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SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies

Primary Purpose

Type 2 Diabetes

Status

Completed

Phase

Phase 4

Locations

Netherlands

Study Type

Interventional

Intervention

Liraglutide

Sitagliptin

Exenatide

Liraglutide placebo

Sitagliptin placebo

Exenatide placebo

L-NMMA

About this trial

This is an interventional treatment trial for Type 2 Diabetes focused on measuring GLP-1 Receptor Agonists, DPP-4 inhibitors

Eligibility Criteria

35 Years - 75 Years (Adult, Older Adult)All SexesAccepts 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

Sites / Locations

VU University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm Type

Experimental

Placebo Comparator

Experimental

Placebo Comparator

Other

Arm Label

Liraglutide (main study, long-term intervention)

Sitagliptin (main study, long-term intervention)

Placebo (main study, long-term intervention)

Exenatide (main study, acute intervention)

Placebo (main study, acute intervention)

Acute MRI intervention study

Pilot-study

Arm Description

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

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

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

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

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

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.

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

Outcomes

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.

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.

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.

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:

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

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:

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

Full Information

NCT ID

NCT01744236

First Posted

December 4, 2012

Last Updated

December 8, 2015

Sponsor

Amsterdam UMC, location VUmc

Collaborators

EU FP7: SAFEGUARD consortium

1. Study Identification

Unique Protocol Identification Number

NCT01744236

Brief Title

SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies

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).

Study Type

Interventional

2. Study Status

Record Verification Date

December 2015

Overall Recruitment Status

Completed

Study Start Date

April 2013 (undefined)

Primary Completion Date

August 2015 (Actual)

Study Completion Date

August 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Amsterdam UMC, location VUmc

Collaborators

EU FP7: SAFEGUARD consortium

4. Oversight

Data Monitoring Committee

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Type 2 Diabetes

Keywords

GLP-1 Receptor Agonists, DPP-4 inhibitors

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 4

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Allocation

Randomized

Enrollment

70 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Liraglutide (main study, long-term intervention)

Arm Type

Experimental

Arm Description

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

Arm Title

Sitagliptin (main study, long-term intervention)

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo (main study, long-term intervention)

Arm Type

Placebo Comparator

Arm Description

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

Arm Title

Exenatide (main study, acute intervention)

Arm Type

Experimental

Arm Description

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

Arm Title

Placebo (main study, acute intervention)

Arm Type

Placebo Comparator

Arm Description

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

Arm Title

Acute MRI intervention study

Arm Type

Other

Arm 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.

Arm Title

Pilot-study

Arm Type

Other

Arm Description

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

Intervention Type

Drug

Intervention Name(s)

Liraglutide

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Sitagliptin

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Exenatide

Intervention Description

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

Intervention Type

Drug

Intervention Name(s)

Liraglutide placebo

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Sitagliptin placebo

Intervention Description

Sitagliptin-placebo be given once daily for 12 weeks.

Intervention Type

Drug

Intervention Name(s)

Exenatide placebo

Intervention Description

Exenatide-placebo (saline) will be administered intravenously

Intervention Type

Drug

Intervention Name(s)

L-NMMA

Primary Outcome Measure Information:

Title

Time Frame

12 weeks

Title

Time Frame

12 weeks

Title

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

Secondary Outcome Measure Information:

Title

Description

Time Frame

12 weeks

Title

Description

Effective renal plasma flow (ERPF) Renal tubular function Renal damage, measured by urine biomarkers

Time Frame

12 weeks

Title

Description

Time Frame

12 weeks

10. Eligibility

Sex

All

Minimum Age & Unit of Time

35 Years

Maximum Age & Unit of Time

75 Years

Accepts Healthy Volunteers

Eligibility 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

M.H.H. Kramer, MD PhD

Organizational Affiliation

Amsterdam UMC, location VUmc

Official's Role

Principal Investigator

Facility Information:

Facility Name

VU University Medical Center

City

Amsterdam

ZIP/Postal Code

1081HV

Country

Netherlands

12. IPD Sharing Statement

Citations:

PubMed Identifier

33429063

Citation

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.

Results Reference

derived

PubMed Identifier

27627981

Citation

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.

Results Reference

derived

PubMed Identifier

27585605

Citation

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. Erratum In: Diabetes Care. 2019 Mar;42(3):494.

Results Reference

derived

PubMed Identifier

27451030

Citation

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.

Results Reference

derived

PubMed Identifier

27038451

Citation

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.

Results Reference

derived

PubMed Identifier

26586327

Citation

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.

Results Reference

derived

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SAFEGUARD: Pleiotropic Effects of Incretin Based Therapies

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