Clinical trial NCT01208012: Impact of Liraglutide on Endothelial Function and Microvascular Blood Flow in Type 2 Diabetes Mellitus
Official title: Impact of Liraglutide on Endothelial Function and Microvascular Blood Flow in Type 2 Diabetes Mellitus
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes Mellitus treatment Metformin
Lead sponsor: ikfe-CRO GmbH
Sponsor class: INDUSTRY
Collaborators: name: Novo Nordisk A/S
name: IKFE Institute for Clinical Research and Development
First posted: 2010-09-23
Enrollment: 44
Sex: ALL
Minimum age (years): 30
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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%. 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.

Eligibility criteria: Inclusion Criteria:

1. Diabetes Mellitus type 2
2. HbA1c ≥ 5.5% and ≤ 7.0%
3. Treatment with Metformin (daily dose 500 - 3000 mg monotherapy, the past 3 months)
4. Age 30 - 65 years

Exclusion Criteria:

1. Pre-treatment with PPAR gamma agonists or DPP IV inhibitors or GLP-1 analogues within the last three months
2. History of type 1 Diabetes Mellitus
3. No full legal mental and physical ability to give informed consent
4. Uncontrolled hypertension (systolic blood pressure \> 160 mmHg and/or diastolic blood pressure \> 90 mmHg)
5. Anamnestic acute and chronic infections
6. Inflammatory bowel disease and/or diabetic gastroparesis
7. Anamnestic history of epilepsy
8. Anamnestic history of hypersensitivity to the study drugs or to drugs with similar chemical structures
9. History of severe or multiple allergies
10. Treatment with any other investigational drug within 3 months before trial entry
11. Progressive fatal disease
12. History of drug or alcohol abuse in the past 2 years
13. Liver disease with ASAT or ALAT above 3 times the upper normal limit
14. Serum potassium \> 5.5 mmol/L
15. Moderate to Severe Kidney disease with a GFR ≤ 60 ml/min
16. Pregnancy or breast feeding
17. 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
18. 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
19. History of dehydration, diabetic precoma, diabetic ketoacidosis or diabetic gastroparesis
20. Acute (within the previous 2 days) or scheduled investigation with iodine containing radiopaque material
21. Acute myocardial infarction, open heart surgery or cerebral event (stroke/TIA) within the previous 6 months
22. Anamnestic uncontrolled unstable angina pectoris, pericarditis, myocarditis, endocarditis, haemodynamic relevant aortic stenosis, aortic aneurysma or heart insufficiency NYHA III or IV
23. Anamnestic recent pulmonary embolism or pulmonary insufficiency
24. Smoking within the last 6 months (\> 1 cigarette/day)
25. Planned change in antidiabetic, lipid lowering or blood pressure medication

Primary outcomes:
measure: The difference in increase of retinal blood flow after flicker stimulation of retinal endothelial cells
timeFrame: timepoint 0 and after 6 and 12 weeks
Secondary outcomes:
measure: Central vascular elasticity
timeFrame: timepoint 0 and after 6 and 12 weeks
measure: Skin endothelial function and Skin oxygenation
timeFrame: timepoint 0 and after 6 and 12 weeks
measure: Blood glucose control
timeFrame: timepoint 0 and after 6 and 12 weeks
measure: Blood glucose control
timeFrame: up to 2 weeks before baseline and after 6 and 12 weeks after baseline
measure: Change of biomarkers of sub-clinical inflammation and cardiovascular risk
timeFrame: timepoint 0 and after 6 and 12 weeks
measure: Change of biomarker of heart failure
timeFrame: timepoint 0 and after 6 and 12 weeks
measure: Insulin/ intact Proinsulin ratio, C-peptide
timeFrame: timepoint 0 and after 6 and 12 weeks
measure: Change of body weight
timeFrame: up to 2 weeks before baseline and after 6 and 12 weeks after baseline
measure: Safety evaluation
timeFrame: up to 2 weeks before baseline and after 12 weeks post baseline
Other outcomes:
Locations:
city: Mainz
country: Germany
facility: IKFE Institute for Clinical Research and Development
Study officials:
affiliation: Ikfe GmbH
name: Thomas Forst, Prof. Dr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.