Study Looking at Cardiovascular Effects of Exenatide, Its Blood Pressure Lowering Effect and Its Mechanisms
Condition: Type 2 Diabetes
Study type: Interventional

Summary: 
      Exenatide is a new drug which lowers blood sugar (glucose) levels for people with type 2
      diabetes. It has significant advantages over other treatments such as insulin as it causes
      weight loss in a group of people that is generally overweight. Data from studies involving
      exenatide have shown that it also has an effect on blood pressure. The mechanism for the
      blood pressure lowering effect is not known and has not been investigated previously.
      Exenatide may have an effect on blood vessels throughout the body and gut to reduce blood
      pressure. 12 healthy men (18-45yr) will be studied on 2 occasions. Limb blood flow, skin
      blood flow, gut blood flow, blood pressure, and heart rate will be measured half hourly for 4
      hours. Blood samples (3ml) for insulin and glucose determination will be taken via a cannula
      and 3-way tap at the same time points. A dose of either 5μg exenatide or saline will be
      injected under the skin of the abdomen and a breakfast will be provided during the study. A
      urine collection will be made over the duration of the study.
    

Detailed description: 
      Background:

      Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from the L-cells of the gut
      following a meal (1). GLP-1 has multiple modes of action, including to augment the usual rise
      in insulin release and decrease in glucagon that follows carbohydrate ingestion (2). GLP-1
      therefore plays a part in glucose homeostasis. GLP-1 secretion is reduced in patients with
      type 2 diabetes (T2DM) and extended-action GLP-1 agonists or mimetics are currently being
      introduced for use as glucose lowering medications. The peptide exendin-4 has considerable
      homology with GLP-1 but is resistant to degradation by the enzyme Dipeptidyl peptidase-4
      (DPP-IV) and so has a much longer duration of action. The synthetic exendin, 'Exenatide', is
      a novel GLP-1 mimetic which has recently been licensed for the treatment for T2DM and has
      shown to be an effective glucoregulatory agent when administered as a twice- daily
      subcutaneous injection (11).

      GLP-1 agonists give a low risk of significant hypoglycaemia as effects on insulin and
      glucagon are largely glucose-dependent. In addition, considerable weight loss is often
      observed with GLP-1 agonists in clinical practice, and these drugs are currently being
      considered in treating obesity, even outside the context of diabetes.

      A moderate blood-pressure (BP) lowering effect of GLP-1 agonists has also been noted as a
      secondary outcome measure in large clinical trials in patients with T2DM. In one such study,
      Exenatide was associated with a reduction in systolic/diastolic BP of 5/2 mmHg The mechanism
      for this apparent hypotensive effect is not known. An infusion of GLP-1 agonists induces a
      natriuresis, which may contribute to a reduction in BP.

      Aims:

      The aim of this study is to assess the cardiovascular effects of Exenatide in young, healthy,
      non-obese male subjects. We propose to compare the effect of Exenatide vs. placebo and study
      the cardiovascular effects by a number of non invasive techniques.

      Experimental protocol and methods:

      12 healthy male subjects aged 18-45 years with BMI 20-27 kg/m2 will be recruited. Subjects
      will attend for an initial screening visit and initial assessments. This will enable
      familiarization with the room and equipment to be used. On arrival at the laboratory,
      subjects will be asked to void their bladder and a urine collection will be commenced.
      Subjects will be asked to wear shorts during the study and rest semi-supine on a hospital
      bed. They will place their hand in a heated hand warming unit and an intravenous cannula will
      be inserted, for arterialized venous blood sampling,. Subjects will rest for 1hour before
      receiving either Exenatide or placebo injection. Measurements of Limb blood flow (by venous
      occlusion plethysmography); skin blood flow (by laser Doppler); blood pressure, heart rate
      (HR) and cardiac output (by Finometry™);and regional blood flow (by ultrasound imaging and
      flow velocity measurement of the superior mesenteric arteries (SMA) will take place every
      30minutes. Blood sampling for insulin and glucose will be carried out every 15minutes
      throughout the study. Subjects will rest for 120 minutes after injection with measurements
      every 30 minutes as before with blood sampling every 15 minutes until 120 minutes post
      injection. Subjects will receive a high carbohydrate breakfast 60 minutes post injection.
      Urine will be collected during the study to assess urinary sodium excretion.

      Measurable end points/statistical power of the study:

      Our primary end point will be to measure meal induced changes in superior mesenteric (SMA)
      blood flow in the 2 groups (Exenatide vs. placebo.)Secondary endpoints will be measures
      including: BP, HR, Limb Blood Flow, Skin Blood Flow, and peripheral resistance responses when
      fasted and after eating- (both Exenatide and placebo groups).

      From previous studies we calculated that SMA blood flow at rest = 346 (27) ml/min and peak
      SMA blood flow after high carbohydrate meal = 611(80) ml/min. With 12 subjects, a reduction
      in blood flow of 71ml/min, following Exenatide injection, would be required if powered at
      80%.
    

Intervention name(s): Exenatide; Saline
Intervention type(s): Drug; Drug
Intervention description(s): single dose of 5 microg Exenatide. Subcutaneous administration; subcutaneous administration of 0.9% saline solution (0.02 ml)
Other intervention name(s): Byetta; 0.9% Saline solution
Intervention MeSH terms: Exenatide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: blood pressure; superior mesenteric artery blood flow; cardiovascular effects; Exenatide