SA JOURNAL OF DIABETES & VASCULAR DISEASE
EDITORIAL
VOLUME 7 NUMBER 2 • JUNE 2010
51
GLP-1 agonists: a novel treatment for South African
diabetic patients
BERND ROSENKRANZ
T
ype 2 diabetes has become an epidemic worldwide, including
in South Africa, where it is the sixth most common cause
of death.
1
Treatment strategies to combat hyperglycaemia
reduce complications in these patients.
2
Conventional antidiabetics
all have their own limitations, especially weight gain and the risk of
hypoglycaemia. There is therefore a clear need for novel treatment
options, given alone or as combination therapy. New medications
should exhibit an ideal glucose-lowering efficacy profile, be
extremely safe in a broad range of patients and ultimately reduce
co-morbidities and complications of diabetes.
3
The most recent addition to the spectrum of antidiabetic drugs
in South Africa is the exendin-based glucagon-like peptide-1 (GLP-
1) receptor agonist, exenatide. What will the role of this novel drug
be in the management of patients with type 2 diabetes?
The gastrointestinal hormone (incretin) GLP-1 has been one of
the main targets for development of new antidiabetic treatments
in the past decade, as recently discussed in this journal.
1,4
GLP-1 is
secreted by the L-cells of the small intestine after food ingestion, and
potentiates pancreatic insulin secretion.
5
Since the insulinotropic
effect of GLP-1 is better preserved in type 2 diabetic patients
than that of the incretin, gastric inhibitory polypeptide (glucose-
dependent insulinotropic peptide, GIP), drug-discovery efforts have
focused on GLP-1 as therapeutic target.
6
GLP-1-based therapeutics stimulate insulin secretion glucose-
dependently and therefore result in a more physiological pattern
of insulin secretion with less hypoglycaemia than with conventional
treatments. GLP-1 agonists show additional potentially beneficial
effects such as improvement of endothelial function.
7,8
In patients
with type 1 diabetes,
9
and in islet-transplant recipients with allograft
dysfunction,
10
beta-cell mass is increased or preserved. The potential
clinical benefits of these additional effects, however, remain to be
demonstrated in large, controlled, clinical trials.
Native GLP-1 is rapidly degraded by dipeptidyl-peptidase IV (DPP-
IV).
5,11
Therefore, GLP-1-based therapeutics include two different
classes of drugs: (a) the more stable GLP-1 agonists: exenatide
(synthetic exendin-4 analogue, 53% homology with GLP-1),
liraglutide (human GLP-1 analogue, 97% homology) (see page
70), albiglutide (GLP-1 conjugated to albumin), taspoglutide (93%
homology), and a recombinant exendin-4 conjugated to albumin;
and (b) the DPP-IV inhibitors: sitagliptin, vildagliptin and saxagliptin.
While GLP-1 agonists are peptides and must be administered
subcutaneously, DPP-IV inhibitors can be given orally. Liraglutide
and sitagliptin are available in Europe and in the USA, whereas
vildagliptin is currently approved only in Europe. Other products are
in various stages of development.
Exenatide was introduced as type 2 diabetes therapy in the
USA in 2005, and subsequently in Europe following a positive
opinion by the European Medicines Agency (EMA) in 2006. It was
registered in South Africa in December 2008 and launched in this
country in April 2010 after clarification of the reimbursement of the
drug. The indication is for treatment of type 2 diabetes mellitus,
in combination with metformin and/or sulfonylureas in patients
who have not achieved adequate glycaemic control on maximally
tolerated doses of these oral therapies.
12
Exenatide lowers postprandial glucose, increases insulin
secretion, reduces postprandial glucagon secretion, slows gastric
emptying and reduces caloric intake in type 2 diabetic patients.
13
It may halt or reverse the progressive loss of beta-cell function in
this patient population by improving insulin deficiency, beta-cell
secretory defects and reduced beta-cell mass.
4,14
In large, controlled,
clinical trials, efficacy was demonstrated by a decrease in HbA
1c
of
approximately 0.5–1.0% over 30 weeks.
3,5,12,15
This was associated
with no weight gain or loss (about 1.5–3 kg over 30 weeks) and a
lower risk of hypoglycaemia than with conventional antidiabetics.
In the 30-week clinical studies, up to 46% of exenatide-
treated patients achieved the target goals for HbA
1c
≤
7.0%, as
recommended by the American Diabetes Association (ADA)
guidelines, compared with up to 13% of placebo-treated patients.
5
Although the drug has potentially beneficial effects on systolic
blood pressure, cardiovascular function and lipid profiles,
3,4,8,14
confirmatory clinical studies using hard cardiovascular endpoints
are not available.
Like other antidiabetic treatments, exenatide must be given on
a long-term basis to sustain its beneficial effects. This has been
shown in a group of 69 metformin-treated patients with type 2
diabetes,
16
of whom 36 received exenatide and 33 insulin glargine.
Correspondence to: Bernd Rosenkranz
Division of Pharmacology, Department of Medicine, University of
Stellenbosch, Tygerberg, Cape Town
Tel: +27 (0)21 938-9331
Cell: 082 955 0017
e-mail:
S Afr J Diabetes Vasc Dis
2010;
7
: 51–53
Bernd Rosenkranz
