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

Diabetes Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00683735
• Other study ID #: DZBL 2008-Nauck-01
• Secondary ID: EudraCT: 2008-00
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: May 21, 2008
• Last updated: December 17, 2015
• Start date: February 2009
• Est. completion date: December 2013

Study information

• Verified date: December 2015
• Source: Diabeteszentrum Bad Lauterberg im Harz
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Ethics Commission
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 20
• Est. completion date: December 2013
• Est. primary completion date: December 2012
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 30 Years to 75 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes

Intervention

Drug:
• Sitagliptin
100 mg once daily in the morning
• Metformin
up to 2000 mg/day
• Placebo
500mg 1-0-0-0
• Placebo
100mg 1-0-0-0

Locations

Country	Name	City	State
Germany	Diabeteszentrum Bad Lauterberg	Bad Lauterberg

Sponsors (1)

Lead Sponsor	Collaborator
Michael A. Nauck

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Yes
Secondary	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	Yes