Lixisenatide-The Effects on Glucose and Lipid Metabolism in Type 2 Diabetes

NCT02049034 | Completed Phase 4

• 2 other identifiers: LIXISL066842013-002826-22
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

Glucagon-like-peptide-1 (GLP-1) analogues are a new treatment for type 2 diabetes, which have recently been shown to have beneficial effects on weight, glycaemic control and postprandial triglyceride concentrations. Postprandial hypertriglyceridaemia, which is associated with an increased risk of cardiovascular disease, is a feature of type 2 diabetes. Hypertriglyceridaemia is due to excess triglyceride-rich lipoproteins (TRL) which consist of very low-density lipoproteins, (VLDL) synthesised by the liver which contain the higher molecular weight form of apolipoproteinB (apoB), apoB-100, and chylomicrons which are synthesised in the intestine in response to an intake of dietary fat and contain the lower molecular weight form of apoB, apoB-48. A recent study has shown that GLP-1 receptor signalling is required for the control of postprandial lipoprotein synthesis and secretion in hamsters and mice. GLP-1 was shown to reduce apoB-48 TRL production while a GLP-1 receptor antagonist increased apoB-48 TRL production. This study will investigate the effect of the GLP-1 analogue lixisenatide compared with placebo, in a double blind crossover study, on postprandial triglyceride metabolism in 12 patients with type 2 diabetes. Chylomicron and VLDL production and clearance rates will be measured in a repeated meal study by labelling apoB-100 and apoB-48 and by labelling triglycerides using stable isotope methodology. Glucose flux in response to a mixed fluid meal will also be investigated using stable isotope methodology. Gastric emptying and post heparin LPL activity will be measured. The hypothesis is that i\] lixisenatide will lower postprandial glycaemia due to a decrease in endogenous glucose output and an increase in glucose clearance by peripheral tissues as a result of an improvement in insulin sensitivity.

Conditions

Type 2 Diabetes

Keywords

GLP-1 agonist; Lixisenatide; Postprandial glucose metabolism; Postprandial lipid metabolism; Gastric emptying; Lipoprotein lipase activity

Outcome Measures

Primary Outcomes (1)

• Postprandial glucose kinetics

  The study is a double blind cross over study comparing placebo injection with lixisenatide injection. The results will not be known until the investigator is unblinded. An intravenous infusion of \[6,6 2H2\] glucose will enable the quantification of endogenous hepatic glucose output while addition of \[U13C\] glucose to a mixed meal will enable the calculation of the contribution of meal derived glucose to postprandial glucose. Enrichment of plasma samples with 2H2 glucose and 13C glucose will be measured by gas chromatography mass spectroscopy (GCMS). Glucose uptake during the postprandial period will then be determined from these measures of glucose output and the glucose concentration at each time point. During this study, gastric emptying will be measured by oral administration of 1000mg acetaminophen.

  Two years

Secondary Outcomes (1)

• Postprandial and intestinal triglyceride-rich lipoproteins (TRL) kinetics

  Two years

Other Outcomes (1)

• Post heparin lipoprotein lipase activity

  Two years

Study Arms (2)

Placebo

PLACEBO COMPARATOR

Placebo for lixisenatide is supplied as green and purple colored disposable pen-injectors containing 3 mL of a sterile aqueous solution.

Other: Lixisenatide; Other: Placebo

Lixisenatide

EXPERIMENTAL

Lixisenatide and placebo are considered as investigational medicinal product (IMP). Metformin is not considered an investigational product but concomitant allowed antidiabetic medications. Lixisenatide is supplied as disposable pre-filled pen for subcutaneous injection: 10mcg Lixisenatide green pens; 20 mcg Lixisenatide purple pens. Dose titration-10mcg Lixisenatide for 14 days, 20 mcg for 14 days.

Other: Lixisenatide; Other: Placebo

Interventions

Lixisenatide OTHER

Lixisenatide and placebo are considered as investigational medicinal product (IMP). Metformin is not considered an investigational product but concomitant allowed antidiabetic medications. Lixisenatide is supplied as disposable pre-filled pen for subcutaneous injection: 10mcg Lixisenatide green pens; 20 mcg Lixisenatide purple pens. Dose titration-10mcg Lixisenatide for 14 days, 20 mcg for 14 days.

Also known as: GLP-1 agonist, Lyxumia

Lixisenatide; Placebo

Placebo OTHER

Placebo for lixisenatide is supplied as green and purple colored disposable pen-injectors containing 3 mL of a sterile aqueous solution.

Lixisenatide; Placebo

Eligibility Criteria

• Age: 40 Years - 65 Years
• Sex: male
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects with type 2 diabetes inadequately controlled by metformin.
• Stable diabetes management over last 3 months: metformin dose unchanged. HbA1c not known to have changed by \>0.5% over 3 months.
• Caucasian
• Male
• years (inclusive)
• HbA1c 7.5-9.5% (inclusive)
• BMI 27-40 kg/m2 (inclusive)
• Able and willing to self-administer placebo/lixisenatide injection
• Able and willing to perform self-blood glucose monitoring.
• Able and willing to wear a Continuous Glucose Monitoring System (CGMS) for 3 days

You may not qualify if:

• Subjects treated with insulin, any oral hypoglycaemic agents (OHA) (other than metformin), any insulin secretagogue or Thiazolidinediones (TZDs)
• A history of heavy alcohol use (\>12 to 15 g of alcohol per day)
• Arteriopathy
• History of significant coronary artery disease (myocardial infarction, surgical or percutaneous \[balloon and/or stent\] coronary revascularization procedure, or coronary angiography showing at least one stenosis ≥ 50% in a major epicardial artery or branch vessel)
• Ischemic cerebrovascular disease, including:
• History of ischemic stroke.
• History of carotid arterial disease as documented by ≥ 50 % stenosis documented by carotid ultrasound, magnetic resonance imaging or angiography, with or without neurological sequelae.
• Atherosclerotic peripheral arterial disease, as documented by history of amputation due to vascular disease; history of surgical or percutaneous revascularization procedure; current symptoms of intermittent claudication confirmed by an ankle-brachial pressure index less than 0.9
• Hepatic disease: alanine transaminase (ALT) \>3 times upper limit of normal (ULN)
• Renal disease: estimated glomerular filtration rate (Cockroft-Gault equation) less than 40ml/minute.
• Subjects receiving fibrates or weight reducing drugs
• Mental incapacity
• Unwillingness or a language barrier precluding adequate understanding or co-operation
• Fasting plasma triglycerides \>4.0 mmol/l
• Systolic blood pressure \>160 mmHg on 2 occasions, measured at least 10-minutes apart

Sponsors & Collaborators

• University of Surrey: lead
• Sanofi: collaborator

Study Sites (1)

University of Surrey FHMS Diabetes and Metabolic Medicine

Guildford, Surrey, GU2 7WG, United Kingdom

Location

Related Publications (1)

• Whyte MB, Shojaee-Moradie F, Sharaf SE, Jackson NC, Fielding B, Hovorka R, Mendis J, Russell-Jones D, Umpleby AM. Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance. J Clin Endocrinol Metab. 2019 Feb 1;104(2):359-368. doi: 10.1210/jc.2018-01176.

  PMID: 30215735 DERIVED

Related Links

• Whyte MB, Shojaee-Moradie F, Sharaf SE, et al. Lixisenatide Reduces Chylomicron Triacylglycerol by Increased Clearance. J Clin Endocrinol Metab. 2019;104(2):359-368.

MeSH Terms

Conditions

Diabetes Mellitus, Type 2

Interventions

lixisenatide

Condition Hierarchy (Ancestors)

Diabetes Mellitus; Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases

Study Officials

• David Russell-Jones, MBBS PhD

  Royal Surrey County Hospital NHS Foundation Trust

  STUDY CHAIR

• Margot Umpleby, BA, PhD

  University of Surrey

  STUDY DIRECTOR

• Martin Whyte, MBBS, PhD

  University of Surrey

  PRINCIPAL INVESTIGATOR

• Fariba Shojaee-Moradie, BSc, PhD

  Royal Surrey County Hospital & University of Surrey

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Placebo to IMP (lixisenatide) or IMP (lixisenatide) to placebo

Study Record Dates

• First Submitted: December 18, 2013
• First Posted: January 29, 2014
• Study Start: January 1, 2014
• Primary Completion: January 1, 2016
• Study Completion: January 1, 2016
• Last Updated: December 16, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

GB (1)