Effect of Liraglutide on Cardiovascular Endpoints in Diabetes Mellitus Type 2 Patients

NCT01761318 | Completed Phase 4

• 2 other identifiers: 3792012-001623-12
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Diabetes Mellitus Type 2; Metabolic Syndrome; Cardiovascular Disease; Diastolic Dysfunction; Fatty Liver

Keywords

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

Outcome Measures

Primary Outcomes (11)

• Stroke volume

  Change from baseline in ml: difference between groups

  0 and 26 weeks

• Ejection Fraction

  Change from baseline in percentage: difference between groups

  0 and 26 weeks

• Cardiac output

  Change from baseline in L/min: difference between groups

  0 and 26 weeks

• Cardiac index

  Change from baseline in L/min/m2: difference between groups

  0 and 26 weeks

• Peak ejection rate

  Change from baseline in ml end-diastolic volume/sec: difference between groups

  0 and 26 weeks

• Early peak filling rate

  Change from baseline in ml end-diastolic volume/sec: difference between groups

  0 and 26 weeks

• Early deceleration peak

  Change from baseline in ml/sec: difference between groups

  0 and 26 weeks

• Atrial peak filling rate

  Change from baseline in ml/sec: difference between groups

  0 and 26 weeks

• Early deceleration peak / Atrial peak filling rate (E/A ratio)

  Change from baseline of the ratio: difference between groups

  0 and 26 weeks

• Peak mitral annulus longitudinal motion

  Change from baseline in cm/sec: difference between groups

  0 and 26 weeks

• Left ventricular filling pressure (= early peak filling rate / peak mitral annulus longitudinal motion)

  Change from baseline in mmHg: difference between groups

  0 and 26 weeks

Secondary Outcomes (14)

• Aorta and carotid vessel wall imaging

  0 and 26 weeks

• Aorta and carotid vessel wall imaging

  0 and 26 weeks

• Aorta and carotid vessel wall imaging

  0 and 26 weeks

• Aorta and carotid vessel wall imaging

  0 and 26 weeks

• Aorta and carotid vessel wall imaging

  0 and 26 weeks

Other Outcomes (23)

• Anthropometric measurements

  0, 4, 8, 12, 16, 20, 26 weeks

• Waist / hip ratio

  0, 4, 8, 12, 16, 20, 26 weeks

• Systolic blood pressure

  0, 4, 8, 12, 16, 20, 26 weeks

Study Arms (2)

Liraglutide

ACTIVE COMPARATOR

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

Liraglutide-placebo

PLACEBO COMPARATOR

Liraglutide placebo: Solution for injection; Flexpen 3 ml. Dosage: same as Liraglutide Duration: 26 weeks

Drug: Liraglutide - Placebo

Interventions

Liraglutide DRUG

Preparation and labelling of Investigational Medicinal Product: Liraglutide 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.

Also known as: 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

Liraglutide

Liraglutide - Placebo DRUG

Preparation and labelling of Investigational Medicinal Product: Liraglutide - 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.

Also known as: Placebo

Liraglutide-placebo

Eligibility Criteria

• Age: 18 Years - 69 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent
• Age \> 18 years and \< 70 years
• BMI \> 25 kg/m2
• DM2 treated with metformin, metformin + SU derivative, metformin + SU derivative + insulin, or metformin + insulin 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

You may not qualify if:

• Use of thiazolidinediones (TZD), GLP-1 analogues, DPP-IV inhibitors, fibrates, prednisone, cytostatic or 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

Sponsors & Collaborators

• Leiden University Medical Center: lead
• Novo Nordisk A/S: collaborator

Study Sites (1)

Leiden University Medical Center

Leiden, 2333 ZA, Netherlands

Location

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• Straat ME, Martinez-Tellez B, van Eyk HJ, Bizino MB, van Veen S, Vianello E, Stienstra R, Ottenhoff THM, Lamb HJ, Smit JWA, Jazet IM, Rensen PCN, Boon MR. Differences in Inflammatory Pathways Between Dutch South Asians vs Dutch Europids With Type 2 Diabetes. J Clin Endocrinol Metab. 2023 Mar 10;108(4):931-940. doi: 10.1210/clinem/dgac598.

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• Dekkers IA, Bizino MB, Paiman EHM, Smit JW, Jazet IM, de Vries APJ, Lamb HJ. The Effect of Glycemic Control on Renal Triglyceride Content Assessed by Proton Spectroscopy in Patients With Type 2 Diabetes Mellitus: A Single-Center Parallel-Group Trial. J Ren Nutr. 2021 Nov;31(6):611-619. doi: 10.1053/j.jrn.2020.09.006. Epub 2020 Dec 5.

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• van Eyk HJ, Paiman EHM, Bizino MB, IJzermans SL, Kleiburg F, Boers TGW, Rappel EJ, Burakiewicz J, Kan HE, Smit JWA, Lamb HJ, Jazet IM, Rensen PCN. Liraglutide decreases energy expenditure and does not affect the fat fraction of supraclavicular brown adipose tissue in patients with type 2 diabetes. Nutr Metab Cardiovasc Dis. 2020 Apr 12;30(4):616-624. doi: 10.1016/j.numecd.2019.12.005. Epub 2019 Dec 13.

  PMID: 32127340 DERIVED

• Bizino MB, Jazet IM, de Heer P, van Eyk HJ, Dekkers IA, Rensen PCN, Paiman EHM, Lamb HJ, Smit JW. Placebo-controlled randomised trial with liraglutide on magnetic resonance endpoints in individuals with type 2 diabetes: a pre-specified secondary study on ectopic fat accumulation. Diabetologia. 2020 Jan;63(1):65-74. doi: 10.1007/s00125-019-05021-6. Epub 2019 Nov 5.

  PMID: 31690988 DERIVED

• van Eyk HJ, Blauw LL, Bizino MB, Wang Y, van Dijk KW, de Mutsert R, Smit JWA, Lamb HJ, Jazet IM, Rensen PCN. Hepatic triglyceride content does not affect circulating CETP: lessons from a liraglutide intervention trial and a population-based cohort. Sci Rep. 2019 Jul 10;9(1):9996. doi: 10.1038/s41598-019-45593-2.

  PMID: 31292457 DERIVED

• Bizino MB, Jazet IM, Westenberg JJM, van Eyk HJ, Paiman EHM, Smit JWA, Lamb HJ. Effect of liraglutide on cardiac function in patients with type 2 diabetes mellitus: randomized placebo-controlled trial. Cardiovasc Diabetol. 2019 Apr 30;18(1):55. doi: 10.1186/s12933-019-0857-6.

  PMID: 31039778 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Metabolic Syndrome; Cardiovascular Diseases; Fatty Liver

Interventions

Liraglutide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Insulin Resistance; Hyperinsulinism; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Glucagon-Like Peptide 1; Glucagon-Like Peptides; Proglucagon; Gastrointestinal Hormones; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists

Study Officials

• Maurice B Bizino, MD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

• Jan WA Smit, MD PhD

  University Nijmegen Medical Centre

  STUDY CHAIR

• Hildo J Lamb, MD PhD

  Leiden University Medical Center

  STUDY DIRECTOR

• Albert de Roos, MD PhD

  Leiden University Medical Center

  STUDY CHAIR

• Ingrid M Jazet, MD PhD

  Leiden University Medical Center

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: M.B. Bizino, MD

Study Record Dates

• First Submitted: December 20, 2012
• First Posted: January 4, 2013
• Study Start: November 1, 2013
• Primary Completion: March 1, 2016
• Study Completion: March 1, 2016
• Last Updated: May 5, 2016

Record last verified: 2016-05

Locations

NL (1)