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GLP-1 has a short half- life of
1–2 minutes before it is degraded
by the enzyme ditheyl-peptidase-4
Therefore, by increasing the
action of GLP-1 by either introducing
analogues of the peptide, or slowing
it’s degradation, the beneficial effects
on glucose metabolism are likely to be
enhanced. GLP-1 receptor agonists bind
to GLP-1 receptors and mimic the action
of endogenous GLP-1, and are therefore
often referred to as incretin mimetics.
Incretin enhancers inhibit the enzyme
that causes degradation of incretin
and DDP-4 inhibitors increase
GLP-1 exposure which results in a
glucose-dependent stimulation of alpha
and beta cells in the pancreas.
the normal glucagon response to
hypoglycaemia is not impaired by GLP-1
agonists and DDP-4 inhibitors, leading
to a low risk of hypoglycaemia.
Beta cell functioning has also been
improved in some patients using
There is a diminished
incretin response in some patients
who have type 2 diabetes which may
therefore lead to even greater benefit
of treatment with these agents in this
group of patients.
Two GLP-1 analogues are available in
Australia, exenatide and liraglutide.
Exenatide was first added to the
PBS in August 2010.
are administered by subcutaneous
Exenatide is a synthetic derivative of the
exendin-4, a GLP-1 agonist that occurs
naturally in the Gila monster lizard.
This agent has a natural resistance
to degradation by DDP-4 giving it a
half-life of 2.4 hours which allows it to
be administered twice daily.
also an extended release formulation
of exenatide available, which has been
achieved by encapsulating the drug into
Liraglutide has an
amino acid sequence 97% the same as
GLP-1 with the change resulting in its
ability to interact with serum albumin,
delaying the time until degradation
by DDP-4 resulting in a half-life of
12 This allows liraglutide to be
administered once daily.
Exenatide is indicated in type 2 diabetes
with metformin and/or a sulfonylurea,
or with metformin and a basal insulin.
Only the twice daily products are
available on the PBS (Byetta) and there
are several criteria that need to be met
for PBS subsidy, of which concomitant
use of insulin is not one.
is indicated for use in type 2 diabetes
with metformin and/or a sulfonylurea
when these agents are inadequate.
Liraglutide is not yet available on
An advantageous effect in most patients
with type 2 diabetes is that GLP-1
agonists tend to cause a weight loss of
2–3 kg early in therapy. The long-term
effects on weight are not known.
Table 1. Summarises the GLP-1 agonists available in Australia
0.5 mcg subcutaneously
twice daily, increasing to
10 mcg twice daily after
four weeks if tolerated.
Administer up to 60 minutes
before 2 main meals at least
6 hours apart (preferably
breakfast and the evening
16 This agent should
not be administered after
a meal, therefore if the
patient misses their dose,
they can continue using
the medication at their next
Alternate product is dosed at
2 mg subcutaneously once
are common, e.g.
and a feeling of
when CrCl <30
There may be
an increase in
in patients with
In patients using exenatide, up to 50% will
develop antibodies to the agent, which occurs
more frequently in the once weekly dose
compared to twice daily dosing. There may be
a reduction in efficacy in these patients and an
increased rate of injection site reactions.
The dose of sulfonylurea or insulin may require
reduction when used in combination with
exenatide due to hypoglycaemia.
Exenatide may interfere with the absorption of
some medicines, for example, antibiotics should
be taken 1 hour before or 4 hours after exenatide
There are no marked changes to pharmacokinetics
based on age alone, however renal function may
reduce clearance of exenatide.
16 As the agent is
primarily renally cleared, there is not expected
to be any effects on blood concentration from
Initiate at 0.6 mg once daily,
increasing after at least one
week to 1.2mg once daily.
May increase if necessary
and tolerated to 1.8 mg daily.
No dosage adjustment is
required based on age.
Adverse effects may
be more common
in the elderly.
There is limited
about the use
Although anti-liraglutide antibodies may develop,
they do not appear to be associated with a
reduction in efficacy and there has not been an
increase in adverse effects observed.
Pharamcokinetics are not altered by age, gender,
There may be a reduction in effectiveness in
patients with liver disease.
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