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VOLUME 9 NUMBER 2 • JUNE 2012
CONFERENCE REPORT
SA JOURNAL OF DIABETES & VASCULAR DISEASE
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 hypogly-
caemia; 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 commentedonher 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 best
change in HbA
1c
level, with 49% of patients
achieving HbA
1c
levels of < 6.5%, and 63%
achieving HbA
1c
< 7.0%. In an exenatide
monotherapy trial, an average weight loss
of 3 kg was evident in patients. ‘However,
a number of patients lost significantly more
weight, with those on the higher dose (10
µg) losing the most weight’, Dr Kok stressed.
Also of note was evidence of beta-cell
protection, particularly as loss of beta-cell
mass prior to diagnosis is estimated to be
as much as 70%. In these trials, exenatide
was used as monotherapy or in combination
with metformin, sulfonylureas (SFUs) and
thiazolidinediones (TZDs). Exenatide can be
safely used with insulin.
14
The LEAD-3 trial compared monotherapy
with liraglutide (1.2 and 1.8 mg) against
glimepiride (sulfonylurea) monotherapy. It
was found that the 1.8-mg liraglutide dose
proved most effective in HbA
1c
level change
from baseline, with 42% achieving target
of < 6.5% and 51% achieving target of <
7.0%, while 27.8% of glimepiride-treated
patients reached an HbA
1c
level of < 7%.
The use of liraglutide also showed a
2.8-kg weight benefit over glimepiride,
as well as significant benefits in reducing
hypoglycaemic events. A trial comparing
liraglutide and metformin therapy to
therapy with both agents and added insulin
detemir showed that the greater the beta-
cell mass (as assessed by baseline HbA
1c
level) at initiation of liraglutide, the better
the treatment outcomes, most likely due to
greater beta-cell protection.
In summary, Dr Kok noted that liraglutide
canbeusedasmonotherapyor incombination
with metformin, a sulphonylurea or a TZD.
The concurrent use of liraglutide with insulin
is still under investigation.
Source
Dr Adri Kok, Johannesburg.
Early treatment prevents loss
of glycaemic control and beta-cell function
.
Campbell, RK. Clarifying the role of incretin-based
therapies in the treatment of type 2 diabetes mellitus.
Clin Therapeut
2011;
33
(5); 511–527.
Incretin-based therapies in clinical
practice
Research. He is principal investigator on a
number of international phase II, III and IV
trials.
Key challenges to be addressed as T2DM
progresses are a decline in beta-cell function
andbeta-cellmass,adeteriorationinglycaemic
control and an increase in cardiovascular
disease. Data from the ACCORD, ADVANCE,
UKPDS and VADT trials have indicated that
delayed treatment of T2DM can increase the
risk of cardiovascular mortality.
Anti-diabetic agents themselves may
contributetothedevelopmentofcardiovascular
disease. As early as the 1970s, the UGDP study
indicated adverse cardiovascular outcome with
the use of early sulfonylureas (tolbutamide).
Newer agents within the sulfonylurea family
may have varying and reduced degrees of
adverse cardiovascular outcome.
The availability of incretin-based therapies
addresses some of the concerns surrounding
progression and treatment of T2DM. Dr
Kumar summarised clinical trial data on
the safety and efficacy of these therapies,
showing successfully improved glycaemic
control with a low risk of hypoglycaemia and
the added benefit of being weight neutral
(DPP-4 inhibitors) or resulting in weight loss
(GLP-1 receptor agonists).
Evidence of preservation of beta-cell
function also emerged. ‘There is limited
information on the cardiovascular actions of
incretin-based therapy. Short-term studies
in human subjects demonstrate modest,
yet beneficial action on cardiac function in
patients with ischaemic heart disease. These
agents also decrease blood pressure and
have been shown to reduce inflammation in
pre-clinical studies’, Prof Kumar noted.
The early advocation of incretin-based
therapy in the AACE/ACE (American
Association of Clnical Endocrinologists/
American college of Endocrinology)
algorithm underscores the need for those
agents to be in our armamentarium –
Prof Kumar, Patna, India
Dr Ajay Kumar,
consultant physician and
diabetologist. Director of
the Diabetes Care and
Research Centre in Patna,
India. He also holds a
position at the University
of Newcastle, Australia and is a committee
member of the Indian Council of Medical
Although impressed with the very prom-
ising results of clinical trials, Dr Kumar did
emphasise that the true potential of any ther-
apy cannot be fully determined until it has
been extensively used in clinical practice, and
that costs, particularly in developing econo-
mies such as India, are a limiting factor.
Recent findings from the Association
of British Clinical Diabetologists (ABCD)
suggest that the GLP-1 receptor agonists