Quantification of the Dipeptidyl Peptidase (DPP)-4 Inhibition-mediated Enhancement of the Activity of the Entero-insular Axis
|Diabetes||Drug: Sitagliptin Drug: Metformin Drug: Placebo||Phase 2 Phase 3|
|Study Design:||Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double Blind (Participant, Care Provider)
Primary Purpose: Treatment
|Official Title:||Quantification of the DPP-4 Inhibition-mediated Enhancement of the Activity of the Entero-insular Axis|
- To assess the effect of co-administration of sitagliptin and metformin compared to placebo on the incretin effect (based on the comparison of the insulin secretory response to oral glucose load and an 'isoglycaemic' intravenous glucose load) [ Time Frame: 24 weeks ]
- To assess the effect of sitagliptin compared with placebo on the incretin effect (based on the comparison of the insulin secretory response to oral glucose load and an 'isoglycaemic' intravenous glucose load) [ Time Frame: 24 weeks ]
|Study Start Date:||February 2009|
|Study Completion Date:||December 2013|
|Primary Completion Date:||December 2012 (Final data collection date for primary outcome measure)|
Active Comparator: Treatment A
sitagliptin and placebo
100 mg once daily in the morningDrug: Placebo
Active Comparator: Treatment B
placebo and metformin
up to 2000 mg/dayDrug: Placebo
Active Comparator: Treatment C
sitagliptin and metformin
100 mg once daily in the morningDrug: Metformin
up to 2000 mg/day
Placebo Comparator: Treatment D
500mg 1-0-0-0Drug: Placebo
A new class of antidiabetic agents, the DPP-4 inhibitors, are thought to protect endogenously secreted incretin hormones (e.g., GLP-1 and GIP) from proteolytic degradation and inactivation. Since GLP-1 has antidiabetogenic properties, an augmentation of meal-related responses of intact, biologically active GLP-1 can be expected to increase the impact of incretin stimulation to insulin secretory responses. The incretin effect in type 2 diabetic patients is reduced due to an impaired secretion of GLP-1 and a reduced insulinotropic effectiveness of GIP. Therefore, sitagliptin (DPP-4 inhibitor) will be studied in 20 type 2-diabetic patients, who will be treated sequentially (crossover design) with (a) placebo, (b) metformin alone, (c) Sitagliptin alone, and (d) a combination of metformin and Sitagliptin for periods of 6 days (with a washout period of 3 days between treatment. The insulin secretory response (insulin, C-peptide, insulin secretion rates determined by deconvolution analysis) will be compared between experiments with oral glucose (75 g) and "isoglycaemic" intravenous glucose infusions (20% glucose i.v.). The difference represents the "incretin effect". It is expected that the incretin effect in type 2-diabetic patients will be enhanced with sitagliptin treatment, especially combined with metformin.
A secondary objective is to relate the potential increase in the % incretin contribution to insulin secretory response after oral glucose (incretin effect) to changes in the oral glucose-induced response of intact GLP-1 and GIP (measured by specific RIAs). Thus, it will be established, to which degree sitagliptin acts as an "incretin enhancer" in type 2 diabetic patients.
This study will also determine how the combination of sitagliptin to metformin affects the incretin response and insulin secretory response. Metformin is a standard and widely used antihyperglycemic agent which lowers glycemic levels primarily through suppression of hepatic glucose output and improvement in peripheral insulin resistance, resulting in increased glucose transport and utilization by skeletal muscle. There are data to suggest that metformin increases endogenous GLP-1 levels in response to an oral glucose load in obese humans (1).
Therefore it is of relevance to confirm this novel activity of metformin in patients with type 2 diabetes, and to assess potential functional consequences regarding the incretin effect.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00683735
|Diabeteszentrum Bad Lauterberg|
|Bad Lauterberg, Germany, 37431|
|Principal Investigator:||Michael A. Nauck, Prof. Dr.||Diabeteszentrum Bad Lauterberg|