CARDIOVASCULAR JOURNAL OF AFRICA • Vol 23, No 5, June 2012
290
AFRICA
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 can be used as monotherapy
or in combination 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
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
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 and beta-cell mass, a
deterioration in glycaemic 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 contribute to the development of
cardiovascular 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
Although impressed with the very
promising results of clinical trials, Dr
Kumar did emphasise that the true
potential of any therapy cannot be fully
determined until it has been extensively
used in clinical practice, and that costs,
particularly in developing economies
such as India, are a limiting factor.
Recent findings from the Association
of British Clinical Diabetologists (ABCD)
suggest that the GLP-1 receptor agonists
exenatide and liraglutide have been
widely used in clinical practice in the
UK since 2008 and 2009, respectively.
15
Improvements in glycaemic control
and body weight in the clinical setting
correlate with that observed in the trial
setting.
With experience from his own
practice, Dr Kumar commented that
incretin therapies were superior to
insulin, sulfonylureas and thiazides for
weight advantage and avoidance of
hypoglycaemia. With an excellent safety
and tolerability profile (nausea usually
settles within a week), incretin therapy
has high acceptability in patients.
Furthermore, Dr Kumar finds
incretin therapy suitable for use in the
patient failing metformin; and has noted
efficacy in combination with almost
all other oral anti-diabetic agents (as
well as insulin) at different stages of the
natural history of disease progression.
Cost as a limiting factor was the only
disadvantage highlighted, with Dr Kumar
postulating that he expects this to also be
a disadvantage for use in South Africa.
Source
Ussher JR, Drucker DJ. Cardiovascular Biology
of the Incretin System.
Endocrine Rev
2012;
33
:
187–215.
Incretins in combination with
insulin
The rationale for using incretin mimetics
with insulin was discussed by Prof
Mahomed Omar (South Africa) and Dr
Ajay Kumar (India) with reference to
relevant studies.
Adding incretins to insulin-
treated patients
‘At the outset, this approach should seek
to mitigate the problems associated with
