Clinical trial NCT02308254: Drug Trial of Lixisenatide on Gastric Emptying and Blood Pressure Drops in Type 2 Diabetics and Healthy People
Official title: Effects of Lixisenatide on Gastric Emptying, Glycaemia and 'Postprandial' Blood Pressure in Type 2 Diabetes and Healthy Subjects.
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE1
PHASE2
Conditions: Diabetes Mellitus
Gastroparesis
Keywords: Blood pressure
Gastric emptying
Glycemia
Appetite
Incretin Hormones
Superior mesenteric artery blood low
Lead sponsor: Royal Adelaide Hospital
Sponsor class: OTHER
Collaborators: name: Sanofi
name: National Health and Medical Research Council, Australia
First posted: 2014-12-04
Enrollment: 30
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Blood Pressure
timeFrame: 4.5 hours per study
Secondary outcomes:
measure: Heart rate
timeFrame: 4.5 hours per study
measure: Gastric emptying rate
timeFrame: 3 hours per study
measure: Blood glucose concentration
timeFrame: 3 hours per study
Other outcomes:
measure: Intragastric distribution
timeFrame: 3 hours per study
measure: Gastrointestinal hormone release (concentrations of GLP-1, GIP, C-peptide and 3-OMG)
timeFrame: 4.5 hours per study
measure: Superior mesenteric artery blood flow
timeFrame: 3.5 hours per study
measure: Appetite (visual analogue questionnaire)
timeFrame: 4.5 hours per study
measure: Cardiac output
timeFrame: 3.5 hours per study
measure: Stroke volume
timeFrame: 3.5 hours per study
Locations:
city: Adelaide
country: Australia
facility: Discipline of Medicine, Royal Adelaide Hospital
state: South Australia
Study officials:
affiliation: University of Adelaide, Royal Adelaide Hospital
name: Karen L Jones, PhD
role: PRINCIPAL_INVESTIGATOR
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