EDITORIAL
SA JOURNAL OF DIABETES & VASCULAR DISEASE
52
VOLUME 7 NUMBER 2 • JUNE 2010
After cessation of both drugs at 52 weeks of treatment, beta-
cell function and glycaemic control returned to pre-treatment
values after a four-week off-drug period, confirming the need for
continuous treatment.
The drug is administered subcutaneously, twice daily because
of its short half-life (about 2.4 h). In order to improve tolerability,
treatment should be initiated with a dose of 5
μ
g, which should
subsequently be increased to 10
μ
g as required. The dossier for
a sustained-release (microsphere) formulation allowing a once-
weekly dosing was submitted to the FDA in 2009. This application
is currently under review; a reply to the FDA complete response
letter was submitted by the manufacturer in April 2010. The new
formulation is not currently approved by any regulatory agencies.
Many diabetic patients suffer from upper and lower
gastrointestinal symptoms.
17
Treatment with antidiabetic drugs
including exenatide contributes to these complaints. In clinical
trials, 30 to 45% of treated patients experienced at least one
episode of nausea, vomiting and/or diarrhoea during exenatide
treatment.
2
Mild to moderate hypoglycaemia has been reported
when the drug was given in combination with a sulfonylurea and/
or possibly metformin (40% of treated patients). Other side effects
of exenatide include decreased appetite, headache, dizziness,
hyperhydrosis, feeling jittery or asthenia.
12
Side effects tend to
abate with time. In controlled clinical long-term registration trials,
8% of exenatide-treated patients withdrew from treatment due to
adverse events (3% for placebo and 1% for insulin).
Post-marketing cases of acute, mostly reversible pancreatitis have
been reported (0.27 events per 1 000 patient-years).
18
Although
a cohort analysis using a large USA database did not confirm
an association of acute pancreatitis with exenatide or sitagliptin
treatment compared to metformin/glibenclamide,
19
this does not
exclude a possible drug-related causality.
5,20
It is recommended
that patients should be informed of the characteristic symptoms
of pancreatitis, and to discontinue treatment in patients exhibiting
such symptoms.
12
From April 2005 to October 2008, the FDA has received 78
cases of acute renal failure or renal insufficiency.
21,22
The drug
should not be used in patients with severe renal impairment
[creatinine clearance rate (CLcr)
<
30 ml/min], and patients should
be monitored carefully for the development of kidney dysfunction.
Elimination of exenatide is reduced in patients with kidney disease,
but these changes do not warrant a dosage adjustment in patients
with mild to moderate renal impairment (CLcr
>
30 ml/min).
23
Low- or high-titre anti-exenatide antibody formation was
observed in 44% of patients. The presence of antibodies was not
usually associated with a loss of efficacy in drug-naïve patients,
12
or
with an increase in treatment-emergent adverse events (TEAEs) in
patients re-exposed to the drug.
24
The effect of exenatide on gastric emptying may reduce the
extent and rate of absorption of other drugs given orally. Examples
include paracetamol, lovastatin, digoxin, lisinopril and ethinyl
estradiol (as a combination contraceptive).
12
No dosage adjustment
has been recommended for any of these drugs. Increased INR has
been reported during concomitant use of warfarin and exenatide,
in some cases associated with bleeding. INR should be monitored
during initiation or dosage increase of exenatide in patients on
warfarin or coumarol derivatives.
In the past decade, new antidiabetic drugs (with novel
mechanisms of action or pharmacokinetic/pharmacodynamic time
profiles) have sparked a debate about their safety and risk–benefit
profiles after regulatory approval. This is not surprising, since these
medications are administered to a large number of patients for a
long time, whereas information about their safety is still limited
by the time their marketing authorisation is granted. Knowledge
about the safety profile of exenatide will therefore evolve further
with increased post-marketing experience.
Cost effectiveness of treatment with exenatide has been assessed
using USA
25,26
and UK databases.
27
Exenatide therapy was associated
with significantly higher overall and diabetes-related treatment
costs, although annual total direct medical costs were usually less
in exenatide-treated patients than in the comparator group in the
USA.
28
In the USA, the increasing use of new antidiabetics such as
glitazones, new insulins, sitagliptin and exenatide largely account
for the increase in the mean cost per prescription for type 2 diabetic
patients (from $56 in 2001 to $76 in 2007).
29
The interpretation
of such cost-efficiency analyses must take into account the health
system of the country involved and the applied methodology. The
cost effectiveness of exenatide in the South African context is as
yet unknown.
Considering all of the above, what is the role of exenatide as new
treatment option in the management of type 2 diabetic patients?
The most recent (2009) joint consensus statement of the ADA
and the European Association for the Study of Diabetes (EASD)
2
recommends initiating insulin treatment at a much earlier stage than
suggested by previous guidelines. Using this algorithm, exenatide
should be considered as ‘second-tier’ option in selected clinical
settings, especially when hypoglycaemia is particularly undesirable
(e.g. in patients who have hazardous jobs) or if promotion of
weight loss is a major consideration and the HbA
1c
level is close
to target (
<
8.0%). It remains to be seen if the algorithm for the
management of type 2 diabetic patients will in the future include
exenatide and other novel therapeutic options for earlier use, once
evidence regarding sustained efficacy and safety accumulates.
30
The UK National Institute of Health and Clinical Excellence
(NICE)
31
suggests exenatide as a third-line treatment option added
to metformin and a sulfonylurea in patients with a body mass
index (BMI)
≥
35 kg/m
2
, who are concerned about their body
weight, although there has been a debate about this restriction to
patients with a high BMI.
32
Exenatide may also be used in patients
with a BMI
<
35 kg/m
2
, in whom insulin would have substantial
occupational implications or weight loss would benefit other
serious co-morbidities related to obesity. Treatment should only be
continued in patients who achieve a reduction of HbA
1c
of at least
1.0% and a weight loss of at least 3% of initial body weight over
six months.
In conclusion, exenatide will supplement the successful
management of patients with type 2 diabetes in South Africa.
Further post-marketing risk–benefit evidence as well as cost-
effectiveness considerations will assist in judging the contribution
of this novel drug to the treatment algorithm in the private and
public sectors in this country in the future.
References
Incretin therapy: A new treatment modality in the fight against the worldwide
1.
diabetes epidemic.
S Afr J Diabetes Vasc Dis
2009;
6
: 83–84.
Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, Zinman
2.
B. Medical management of hyperglecemia in type 2 diabetes: A consensus
algorithm for the initiation and adjustment of therapy.
Diabetes Care
2009;
32
:
193–203.
Drucker DJ, Sherman SI, Gorelick FS, Bergenstal RM, Sherwin RS, Buse JB. Incretin-
3.
