Effect of Liraglutide on Cardiovascular Endpoints in Diabetes Mellitus Type 2 Patients (MAGNA VICTORIA)

This study is not yet open for participant recruitment.

Verified February 2013 by Leiden University Medical Center

Sponsor:

Collaborator:

Novo Nordisk

Information provided by (Responsible Party):

M.B. Bizino, MD, principal investigator, Leiden University Medical Center

ClinicalTrials.gov Identifier:

NCT01761318

First received: December 20, 2012

Last updated: February 11, 2013

Last verified: February 2013

History of Changes

Purpose

The most important cause of mortality amongst DM2 patients is cardiovascular disease. An early finding of cardiovascular disease in DM2 and obesity is diastolic dysfunction. Diastolic dysfunction is an independent predictor of mortality and has been shown to improve in patients on a low calorie diet. The improvement of diastolic function was associated with a reduction in triglyceride accumulation in the heart and liver. A relatively new widely prescribed therapeutic agent for DM2 patients is Liraglutide (Victoza®). Liraglutide is a Glucagon Like Peptide - 1 homologue that improves glucose homeostasis and reduces blood pressure and body weight. Next to the induction of weight loss, which is potentially beneficial for cardiac function, GLP-1 therapy might have a direct advantageous effect on the cardiovascular system. However, the effect of Liraglutide on cardiovascular function has not been investigated yet. The investigators hypothesize that treatment of DM2 patients with Liraglutide is associated with improvement of cardiovascular function and a reduction of triglyceride accumulation in end-organs.

Condition	Intervention	Phase
Diabetes Mellitus Type 2 Metabolic Syndrome Cardiovascular Disease Diastolic Dysfunction Fatty Liver	Drug: Liraglutide	Phase 4

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Treatment
Official Title:	Magnetic Resonance Assessment of Victoza Efficacy in the Regression of Cardiovascular Dysfunction In Type 2 Diabetes Mellitus

Resource links provided by NLM:

MedlinePlus related topics: Diabetes Diabetes Type 2 Metabolic Syndrome

Drug Information available for: Glucagon Liraglutide

U.S. FDA Resources

Further study details as provided by Leiden University Medical Center:

Primary Outcome Measures:

Stroke volume [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference in ml between groups at 26 weeks
Ejection Fraction [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference in percentage between groups at 26 weeks
Cardiac output [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups in L/min at 26 weeks
Cardiac index [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups in L/min/m2 at 26 weeks
Peak ejection rate [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups in ml end-diastolic volume/sec at 26 weeks
Early peak filling rate [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups in end-diastolic volume/second at 26 weeks
Early deceleration peak [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups in ml/sec at 26 weeks
Atrial peak filling rate [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups in ml/sec at 26 weeks
Early deceleration peak / Atrial peak filling rate (E/A ratio) [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups of the ratio at 26 weeks
Peak mitral annulus longitudinal motion [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups in cm/s at 26 weeks
Left ventricular filling pressure (= early peak filling rate / peak mitral annulus longitudinal motion) [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups in mmHg at 26 weeks

Secondary Outcome Measures:

Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of total vessel wall area in mm2
Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks in average vessel wall thickness (mm)
Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of minimum vessel wall thickness (mm)
Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of maximum vessel wall thickness (mm)
Aorta and carotid vessel wall imaging [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of vascular distensibility (pulse wave velocity)
Adipose tissue distribution [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of the ratio subcutaneous fat / visceral abdominal fat
Total body fat [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of total fat volume
Epicardial fat volume [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of epicardial fat volume in cm3
Magnetic Resonance Spectroscopy of the heart [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of myocardial triglyceride content (percentage)
Magnetic Resonance Spectroscopy of the liver [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of triglyceride content in the liver (steatosis)
Magnetic Resonance Spectroscopy of the kidney [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks of renal triglyceride content (percentage)
HBA1C [ Time Frame: 0,8, 12, 16 and 26 weeks ] [ Designated as safety issue: No ]
Measurements will be used to guide therapeutic management

The outcome measure glycemic control will be based on the average HBA1C level of all measurements and regards the difference between groups of this average.
Fasting blood glucose level [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: Yes ]
Fasting blood glucose levels will be used to guide therapeutic management and for safety reasons.

