SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies
NCT ID: NCT01744236
Last Updated: 2015-12-09
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE4
70 participants
INTERVENTIONAL
2013-04-30
2015-08-31
Brief Summary
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Detailed Description
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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:
* acute study = acute infusion with exenatide or placebo (to assess the cardiovascular and renal effects)
* long-term study = 12 weeks of treatment with liraglutide, sitagliptin or placebo (to assess the cardiovascular, renal and gastrointestinal effects)
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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
DOUBLE
Study Groups
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Liraglutide (main study, long-term intervention)
This arm (n=20) will receive liraglutide 1.8mg and sitagliptin-placebo during 12 weeks
Liraglutide
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.
Sitagliptin placebo
Sitagliptin-placebo be given once daily for 12 weeks.
Sitagliptin (main study, long-term intervention)
This arm (n=20) will receive sitagliptin 100mg and liraglutide-placebo during 12 weeks
Sitagliptin
Sitagliptin 100mg will be given once daily for 12 weeks.
Liraglutide placebo
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.
Placebo (main study, long-term intervention)
This arm (n=20) will receive liraglutide-placebo and sitagliptin-placebo during 12 weeks
Liraglutide placebo
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
Sitagliptin-placebo be given once daily for 12 weeks.
Exenatide (main study, acute intervention)
Prior to the 12-week intervention study, a GLP-1 receptor agonist (exenatide) will be administered intravenously (n=30).
Exenatide
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
Placebo (main study, acute intervention)
Prior to the 12-week intervention study, placebo will be administered intravenously (n=30).
Exenatide placebo
Exenatide-placebo (saline) will be administered intravenously
Acute MRI intervention study
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.
Exenatide
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
Exenatide placebo
Exenatide-placebo (saline) will be administered intravenously
Pilot-study
In 10 healthy obese subjects, a crossover trial with acute infusion of exenatide, placebo and L-NMMA is performed.
Exenatide
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
Exenatide placebo
Exenatide-placebo (saline) will be administered intravenously
L-NMMA
Interventions
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Liraglutide
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.
Sitagliptin
Sitagliptin 100mg will be given once daily for 12 weeks.
Exenatide
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
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
Sitagliptin-placebo be given once daily for 12 weeks.
Exenatide placebo
Exenatide-placebo (saline) will be administered intravenously
L-NMMA
Eligibility Criteria
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Inclusion Criteria
* Females must be post-menopausal (no menses \>1 year).
* Type 2 diabetes (HbA1c 6.5-9% DCCT or 48-75 mmol/mol IFCC), who are being treated with a stable dose of oral antihyperglycemic agents (either metformin alone, SU alone or a combination of metformin and SU) for at least 3 months prior to inclusion.
* BMI 25 - 40 kg/m2
* Caucasian
* Signed informed consent
Exclusion Criteria
* Current / chronic use of the following medication: thiazolidinediones, GLP-1RA, DPP-4i, glucocorticoids, NSAIDs, insulin, antimicrobial agents, chemotherapeutics or immune suppressants. Subjects on diuretics will only be excluded when these drugs (e.g. hydrochlorothiazide) cannot be stopped for the duration of the study.
* History of or actual pancreatic disease or impaired pancreatic exocrine function
* Active liver disease
* History of or actual malignancy (with the exception of basal cell carcinoma)
* Current urinary tract infection and active nephritis
* Recent (\<6 months) history of cardiovascular disease, including acute coronary syndrome, stroke, transient ischemic neurologic disorder or chronic heart failure (New York Heart Association grade II-IV)
* Current atrial fibrillation
* Chronic infectious or auto-immune disease
* Substance and/or alcohol abuse
* History of allergy/hypersensitivity to any of the test agents
* Complaints compatible with or established gastroparesis and/or neurogenic bladder
* Any condition that has been recognized as a contra-indication for the use of GLP-1RA and DPP-4i, as listed in the respective SPCs
* History of or actual (severe) mental illness
* Inability to understand the study protocol and/or inability to give informed consent
* History of claustrophobia or presence of metal objects/implants (because of MRI protocol)
For the preceding Pilot study, we will include:
* Males
* Age between 18 and 50 years
* BMI 25 - 40 kg/m2
* Caucasian
* Subjects with a fasting plasma glucose ≥5.6 mmol/L, a 2-hour glucose of ≥7.8 mmol/L after a 75-grams oral glucose tolerance test, or a HbA1c of ≥6.5%
* Subjects using any kind of medication
35 Years
75 Years
ALL
Yes
Sponsors
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EU FP7: SAFEGUARD consortium
UNKNOWN
Amsterdam UMC, location VUmc
OTHER
Responsible Party
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M.H.H. Kramer
Professor
Principal Investigators
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M.H.H. Kramer, MD PhD
Role: PRINCIPAL_INVESTIGATOR
Amsterdam UMC, location VUmc
Locations
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VU University Medical Center
Amsterdam, , Netherlands
Countries
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References
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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.
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.
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.
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.
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.
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.
Related Links
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The website of the European project SAFEGUARD
Other Identifiers
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U1111-1130-8248
Identifier Type: OTHER
Identifier Source: secondary_id
2012-003256-36
Identifier Type: EUDRACT_NUMBER
Identifier Source: secondary_id
DC2012SAFE001
Identifier Type: -
Identifier Source: org_study_id