Type 2 Diabetes
Conditions
Keywords
GLP-1, GIP, Incretin hormones, DPP-IV inhibitor, Hyperglycaemic clamp, Meal test
Brief summary
We wish to evaluate the effect of long term treatment with a DPP-IV inhibitor on the function of the incretin hormones Hypothesis We hypothesize that that a gradual improvement in metabolic control induced by DPP-IV inhibitor (Januvia®) treatment significantly ameliorates the impaired secretion and potency of GLP-1 and leads to a restoration of the lost action of GIP.
Detailed description
Background The incretin effect, primarily mediated by the peptide hormones GIP and GLP-1, is known to be impaired in patients with type 2 diabetes, and characterised by reduced GLP-1 secretion and potency and a lack of responsiveness to the insulinotropic effect of GIP. The cause of this defect remains unknown, but exogenous administration of GLP-1 has shown promising results in attempts to restore the incretin effect. Due to rapid degradation of both incretin hormones by the enzyme dipeptidyl-peptidase IV (DPP-IV), treatment strategies now focus on GLP-1 analogues and prevention of hormone degradation through DPP-IV inhibition. Hypothesis We hypothesize that that a gradual improvement in metabolic control induced by DPP-IV inhibitor (Januvia®) treatment significantly ameliorates the impaired secretion and potency of GLP-1 and leads to a restoration of the lost action of GIP. Objective To assess the effect of three months treatment with Januvia®, administered as tablets once daily, on metabolic control in metformin treated patients with type 2 diabetes, measured as increases in incretin hormones and insulin secretion. Efficacy end points Primary efficacy end point in trial part one is the relative increase in meal-induced total GLP-1 secretion after one and twelve weeks of Januvia® treatment. Primary efficacy end point in part two is restoration of the insulinotropic effect of GIP, measured as the relative increase in GIP induced amplification of the late phase insulin secretion (AUC) response to glucose after 12 weeks of Januvia® treatment. Secondary objectives are examination of GLP-2, somatostatin, glucagon, peptide-YY and two glycaemic control parameters (HbA1c and fasting plasma glucose) Design This is a single centre, randomized, double blinded, placebo controlled trial. The trial consists of two parts, each consisting of three months of inhibitor treatment. In each part, 24 patients, recruited from the Diabetes Outpatient Clinic of Gentofte University Hospital, will be randomized to a treatment supplement of either Januvia® or placebo. Procedures During the trial, patients will be tested with well established procedures. In part one, patients will undergo a standardized meal test and two β-cell secretory capacity tests. In part two, patients will undergo standardized hyperglycaemic GIP, GLP-1 and saline clamps. Safety The trial has a short time span of only three months. With more than ten visits during this time and regular blood sampling, the patients are well monitored.
Interventions
DRUGJanuvia
200 mg t.i.d
DRUGPlacebo
Placebo
Sponsors
Merck Sharp & Dohme LLC
University Hospital, Gentofte, Copenhagen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes diagnosed according to and in accordance with the WHO criteria * Metformin treatment of ≥ 1 gram * 7,5 % ≤ HbA1c ≤ 10% * Age \> 18 * BMI ≥ 25 kg/m2 * Informed consent * Contraception, if appropriate
Exclusion criteria
* Proliferating retinopathy * Uremia, end stage renal disease, diabetic nephropathy or any other cause of impaired renal function with s-creatinine \> 130 µM and/or albuminuria (\>300 mg/day) * Liver disease with ALAT and/or ASAT \> 2 x normal value * Complicated coronary artery disease, NYHA group III and IV * Positive screening for islet cell auto antibodies and/or GAD-65 auto antibodies * Occurrence of type 1 diabetes in first degree relatives * Anaemia * Pregnancy and/or breast feeding * Treatment with medication affecting insulin secretion * non-compliance Withdrawal criteria * The subject may withdraw at will at any time * Pregnancy discovered during the trial * Severe illness * Unacceptable side effects * If self-measured fasting plasma glucose on three consecutive days exceeds 15 mM, the result is repeated in an immediately scheduled visit, and no treatable intercurrent cause for the hyperglycaemia can be found.