SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies

This study is currently recruiting participants.
Verified May 2013 by VU University Medical Center
Sponsor:
Collaborator:
EU FP7: SAFEGUARD consortium
Information provided by (Responsible Party):
M. Diamant, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01744236
First received: December 4, 2012
Last updated: May 29, 2013
Last verified: May 2013
  Purpose

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.


Condition Intervention Phase
Type 2 Diabetes
Drug: Liraglutide
Drug: Sitagliptin
Drug: Exenatide
Drug: Liraglutide placebo
Drug: Sitagliptin placebo
Drug: Exenatide placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: A Phase IV, Randomized, Double-blind, Placebo-controlled, Parallel-group Trial to Assess the Effect of 12-week Treatment With the Glucagon-like Peptide-1 Receptor Agonist (GLP-1RA) Liraglutide or Dipeptidyl Peptidase-4 Inhibitor (DPP-4i) Sitagliptin on the Cardiovascular, Renal and Gastrointestinal System in Insulin-naïve Patients With Type 2 Diabetes (T2DM).

Resource links provided by NLM:


Further study details as provided by VU University Medical Center:

Primary Outcome Measures:
  • 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. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
  • 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. [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • 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: [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    • Blood pressure and heart rate
    • Hemodynamic variables (blood pressure, heart rate, stroke volume, cardiac output/-index/-contractility, systemic vascular resistance) derived from non-invasive beat-to-beat finger blood pressure measurements
    • Cardiac autonomic nervous system function
    • Microvascular function and vasomotion
    • Arterial stiffness
    • Lipid spectrum
    • Glycemic variables (HbA1c, fasting and postprandial glucose)
    • Body anthropometrics: body weight, height, BMI and waist circumference
    • Body fat content

  • 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: [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    • Effective renal plasma flow (ERPF)
    • Renal tubular function
    • Renal damage, measured by urine biomarkers

  • Changes from baseline following 12-week treatment with GLP-1RA or DPP-4i (long-term effects) on the following gastrointestinal parameters: [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    • Pancreatic exocrine function
    • Pancreatic structure
    • Pancreatic enzymes
    • Gallbladder emptying speed
    • Liver enzymes
    • Hepatic structure/steatosis
    • Gastric emptying


Estimated Enrollment: 68
Study Start Date: April 2013
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Liraglutide (long-term study)
This arm (n=20) will receive liraglutide 1.8mg and sitagliptin-placebo during 12 weeks
Drug: 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.
Drug: Sitagliptin placebo
Sitagliptin-placebo be given once daily for 12 weeks.
Experimental: Sitagliptin (long-term study)
This arm (n=20) will receive sitagliptin 100mg and liraglutide-placebo during 12 weeks
Drug: Sitagliptin
Sitagliptin 100mg will be given once daily for 12 weeks.
Drug: 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 Comparator: Placebo (long-term study)
This arm (n=20) will receive liraglutide-placebo and sitagliptin-placebo during 12 weeks
Drug: 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.
Drug: Sitagliptin placebo
Sitagliptin-placebo be given once daily for 12 weeks.
Experimental: Exenatide (acute study)
Prior to the 12-week intervention study, a GLP-1 receptor agonist (exenatide) will be administered intravenously (n=30).
Drug: 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 Comparator: Placebo (acute study)
Prior to the 12-week intervention study, placebo will be administered intravenously (n=30).
Drug: Exenatide placebo
Exenatide-placebo (saline) will be administered intravenously

Detailed Description:

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 patients with T2DM.

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
  • long-term study = 12 weeks of treatment with liraglutide, sitagliptin or placebo
  Eligibility

Ages Eligible for Study:   35 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age between 35 and 70 years.
  • 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:

  • 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
  • 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

The exclusion criteria for the preceding pilot study are similar to the exclusion criteria of the main study, with the additions of:

  • 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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01744236

Contacts
Contact: Mark M Smits, MD +31(0)20-4440541 mm.smits1@vumc.nl

Locations
Netherlands
VU University Medical Center Recruiting
Amsterdam, Netherlands, 1016NZ
Contact: Mark M Smits, MD    +31(0)20-4440541    mm.smits1@vumc.nl   
Principal Investigator: M Diamant, MD PhD FRCPE         
Sub-Investigator: Mark M Smits, MD         
Sponsors and Collaborators
VU University Medical Center
EU FP7: SAFEGUARD consortium
Investigators
Principal Investigator: M. Diamant, MD PhD FRCPE VU University Medical Center
  More Information

Additional Information:
No publications provided

Responsible Party: M. Diamant, Professor, VU University Medical Center
ClinicalTrials.gov Identifier: NCT01744236     History of Changes
Other Study ID Numbers: DC2012SAFE001, U1111-1130-8248, 2012-003256-36
Study First Received: December 4, 2012
Last Updated: May 29, 2013
Health Authority: The Netherlands: CCMO (Central Committee on Research inv. Human Subjects)

Keywords provided by VU University Medical Center:
GLP-1 Receptor Agonists, DPP-4 inhibitors

Additional relevant MeSH terms:
Diabetes Mellitus
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Glucagon-Like Peptide 1
Exenatide
Sitagliptin
Dipeptidyl-Peptidase IV Inhibitors
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Hypoglycemic Agents
Protease Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 17, 2014