None listed
Conditions
Brief summary
The trial will follow a randomised, double-blind, placebo-controlled parallel group design. After providing written, informed consent, each subject will attend the Nuclear Medicine Department in the morning (0800) after an overnight fast under “baseline” conditions (day 0). If the subject is normally prescribed metformin, this will be held while fasting and will be taken with the first meal following gastric emptying study. The investigators will confirm the prescribed metformin dose and check that this remains stable at each visit. A standardised meal will be provided the evening before the study. An intravenous cannula will be inserted in each forearm, one for blood sampling and the other for IV infusion of glucose tracer (initial bolus of 28 micromol.kg-1 6,6-2H2 glucose, followed by continuous infusion at a rate of 0.28 micromol.min-1.kg-1 from t = -210 until t = 240 min). At t = -5min, a meal will be given while the subject sits against a gamma camera, consisting of 300ml 25% dextrose labelled with 20MBq 99mTc-calcium phytate, and also containing 1.5g [U-13C] glucose, and 1000mg paracetamol to measure gastric emptying simultaneously by the paracetamol absorption test. The meal will be consumed within 5 minutes. Gastric emptying will be assessed from the time of ingestion of the meal and for 240 min afterwards. Venous blood (~3 mL) will be sampled at t= -210, -20, -10, 0, 15, 30, 45, 60, 90, 120, 150, 180 and 240 min for subsequent analysis of blood glucose and plasma glucose tracer concentrations, and additional samples (~10 ml volume) at t = -210, -30, 0, 15, 30, 60, 90, 120, 150, 180 and 240 min, for measurement of plasma insulin, C-peptide, and glucagon. A further sample (5 mL) will be collected at t = -210 min to measure HbA1C and fructosamine. Heart rate and blood pressure will be monitored every 3 minutes between t = -60 min and t =240 min using an automated recording device ((DINAMAP ProCare 100, GE Medical Systems, Milwaukee, WI, USA). At the conclusion of the study, subjects will be offered a light meal before they leave the laboratory. On the following day (day 1), each subject will then commence a 56 day (8 week) intervention consisting of lixisenatide or matching placebo (saline) administered subcutaneously once daily, 30 min before breakfast, as detailed below. On the final day (day 56), he or she will return to the department for a second gastric emptying study that will be identical to the study protocol for day 0, other than for administration of the final dose of lixisenatide or placebo 30 min before meal ingestion. Intervention The intervention will consist of 56 days treatment with either lixisenatide or placebo (saline). Dosing of lixisenatide will be “stepped up” according to the following schedule: - 5 mcg days 1-7, 10 mcg days 8-14, 20 mcg days 15-56
Interventions
The intervention will consist of 56 days treatment with either lixisenatide or placebo (saline). Dosing of lixisenatide will be “stepped up” according to the following schedule:
- 5 mcg subcut, once daily on days 1-7, 10 mcg subcut, once daily on days 8-14, and 20 mcg subcut, once daily on days 15-56
- Patients will have a diary and will need to sign each time an injection was given.
- Patients self administer their injections
Sponsors
Central Adelaide Local Health Network
Study design
Allocation
Randomised controlled trial
Intervention model
Parallel
Primary purpose
Treatment
Masking
Blinded (masking used) (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
All
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Males or females aged greater than 40 years If females are premenopausal they must have had either a tubal ligation or hysterectomy i.e. are not fertile. Type 2 diabetes treated with metformin for greater than or equal to 3 months HbA1c between 6.5 and 9% Duration of known diabetes greater than or equal to 2 years Haemoglobin above the lower limit of the normal range (i.e. greater than 135 g/L for men and 115 g/L for women), and ferritin above the lower limit of normal (i.e. greater than 10 mcg/L)
Exclusion criteria
Evidence of renal, hepatic or cardiovascular disease, pancreatitis, gastric surgery, or known gastroparesis. Renal disease: creatinine clearance (mL/min) will be calculated using the Cockcroft-Gault equation. Subjects will be excluded if creatinine clearance is estimated at less than 30 mL/min. Hepatic disease: subjects will be excluded if there is documented cirrhosis or transaminases or alkaline phosphatase elevated more than 2 times the upper limit of normal. Cardiovascular disease: admission to hospital with heart failure, myocardial infarction or stroke within previous 6 months. Previous exposure to GLP-1 receptor agonists Use of drugs potentially affecting gastrointestinal motility (opiates, anticholinergics, levodopa, clonidine, nitrates, , phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, tegaserod, or erythromycin) Use of any agent other than metformin for control of glycaemia Premenopausal females, unless they have had a tubal ligation or hysterectomy Presence of definite autonomic nerve damage (as assessed by standardised cardiovascular reflex tests) Participation in any research studies involving exposure to ionising radiation within the previous 12 months Vegetarian diet Intake of greater than 20 g alcohol on a daily basis, or cigarette smoking Volunteers who have donated blood in the preceding 3 months
Outcome results
None listed