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SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by VU University Medical Center
Sponsor:
Collaborator:
EU FP7: SAFEGUARD consortium
Information provided by (Responsible Party):
M.H.H. Kramer, VU University Medical Center
ClinicalTrials.gov Identifier:
NCT01744236
First received: December 4, 2012
Last updated: June 20, 2014
Last verified: June 2014
  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
Drug: L-NMMA
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 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: [ Time Frame: 12 weeks ] [ Designated as safety issue: No ]
    • Pancreatic exocrine function (* In the acute intervention only exocrine pancreatic function is assessed)
    • Pancreatic structure
    • Pancreatic enzymes
    • Gallbladder emptying speed
    • Liver enzymes
    • Hepatic structure/steatosis
    • Gastric emptying


Estimated Enrollment: 70
Study Start Date: April 2013
Estimated Primary Completion Date: August 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Liraglutide (main study, long-term intervention)
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 (main study, long-term intervention)
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 (main study, long-term intervention)
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 (main study, acute intervention)
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 (main study, acute intervention)
Prior to the 12-week intervention study, placebo will be administered intravenously (n=30).
Drug: 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.
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
Drug: 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.
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
Drug: Exenatide placebo
Exenatide-placebo (saline) will be administered intravenously
Drug: L-NMMA

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 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.

  Eligibility

Ages Eligible for Study:   35 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Age between 35 and 75 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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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, 1081HV
Contact: Mark M Smits, MD    +31(0)20-4440541    mm.smits1@vumc.nl   
Principal Investigator: M.H.H. Kramer, MD PhD         
Sub-Investigator: M.M. Smits, MD         
Sub-Investigator: D.H. van Raalte, MD PhD         
Sub-Investigator: L. Tonneijck, MD         
Sponsors and Collaborators
VU University Medical Center
EU FP7: SAFEGUARD consortium
Investigators
Principal Investigator: M.H.H. Kramer, MD PhD VU University Medical Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.H.H. Kramer, 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: June 20, 2014
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
Endocrine System Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Dipeptidyl-Peptidase IV Inhibitors
Exenatide
Glucagon-Like Peptide 1
Liraglutide
Sitagliptin
Enzyme Inhibitors
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Hypoglycemic Agents
Incretins
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Physiological Effects of Drugs
Protease Inhibitors

ClinicalTrials.gov processed this record on November 25, 2014