Diabetes Mellitus, Type 2Phase 4NCT01208012
Impact of Liraglutide on Endothelial Function and Microvascular Blood Flow in Type 2 Diabetes Mellitus
A Phase 4 study testing Victoza® in people with Diabetes Mellitus, Type 2, run by ikfe-CRO GmbH at 1 site in Germany.
Trial summary
The trial is a phase IV clinical trial investigating the impact of Liraglutide on endothelial function and microvascular blood flow in 44 patients with type 2 diabetes mellitus aged 30-65 and HbA1c ranging from ≥ 5.5% ≤ 7.0%. Read more about this study
- Who is it for?
- Ages 30 to 65 years
- Conditions the study is for
- Diabetes Mellitus, Type 2
- What is being tested?
- Victoza®
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 44 participants
- Where
- 1 siteGermany
- Study dates
- Apr 2010to Nov 2010
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 30 to 65 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diabetes Mellitus type 2
- HbA1c ≥ 5.5% and ≤ 7.0%
- Treatment with Metformin (daily dose 500 - 3000 mg monotherapy, the past 3 months)
- Age 30 - 65 years
Who cannot join
- Pre-treatment with PPAR gamma agonists or DPP IV inhibitors or GLP-1 analogues within the last three months
- History of type 1 Diabetes Mellitus
- No full legal mental and physical ability to give informed consent
- Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 90 mmHg)
- Anamnestic acute and chronic infections
- Inflammatory bowel disease and/or diabetic gastroparesis
Show all 25Show fewer
- Anamnestic history of epilepsy
- Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures
- History of severe or multiple allergies
- Treatment with any other investigational drug within 3 months before trial entry
- Progressive fatal disease
- History of drug or alcohol abuse in the past 2 years
- Liver disease with ASAT or ALAT above 3 times the upper normal limit
- Serum potassium > 5.5 mmol/L
- Moderate to Severe Kidney disease with a GFR ≤ 60 ml/min
- Pregnancy or breast feeding
- Sexually active woman of childbearing potential not practicing a highly effective method of birth control as defined as those which result in a low failure rate (i.e. less than 1% per year) when used consistently and correctly such as implants, injectables, combined oral contraceptives, hormonal IUDs, sexual abstinence or vasectomised partner
- Have had more than one unexplained episode of severe hypoglycaemia (defined as requiring assistance of another person due to disabling hypoglycaemia) within 6 months prior to screening visit
- History of dehydration, diabetic precoma, diabetic ketoacidosis or diabetic gastroparesis
- Acute (within the previous 2 days) or scheduled investigation with iodine containing radiopaque material
- Acute myocardial infarction, open heart surgery or cerebral event (stroke/TIA) within the previous 6 months
- Anamnestic uncontrolled unstable angina pectoris, pericarditis, myocarditis, endocarditis, haemodynamic relevant aortic stenosis, aortic aneurysma or heart insufficiency NYHA III or IV
- Anamnestic recent pulmonary embolism or pulmonary insufficiency
- Smoking within the last 6 months (> 1 cigarette/day)
- Planned change in antidiabetic, lipid lowering or blood pressure medication
Trial locations and contacts
1 site in 1 country.
Germany1 site
IKFE Institute for Clinical Research and Development
Mainz, 55116
About this study
The trial is a phase IV clinical trial investigating the impact of Liraglutide on endothelial function and microvascular blood flow in 44 patients with type 2 diabetes mellitus aged 30-65 and HbA1c ranging from ≥ 5.5% ≤ 7.0%. The patients will be randomized into two study arms, one arm will be treated with Metformin monotherapy, the second arm will be treated with Metformin and Liraglutide at an increasing dose (0.6 mg/day to 1.8 mg/day.)
Read the detailed description
Type 2 Diabetes Mellitus (DM) is associated with increased cardiovascular risk and the majority of type 2 diabetic patients die due to the vascular complications of Diabetes Mellitus. In type 2 diabetic patients, an early marker in the biogenesis of atherosclerosis and cardiovascular disease is the occurrence of endothelial dysfunction with subsequent deterioration in micro- and macrovascular blood flow and tissue supply. Also several mechanistic pathways linking Diabetes Mellitus with endothelial dysfunction and cardiovascular complications are postulated. Recent studies aimed to investigate the vasoprotective effect of strict glycaemic control using conventional treatment algorithms failed to reduce cardiovascular risk in patients with Diabetes Mellitus type 2. Numerous pharmacological drugs are available to reduce blood glucose levels in type 2 diabetic patients. Beside comparable glucose lowering efficacy, some of them evolve limited or even adverse effects on vascular function and cardiovascular risk. Therefore, ideally new treatments in Diabetes Mellitus type 2 provide more than just reducing blood glucose values. Future treatments in type 2 Diabetes Mellitus will be judged on their potency to affect the cardiovascular risk profile in patients with Diabetes Mellitus type 2.
