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| ID | Type | Description | Link |
|---|---|---|---|
| U1111-1130-8248 | Other Identifier | WHO Universal Trial Number | |
| 2012-003256-36 | EudraCT Number |
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| Name | Class |
|---|---|
| EU FP7: SAFEGUARD consortium | UNKNOWN |
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The aim of this study is to detail the (mechanisms underlying the) actions of the GLP-1 receptor agonists and DPP-4 inhibitors on the cardiovascular, renal and gastrointestinal systems in patients with Type 2 Diabetes Mellitus.
GLP-1 receptors are present in most organ systems of the human body, and pharmacological interventions enhancing GLP-1 activity may influence the function of these organs. The use of GLP-1 receptor agonists (GLP-1RA) and DPP-4 inhibitors (DPP-4i) has been associated with an increased heart rate, acute pancreatitis and acute renal failure. To date, studies in humans detailing the effects of these drugs on these organ systems, biological processes and underlying mechanisms, which could explain these associations, are lacking.
Therefore, as part of the EU-FP7 SAFEGUARD program, the present study will aim to detail the (mechanisms underlying the) actions of GLP-1RA and DPP-4i on the cardiovascular, renal and gastrointestinal system in healthy obese subjects and patients with T2DM.
In the main study, sixty patients with type 2 diabetes will undergo two interventions within the same protocol in order to assess changes in the outcome parameters:
In a substudy (termed 'acute MRI study'), twelve patients with type 2 diabetes will undergo an additional acute intervention study with exenatide (to assess the pancreatic effects)
In a substudy (termed 'pilot-study'), ten healthy obese subjects will undergo a similar acute study like the patients with type 2 diabetes (to assess the cardiovascular and renal effects). Moreover, in these healthy subjects, the effects of exenatide during L-NMMA infusion will be assessed.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Liraglutide (main study, long-term intervention) | Experimental | This arm (n=20) will receive liraglutide 1.8mg and sitagliptin-placebo during 12 weeks |
|
| Sitagliptin (main study, long-term intervention) | Experimental | This arm (n=20) will receive sitagliptin 100mg and liraglutide-placebo during 12 weeks |
|
| Placebo (main study, long-term intervention) | Placebo Comparator | This arm (n=20) will receive liraglutide-placebo and sitagliptin-placebo during 12 weeks |
|
| Exenatide (main study, acute intervention) | Experimental | Prior to the 12-week intervention study, a GLP-1 receptor agonist (exenatide) will be administered intravenously (n=30). |
|
| Placebo (main study, acute intervention) | Placebo Comparator | Prior to the 12-week intervention study, placebo will be administered intravenously (n=30). |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Liraglutide | Drug | Liraglutide will be started with a titration period of 2 weeks (week 1: 0.6mg once daily and week 2: 1.2mg once daily). If liraglutide is well tolerated it will be continued for 10 more weeks in a dosage of 1.8mg once daily. |
| Measure | Description | Time Frame |
|---|---|---|
| Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on resting heart rate variability, as derived from electrocardiographic measurements. | 12 weeks | |
| Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on Glomerular Filtration Rate, measured by the inulin-clearance technique. | 12 weeks | |
| Changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on pancreatic exocrine function, measured as fecal Elastase-1. | 12 weeks |
| Measure | Description | Time Frame |
|---|---|---|
| Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following cardiovascular parameters: |
|
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Inclusion Criteria:
Exclusion Criteria:
For the preceding Pilot study, we will include:
The exclusion criteria for the preceding pilot study are similar to the exclusion criteria of the main study, with the additions of:
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| Name | Affiliation | Role |
|---|---|---|
| M.H.H. Kramer, MD PhD | Amsterdam UMC, location VUmc | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| VU University Medical Center | Amsterdam | 1081HV | Netherlands |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33429063 | Derived | Smits MM, Fluitman KS, Herrema H, Davids M, Kramer MHH, Groen AK, Belzer C, de Vos WM, Cahen DL, Nieuwdorp M, van Raalte DH. Liraglutide and sitagliptin have no effect on intestinal microbiota composition: A 12-week randomized placebo-controlled trial in adults with type 2 diabetes. Diabetes Metab. 2021 Sep;47(5):101223. doi: 10.1016/j.diabet.2021.101223. Epub 2021 Jan 8. | |