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| the Relative Increase in Meal-induced Total GLP-1 Secretion | 12 weeks | Patients will be followed for 12 weeks with three meal test examinations; before treatment, after 1 week of treatment and after 12 weeks of treatment. Primary outcome is AUC GLP-1 (pM x 120 as stated). |
| Restoration of the Insulinotropic Effect of GIP | 12 weeks | Restoration of the insulinotropic effect of GIP measured as the relative increase in GIP induced amplification of the late phase insulin secretion (AUC) response to glucose. Patients will be followed for 12 weeks with examinations after 1 and after 12 weeks of treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Examination of GLP-2, Somatostatin, Glucagon, Peptide-YY and Two Glycaemic Control Parameters (HbA1c and Fasting Plasma Glucose) | 12 weeks | Secondary objectives are examination of GLP-2, somatostatin, glucagon, peptide-YY and two glycaemic control parameters (HbA1c and fasting plasma glucose). Patients will be followed for 12 weeks with three examinations; before, during and after the treatment |
Countries
Denmark
Participant flow
Recruitment details
Patients recruited from Jan. 2008 to Dec 2009 through out-patient clinic and advertisement
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo treatment | 24 |
| Januvia Active treatment | 25 |
| Total | 49 |
Baseline characteristics
| Characteristic | Januvia | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 25 Participants | 23 Participants | 48 Participants |
| Age, Continuous | 60 years | 60 years | 60 years |
| Region of Enrollment Denmark | 25 participants | 24 participants | 49 participants |
| Sex: Female, Male Female | 12 Participants | 11 Participants | 23 Participants |
| Sex: Female, Male Male | 13 Participants | 13 Participants | 26 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 0 | 0 / 0 |
| serious Total, serious adverse events | 0 / 0 | 0 / 0 |
Outcome results
Primary
Restoration of the Insulinotropic Effect of GIP
Restoration of the insulinotropic effect of GIP measured as the relative increase in GIP induced amplification of the late phase insulin secretion (AUC) response to glucose. Patients will be followed for 12 weeks with examinations after 1 and after 12 weeks of treatment.
Time frame: 12 weeks
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Restoration of the Insulinotropic Effect of GIP | After 1 week | 17.8 pM x 120 min | Standard Error 3 |
| Placebo | Restoration of the Insulinotropic Effect of GIP | After 12 weeks | 19.7 pM x 120 min | Standard Error 3.7 |
| Januvia | Restoration of the Insulinotropic Effect of GIP | After 1 week | 21.3 pM x 120 min | Standard Error 4.3 |
| Januvia | Restoration of the Insulinotropic Effect of GIP | After 12 weeks | 30.0 pM x 120 min | Standard Error 6.2 |
Primary
the Relative Increase in Meal-induced Total GLP-1 Secretion
Patients will be followed for 12 weeks with three meal test examinations; before treatment, after 1 week of treatment and after 12 weeks of treatment. Primary outcome is AUC GLP-1 (pM x 120 as stated).
Time frame: 12 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | the Relative Increase in Meal-induced Total GLP-1 Secretion | 2591 pM x 120 min | Standard Deviation 358 |
| Januvia | the Relative Increase in Meal-induced Total GLP-1 Secretion | 3959 pM x 120 min | Standard Deviation 877 |
Secondary
Examination of GLP-2, Somatostatin, Glucagon, Peptide-YY and Two Glycaemic Control Parameters (HbA1c and Fasting Plasma Glucose)
Secondary objectives are examination of GLP-2, somatostatin, glucagon, peptide-YY and two glycaemic control parameters (HbA1c and fasting plasma glucose). Patients will be followed for 12 weeks with three examinations; before, during and after the treatment
Time frame: 12 weeks