Liraglutide is a Glucagon-like peptide-1 (GLP-1) analogue shown to be effective in the treatment of type 2 Diabetes Mellitus. Liraglutide was shown to improve blood glucose levels not only by stimulating insulin secretion from the β cell, but also by improving the conversion of intact proinsulin into insulin and C-peptide in the granula of the β cell. While in rodents, GLP-1 and its analogues showed an increase in β cell regeneration and an inhibitory effect on β cell apoptosis, the effect of GLP-1 analogues on β cell mass in humans is less clear. Beyond its effects on β cells, Liraglutide and other GLP1 analogues were shown to suppress the glucagon release from α cells and to evolve a supportive effect on weight reduction by central and probably peripheral effects.
Beside these effects of GLP-1-analogues on β cell physiology and glucose metabolism, recent studies suggested several pleiotrophic effects of GLP-1 treatment which go beyond glycaemic control. Receptors for GLP-1 have been located in myocardial and endothelial cells, and GLP-1 supplementation was found to improve myocardial and endothelial function in diabetic and in non-diabetic subjects. In endothelial cells, isolated from human coronary arteries, GLP-1 rapidly activates endothelial nitric oxide synthase (eNOS) and stimulates nitric oxide (NO) production, promotes cell proliferation and inhibits glucolipoapoptosis. In addition, in transformed vascular endothelial cells, GLP-1 protects endothelial dysfunction incurred by tumor necrosis factor-α (TNF-α) through the modulation of the expression of vascular adhesion molecules and plasminogen activator inhibitor-1 (PAI-1). Chronic administration of GLP-1 analogues is associated with a significant reduction in blood pressure. Therefore it seems conceivable, that in patients with Diabetes Mellitus type 2, treatment with the GLP-1 analog Liraglutide might improve the cardiovascular risk profile beyond glucose control by stimulating endothelial NO release and by improving endothelial function.
The goal of our study is to investigate the vascular and endothelial effects of adding Liraglutide treatment to type 2 diabetic patients previously treated with Metformin.
- Conditions
- Diabetes Mellitus, Type 2
- Being tested
- Victoza®
- Keywords
- Diabetes Mellitus treatment Metformin
- Medical subject headings
- Diabetes Mellitus, Type 2
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Victoza®Drug
Also called Victoza®, Liraglutide
Patients taking Metformin at individual dose and Liraglutide 0.6 mg once daily for the 1st week, 1.2 mg daily for another 5 weeks, 1.8 mg daily for another 6 weeks. When arrived at the dosage of 1.8 mg daily and the dose is not tolerated by the patient, the dose of Liraglutide can be decreased.Liraglutide is injected in the subcutaneous tissue once daily
| Study group | Role | What they receive |
|---|---|---|
| Metformin | No intervention | Patients taking Metformin at individual dose |
| Metformin and Liraglutide | Experimental | Patients taking Metformin at individual dose and Liraglutide 0.6 mg once daily for the 1st week, 1.2 mg daily for another 5 weeks, 1.8 mg daily for another 6 weeks. Receives: Drug: Victoza® |
What is being measured
The primary outcome is the main question the study is designed to answer.
The difference in increase of retinal blood flow after flicker stimulation of retinal endothelial cells
Retinal capillary blood flow will be assessed using scanner laser doppler flowmetry.
Measured: timepoint 0 and after 6 and 12 weeks
Secondary outcomes (9)
Central vascular elasticity
Central arterial elasticity will be measured by Pulse wave velocity.
Measured: timepoint 0 and after 6 and 12 weeks
Skin endothelial function and Skin oxygenation
Microvascular skin blood flow and postcapillary tissue oxygenation (sO2)will be measured.
Measured: timepoint 0 and after 6 and 12 weeks
Blood glucose control
Fasting plasma glucose will be measured.
Measured: timepoint 0 and after 6 and 12 weeks
Blood glucose control
HbA1c will be maesured.
Measured: up to 2 weeks before baseline and after 6 and 12 weeks after baseline
Change of biomarkers of sub-clinical inflammation and cardiovascular risk
Biomarkers PAI-1, hsCRP, VCAM, E-selectin and ADMA will be measured.
Measured: timepoint 0 and after 6 and 12 weeks
Change of biomarker of heart failure
NT-pro BNP will be measured.
Measured: timepoint 0 and after 6 and 12 weeks
Insulin/ intact Proinsulin ratio, C-peptide
Insulin Intact Proinsulin and C-peptide will be maesured.
Measured: timepoint 0 and after 6 and 12 weeks
Change of body weight
Body weight will be measured.