Outcome measure: the difference between groups of the average of all measurements.

Other Outcome Measures:

Anthropometric measurements [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: No ]
Lenght, body weight and calculated BMI.

Outcome measure: difference between groups at 26 weeks of body weight in kg (and BMI in kg/m2)
Waist / hip ratio [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: No ]
Waist circumference divided by hip circumference.

Outcome measure: difference between groups at 26 weeks
Systolic blood pressure [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: No ]
Measurements for routine clinical management

Outcome measure: difference between groups at 26 weeks (mmHg)
Diastolic blood pressure [ Time Frame: 0, 4, 8, 12, 16, 20, 26 weeks ] [ Designated as safety issue: No ]
Measurements for routine clinical management

Outcome measure: difference between groups at 26 weeks (mmHg)
Resting Energy Expenditure [ Time Frame: 0, 4, 12, 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 4, 12 and 26 weeks.

Measurement with indirect calorimetry (Jaeger, OxyconPro)
Immunological analysis [ Time Frame: 0, 26 weeks ] [ Designated as safety issue: No ]
Fluorescence-Activated Cell Sorting (FACS).

Difference between groups at 26 weeks is an outcome measure as well as difference within group from baseline (0 vs 26 weeks)
Immunological analysis [ Time Frame: 0, 26 weeks ] [ Designated as safety issue: No ]
Peripheral Blood Mononuclear Cell isolation to analyze immunological activation and status of subjects. Both quantification of white blood cells (T-cells, B-cells, macrophages) and functional analysis will be performed.+

Difference between groups at 0 and 26 weeks is an outcome measure as well as difference within group from baseline (0 vs 26 weeks)
Fasting insulin level [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks
Leptin [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks
Glucagon [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks
Adiponectin [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 26 weeks
CETP [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]
Cholesteryl ester transfer protein

Difference between groups at 4, 12 and 26 weeks
High Sensitive C Reactive Protein [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 0, 4, 12 and 26 weeks
Free Fatty Acids [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 0, 4, 12 and 26 weeks
Cholesterol level (total, HDL and LDL) [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 4, 12 and 26 weeks
Liver function tests (ALT, AST, AF, GGT) [ Time Frame: 0, 4, 12 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 4, 12 and 26 weeks
Triglycerides [ Time Frame: 0, 4 , 12 and 26 weeks ] [ Designated as safety issue: No ]
Difference between groups at 4, 12 and 26 weeks
QUICKI [ Time Frame: 0 and 26 weeks ] [ Designated as safety issue: No ]
Quantitative Insulin Sensitivity Check Index

Difference between groups at 26 weeks

Estimated Enrollment:	50
Study Start Date:	April 2013
Estimated Study Completion Date:	December 2015
Estimated Primary Completion Date:	December 2015 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Liraglutide Liraglutide: Solution for subcutaneous injection 6 mg/ml; Flexpen 3 ml. Dose: s.c. 0,6 mg (0,1 mL) once daily. After 1 week, the dose will be increased to 1,2 mg (0,2 mL) once daily. If tolerated, after 1 week, dose will be increased to 1.8 mg (0,3 mL) once daily. In case of a hypoglycaemic episode, the dosage of oral blood glucose lowering medicaments will be adjusted first. If hypoglycaemia persists, Liraglutide / Liraglutide placebo will be adjusted on the basis of clinical parameters. Duration: 26 weeks	Drug: Liraglutide Preparation and labelling of Investigational Medicinal Product: Liraglutide and placebo will be packed and labeled by Novo Nordisk A/S and provided in non-subject specific boxes. Labeling will be in accordance with Annex 13, local law and trial requirements. The examples of labels are not readily available, but will be supplied when received from Novo Nordisk. Drug accountability: Drug accountability will be cared for by the Department of Clinical Pharmacy of the LUMC. The trial product will be dispensed to each subject as required according to treatment group by the clinical pharmacist. No trial product will be dispensed to any person not enrolled in the trial. Other Names: Trade name: Victoza EV Product Code: SUB25238 Name of the Marketing Authorisation Holder: Novo Nordisk Marketing Authorisation number: EU/1/09/529/001 ATC code: A10BX07 CAS number 204656-20-2
Placebo Comparator: Liraglutide-placebo Liraglutide placebo: Solution for injection; Flexpen 3 ml. Dosage: same as Liraglutide Duration: 26 weeks

