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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
Michael A. Nauck, Diabeteszentrum Bad Lauterberg im Harz
ClinicalTrials.gov Identifier:
NCT00683735
First received: May 21, 2008
Last updated: September 4, 2013
Last verified: September 2013
  Purpose

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.


Condition Intervention Phase
Diabetes
Drug: Sitagliptin
Drug: Metformin
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver)
Primary Purpose: Treatment
Official Title: Quantification of the DPP-4 Inhibition-mediated Enhancement of the Activity of the Entero-insular Axis

Resource links provided by NLM:


Further study details as provided by Diabeteszentrum Bad Lauterberg im Harz:

Primary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]

Estimated Enrollment: 20
Study Start Date: February 2009
Estimated Study Completion Date: December 2013
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Treatment A
sitagliptin and placebo
Drug: Sitagliptin
100 mg once daily in the morning
Drug: Placebo
500mg 1-0-0-0
Active Comparator: Treatment B
placebo and metformin
Drug: Metformin
up to 2000 mg/day
Drug: Placebo
100mg 1-0-0-0
Active Comparator: Treatment C
sitagliptin and metformin
Drug: Sitagliptin
100 mg once daily in the morning
Drug: Metformin
up to 2000 mg/day
Placebo Comparator: Treatment D
placebo
Drug: Placebo
500mg 1-0-0-0
Drug: Placebo
100mg 1-0-0-0

Detailed 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.

  Eligibility

Ages Eligible for Study:   30 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00683735

Locations
Germany
Diabeteszentrum Bad Lauterberg
Bad Lauterberg, Germany, 37431
Sponsors and Collaborators
Michael A. Nauck
Investigators
Principal Investigator: Michael A. Nauck, Prof. Dr. Diabeteszentrum Bad Lauterberg
  More Information

No publications provided

Responsible Party: Michael A. Nauck, Prof. Dr. med., Diabeteszentrum Bad Lauterberg im Harz
ClinicalTrials.gov Identifier: NCT00683735     History of Changes
Other Study ID Numbers: DZBL 2008-Nauck-01, EudraCT: 2008-001663-11
Study First Received: May 21, 2008
Last Updated: September 4, 2013
Health Authority: Germany: Ethics Commission

Keywords provided by Diabeteszentrum Bad Lauterberg im Harz:
Incretin, DPP-4, metformin, sitagliptin, insulin secretion

Additional relevant MeSH terms:
Sitagliptin
Metformin
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 17, 2014