Measured: up to 2 weeks before baseline and after 6 and 12 weeks after baseline
Safety evaluation
The safety evaluation includes:
- Metabolic parameters indicating hepatic function (ALAT, ASAT, γ-GT)
- Blood analysis (Alkaline Phosphatase, Blood cell count)
- Change in pancreas function (Amylase, Lipase)
- Change in renal function (Creatinine, Potassium)
- Change in thyroid function (Calcitonin)
- Vital signs (Blood Pressure, Radial Pulse, ECG)
- β-HCG (only female patients of childbearing potential)
- Adverse Events
- Adverse Drug Reactions
Measured: up to 2 weeks before baseline and after 12 weeks post baseline
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Sep 2010 (estimated)
- Study startApr 2010
- Primary completionNov 2010
- Study completionNov 2010
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Diabetes Mellitus, Type 2Studies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 44 participants (actual)
Sponsor and investigators
- Lead sponsor
- ikfe-CRO GmbH
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- Novo Nordisk A/S, IKFE Institute for Clinical Research and Development
- Investigators
- Thomas Forst, Prof. Dr., Principal investigator, Ikfe GmbH
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01208012
- Sponsor's protocol ID
- Lira-Vasc-001
- Status last verified
- Mar 2011
- First submitted
- 17 Sep 2010
- Last updated
- 15 Mar 2011
- Results posted
- No
- Data monitoring committee
- No
Publications
Forst T, Michelson G, Ratter F, Weber MM, Anders S, Mitry M, Wilhelm B, Pfutzner A. Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function. Diabet Med. 2012 Sep;29(9):1115-8. doi: 10.1111/j.1464-5491.2012.03589.x.
PubMed 22288732
Study at a glance
From the registry record, last updated by the sponsor on 15 Mar 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Impact of Liraglutide on Endothelial Function and Microvascular Blood Flow in Type 2 Diabetes Mellitus
- ClinicalTrials.gov ID
- NCT01208012
- Acronym / sponsor ID
- Lira-Vasc-001
- Conditions
- Diabetes Mellitus, Type 2
- Keywords
- Diabetes Mellitus treatment Metformin
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 44 participants (actual)
- Lead sponsor
- ikfe-CRO GmbHIndustry (pharma, biotech, devices)
- Collaborators
- Novo Nordisk A/S, IKFE Institute for Clinical Research and Development
- Study start
- Apr 2010
- Primary completion
- Nov 2010 (actual)
- Study completion
- Nov 2010 (actual)
- First posted
- 23 Sep 2010 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The trial is a phase IV clinical trial investigating the impact of Liraglutide on endothelial function and microvascular blood flow in 44 patients with type 2 diabetes mellitus aged 30-65 and HbA1c ranging from ≥ 5.5% ≤ 7.0%. The patients will be randomized into two study arms, one arm will be treated with Metformin monotherapy, the second arm will be treated with Metformin and Liraglutide at an increasing dose (0.6 mg/day to 1.8 mg/day.)
Detailed description
Type 2 Diabetes Mellitus (DM) is associated with increased cardiovascular risk and the majority of type 2 diabetic patients die due to the vascular complications of Diabetes Mellitus. In type 2 diabetic patients, an early marker in the biogenesis of atherosclerosis and cardiovascular disease is the occurrence of endothelial dysfunction with subsequent deterioration in micro- and macrovascular blood flow and tissue supply. Also several mechanistic pathways linking Diabetes Mellitus with endothelial dysfunction and cardiovascular complications are postulated. Recent studies aimed to investigate the vasoprotective effect of strict glycaemic control using conventional treatment algorithms failed to reduce cardiovascular risk in patients with Diabetes Mellitus type 2. Numerous pharmacological drugs are available to reduce blood glucose levels in type 2 diabetic patients. Beside comparable glucose lowering efficacy, some of them evolve limited or even adverse effects on vascular function and cardiovascular risk. Therefore, ideally new treatments in Diabetes Mellitus type 2 provide more than just reducing blood glucose values. Future treatments in type 2 Diabetes Mellitus will be judged on their potency to affect the cardiovascular risk profile in patients with Diabetes Mellitus type 2.
Liraglutide is a Glucagon-like peptide-1 (GLP-1) analogue shown to be effective in the treatment of type 2 Diabetes Mellitus. Liraglutide was shown to improve blood glucose levels not only by stimulating insulin secretion from the β cell, but also by improving the conversion of intact proinsulin into insulin and C-peptide in the granula of the β cell. While in rodents, GLP-1 and its analogues showed an increase in β cell regeneration and an inhibitory effect on β cell apoptosis, the effect of GLP-1 analogues on β cell mass in humans is less clear. Beyond its effects on β cells, Liraglutide and other GLP1 analogues were shown to suppress the glucagon release from α cells and to evolve a supportive effect on weight reduction by central and probably peripheral effects.
