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Diabetes Management Incretin Mimetics
insulin levels return toward basal levels and plasma glucose stabilizes Exenatide and Liraglutide—
when normal fasting plasma glucose concentrations are reached.
5
This The Glucagon-like Peptide-1 Receptor Agonists
glucose dependence implies that drugs targeting the incretin system Basic Properties
should have a low inherent risk of inducing hypoglycemia. Exenatide (synthetic exendin-4) is a recombinant peptide based on a
salivary product of the ‘gila monster’ lizard (Heloderma suspectum).
15
GLP-1 also has a number of other effects that could benefit individuals Exenatide is a 39-amino-acid peptide that has a 53% identical sequence
with type 2 diabetes. In vitro and animal studies have demonstrated that to human GLP-1. Exenatide is a GLP-1 mimetic with similar potency to
native GLP-1 promotes beta-cell neogenesis and preservation, so GLP-1 native GLP-1 but with partial resistance to DPP-4.
16
treatment could potentially help to preserve beta-cell mass and improve
beta-cell function in patients with type 2 diabetes.
6
GLP-1 promotes Exenatide was approved in the US in 2005 as an add-on therapy to
satiety, slows gastric emptying, and is associated with reduced energy improve glycemic control in patients with type 2 diabetes who have not
intake in humans,
7
suggesting that GLP-1 receptor agonists may support achieved adequate glycemic control with metformin, a sulfonylurea
weight reduction. GLP-1 increases renal sodium excretion and has (SU), a thiazolidione (TZD), or combinations of metformin and an SU or
favorable effects on endothelial dysfunction, factors that can potentially TZD.
15
European marketing approval was gained in 2006 for combined
explain the decrease in systolic blood pressure observed after long-term therapy with metformin, SUs, TZDs, or combinations of oral antidiabetes
treatment with GLP-1 agonists.
8,9
GLP-1 also has beneficial effects on the drugs (OADs).
17
heart, such as protecting myocardial cells in ischemic reperfusion injury
models and improving cardiac function following acute myocardial Following subcutaneous injection, exenatide reaches peak plasma levels
infarction.
6,10,11
These actions could provide benefits for patients with at approximately two hours, has a plasma half-life of around three to four
type 2 diabetes and associated comorbidities. hours, and induces reductions in glucose concentrations for five to seven
hours.
18,19
This means that exenatide requires twice-daily dosing 0–60
While exogenous continuous administration of native GLP-1 showed minutes before a meal and primarily acts to control post-prandial blood
therapeutic potential,
5
the use of recombinant human GLP-1 would glucose after breakfast and dinner.
19
Exenatide is predominantly
not be clinically useful. Recombinant GLP-1 cannot be administered eliminated by glomerular filtration, therefore dosage escalation should
orally and the native peptide is rapidly degraded by dipeptidyl be carried out cautiously in patients with moderate renal impairment and
peptidase-4 (DPP-4) following intravenous injection, giving it an in vivo it is not recommended for individuals with end-stage renal disease or
half-life of only two minutes.
12
It has therefore been necessary to severe renal impairment.
15
A long-acting exenatide formulation requiring
develop mimetics or analogs of human GLP-1 that are much more once-weekly dosing is also currently in clinical development.
19–21
resistant to DPP-4 degradation than the native hormone. This strategy
has produced the GLP-1 receptor agonists exenatide and liraglutide, Liraglutide, the first once-daily human GLP-1 analog, is approved for use
which are administered by subcutaneous injection. in the EU
22
and is still under FDA review in the US. It is a synthetic analog
of human GLP-1 with a 97% identical amino acid sequence that has been
Another strategy has been to develop inhibitors of DPP-4 to enable modified by the addition of a fatty acid side chain and a glutamic acid
concentrations of native GLP-1 to increase. This approach is less spacer. This means that liraglutide self-associates into heptamers, which
specific, however, as DPP-4 inhibitors also increase endogenous delays absorption from the injection site.
23
Once in the circulation, the
GIP concentrations. Two DPP-4 inhibitors, sitagliptin and saxagliptin, fatty acid side chain may provide the molecule with partial resistance to
are currently approved in the US. Sitagliptin, vildagliptin, and DPP-4 via reversible binding to serum albumin. These attributes mean
saxagliptin are approved in the EU. Another DPP-4 agent, alogliptin, that following a single dose of liraglutide, peak plasma levels are reached
has postponed its US and EU approval submissions in order to carry after nine to 12 hours and the drug has a half-life of 13 hours.
24
In
out additional safety studies, as required by the US Food and Drug addition, liraglutide achieves increased plasma concentrations for up to
Administration (FDA). 24 hours following a single subcutaneous injection and steady-state
levels are achieved quickly, which supports once-daily dosing.
24,25
It can
One important difference between these two therapeutic approaches is be administered at any time of day irrespective of meals, although
that GLP-1 receptor agonists induce pharmacological levels of GLP-1 individual users should inject at the same time each day. Liraglutide is
activity, while DPP-4 inhibitors preserve physiological levels. In addition, metabolized in the same way as large endogenous proteins and there is
while GLP-1 receptor agonists act only through GLP-1, inhibition of DPP- no single organ responsible for elimination.
22
The European approval
4 is likely to affect concentrations of both GLP-1 and GIP, as these recommends that liraglutide can be used without dose adjustment in
molecules are both substrates for the DPP-4 enzyme.
13
patients with mild renal impairment.
22
However, given limited therapeutic
experience in patients with moderate renal impairment and a lack of
While GLP-1 concentrations are reduced in individuals with type 2 therapeutic experience in patients with severe renal impairment, use in
diabetes, however, its insulinotrophic action is relatively well these populations is not recommended.
22
preserved.
13,14
By contrast, while GIP concentrations are largely
unaffected in type 2 diabetes, its insulinotropic action is impaired.
13
Clinical Efficacy
These characteristics of GLP-1 receptor agonists and DPP-4 inhibitors The clinical efficacy of exenatide has been examined in a large number of
result in functional differences between the two approaches, which clinical trials including the AMIGO (AC2993: Diabetes Management for
will now be discussed. Improving Glucose Outcomes) studies.
26–28
Glycated hemoglobin (HbA
1c
)
58 US ENDOCRINOLOGY
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