SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies

NCT01744236 | Completed Phase 4

• 3 other identifiers: DC2012SAFE001U1111-1130-82482012-003256-36
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Type 2 Diabetes

Keywords

GLP-1 Receptor Agonists, DPP-4 inhibitors

Outcome Measures

Primary Outcomes (3)

• 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

Secondary Outcomes (3)

• 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:

  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

Study Arms (7)

Liraglutide (main study, long-term intervention)

EXPERIMENTAL

This arm (n=20) will receive liraglutide 1.8mg and sitagliptin-placebo during 12 weeks

Drug: Liraglutide; Drug: Sitagliptin placebo

Sitagliptin (main study, long-term intervention)

EXPERIMENTAL

This arm (n=20) will receive sitagliptin 100mg and liraglutide-placebo during 12 weeks

Drug: Sitagliptin; Drug: Liraglutide placebo

Placebo (main study, long-term intervention)

PLACEBO COMPARATOR

This arm (n=20) will receive liraglutide-placebo and sitagliptin-placebo during 12 weeks

Drug: Liraglutide placebo; Drug: Sitagliptin placebo

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).

Drug: Exenatide

Placebo (main study, acute intervention)

PLACEBO COMPARATOR

Prior to the 12-week intervention study, placebo will be administered intravenously (n=30).

Drug: Exenatide placebo

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.

Drug: Exenatide; Drug: Exenatide placebo

Pilot-study

OTHER

In 10 healthy obese subjects, a crossover trial with acute infusion of exenatide, placebo and L-NMMA is performed.

Drug: Exenatide; Drug: Exenatide placebo; Drug: L-NMMA

Interventions

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.

Liraglutide (main study, long-term intervention)

Sitagliptin DRUG

Sitagliptin 100mg will be given once daily for 12 weeks.

Sitagliptin (main study, long-term intervention)

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

Acute MRI intervention study; Exenatide (main study, acute intervention); Pilot-study

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.

Placebo (main study, long-term intervention); Sitagliptin (main study, long-term intervention)

Sitagliptin placebo DRUG

Sitagliptin-placebo be given once daily for 12 weeks.

Liraglutide (main study, long-term intervention); Placebo (main study, long-term intervention)

Exenatide placebo DRUG

Exenatide-placebo (saline) will be administered intravenously

Acute MRI intervention study; Pilot-study; Placebo (main study, acute intervention)

L-NMMA DRUG

Pilot-study

Eligibility Criteria

• Age: 35 Years - 75 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 35 and 75 years.
• Females must be post-menopausal (no menses \>1 year).
• BMI 25 - 40 kg/m2
• Caucasian
• Signed informed consent

You may not qualify if:

• GFR \< 60 mL/min/1.73m2
• 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

Sponsors & Collaborators

• Amsterdam UMC, location VUmc: lead
• EU FP7: SAFEGUARD consortium: collaborator

Study Sites (1)

VU University Medical Center

Amsterdam, 1081HV, Netherlands

Location

Related Publications (6)

• 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.

  PMID: 33429063 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.

  PMID: 27627981 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.

  PMID: 27585605 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.

  PMID: 27451030 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.

  PMID: 27038451 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.

  PMID: 26586327 DERIVED

Related Links

• The website of the European project SAFEGUARD

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

Liraglutide; Sitagliptin Phosphate; Exenatide; omega-N-Methylarginine

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines; Peptides; Amino Acids, Peptides, and Proteins; Venoms; Complex Mixtures; Toxins, Biological; Biological Factors; Arginine; Amino Acids, Basic; Amino Acids; Amino Acids, Diamino; Amino Acids, Essential

Study Officials

• M.H.H. Kramer, MD PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: December 4, 2012
• First Posted: December 6, 2012
• Study Start: April 1, 2013
• Primary Completion: August 1, 2015
• Study Completion: August 1, 2015
• Last Updated: December 9, 2015

Record last verified: 2015-12

Locations

NL (1)