| 27627981 |
| Label | URL |
|---|---|
| The website of the European project SAFEGUARD | View source |
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| ID | Term |
|---|---|
| D003924 | Diabetes Mellitus, Type 2 |
| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
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| ID | Term |
|---|---|
| D000069450 | Liraglutide |
| D000068900 | Sitagliptin Phosphate |
| D000077270 | Exenatide |
| D019323 | omega-N-Methylarginine |
| ID | Term |
|---|---|
| D052216 | Glucagon-Like Peptide 1 |
| D004763 | Glucagon-Like Peptides |
| D052336 | Proglucagon |
| D005768 | Gastrointestinal Hormones |
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| Acute MRI intervention study | Other | In a subset of 12 patients with type 2 diabetes, a crossover trial with acute infusion of exenatide and placebo is performed. This is done prior to the 12-week intervention study. |
|
| Pilot-study | Other | In 10 healthy obese subjects, a crossover trial with acute infusion of exenatide, placebo and L-NMMA is performed. |
|
| Sitagliptin | Drug | Sitagliptin 100mg will be given once daily for 12 weeks. |
|
| Exenatide | Drug | Exenatide will be administered intravenously with a loading dose of 50ng/min for 30 minutes, followed by a maintenance dose of 25ng/min during the rest of the tests |
|
| Liraglutide placebo | Drug | Liraglutide-placebo will be started with a titration period of 2 weeks (week 1: 0.6mg once daily and week 2: 1.2mg once daily). It will be continued for 10 more weeks in a dosage of 1.8mg once daily. |
|
| Sitagliptin placebo | Drug | Sitagliptin-placebo be given once daily for 12 weeks. |
|
| Exenatide placebo | Drug | Exenatide-placebo (saline) will be administered intravenously |
|
| L-NMMA | Drug |
|
| 12 weeks |
| Changes from baseline following infusion of GLP-1RA (acute effects) and the changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following renal parameters: |
| 12 weeks |
| Changes from baseline following infusion of GLP-1RA (acute effects*) and changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following gastrointestinal parameters: |
| 12 weeks |
| Derived |
| Smits MM, Tonneijck L, Muskiet MH, Kramer MH, Pouwels PJ, Pieters-van den Bos IC, Hoekstra T, Diamant M, van Raalte DH, Cahen DL. Twelve week liraglutide or sitagliptin does not affect hepatic fat in type 2 diabetes: a randomised placebo-controlled trial. Diabetologia. 2016 Dec;59(12):2588-2593. doi: 10.1007/s00125-016-4100-7. Epub 2016 Sep 15. |
| 27585605 | Derived | Tonneijck L, Smits MM, Muskiet MH, Hoekstra T, Kramer MH, Danser AH, Ter Wee PM, Diamant M, Joles JA, van Raalte DH. Renal Effects of DPP-4 Inhibitor Sitagliptin or GLP-1 Receptor Agonist Liraglutide in Overweight Patients With Type 2 Diabetes: A 12-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Diabetes Care. 2016 Nov;39(11):2042-2050. doi: 10.2337/dc16-1371. Epub 2016 Sep 1. |
| 27451030 | Derived | Smits MM, Tonneijck L, Muskiet MH, Hoekstra T, Kramer MH, Diamant M, Nieuwdorp M, Groen AK, Cahen DL, van Raalte DH. Biliary effects of liraglutide and sitagliptin, a 12-week randomized placebo-controlled trial in type 2 diabetes patients. Diabetes Obes Metab. 2016 Dec;18(12):1217-1225. doi: 10.1111/dom.12748. Epub 2016 Aug 30. |
| 27038451 | Derived | Tonneijck L, Smits MM, Muskiet MHA, Hoekstra T, Kramer MHH, Danser AHJ, Diamant M, Joles JA, van Raalte DH. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial. Diabetologia. 2016 Jul;59(7):1412-1421. doi: 10.1007/s00125-016-3938-z. Epub 2016 Apr 1. |
| 26586327 | Derived | Smits MM, Tonneijck L, Muskiet MH, Hoekstra T, Kramer MH, Pieters IC, Cahen DL, Diamant M, van Raalte DH. Cardiovascular, renal and gastrointestinal effects of incretin-based therapies: an acute and 12-week randomised, double-blind, placebo-controlled, mechanistic intervention trial in type 2 diabetes. BMJ Open. 2015 Nov 19;5(11):e009579. doi: 10.1136/bmjopen-2015-009579. |
| D004700 | Endocrine System Diseases |
| D006728 |
| Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |
| D014230 | Triazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D011719 | Pyrazines |
| D010455 | Peptides |
| D000602 | Amino Acids, Peptides, and Proteins |
| D014688 | Venoms |
| D045424 | Complex Mixtures |
| D014118 | Toxins, Biological |
| D001685 | Biological Factors |
| D001120 | Arginine |
| D024361 | Amino Acids, Basic |
| D000596 | Amino Acids |
| D000599 | Amino Acids, Diamino |
| D000601 | Amino Acids, Essential |