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

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ClinicalTrials.gov Identifier: NCT00683735
Recruitment Status : Completed
First Posted : May 23, 2008
Last Update Posted : December 18, 2015
Sponsor:
Information provided by (Responsible Party):

Study Description
Brief 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.

Condition or disease Intervention/treatment Phase
Diabetes Drug: Sitagliptin Drug: Metformin Drug: Placebo Phase 2 Phase 3

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.


Study Design

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Official Title: Quantification of the DPP-4 Inhibition-mediated Enhancement of the Activity of the Entero-insular Axis
Study Start Date : February 2009
Primary Completion Date : December 2012
Study Completion Date : December 2013

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arms and Interventions

Arm Intervention/treatment
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


Outcome Measures

Primary Outcome Measures :
  1. 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 ]

Secondary Outcome Measures :
  1. 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 ]

Eligibility Criteria

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Ages Eligible for Study:   30 Years to 75 Years   (Adult, Senior)
Sexes Eligible for Study:   All
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): 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

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
First Posted: May 23, 2008    Key Record Dates
Last Update Posted: December 18, 2015
Last Verified: December 2015

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

Additional relevant MeSH terms:
Metformin
Sitagliptin Phosphate
Hypoglycemic Agents
Physiological Effects of Drugs
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Dipeptidyl-Peptidase IV Inhibitors
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action