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

Michael A. Nauck

Status and phase: Completed; Phase 3; Phase 2

Conditions: Diabetes

Treatments: Drug: Metformin; Drug: Sitagliptin; Drug: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT00683735

DZBL 2008-Nauck-01

EudraCT: 2008-001663-11

Details and patient eligibility

About

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.

Full 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.

Enrollment: 20 patients

Sex: All

Ages: 30 to 75 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: Double Blind

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20 participants in 4 patient groups, including a placebo group

Treatment A

Active Comparator group

Description:

sitagliptin and placebo

Treatment:

Drug: Placebo

Drug: Placebo

Drug: Sitagliptin

Treatment B

Active Comparator group

Description:

placebo and metformin

Treatment:

Drug: Metformin

Drug: Placebo

Drug: Placebo

Treatment C

Active Comparator group

Description:

sitagliptin and metformin

Treatment:

Drug: Metformin

Drug: Sitagliptin

Treatment D

Placebo Comparator group

Description:

placebo

Treatment:

Drug: Placebo

Drug: Placebo