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Therapeutics Review
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EXENATIDE: A NEW STEP IN
TYPE 2 DIABETES TREATMENT
Sandra Waddingham
Diabetes Co-ordinator
North Lancs PCT
E
xenatide (Byetta) is the first glucagon-like peptide-1 analogue (GLP-1 analogue) to be
approved for the treatment of type 2 diabetes. It is a twice-daily injection, currently
prescribable only by consultants, given before breakfast and before the evening meal.
The early signs are that this new and different medicine has the potential to be very
exciting for both patients and healthcare professionals. Studies show a reduction in HbA1c as
well as steady weight loss – every diabetic’s dream! In this article, we look at how exenatide
works, where it fits into current practice and the pros and cons of this new preparation.
Exenatide was discovered as a protein that occurs naturally
in the saliva of the Gila monster lizard. The protein was
found to be similar in structure to the GLP-1 incretin
hormone, which is released from the intestine during food
digestion and prompts insulin secretion. GLP-1 occurring in
lizard spit has a much longer half-life than that which
occurs in the human gut, which is approximately two
minutes in humans. It was therefore chemically
synthesised and developed for use in type 2 diabetes.
TYPE 2 DIABETES
There are approximately 1.8 million people with type 2
diabetes in the UK, and it is predicted that the numbers will
continue to rise. The ageing population and increasing
levels of obesity are significant factors in the increasing
numbers.
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People most at risk of type 2 diabetes are mature adults
with a sedentary lifestyle, and a tendency to be overweight.
Family history of diabetes also increases the risk, and
women with a history of gestational diabetes are also more
likely to develop the disease.
INSULIN RESISTANCE
Type 2 diabetes is characterised by insulin resistance, which
means that the body is producing insulin but is unable to
respond to it. The pancreas reacts by producing more
insulin and eventually the over-worked pancreas begins to
fail. Glycaemic control deteriorates gradually over the years,
continuing after diabetes is diagnosed.
There are several drugs on the market to improve blood
glucose control and all have pros and cons. Sulphonylureas,
glitazones and insulin are associated with weight gain,
causing many patients to gain weight steadily over the
years. This weight gain increases insulin resistance, making
blood glucose control a continuing challenge requiring the
addition of further hypoglycaemic agents. A patient will
typically start management with diet alone, but will need
tablets as their diabetes progresses. The longer a patient
has had diabetes, the more likely they are to be taking
several different preparations to maintain glucose control.
Many people will eventually need insulin in addition to
tablets to treat their diabetes.
Exenatide is a new class of drug that works differently
from existing preparations. It does not cause weight gain
and many patients experience steady weight loss. The new
agent works only in the presence of glucose and so reduces
the risk of hypoglycaemia.
glucose and so reduces
cExenatide works only in the presencetheofrisk
of hypoglycaemiad
THE INCRETIN EFFECT
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Peptide hormones known as incretins are released
into the blood stream during food digestion. These,
in turn, prompt the secretion of insulin from beta
cells in the pancreas, and also inhibit the production
of glucagon from alpha cells. The specific incretins
involved in this action are known as glucosedependent insulinotropic polypeptide (GIP) and
glucagon-like peptide-1 (GLP-1).
In people with type 2 diabetes or impaired glucose
tolerance this effect is either reduced or absent. This
means that GLP-1 and GIP are unable to stimulate
beta cells in the pancreas to produce sufficient
insulin to metabolise the carbohydrates in food
eaten. Exenatide mimics GLP-1 that occurs naturally,
therefore promoting better glycaemic control.
THE EFFECT OF EXENATIDE ON BLOOD
GLUCOSE
Exenatide is glucose-dependent so it stimulates the
pancreas to produce only the amount of insulin
required to deal with the glucose load. As glucose
levels fall, insulin levels are also reduced. This
means there is no risk of hypoglycaemia with
exenatide. However, this new drug is licensed to be
used in combination with sulphonylureas, which
might give rise to hypoglycaemia, so care should be
taken, particularly in the early stages of treatment
with exenatide. It might be necessary to reduce or
stop the sulphonylurea in some patients.
GLP-1 and GIP also suppress the secretion of
glucagon from alpha cells in the pancreas, which, in
turn, decreases the amount of glucose from the liver.
However, this action does not affect the normal
mechanism and response to hypoglycaemia. The end
result should be lower blood glucose levels. Overall,
studies have demonstrated a reduction in HbA1c of
up to 1%.
EXENATIDE AND WEIGHT
GLP-1 slows gastric emptying so that the patient
experiences satiety sooner, leading to a reduced
appetite and food intake. In this way, the person
taking exenatide steadily loses weight. Studies have
shown an average weight loss of 1.6-2.8 kg over 30
weeks, which is sustained at 52-week follow-up. The
effect of slower gastric emptying also leads to a
slower rate of glucose absorption into the blood stream,
resulting in a steadier climb in blood glucose levels.
How exenatide works
• Increases insulin secretion from the
pancreas, without the risk of hypoglycaemia.
• Suppresses glucagon secretion from alpha
cells in the pancreas, which reduces the
amount of glucose produced by the liver.
• Slows gastric emptying, giving the patient a
feeling of fullness, which reduces the
appetite and increases satiety.
OTHER CONSIDERATIONS OF SLOW
GASTRIC EMPTYING
While slow gastric emptying can be advantageous it
may also reduce the rate of absorption of oral
medication as well as food. Nurses need to be
aware and advise patients accordingly. Medicines
that need to be taken with food should ideally be
taken with a meal when exenatide is not going to be
given. Particular care should be taken with
contraceptives and antibiotics and patients should
be advised to take these at least one hour before
their exenatide injection. Proton pump inhibitors
(lansoprazole, omeprazole) should be taken one
hour before or more than four hours after exenatide.
