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DRUG TRENDS
SA JOURNAL OF DIABETES & VASCULAR DISEASE
100
VOLUME 9 NUMBER 2 • JUNE 2012
Drug Trends
Saxagliptin (Onglyza) launched in South Africa
T
he DPP-4 inhibitor saxagliptin was
launched recently at a series of clini-
cal meetings in South Africa, arranged by
Astra Zeneca and Bristol Myers Squibb. This
incretin-enhancing agent is recommended
for early use with lifestyle therapy in type
2 diabetes patients who are also on met-
formin and other anti-diabetic agents, to
help regain glucose control.
Dr Wayne May, endocrinologist and CDE
practitioner based in Cape Town pointed
out that clinicians need to tell their patients
that diabetes is a chronic condition which
progresses over time and that current treat-
ment cannot halt this progression. Lifestyle
modification is the cornerstone of therapy,
but as lifestyle efforts (weight loss, exercise)
diminish, the need for more complex regi-
mens is inevitable.
‘What patients fear at this juncture is
hypoglycaemia, which even though adju-
dicated as mild, not severe, hypoglycae-
mia is experienced as feelings of extreme
confusion, anxiety, irritability and sweaty
discomfort. Hypoglycaemia also reduces
a patient’s satisfaction with their diabetes
therapy and interferes with overall compli-
ance.’
Weight gain is also a major concern for
patients. Although metformin as first-level
treatment for type 2 diabetes does not cause
weight gain, most subsequent therapies do.
In the UKPDS study series, patients gained
up to 8 kg in 12 years, while in the ADOPT
trial, average weight gain was 4.8 kg in five
years.
1,2
‘Sulphonylureas and insulin are the
worst offenders with regard to weight gain’,
Dr May noted. ‘In order to reduce overall car-
diovascular risk, we also need to hit out on all
fronts: lowering cholesterol and blood pres-
sure, and keeping glucose levels to target.’
Supporting this approach, Dr Stephan
Jacob from the Institute for Cardio-
Metabolic Prevention and Therapy, University
of Tubingen, Germany, noted that lowering
blood pressure and cholesterol levels reduces
the risk of cardivascular events to a greater
degree than achieving lower HbA
1c
levels.
‘In my view, this is because, in the diabe-
tes world, we set out primarily to beat HbA
1c
,
particularly after the disappointing results of
the UKPDS study on macrovascular compli-
cations, presented in 1999 at the EASD in
Barcelona. In the UKPDS, metformin therapy
was the only winner, and after UKPDS, we
thought that we should reach for lower
HbA
1c
levels to obtain macrovascular ben-
efits’, he said.
More than 25 000 patients participated
in the ACCORD, VADT and ADVANCE
studies,
3-5
in which near-normal glycaemic
control should be achieved, targeting HbA
1c
levels of lower than 6.5 to 7%. However,
ACCORD needed to be stopped early due to
an increased mortality of 22% in the inten-
sive glucose-control arm.
One important side effect of intensified
therapy was seen more frequently: weight
gain and hypoglycaemia. This was a sur-
prise, as when these trials were planned,
the importance of hypoglycaemic events
was not considered to be so relevant.
‘In fact, the analysis following the VADT
study of the factors most predictive of future
cardiovascular death showed that the occur-
rence of a severe hypoglyacaemic event
was a better predictor of mortality than a
prior myocardial infarction or other vascular
event’, Dr Jacob stressed. In the ADVANCE
study, severe hypoglycaemia was also asso-
ciated with a greater risk of both micro- and
macrovascular events.
‘In addition, in the older patient (mean
age 65 years), it has been shown that risk
of dementia was correlated with episodes of
hypoglycaemia. The greater attributable risk
of dementia was 2.39% per year in individ-
uals with a history of hypoglycaemia, com-
pared to those without hypoglycaemia’.
6
‘We need to change our paradigm of
treatment and follow the physiological route
of better glucose control without hypogly-
caemia and weight gain, and not use the
reactive approach of intensifying therapy
only when the HbA
1c
level deteriorates’, Dr
Jacobs recommended.
‘Referring to the newer agents, the best
agent to add to metformin is either a DPP-4
inhibitor or a GLP-1 agonist, which do not
adversely affect cardio-metabolic risk by
enhancing weight gain or inducing hypogly-
caemic episodes’, Dr Jacob pointed out.
Saxagliptin usage
7
has been shown to
have a very low rate of hypoglycaemia,
similar to placebo, when added tometformin
and other agents, and with no significant
weight gain. ‘Treatment with saxagliptin
when extrapolated over the long term does
much better than the sulphonylureas’, Dr
Jacob said.
‘The evaluation of cardiovascular safety
with saxagliptin
8
is very reassuring as there is
no evidence that it increases cardiovascular
risk when used as monotherapy or in com-
bination with other agents. In fact, a long-
term outcome study is currently underway,
the SAVOR-TIMI 53 trial, which is 18 months
into execution and the results should be
available in 2015’, Dr Jacob pointed out.
Patients who will benefit most from
saxagliptin use are newly diagnosed patients
with type 2 diabetes who are compliant
with lifestyle changes. Also, all patients who
should never have a hypoglycaemic event
are ideal candidates for saxagliptin, such as
truck and regular motor car drivers, elderly
patients and those who have already had a
myocardial infarction.
Julia Aalbers
UKPDS. Intensive blood glucose control with
1.
sulphonylureasor insulincomparedwithconventional
treatment and risk of complications in patients with
type 2 diabetes (UKPDS 33) UK Prospective Diabetes
Study.
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2.
et al.
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et al
. Poor
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