Drug Trial of Lixisenatide on Gastric Emptying and Blood Pressure Drops in Type 2 Diabetics and Healthy People
Drug Trial of Lixisenatide on Gastric Emptying and Blood Pressure Drops in Type 2 Diabetics and Healthy People
The purpose of this study is to determine the effects of the drug lixisenatide on blood sugar
 levels, stomach emptying, blood pressure and heart rate, release of gut hormones and blood
 flow in the gut after a glucose drink in both healthy subjects and people with type 2
 diabetes. If lixisenatide is shown to be effective, it would encourage ongoing evaluation of
 its potential use in the management of the falls in blood pressure following a meal in
 diabetic patients.
Lixisenatide is a drug that has been shown to reduce postprandial glycaemia in people with
 type 2 diabetes and is now approved for use in Australia. Although slowing of gastric
 emptying is likely to be the dominant mechanism by which lixisenatide reduces postprandial
 glycaemia after a meal, the effects of lixisenatide on gastric emptying have hitherto not
 been quantified by the 'gold standard' technique of scintigraphy. The study would determine
 and evaluate for the first time the magnitude of, and the relationship between lixisenatide
 on glycaemia with those on gastric emptying with scintigraphy. This information will be of
 fundamental significance to the effective use of lixisenatide in the management of people
 with type 2 diabetes that suffer from postprandial hypotension.

 Postprandial hypotension represents an important clinical disorder that occurs frequently in
 the elderly and people with type 2 diabetes and for which current management is suboptimal.
 While the mechanisms mediating postprandial hypotension are poorly understood, impaired
 regulation of splanchnic blood flow, gastric distension, the rate of small intestinal
 delivery and neural and hormonal mechanisms have been identified as possible
 pathophysiological mechanisms. Meal ingestion is associated with splanchnic blood pooling and
 a consequent reduction in venous return of blood to the heart. In healthy young and older
 individuals, with intact baroreflex mechanisms, these changes induce a rise in heart rate,
 stoke volume and cardiac output leading to a compensatory rise in blood pressure. However,
 patients with postprandial hypotension, these responses are inadequate to maintain blood
 pressure. The magnitude of the fall in blood pressure is greater when gastric emptying is
 more rapid and that slowing gastric emptying can markedly attenuate the postprandial fall in
 blood pressure in both healthy older subjects and type 2 patients.

 There is currently no information about the effect of lixisenatide on postprandial blood
 pressure and splanchnic blood flow in patients with type 2 diabetes.

 The purpose of this study would determine whether lixisenatide reduces the postprandial fall
 in blood pressure and related effects of gastric emptying to those on blood pressure, heart
 rate and splanchnic blood flow.

 The use of lixisenatide on appetite and energy intake and how these relate to effects of
 gastric emptying is lacking.

 It is hypothesized that lixisenatide will slow gastric emptying of oral glucose; attenuate
 both fasting and the postprandial rise in blood glucose; attenuate the magnitude of the fall
 in blood pressure, rise in heart rate and increase in SMA flow and reduce hunger, increase
 fullness and decrease energy intake at a buffet meal with greater effects in patients with
 type 2 diabetes that healthy subjects.
Inclusion Criteria:

 -  Healthy subjects:

 -  Male or female (females using appropriate contraceptive method or willing to
 undergo pregnancy test)

 -  Body Mass Index (BMI) 19 - 30 kg/m2

 -  Type 2 Diabetic Patients:

 -  As per "healthy subjects"

 -  Type 2 diabetes (World Health Organisation (WHO) criteria) managed by diet alone
 or on metformin

 -  Glycated haemoglobin >6.0% and <8.5%

 Exclusion Criteria:

 -  Subjects with a history of severe respiratory, cardiovascular, hepatic and/or renal
 disease (severe in that the social or physical manifestations of the disease, or
 living with the condition, impact negatively and significantly on the individuals'
 ability to lead a normal day to day life), chronic alcohol abuse or epilepsy (excluded
 by history) or if iron status, or liver function tests are outside the following
 ranges:

 1. Alanine aminotransferase (ALT) 0 - 55 U/L

 2. Alkaline phosphatase 30 - 110 U/L

 3. Aspartate transaminase 0 - 45 U/L

 4. Amylase and/or lipase >3 x ULN

 5. Bilirubin 6 - 24 mmol/L

 6. Ferritin 15 - 200 ng/mL (females); 30 - 300 ng/mL (males)

 7. Haemoglobin 115 - 155 g/L (females); 135 - 172 g/L (males)

 -  Subjects with a creatinine clearance cut-off of <50 ml/min

 -  Subjects requiring medication likely to influence blood pressure or gastrointestinal
 function

 -  Subjects with a past history of gastrointestinal disease, including known
 gastroparesis, significant upper gastrointestinal symptoms and previous gastric
 surgery

 -  Subjects with a past history of unexplained pancreatitis, chronic pancreatitis,
 pancreatectomy

 -  Subjects with a current or prior history of c-cell carcinoma

 -  Smoking > 10 cigarettes/day

 -  Alchohol consumption > 20 g/day

 -  Subjects who have donated blood in the previous 12 weeks

 -  Women of childbearing potential with no effective contraceptive method (defined as
 premenopausal, not surgically sterile women for at least 3 months prior to the time of
 screening) must have a confirmed negative urine B-hCG pregnancy test at screening
 visit. They must also use an effective contraceptive method throughout the study, and
 agree to repeat urine pregnancy test at designated visits.

 -  Lactation