SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies

Amsterdam UMC, location VUmc

Status and phase: Completed; Phase 4

Conditions: Type 2 Diabetes

Treatments: Drug: Exenatide; Drug: Sitagliptin placebo; Drug: Liraglutide; Drug: Liraglutide placebo; Drug: L-NMMA; Drug: Sitagliptin; Drug: Exenatide placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT01744236

U1111-1130-8248 (Other Identifier)

2012-003256-36 (EudraCT Number)

DC2012SAFE001

Details and patient eligibility

About

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.

Full 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.

Enrollment: 70 patients

Sex: All

Ages: 35 to 75 years old

Volunteers: Accepts Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

---

70 participants in 7 patient groups, including a placebo group

Liraglutide (main study, long-term intervention)

Experimental group

Description:

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

Treatment:

Drug: Liraglutide

Drug: Sitagliptin placebo

Sitagliptin (main study, long-term intervention)

Experimental group

Description:

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

Treatment:

Drug: Liraglutide placebo

Drug: Sitagliptin

Placebo (main study, long-term intervention)

Placebo Comparator group

Description:

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

Treatment:

Drug: Sitagliptin placebo

Drug: Liraglutide placebo

Exenatide (main study, acute intervention)

Experimental group

Description:

Prior to the 12-week intervention study, a GLP-1 receptor agonist (exenatide) will be administered intravenously (n=30).

Treatment:

Drug: Exenatide

Placebo (main study, acute intervention)

Placebo Comparator group

Description:

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

Treatment:

Drug: Exenatide placebo

Acute MRI intervention study

Other group

Description:

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.

Treatment:

Drug: Exenatide placebo

Drug: Exenatide

Pilot-study

Other group

Description:

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

Treatment:

Drug: Exenatide placebo

Drug: Exenatide

Drug: L-NMMA