Beside these effects of GLP-1-analogues on β cell physiology and glucose metabolism, recent studies suggested several pleiotrophic effects of GLP-1 treatment which go beyond glycaemic control. Receptors for GLP-1 have been located in myocardial and endothelial cells, and GLP-1 supplementation was found to improve myocardial and endothelial function in diabetic and in non-diabetic subjects. In endothelial cells, isolated from human coronary arteries, GLP-1 rapidly activates endothelial nitric oxide synthase (eNOS) and stimulates nitric oxide (NO) production, promotes cell proliferation and inhibits glucolipoapoptosis. In addition, in transformed vascular endothelial cells, GLP-1 protects endothelial dysfunction incurred by tumor necrosis factor-α (TNF-α) through the modulation of the expression of vascular adhesion molecules and plasminogen activator inhibitor-1 (PAI-1). Chronic administration of GLP-1 analogues is associated with a significant reduction in blood pressure. Therefore it seems conceivable, that in patients with Diabetes Mellitus type 2, treatment with the GLP-1 analog Liraglutide might improve the cardiovascular risk profile beyond glucose control by stimulating endothelial NO release and by improving endothelial function.
The goal of our study is to investigate the vascular and endothelial effects of adding Liraglutide treatment to type 2 diabetic patients previously treated with Metformin.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Metformin | No intervention | –Patients taking Metformin at individual dose |
| Metformin and Liraglutide | Experimental | Drug: Victoza®Patients taking Metformin at individual dose and Liraglutide 0.6 mg once daily for the 1st week, 1.2 mg daily for another 5 weeks, 1.8 mg daily for another 6 weeks. |
Who may qualify
- Ages
- 30 to 65 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (4 listed)
- Diabetes Mellitus type 2
- HbA1c ≥ 5.5% and ≤ 7.0%
- Treatment with Metformin (daily dose 500 - 3000 mg monotherapy, the past 3 months)
- Age 30 - 65 years
Key exclusion criteria (25 listed)
- Pre-treatment with PPAR gamma agonists or DPP IV inhibitors or GLP-1 analogues within the last three months
- History of type 1 Diabetes Mellitus
- No full legal mental and physical ability to give informed consent
- Uncontrolled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 90 mmHg)
- Anamnestic acute and chronic infections
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Victoza®Also: Victoza®, LiraglutidePatients taking Metformin at individual dose and Liraglutide 0.6 mg once daily for the 1st week, 1.2 mg daily for another 5 weeks, 1.8 mg daily for another 6 weeks. When arrived at the dosage of 1.8 mg daily and the dose is not tolerated by the patient, the dose of Liraglutide can be decreased.Liraglutide is injected in the subcutaneous tissue once daily | Drug | Metformin and Liraglutide |
Primary outcome
The difference in increase of retinal blood flow after flicker stimulation of retinal endothelial cells
Time frame: timepoint 0 and after 6 and 12 weeks
Retinal capillary blood flow will be assessed using scanner laser doppler flowmetry.
9 secondary outcomes
Central vascular elasticity
Time frame: timepoint 0 and after 6 and 12 weeks
Skin endothelial function and Skin oxygenation
Time frame: timepoint 0 and after 6 and 12 weeks
Blood glucose control
Time frame: timepoint 0 and after 6 and 12 weeks
Blood glucose control
Time frame: up to 2 weeks before baseline and after 6 and 12 weeks after baseline
Change of biomarkers of sub-clinical inflammation and cardiovascular risk
Time frame: timepoint 0 and after 6 and 12 weeks
Change of biomarker of heart failure
Time frame: timepoint 0 and after 6 and 12 weeks
Insulin/ intact Proinsulin ratio, C-peptide
Time frame: timepoint 0 and after 6 and 12 weeks
Change of body weight
Time frame: up to 2 weeks before baseline and after 6 and 12 weeks after baseline
Safety evaluation
Time frame: up to 2 weeks before baseline and after 12 weeks post baseline
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Mar 2011.
- Derived from this study: PubMed 22288732Forst T, Michelson G, Ratter F, Weber MM, Anders S, Mitry M, Wilhelm B, Pfutzner A. Addition of liraglutide in patients with Type 2 diabetes well controlled on metformin monotherapy improves several markers of vascular function. Diabet Med. 2012 Sep;29(9):1115-8. doi: 10.1111/j.1464-5491.2012.03589.x.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Thomas Forst, Prof. Dr. principal investigator
Ikfe GmbH
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Victoza® in people with Diabetes Mellitus, Type 2, run by ikfe-CRO GmbH at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Mar 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
The difference in increase of retinal blood flow after flicker stimulation of retinal endothelial cells (time frame: timepoint 0 and after 6 and 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01208012, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Mar 2011.