Metformin and sulphonylureas are not thought to
be affected by the slow gastric emptying process so
no changes to the timings of these medicines are
necessary.
WHEN SHOULD IT BE USED?
Exenatide can be used in combination with metformin
and/or sulphonylureas when glycaemic control is
inadequate with the maximum tolerated doses of
these oral drugs. Care should be exercised (as
discussed earlier) when initiating exenatide at the
same time as maximum doses of a sulphonylurea. It
might be wise to reduce the dose of SU depending
on blood glucose readings to avoid hypoglycaemia.
Exenatide is not licensed in the UK for use with
insulin or glitazones and can only be prescribed by
a consultant.
INJECTION DETAILS
Exenatide is given subcutaneously up to 60 minutes
before each of the two main meals of the day,
which must be at least six hours apart. The usual
times for injections are before breakfast and before
the evening meal. As exenatide is glucosedependent it would be pointless to give the injection
after a meal. If an injection is missed, it is very
important that the patient understands that the next
dose should be given as usual with no
compensatory measures for the missed dose.
Exenatide is initiated at a dose of 5 micrograms
twice daily for the first month, increasing the dose
to 10 micrograms twice daily thereafter. Many
patients suffer mild to moderate nausea when
treatment is first started, but it is usual for this
symptom to be temporary and it generally settles
down after the first month. The patient would then
stay on 10 micrograms twice daily.
INJECTION SITES
Injection sites for exenatide are the same as for
insulin – usually the thighs and abdomen. The
manufacturer also recommends the upper arm,
although nurses should be aware of the reduced
amount of fatty tissue in this area and ensure the
patient does not risk giving the injection
intramuscularly.
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Therapeutics Review
Howdoes
exenatide
workswork
in type
2 diabetes
How
the treatment
and what
should I expect from it?
The treatment is used with metformin, a sulphonylurea, or both to help
keep your blood glucose under control in four ways:
The medication signals the
pancreas to increase the
amount of insulin produced
after you eat. It acts like the
natural hormones in your body
that help prevent high blood
glucose after meals, which
helps lower your blood glucose.
Lilly UK
2
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1
The treatment
may also reduce
your appetite and
the amount of
food you eat.
3
The treatment helps stop
the liver from making too
much glucose when your
body does not need it,
especially after meals.
4
The treatment helps slow down
how quickly food and glucose
leave the stomach. This helps
prevent high blood glucose
levels after you eat.
POSSIBLE LINK TO INCREASED RISK OF PANCREATITIS
In October 2007, people using exenatide in the USA were given some additional
advice following 30 cases of pancreatitis in people on the drug. In the USA the
following advice was issued, warning that there may be a link between exenatide
and an increased risk of pancreatitis. Therefore patients should be advised that
if they experience unexplained persistent, severe abdominal pain, with or without
vomiting, they should seek immediate medical advice. Exenatide should be
stopped if pancreatitis is suspected and not restarted if it is confirmed.
COST
Exenatide is supplied in a disposable pen. The 5 microgram pen is turquoise
and orange in colour and will allow the user to dial up only a 5 microgram dose.
The 10 microgram pen is similar but is colour-coded turquoise and yellow. Each
pen contains enough exenatide to last for one month and costs £68.24.
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Therapeutics Review
on 5 micrograms daily. Anecdotally, some patients have found that giving the
injection about 10 minutes prior to eating reduces the nausea. Our patients have
been keen to continue treatment and persevered until the symptoms settled. To
date, no patients have withdrawn from exenatide treatment.
Key points
Pros and cons of exenatide
Cons
Reduces HbA1c by up to 1%
Requires two injections daily
Does not induce hypoglycaemia
when used with metformin
Nausea very common in
early stages of treatment
Sustained weight loss in many patients
Comparatively expensive
Possible link to an increased risk
of pancreatitis
THE FUTURE
• Exenatide (Byetta) is a GLP-1 analogue for use in type 2 diabetes
• It is a twice-daily injection taken before breakfast and before the
evening meal
• It is glucose-dependent and therefore must not be taken after food
• Patients start on 5 micrograms twice daily for one month progressing to
10 micrograms twice daily providing any nausea has settled
• Exenatide is licensed for use with metformin and/or sulphonylureas.
• Studies demonstrate a sustained reduction in HbA1c of up to 1%
• Most patients experience sustained weight loss
• One month’s supply costs £68.24
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Pros
Exenatide is currently the only GLP-1 analogue available for treatment. The
possibility of producing a longer-acting exenatide requiring weekly injections is
being explored. Liraglutide is another GLP-1 analogue undergoing trials.
LOCAL EXPERIENCE
In my area, 13 patients have been started on exenatide so far. The main
criterion for its use has been severe obesity. As it is commonplace for people
with diabetes to gain weight when starting insulin, those with severe weight
problems were given priority.
Most of the patients on exenatide are achieving steady weight loss, which is
a great morale boost for them. Most, if not all, have experienced some degree
of nausea. One patient was vomiting up to three times each day when started
• DeFronzo RA, Ratner RE, Han J, et al.
Effects of exenatide (exendin-4) on
glycemic control and weight over 30 weeks in metformin-treated patients with
type 2 diabetes. Diabetes Care 2005; 28: 1092-1100.
• www.diabetes.org.uk
• Summary of product characteristics. http://emc.medicines.org.uk
• Gallwitz B. New therapeutic strategies for the treatment of type 2 diabetes mellitus
based on incretins. Rev Diabet Stud 2005; 2: 61-69.
• Edwards CM.
GLP-1: target for a new class of antidiabetic agents? J R Soc Med
2004; 97: 270-274.