Arms

Assigned Interventions

Active Comparator: Liraglutide

Liraglutide: Solution for subcutaneous injection 6 mg/ml; Flexpen 3 ml.

Dose: s.c. 0,6 mg (0,1 mL) once daily. After 1 week, the dose will be increased to 1,2 mg (0,2 mL) once daily. If tolerated, after 1 week, dose will be increased to 1.8 mg (0,3 mL) once daily. In case of a hypoglycaemic episode, the dosage of oral blood glucose lowering medicaments will be adjusted first. If hypoglycaemia persists, Liraglutide / Liraglutide placebo will be adjusted on the basis of clinical parameters.

Duration: 26 weeks

Drug: Liraglutide

Preparation and labelling of Investigational Medicinal Product:

Liraglutide and placebo will be packed and labeled by Novo Nordisk A/S and provided in non-subject specific boxes. Labeling will be in accordance with Annex 13, local law and trial requirements. The examples of labels are not readily available, but will be supplied when received from Novo Nordisk.

Drug accountability:

Drug accountability will be cared for by the Department of Clinical Pharmacy of the LUMC. The trial product will be dispensed to each subject as required according to treatment group by the clinical pharmacist. No trial product will be dispensed to any person not enrolled in the trial.

Other Names:

Trade name: Victoza
EV Product Code: SUB25238
Name of the Marketing Authorisation Holder: Novo Nordisk
Marketing Authorisation number: EU/1/09/529/001
ATC code: A10BX07
CAS number 204656-20-2

Placebo Comparator: Liraglutide-placebo

Liraglutide placebo: Solution for injection; Flexpen 3 ml.

Dosage: same as Liraglutide

Duration: 26 weeks

Show Detailed Description

Eligibility

Ages Eligible for Study:	18 Years to 69 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Informed consent
Age > 18 years and < 70 years
BMI > 25 kg/m2
DM2 treated with metformin for at least 3 months in the maximum tolerable dosage
HbA1c ≥7% and ≤ 10.0 %
EGFR > 60 ml/min
Normal sitting blood pressure < 150/85 mm Hg and stable for at least one month

Exclusion Criteria:

Use of insulin, thiazolidinediones (TZD), SU derivatives, GLP-1 analogues, DPP-IV inhibitors, fibrates, prednisone, cytostatic o antiretroviral therapy within 6 months prior to the study
Hereditary lipoprotein disease
Psychiatric disorders and / or use of antipsychotic or antidepressant drugs at present or in the past
Hepatic disease (AST/ALT > 2 times reference values)
Endocrine disease other than diabetes mellitus type 2
History or presence of cardiovascular disease
Any significant chronic disease (e.g. inflammatory bowel disease)
Any significant abnormal laboratory results found during the medical screening procedure
Gastrointestinal surgery (e.g. gastric bypass)
Pregnant woman or a woman who is breast-feeding
Female of child-bearing potential intending to become pregnant or is not using adequate contraceptive methods while sexually active
Allergy to intravenous contrast
Known or suspected hypersensitivity to trial products or related products
Chronic pancreatitis or previous acute pancreatitis
Personal history or family history of medullary thyroid carcinoma or personal history of multiple endocrine neoplasia type 2
Claustrophobia
Metal implants or other contraindications for MRI
Recent participation in other research projects within the last 3 months or participation in 2 or more projects in one year

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01761318

Contacts

Contact: Maurice B Bizino, MD	+31715263953	m.b.bizino@lumc.nl
Contact: Hildo J Lamb, MD PhD	+31715266387	h.j.lamb@lumc.nl

Sponsors and Collaborators

Leiden University Medical Center

Novo Nordisk

Investigators

Principal Investigator:	Maurice B Bizino, MD	Leiden University Medical Center
Study Chair:	Jan WA Smit, MD PhD	University Nijmegen Medical Centre
Study Director:	Hildo J Lamb, MD PhD	Leiden University Medical Center
Study Chair:	Albert de Roos, MD PhD	Leiden University Medical Center
Study Chair:	Ingrid M Jazet, MD PhD	Leiden University Medical Center

More Information

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Hammer S, van der Meer RW, Lamb HJ, de Boer HH, Bax JJ, de Roos A, Romijn JA, Smit JW. Short-term flexibility of myocardial triglycerides and diastolic function in patients with type 2 diabetes mellitus. Am J Physiol Endocrinol Metab. 2008 Sep;295(3):E714-8. doi: 10.1152/ajpendo.90413.2008. Epub 2008 Jul 15.

Jonker JT, Lamb HJ, van der Meer RW, Rijzewijk LJ, Menting LJ, Diamant M, Bax JJ, de Roos A, Romijn JA, Smit JW. Pioglitazone compared with metformin increases pericardial fat volume in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010 Jan;95(1):456-60. doi: 10.1210/jc.2009-1441. Epub 2009 Nov 13.

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van der Meer RW, Rijzewijk LJ, de Jong HW, Lamb HJ, Lubberink M, Romijn JA, Bax JJ, de Roos A, Kamp O, Paulus WJ, Heine RJ, Lammertsma AA, Smit JW, Diamant M. Pioglitazone improves cardiac function and alters myocardial substrate metabolism without affecting cardiac triglyceride accumulation and high-energy phosphate metabolism in patients with well-controlled type 2 diabetes mellitus. Circulation. 2009 Apr 21;119(15):2069-77. doi: 10.1161/CIRCULATIONAHA.108.803916. Epub 2009 Apr 6.

Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, Hale PM, Zdravkovic M, Bode B; LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009 Feb 7;373(9662):473-81. Epub 2008 Sep 24.

Marre M, Shaw J, Brändle M, Bebakar WM, Kamaruddin NA, Strand J, Zdravkovic M, Le Thi TD, Colagiuri S; LEAD-1 SU study group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with Type 2 diabetes (LEAD-1 SU). Diabet Med. 2009 Mar;26(3):268-78. doi: 10.1111/j.1464-5491.2009.02666.x.

Responsible Party:	M.B. Bizino, MD, principal investigator, M.B. Bizino, MD, Leiden University Medical Center
ClinicalTrials.gov Identifier:	NCT01761318 History of Changes
Other Study ID Numbers:	379, 2012-001623-12
Study First Received:	December 20, 2012
Last Updated:	February 11, 2013
Health Authority:	European Union: European Medicines Agency

Keywords provided by Leiden University Medical Center:

Diabetes mellitus type 2
Glucagon-Like Peptide 1
Magnetic Resonance Imaging
Magnetic Resonance Spectroscopy
Steatosis

Additional relevant MeSH terms:

Cardiovascular Diseases
Diabetes Mellitus
Diabetes Mellitus, Type 2
Fatty Liver
Metabolic Syndrome X
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Liver Diseases

Digestive System Diseases
Insulin Resistance
Hyperinsulinism
Glucagon-Like Peptide 1
Incretins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 23, 2013

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