Clinical trial NCT02749032: Feed-Back Suppression of Meal-Induced Glucagon-like Peptide 1 (GLP-1) Secretion
Official title: Feed-Back Suppression of Meal-Induced GLP-1 Secretion Mediated Through Elevations in Intact GLP-1 Caused by Dipeptidyl Peptidase 4 (DPP-4) Inhibition: A Randomized, Prospective Comparison of Sitagliptin and Vildagliptin Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 2 Diabetes
Lead sponsor: Diabeteszentrum Bad Lauterberg im Harz
Sponsor class: OTHER
First posted: 2016-04-22
Enrollment: 24
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The present study is a phase I, single-centre, double-blind, randomized, cross-over (3 treatments, 3 treatment periods and 6 sequences), stratified (background medication: metformin vs. diet-only), placebo-controlled study, comparing periods lasting 6-9 days on treatment with repeated doses of vildagliptin, sitagliptin, or placebo, with wash-out periods between treatment periods lasting 21 days minimum.

The study was designed to directly compare the effects of vildagliptin and sitagliptin on incretin hormone responses, glycaemia, and insulin as well as glucagon secretory responses in patients with type 2 diabetes.

Detailed description: Design. The present study is a phase I, single-centre, double-blind, randomized, cross-over (3 treatments, 3 treatment periods and 6 sequences), stratified (background medication: metformin vs. diet-only), placebo-controlled study, comparing periods lasting 6-9 days on treatment with repeated doses of vildagliptin, sitagliptin, or placebo, with wash-out periods between treatment periods lasting 21 days minimum.

Experimental procedures. Meal tests were performed in the morning after an overnight fast. The standardized mixed meal was composed of 2 eggs (100 g), 1 slice (50 g) of whole grain rye bread, 1 slice (50 g) of rye flour bread, 10 g of fat-reduced margarine, 20 g of boiled ham, and 25 g of diet jam, amounting to 450 kcal, 50 % carbohydrate, 20 % protein, and 30 % fat (based on calorie count). Patients were allowed to drink tea (black or fruit-based) or de-caffeinated coffee ad libitum.

Blood sampling. Plasma glucose was determined in capillary samples taken from hyperaemic ear lobes. Venous blood was collected from indwelling venous cannulas placed in a distal forearm vein, for the determination of insulin, C-peptide, glucagon, GLP-1 (total), GLP-1 (intact), glucose-dependent insulinotropic polypeptide (GIP) (total), GIP (intact), and free fatty acids. After drawing basal blood specimens at -15 and 0 min, blood was taken at 15, 30, 45, 60, 90, 120, 180, and 240 min.

Laboratory determinations. Glucose, insulin, C-peptide, total GLP-1 (C-terminally directed assay), intact GLP-1 (sandwich ELISA), total GIP (C-terminally directed assay), intact GIP (N-terminally directed assay) and glucagon were determined.

Eligibility criteria: Inclusion Criteria:

* diabetes mellitus type 2 for more than one year, as defined by the American Diabetes Association
* body-mass-index between 20.0 and 40.0 kg/m² (inclusive),
* glycohaemoglobin (HbA1c) ≤ 8.5%,
* normal vital signs after 10 minutes resting in the supine position: systolic blood pressure 96 mmHg -159 mmHg; diastolic blood pressure 46 mmHg-99 mmHg; heart rate 46-99 bpm
* laboratory parameters within the normal range, or abnormalities judged to be clinically irrelevant by the investigator (serum estimated glomerular filtration rate was enforced to be \> 60 ml/min; hepatic enzymes and bilirubin (unless the subject has documented Gilbert syndrome) had to be \> 3-fold the upper limit of normal)
* women of childbearing potential (less than two years post-menopausal or not surgically sterile for more than 3 months), had to prove a negative serum β-human chorionic gonadotropin (HCG) pregnancy test at screening and a negative urine β-HCG pregnancy test at day 1 on each of the treatment periods, had to use a highly effective method of birth control (failure rate less than 1% per year)
* normal or clinically irrelevant findings in medical history and physical examination

Exclusion Criteria:

* any glucose-lowering drug therapy other than metformin during 3 months before the first treatment period
* any history or presence of clinically relevant cardiovascular, pulmonary, gastro-intestinal, hepatic, renal, metabolic (apart from diabetes mellitus type 2), haematological, neurological, psychiatric, systemic, ocular, gynaecologic, or infectious disease; any acute infectious disease or signs of acute illness
* symptoms of a clinically significant illness in the 3 months before the study, which, according to the investigator's opinion, could interfere with the purposes of the study
* congestive heart failure of New York Heart Association (NYHA) functional class III-IV
* Regular use of any medication other than metformin in the last month before study start with the exception of thyroid hormones, lipid-lowering and antihypertensive drugs, and, if female, with the exception of hormonal contraception or menopausal hormone replacement therapy
* blood loss (\>300 ml, any reason) within 3 months before inclusion, or a haemoglobin \< 11.0 g/dl
* participation in a trial with any investigational drug during the past three months
* presence or history of a drug allergy or clinically significant allergic disease according to the investigator's judgment including any known hypersensitivity to DPP-4 inhibitors
* presence of drug or alcohol abuse (alcohol consumption \> 40 grams / day)
* if female, pregnancy (defined as positive β-HCG blood test), breast-feeding

Primary outcomes:
measure: GLP-1 feedback inhibition
timeFrame: 0-240 min following meal ingestion
Secondary outcomes:
measure: Relationship of the GLP-1 feedback inhibition [%]
timeFrame: 0-240 min following meal ingestion
measure: Differences in glucagon secretion [pmol/l]
timeFrame: 0-240 min following meal ingestion
measure: Differences in insulin secretory responses - Insulin [pmol/l]
timeFrame: 0-240 min following meal ingestion
measure: Differences in insulin secretory responses - c-peptide [pmol/l]
timeFrame: 0-240 min following meal ingestion
measure: Differences in glucose concentrations [mmol/l]
timeFrame: 0-240 min following meal ingestion
measure: Incidence of Treatment-Emergent Adverse Events - Safety and tolerability
timeFrame: From date of screening until the end of study date, assessed for up to 4.7 months
Other outcomes:
Locations:
city: Bad Lauterberg
country: Germany
facility: Diabeteszentrum Bad Lauterberg
state: Niedersachsen
Study officials:
affiliation: Diabeteszentrum Bad Lauterberg
name: Michael A. Nauck, Prof.
role: PRINCIPAL_INVESTIGATOR
References: