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Sponsor: University of Surrey
Conditions: Type 2 Diabetes
Interventions: Lixisenatide, Placebo
Countries: United Kingdom
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.
Sex: MALE
Age: 40 Years to 65 Years
Healthy volunteers: No
Study type: INTERVENTIONAL
Inclusion Criteria:
* 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
* 40-65 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
Exclusion Criteria:
* 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
* Screening amylase and/or lipase \> 3 times ULN or P-calcitonin ≥20 pg/ml (5.9 pmol/L).
* Personal or immediate family history of medullary thyroid cancer (MTC) or genetic condition that predisposes to MTC (e.g. multiple endocrine neoplasia syndromes).
* History of unexplained pancreatitis, chronic pancreatitis, pancreatectomy.
* Any stomach/gastric surgery other than minor endoscopic procedures such as peptic ulcer injection
* Allergic reaction to any GLP-1 receptor agonist or to metacresol.
* Clinically relevant history of gastrointestinal disease associated with prolonged nausea and vomiting.
* Current smokers
* Subject enrolled in another experimental protocol which involves the use of an investigational drug or device- Guildford, Surrey, United Kingdom