Quantification of the Dipeptidyl Peptidase (DPP)-4 Inhibition-mediated Enhancement of the Activity of the Entero-insular Axis
Condition: Diabetes
Study type: Interventional
Phase: Phase 2/Phase 3

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.
    

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.
    

Intervention name(s): Sitagliptin; Metformin; Placebo; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): 100 mg once daily in the morning; up to 2000 mg/day; 500mg 1-0-0-0; 100mg 1-0-0-0
Intervention MeSH terms: Metformin; Sitagliptin Phosphate
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Care Provider)
Primary purpose: Treatment
Keywords: Incretin, DPP-4, metformin, sitagliptin, insulin secretion