Lixisenatide-The Effects on Glucose and Lipid Metabolism in Type 2 Diabetes
Condition: Type 2 Diabetes
MeSH terms: Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

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.
    

Detailed description: 
      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 (Visits 4 and 8) by labelling apoB-100 and apoB-48 with
      1-13C leucine (infusion for 8 hours) and by labelling triglycerides with [1,1,2,3,3-2H5
      ]glycerol (as a bolus injection) and 13C triolein. Blood samples will be taken for 4 hours
      prior to during the 8 hr isotopic infusion to measure the enrichment of apoB-100 and apoB-48
      with 1-13C leucine by gas chromatography mass spectrometry.

      At Visits 3 and 7, glucose flux in response to a mixed fluid meal containing U-13C glucose
      will be investigated. Endogenous glucose production will also be measured by infusing
      [6,6-2H2] glucose for 6hours.

      Gastric emptying will be measured by acetaminophen (1000 mg) absorption. Patients will also
      receive heparin (50U/kg) at the end of the study after 15 minutes a blood sample will be
      taken to determine post heparin lipoprotein lipase (LPL) activity.

      During the study the patients will be asked to monitor their blood glucose for three days
      with continuous glucose monitoring and to fill in a 7 day food diary.

      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.

      ii] lixisenatide will reduce postprandial triglycerides due to a decrease in chylomicron
      production as a result of a direct effect on enterocyte chylomicron assembly and will also
      reduce VLDL secretion from the liver as a result of an improvement in insulin sensitivity.
    

Intervention name(s): Lixisenatide; Placebo
Intervention type(s): Other; Other
Intervention description(s): 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.; Placebo for lixisenatide is supplied as green and purple colored disposable pen-injectors containing 3 mL of a sterile aqueous solution.
Other intervention name(s): GLP-1 agonist; Lyxumia
Intervention MeSH terms: Lixisenatide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Keywords: GLP-1 agonist; Lixisenatide; Postprandial glucose metabolism; Postprandial lipid metabolism; Gastric emptying; Lipoprotein lipase activity