref Type: Electronic Citation; 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 JAR, Johnston DG. Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia. 2004 Jul;47(7):1157-1166. doi: 10.1007/s00125-004-1454-z. 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.
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status ICMJE	Completed
Actual Enrollment ICMJE; (submitted: January 31, 2013)	47
Original Estimated Enrollment ICMJE; (submitted: October 17, 2008)	75
Actual Study Completion Date	November 2012
Actual Primary Completion Date	November 2012 (Final data collection date for primary outcome measure)
Eligibility Criteria ICMJE	Inclusion Criteria: Male and female patients age 18 to 70 years.; Ability to provide written informed consent; Mentally stable and able to comply with the procedures of the study protocol; 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); Stable body weight (+ 5%) for at least 2 weeks; Female Patients: Agree to use adequate contraception if reproductively capable. Adequate contraception includes either a hormonal or barrier method, or surgical sterilization. Exclusion Criteria: Diagnosis of type 1 diabetes; Receiving insulin, exenatide (Byetta®), or sitagliptin (Januvia®) treatment or taking > 2 oral anti-diabetogenic agents for the treatment of diabetes; BMI > 44 kg/m2; Allergy to any sulfa-containing compounds; Uncontrolled hypertension (Systolic Blood Pressure >160 or Diastolic Blood Pressure > 100 mmHg); Uncontrolled hyperlipidemia (triglycerides > 500 or LDL > 160 mg/dl); Elevation of liver function tests > 2 times the upper limit of normal; Estimated Glomerular Filtration Rate (GFR) < 55 ml/min/1.73m2 (46); Hyperkalemia (serum potassium > 5.5 mmol/L); Moderate anemia (hemoglobin concentration < 12 g/dl in men and < 11 g/dl in women); Female patients: pregnant or lactating; Hepatic cirrhosis; Known active alcohol or substance abuse; Active cardiovascular disease; Use of any investigational agent within 6 weeks of the baseline visit; Any medical condition that, in the opinion of the investigator, will interfere with the safe completion of the trial
Sex/Gender	Sexes Eligible for Study: All
Ages	18 Years to 70 Years (Adult, Older Adult)
Accepts Healthy Volunteers	No
Contacts ICMJE	Contact information is only displayed when the study is recruiting subjects
Listed Location Countries ICMJE	United States
Removed Location Countries
Administrative Information
NCT Number ICMJE	NCT00775684
Other Study ID Numbers ICMJE	808425
Has Data Monitoring Committee	No
U.S. FDA-regulated Product	Not Provided
IPD Sharing Statement	Plan to Share IPD: Undecided
Responsible Party	University of Pennsylvania
Study Sponsor ICMJE	University of Pennsylvania
Collaborators ICMJE	Pennsylvania Department of Health
Investigators ICMJE	Principal Investigator: Michael Rickels, M.D., M.S. University of Pennsylvania, Division of Endocrinology, Diabetes & Metabolism
PRS Account	University of Pennsylvania
Verification Date	December 2017
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP