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

NCT02660047 | Completed Phase 4

• 1 other identifier: 2012-001623-12
• Study Type: interventional
• Target: 51
• Locations: 1 country
• Sites: 1

Brief Summary

Among South Asians, in comparison to Western Europeans, there is an increased risk of type 2 diabetes mellitus (DM2) and DM2-related cardiovascular disease. The effect of Liraglutide (Victoza®) on cardiovascular function is therefore investigated in the DM2 patient group of South Asian descent specifically. Liraglutide is a new widely prescribed therapeutic agent for DM2 patients. It is a Glucagon Like Peptide - 1 homologue that improves glucose homeostasis and reduces blood pressure and body weight. The disadvantageous metabolic phenotype as seen in South Asians includes a relatively large total fat mass, with predominately visceral relative to subcutaneous adipose tissue and lower brown adipose tissue volume and activity, accompanied by increased lipid levels. The key elements in the mechanism of action of Liraglutide seem to correspond to the differences in metabolic profile between South Asians and Western Europeans. Diastolic dysfunction, an early finding of cardiovascular disease in DM2 and obesity and an independent predictor of mortality, has been shown to be associated with the amount of triglyceride accumulation in the heart and liver. The investigators hypothesize that Liraglutide has direct advantageous cardiovascular effects and reduces triglyceride accumulation in end-organs, specifically for DM2 patients of South Asian descent.

Conditions

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

Keywords

South Asian descent

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 (12)

• Aorta vessel wall imaging

  0 and 26 weeks

• Carotid vessel wall imaging

  0 and 26 weeks

• Adipose tissue distribution

  0 and 26 weeks

• Total body fat

  0 and 26 weeks

• Epicardial fat volume

  0 and 26 weeks

Other Outcomes (22)

• 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. Dose: same as Liraglutide Duration: 26 weeks

Drug: Liraglutide - Placebo

Interventions

Liraglutide DRUG

Drug: Liraglutide 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

Drug: Liraglutide - Placebo 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: 19 Years - 74 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent
• Age \> 18 years and \< 75 years
• BMI \> 23 kg/m2
• DM2 treated with metformin and/or SU derivative and/or insulin for at least 3 months in stable dosage
• HbA1c ≥ 6.5% and ≤ 11.0% (≥ 47.5 mmol/mol and ≤ 97.4 mmol/mol)
• EGFR \> 30 ml/min

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
• Uncontrolled treated or untreated hypertension (systolic blood pressue ≥ 180 mmHg and/or diastolic blood pressue ≥ 110 mmHg)
• Acute coronary or cerebrovascular event within 30 days prior to study
• Congestive heart failure NYHA III-IV
• 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
• 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

Sponsors & Collaborators

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

Study Sites (1)

Leiden University Medical Center

Leiden, Albinusdreef 2, 2333 ZA, Netherlands

Location

Related Publications (5)

• Natale P, Green SC, Tunnicliffe DJ, Pellegrino G, Toyama T, Strippoli GF. Glucagon-like peptide 1 (GLP-1) receptor agonists for people with chronic kidney disease and diabetes. Cochrane Database Syst Rev. 2025 Feb 18;2(2):CD015849. doi: 10.1002/14651858.CD015849.pub2.

  PMID: 39963952 DERIVED

• Hoekx CA, Martinez-Tellez B, Straat ME, Bizino MB, van Eyk HJ, Lamb HJ, Smit JWA, Jazet IM, Nahon KJ, Janssen LGM, Rensen PCN, Boon MR. Circulating FGF21 is lower in South Asians compared with Europids with type 2 diabetes mellitus. Endocr Connect. 2025 Jan 6;14(2):e240362. doi: 10.1530/EC-24-0362. Print 2025 Feb 1.

  PMID: 39641307 DERIVED

• 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.

  PMID: 36262060 DERIVED

• 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.

  PMID: 33293204 DERIVED

• van Eyk HJ, Paiman EHM, Bizino MB, de Heer P, Geelhoed-Duijvestijn PH, Kharagjitsingh AV, Smit JWA, Lamb HJ, Rensen PCN, Jazet IM. A double-blind, placebo-controlled, randomised trial to assess the effect of liraglutide on ectopic fat accumulation in South Asian type 2 diabetes patients. Cardiovasc Diabetol. 2019 Jul 9;18(1):87. doi: 10.1186/s12933-019-0890-5.

  PMID: 31288820 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

• Elisabeth HM Paiman, MD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

• Huub J van Eyk, MD

  Leiden University Medical Center

  PRINCIPAL INVESTIGATOR

• Hildo J Lamb, MD PhD

  Leiden University Medical Center

  STUDY DIRECTOR

• Jan W Smit, MD PhD

  University Nijmegen Medical Centre

  STUDY CHAIR

• Ingrid M Jazet, MD PhD

  Leiden University Medical Center

  STUDY CHAIR

• Albert M de Roos, 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: MD

Study Record Dates

• First Submitted: January 18, 2016
• First Posted: January 21, 2016
• Study Start: August 1, 2015
• Primary Completion: March 9, 2018
• Study Completion: March 9, 2018
• Last Updated: March 21, 2018

Record last verified: 2018-03

Locations

NL (1)