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VOLUME 9 NUMBER 2 • JUNE 2012
83
SA JOURNAL OF DIABETES & VASCULAR DISEASE
CONFERENCE REPORT
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
performed better in respect of weight loss.
Exenatide ER, however, was superior overall
in terms of side effects. Patient satisfaction
was higher with the injectable GLP-1 agents
than with the oral DPP-4 inhibitors.
Incretin-based therapies: focus on
clinical effectiveness
Jeffrey Wing, chief
physician, professor of
Medicine and clinical
head, Department of
Medicine, Charlotte
Maxeke Johannesburg
Hospital
Dr Wing pointed out that there were
very consistent messages coming through
with regard to the clinical effectiveness of
incretin therapies. ‘Vildagliptin produces
very little hypoglycaemia and is associated
with little or no weight gain, except when
combined with sulphonylureas. There are
convincing data that exenatide lowers blood
glucose, whether used as monotherapy or
in combination with other agents. There
is impressive weight loss and little or no
hypoglycaemia, except when it is used
together with sulphonylureas.
‘The LEAD studies send the same mes-
sage about liraglutide. It produces impressive
reductions in HbA
1c
levels in various combina-
tions, with similarly impressive weight loss and
little or no hypoglycaemia except, once again,
when it is combined with sulphonylureas.’
Looking at the composite endpoints of
HbA
1c
lowering, weight loss and minimis-
ing of hypoglycaemia, Dr Wing assigned the
following grades to the various drugs avail-
able. Both the thiazolidinediones (TZD) and
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 compos-
ite 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
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 pep-
tide-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 prolifera-
tion in pre-clinical models. Circulating GLP-1
is short lived; 80% is degraded within two
minutes by the enzyme dipeptidyl pepti-
dase-4 (DPP-4).
GLP-1 secretion is diminished in patients
withT2DM; however its insulinotropic activity
is maintained, resulting in the targeting of
this hormone for diabetic therapy. Incretin
agents include GLP-1 receptor agonists and
Therearemany challenges andcontradictions
to be overcome where diabetes is concerned,
and we want to have our cake and eat it,
with access to therapeutic options that are
safe, effective, cheap and free of side effects.
This was the view expressed by Dr Wing.
The first challenge is the numbers. ‘There
has been a 98% increase in the number of
diabetics in Africa,
13
and South Africa has
a strikingly high prevalence. According to
the NHLS database, glucose control is poor
in patients treated in the public sector, and
based on the Ampath/
Lancet
databases, the
private sector is not doing any better. Rising
rates of obesity, especially in urban women,
are a further clinical challenge, as one can’t
address glucose control without also looking
at obesity.’
Where contradictions are concerned,
normalising HbA
1c
levels has not yielded the
risk reductions expected. ‘It was thought
that normalisation of HbA
1c
levels would lead
to better cardiovascular outcomes, yet in the
ACCORD trial, intensive glucose lowering
led to increased mortality rates, possibly as a
result of increased hypoglycaemia and highly
significant weight gain’, said Dr Wing.
Soobesityneeds tobeaddressed. Treatment
should not aggravate weight gain, and weight
loss would be a bonus. HbA
1c
levels need to be
lowered to < 7%, and with no hypoglycaemia.
Looking at current drug options, Dr Wing
underscored that metformin is associated with
cardiac protection. ‘So you would need a very
good reason not to start with metformin.
‘As far as the thiazolidinediones (TZD) are
concerned, rosiglitazone is bad, pioglitazone
less so. The sulphonylureas do not yield car-
dioprotection and most do badly relative to
metformin, with the exception of gliclazide.
So there is a real need for new therapies
that lower glucose levels without weight
gain and hypoglycaemia, while providing
the bonus of cardiovascular protection.’