CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 5, June 2012
AFRICA
289
sulphonylureas failed to impress, with
scores of 15 and 33%, respectively.
Exenatide was awarded a 72% pass,
while liraglutide achieved a 78% pass for
achieving composite endpoints.
‘To date, no other class of agent has
achieved this level and incretin therapies,
whether oral or injectable, perform much
better than what we have. High-dose
liraglutide will be leading the way.’ He
added that it seemed almost greedy to
want more, but that liraglutide 1.8 mg
also reduced a secondary risk factor,
namely systolic blood pressure.
‘The era of the incretins has arrived,
and the new guidelines will reflect this’,
Dr Wing concluded. ‘Diabetes is a
progressive condition and the incretins
may well be able to modify the disease
process before overt type 2 diabetes
manifests, delaying beta-cell failure
and providing long-term durability by
preserving beta-cell function.’
Early use of incretin-based
therapies in type 2 diabetes
treatment: clinical benefits
Adri Kok, specialist physician, Union
Hospital, Gauteng. CEO of Faculty of
Consulting Physicians of South Africa,
chairperson of the Medical Advisory
and Ethics Committee of Netcare, and
a director of the South African Private
Practitioners Forum
Type 2 diabetes (T2DM) has traditionally
been managed algorithmically. Following
a T2DM diagnosis, initial interventions
are diet and lifestyle modifications.
The natural disease progression of
T2DM implies that glycaemic control
will continue to deteriorate over time
and once required, oral therapy (usually
metformin first) is prescribed. The dose
of metformin is gradually uptitrated as the
disease worsens, and when the maximal
dose no longer maintains glycaemic
control, a second oral agent may be
added; with more than half of patients
ultimately requiring insulin therapy.
Dr Adri Kok, specialist physician at
Union Hospital (Alberton), expressed her
views that an algorithmic approach to
the management of T2DM is ‘reactive’
and may lead to unacceptable delays
in treatment intensification, leaving
patients exposed to long periods of
hyperglycaemia. Dr Kok expressed
particular concern about those patients
who are diagnosed late, as is often the
case in South Africa.
In patients with an HbA
1c
level > 9%,
the recommendation is to implement the
early use of insulin therapy combined
with oral agents to control initial
hyperglycaemia within two weeks.
Thereafter, the insulin can be withdrawn
and other therapies considered. Dr
Kok emphasised that it is of particular
importance that pathophysiology, over
and above HbA
1c
levels, needs to be
addressed.
To provide better glycaemic control
and improve treatment outcomes, Dr
Kok recommends the implementation of
a more pro-active approach than those
suggested by historical guidelines. The
most recent AACE/ACE guidelines
include multiple options for first-line
monotherapy, including incretin-based
therapy. The incretins are among the
many hormones responsible for glucose
homeostasis.
Incretins,
including
glucagon-
like peptide-1 (GLP-1), are released
by intestinal enteroendocrine cells
in response to a meal. GLP-1 elicits
glucose-dependent insulin secretion;
suppresses glucagon secretion, appetite
and food intake; slows gastric emptying
and stimulates beta-cell proliferation in
pre-clinical models. Circulating GLP-1
is short lived; 80% is degraded within
two minutes by the enzyme dipeptidyl
peptidase-4 (DPP-4).
GLP-1 secretion is diminished
in patients with T2DM; however its
insulinotropic activity is maintained,
resulting in the targeting of this hormone
for diabetic therapy. Incretin agents
include GLP-1 receptor agonists and
DPP-4 inhibitors. GLP-1 receptor agonists
produce effects similar to native GLP-1
and are resistant to degradation by DPP-4.
DPP-4 inhibitors inactivate the enzyme
responsible for GLP-1 degradation.
Exenatide, a synthetic formulation on
exendin-4, has similar effects to native
GLP-1.
Concerns surrounding conventional
oral diabetic therapies include risk of
hypoglycaemia; however, the glucose-
dependant action of incretin-based
therapies provides good glycaemic
control with a low risk of hypoglycaemia.
The incretin agents are also associated
with weight neutrality, or even weight
loss, whereas most conventional therapies
are associated with weight gain. Also
promising are findings that incretin-based
therapy may have beneficial effects on
beta-cell function, potentially slowing
progression of diabetic disease.
Dr Kok commented on her practical
clinical experience, which included
a significant number of patients who
were put on liraglutide therapy through
compassionate-use approval from the
South African Medicines Control Council
(MCC) prior to recent regulatory approval
of liraglutide in South Africa. In her
experience, she had patients losing up to
38 kg of weight while achieving excellent
glycaemic control.
Dr Kok went on to more closely
examine the indications for incretin-based
therapy, specifically the GLP-1 receptor
agonists. There is a body of evidence
supporting the use of GLP-1s across the
continuum of disease progression, both
as monotherapy and in combination with
a number of other agents.
Dr Kok advises an early combination
approach for early management of glucose
levels that can then be maintained. She
noted that as yet, it is not known for how
long beta-cell failure will be delayed with
early use of GLP-1s.
‘Such information should emerge with
the GRADE study (Glycaemia Reduction
Approaches in Diabetes), a cohort of 7
500 recently diagnosed type 2 diabetes
patients. The metabolic effects of five
different agents in combination with
metformin are being compared; as well as
the benefits of early combination therapy
versus sequential therapy in drug-naïve
patients’, Dr Kok said.
Usage trials of exenatide and liraglutide
were then presented. Monotherapy
trials of exenatide at doses of 5 and 10
µg yielded good results. Compared to
placebo, there was a distinct improvement
in HbA
1c
levels, with the higher dose
shown to be more effective in reaching
target HbA
1c
levels of < 7.0%.
An exenatide ER trial showed the
