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Feed-Back Suppression of Meal-Induced Glucagon-like Peptide 1 (GLP-1) Secretion

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ClinicalTrials.gov Identifier: NCT02749032
Recruitment Status : Completed
First Posted : April 22, 2016
Last Update Posted : April 22, 2016
Sponsor:
Information provided by (Responsible Party):
Michael A. Nauck, Diabeteszentrum Bad Lauterberg im Harz

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.


Condition or disease Intervention/treatment Phase
Type 2 Diabetes Other: Mixed meal test Drug: Vildagliptin Drug: Sitagliptin Drug: Placebo Drug: Metformin Other: Diet and exercise Phase 1

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.


Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 24 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
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 Start Date : November 2011
Actual Primary Completion Date : March 2014

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Vildagliptin - stratum diet/exercise

Vildagliptin (50 mg per tablet) was administered orally twice daily (15 minutes prior to breakfast or test meal, on the last day of treatment period) and without a defined temporal relation to dinner in the evening, irrespective of the stratum defined by the background diabetes treatment.

Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test
Mixed meal test 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.

Drug: Vildagliptin
Vildagliptin (50 mg per tablet) was administered orally twice daily (15 minutes prior to breakfast or test meal, on the last day of treatment period) and without a defined temporal relation to dinner in the evening, irrespective of the stratum defined by the background diabetes treatment.

Other: Diet and exercise
Patients treated their diabetes mellitus type 2 with diet/exercise only

Active Comparator: Vildagliptin - stratum metformin

Vildagliptin (50 mg per tablet) was administered orally twice daily (15 minutes prior to breakfast or test meal, on the last day of treatment period) and without a defined temporal relation to dinner in the evening, irrespective of the stratum defined by the background diabetes treatment.

Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test
Mixed meal test 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.

Drug: Vildagliptin
Vildagliptin (50 mg per tablet) was administered orally twice daily (15 minutes prior to breakfast or test meal, on the last day of treatment period) and without a defined temporal relation to dinner in the evening, irrespective of the stratum defined by the background diabetes treatment.

Drug: Metformin
For patients continuing with pre-existing metformin treatment, 1000 mg film coated tablets from commercial sources. In half of the patients (stratum: metformin as background medication), metformin was administered orally twice daily at 1000 mg of active compound during of after breakfast and dinner.

Active Comparator: Sitagliptin - stratum diet/exercise

The dosage of sitagliptin depended on the stratum defined by the background diabetes medication. In patients treated with diet and exercise (no other glucose-.lowering medication), sitagliptin was given as one 100 mg in the morning (15 minutes prior to breakfast or the test meal, on the last day of the treatment period), and a corresponding placebo tablet was administered in the evening (no temporal relation to dinner required).

Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test
Mixed meal test 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.

Drug: Sitagliptin
The dosage of sitagliptin depended on the stratum defined by the background diabetes medication. In patients treated with diet and exercise (no other glucose-.lowering medication), sitagliptin was given as one 100 mg in the morning (15 minutes prior to breakfast or the test meal, on the last day of the treatment period), and a corresponding placebo tablet was administered in the evening (no temporal relation to dinner required).

Other: Diet and exercise
Patients treated their diabetes mellitus type 2 with diet/exercise only

Active Comparator: Sitagliptin - stratum metformin

In patients treated with metformin, sitagliptin (50 mg per tablet) was administered orally twice daily (15 minutes prior to breakfast or test meal, on the last day of treatment period) and without a defined temporal relation to dinner in the evening.

Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test
Mixed meal test 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.

Drug: Sitagliptin
The dosage of sitagliptin depended on the stratum defined by the background diabetes medication. In patients treated with diet and exercise (no other glucose-.lowering medication), sitagliptin was given as one 100 mg in the morning (15 minutes prior to breakfast or the test meal, on the last day of the treatment period), and a corresponding placebo tablet was administered in the evening (no temporal relation to dinner required).

Drug: Metformin
For patients continuing with pre-existing metformin treatment, 1000 mg film coated tablets from commercial sources. In half of the patients (stratum: metformin as background medication), metformin was administered orally twice daily at 1000 mg of active compound during of after breakfast and dinner.

Placebo Comparator: Placebo - stratum diet/exercise

Placebo was administered orally twice daily: 15 minutes prior to breakfast or the test meal on the last day of treatment period) and one dose in the evening (no temporal relation to dinner required).

Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test
Mixed meal test 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.

Drug: Placebo
Placebo was administered orally twice daily: 15 minutes prior to breakfast or the test meal on the last day of treatment period) and one dose in the evening (no temporal relation to dinner required).

Other: Diet and exercise
Patients treated their diabetes mellitus type 2 with diet/exercise only

Placebo Comparator: Placebo - stratum metformin

Placebo was administered orally twice daily: 15 minutes prior to breakfast or the test meal on the last day of treatment period) and one dose in the evening (no temporal relation to dinner required).

Mixed meal test were performed in the morning after an overnight fast.

Other: Mixed meal test
Mixed meal test 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.

Drug: Placebo
Placebo was administered orally twice daily: 15 minutes prior to breakfast or the test meal on the last day of treatment period) and one dose in the evening (no temporal relation to dinner required).

Drug: Metformin
For patients continuing with pre-existing metformin treatment, 1000 mg film coated tablets from commercial sources. In half of the patients (stratum: metformin as background medication), metformin was administered orally twice daily at 1000 mg of active compound during of after breakfast and dinner.




Primary Outcome Measures :
  1. GLP-1 feedback inhibition [ Time Frame: 0-240 min following meal ingestion ]
    Comparison of the percentage reduction or its reciprocal value (times 100) in total GLP-1 (secretion, incremental values above baseline, 0-240 min following meal ingestion) between vildagliptin and sitagliptin treatment relative to placebo treatment.


Secondary Outcome Measures :
  1. Relationship of the GLP-1 feedback inhibition [%] [ Time Frame: 0-240 min following meal ingestion ]
    Relationship of the GLP-1 feedback inhibition [%] by DPP-4 inhibition to meal-related plasma responses of "total" and "intact" incretin hormone concentrations

  2. Differences in glucagon secretion [pmol/l] [ Time Frame: 0-240 min following meal ingestion ]
    Differences in glucagon secretion [pmol/l] between vildagliptin and sitagliptin treatment relative to placebo treatment during mixed meal tests

  3. Differences in insulin secretory responses - Insulin [pmol/l] [ Time Frame: 0-240 min following meal ingestion ]
    Differences in insulin secretory responses due to insulin concentration between vildagliptin and sitagliptin treatment relative to placebo [pmol/l] treatment during mixed meal tests

  4. Differences in insulin secretory responses - c-peptide [pmol/l] [ Time Frame: 0-240 min following meal ingestion ]
    Differences in insulin secretory responses due to c-peptide [pmol/l] concentration between vildagliptin and sitagliptin treatment relative to placebo treatment during mixed meal tests

  5. Differences in glucose concentrations [mmol/l] [ Time Frame: 0-240 min following meal ingestion ]
    Differences in glucose concentrations [mmol/l] between vildagliptin and sitagliptin treatment relative to placebo treatment during mixed meal tests

  6. Incidence of Treatment-Emergent Adverse Events - Safety and tolerability [ Time Frame: From date of screening until the end of study date, assessed for up to 4.7 months ]
    Safety and tolerability of treatments were assessed for A) period between screening visit and first treatment period (3 to 28 days),B) Three treatment periods 7 to 9 days each (21 - 28 days),C) 2 wash-out periods between 21 - 40 days (42 - 80 days), and D) Period between last treatment visit and end of study visit (1 day). In total that are 67 - 136 days (2.2 - 4.7 month). Patients were ask for any adverse events. Incidence of Treatment-Emergent Adverse Events were analysed.



Information from the National Library of Medicine

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Ages Eligible for Study:   30 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

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): NCT02749032


Locations
Germany
Diabeteszentrum Bad Lauterberg
Bad Lauterberg, Niedersachsen, Germany, 37431
Sponsors and Collaborators
Michael A. Nauck
Investigators
Principal Investigator: Michael A. Nauck, Prof. Diabeteszentrum Bad Lauterberg

Responsible Party: Michael A. Nauck, Prof. Dr. med. Michael A. Nauck, Diabeteszentrum Bad Lauterberg im Harz
ClinicalTrials.gov Identifier: NCT02749032     History of Changes
Other Study ID Numbers: DZBL-2010-1
First Posted: April 22, 2016    Key Record Dates
Last Update Posted: April 22, 2016
Last Verified: April 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Additional relevant MeSH terms:
Vildagliptin
Metformin
Sitagliptin Phosphate
Glucagon-Like Peptide 1
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