Quantification of the Dipeptidyl Peptidase (DPP)-4 Inhibition-mediated Enhancement of the Activity of the Entero-insular Axis

Study Overview
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Brief Summary
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Objective: To assess the effect if 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). Hypothesis: Treatment with co-administration of sitagliptin and metformin provides a greater incretin effect compared to placebo.

Detailed Description
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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.

Official Title
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Quantification of the DPP-4 Inhibition-mediated Enhancement of the Activity of the Entero-insular Axis

Conditions
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Diabetes

Intervention / Treatment
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* Drug: Sitagliptin
* Drug: Metformin
* Drug: Placebo
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Type 2-diabetes mellitus BMI 25-35 kg/m2 HbA1c 6.5%-9% (without OHA medication) HbA1c 6%-8.5% (OHA monotherapy with metformin or sulfonylurea) Patient understands the study-procedures Exclusion Criteria: Type 1-diabetes mellitus C-peptide < 0.7ng/mL (0.23 nmol/L) Patient has been taking oral anti-hyperglycemic agent (OHA) within the prior 12 weeks, except metformin or a sulfonylurea Patient has required insulin therapy within the past 12 weeks

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment A<br>sitagliptin and placebo | Drug: Sitagliptin<br>* 100 mg once daily in the morning<br>Drug: Placebo<br>* 500mg 1-0-0-0<br>|
| Active Comparator: Treatment B<br>placebo and metformin | Drug: Metformin<br>* up to 2000 mg/day<br>Drug: Placebo<br>* 100mg 1-0-0-0<br>|
| Active Comparator: Treatment C<br>sitagliptin and metformin | Drug: Sitagliptin<br>* 100 mg once daily in the morning<br>Drug: Metformin<br>* up to 2000 mg/day<br>|
| Placebo Comparator: Treatment D<br>placebo | Drug: Placebo<br>* 500mg 1-0-0-0<br>Drug: Placebo<br>* 100mg 1-0-0-0<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |  | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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) |  | 24 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Incretin, DPP-4, metformin, sitagliptin, insulin secretion