Impact of Liraglutide on Endothelial Function and Microvascular Blood Flow in Type 2 Diabetes Mellitus | RxWiki

Impact of Liraglutide on Endothelial Function and Microvascular Blood Flow in Type 2 Diabetes Mellitus

Overview[ - collapse ][ - ]

Purpose	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.)
Condition	Diabetes Mellitus, Type 2
Intervention	Drug: Victoza®
Phase	Phase 4
Sponsor	ikfe-CRO GmbH
Responsible Party	ikfe-CRO GmbH
ClinicalTrials.gov Identifier	NCT01208012
First Received	September 17, 2010
Last Updated	March 14, 2011
Last verified	March 2011

Tracking Information[ + expand ][ + ]

First Received Date	September 17, 2010
Last Updated Date	March 14, 2011
Start Date	April 2010
Estimated Primary Completion Date	November 2010
Current Primary Outcome Measures	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] [Designated as safety issue: No]Retinal capillary blood flow will be assessed using scanner laser doppler flowmetry.
Current Secondary Outcome Measures	Central vascular elasticity [Time Frame: timepoint 0 and after 6 and 12 weeks] [Designated as safety issue: No]Central arterial elasticity will be measured by Pulse wave velocity. Skin endothelial function and Skin oxygenation [Time Frame: timepoint 0 and after 6 and 12 weeks] [Designated as safety issue: No]Microvascular skin blood flow and postcapillary tissue oxygenation (sO2)will be measured. Blood glucose control [Time Frame: timepoint 0 and after 6 and 12 weeks] [Designated as safety issue: No]Fasting plasma glucose will be measured. Blood glucose control [Time Frame: up to 2 weeks before baseline and after 6 and 12 weeks after baseline] [Designated as safety issue: No]HbA1c will be maesured. Change of biomarkers of sub-clinical inflammation and cardiovascular risk [Time Frame: timepoint 0 and after 6 and 12 weeks] [Designated as safety issue: No]Biomarkers PAI-1, hsCRP, VCAM, E-selectin and ADMA will be measured. Change of biomarker of heart failure [Time Frame: timepoint 0 and after 6 and 12 weeks] [Designated as safety issue: No]NT-pro BNP will be measured. Insulin/ intact Proinsulin ratio, C-peptide [Time Frame: timepoint 0 and after 6 and 12 weeks] [Designated as safety issue: No]Insulin Intact Proinsulin and C-peptide will be maesured. Change of body weight [Time Frame: up to 2 weeks before baseline and after 6 and 12 weeks after baseline] [Designated as safety issue: No]Body weight will be measured. Safety evaluation [Time Frame: up to 2 weeks before baseline and after 12 weeks post baseline] [Designated as safety issue: Yes]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

Descriptive Information[ + expand ][ + ]

Brief Title	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
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.
Study Type	Interventional
Study Phase	Phase 4
Study Design	Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Condition	Diabetes Mellitus, Type 2
Intervention	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. 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 Other Names: Victoza®, Liraglutide
Study Arm (s)	No Intervention: Metformin Patients taking Metformin at individual dose Experimental: Metformin and 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.

Recruitment Information[ + expand ][ + ]

Recruitment Status	Completed
Estimated Enrollment	44
Estimated Completion Date	November 2010
Estimated Primary Completion Date	November 2010
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
Gender	Both
Ages	30 Years
Accepts Healthy Volunteers	No
Contacts	Not Provided
Location Countries	Germany

Administrative Information[ + expand ][ + ]

NCT Number	NCT01208012
Other Study ID Numbers	Lira-Vasc-001
Has Data Monitoring Committee	No
Information Provided By	ikfe-CRO GmbH
Study Sponsor	ikfe-CRO GmbH
Collaborators	Novo Nordisk A/S IKFE Institute for Clinical Research and Development
Investigators	Principal Investigator: Thomas Forst, Prof. Dr. Ikfe GmbH
Verification Date	March 2011

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