SA JOURNAL OF DIABETES & VASCULAR DISEASE
DRUG TRENDS
VOLUME 8 NUMBER 3 • SEPTEMBER 2011
143
after early diagnosis should be aimed for,
along with attempts to reconstitute beta-cell
function and stop or delay the loss thereof.
GLP-1 therefore has very positive implica-
tions. It normalises glucose levels in poorly
controlled type 2 diabetics without increas-
ing hypoglycaemic episodes, given its inbuilt
protective mechanism. As normal levels are
reached, the inhibition of glucagon declines.
Beta-cell apoptosis is inhibited, maintaining
human islets.
GLP-1’s inhibition of gastric emptying
could be the factor associated with the
reduction of nausea over time. It has ben-
eficial effects on the cardiovascular system
and, perhaps most importantly, it has a
direct effect on satiety, appetite and food
intake, which serves as a basis for potential
weight loss. This is the result of its direct
effect on the hypothalamus. ‘The effect on
the hypothalamus is one of the important
factors that distinguishes the GLP-1-recep-
tor agonists from the DPP-4 inhibitors’, said
Prof Schmidt.
The LEAD studies compared liraglutide
to standard treatments for type 2 diabe-
tes, both as monotherapy and in a variety
of combinations. They involved over 4 000
patients. ‘When all the results were com-
bined, it was clear that liraglutide reduced
HbA
1c
levels and that it was clearly superior
or non-inferior to comparator treatments.
It showed strong additive effects and, in a
direct head-to-head comparison, it proved
superior to exenatide’, he continued.
Key findings
In• LEAD-2, more than 75% of patients
lost weight, a mean of 7.7 kg. Both vis-
ceral and subcutaneous fat was lost, and
the weight loss remained stable over two
years.
LEAD-3 c
•
onfirmed that liraglutide was
not associated with any hypoglycaemia.
Hypoglycaemia only occurred when it
was used in combination with a sulpho-
nylurea.
LEAD-6 evaluated liraglutide against
•
exenatide. While both treatments low-
ered HbA
1c
levels and body weight, the
most important outcome was that liraglu-
tide produced much less nausea.
The most important cardiovascular find-
•
ing was that liraglutide was associated
with a substantial reduction in systolic
blood pressure – which was shown in
LEAD-4. It could therefore be considered
a moderate antihypertensive that reduces
the risk of two important clinical end-
points, namely stroke and MI.
Liraglutide may modify food preferences
•
towards healthier diets.
A single dose of liraglutide restores beta-
•
cell sensitivity. This immediate resensitisa-
tion is a very important phenomenon.
Relative to the DPP-4 inhibitor, sitaglip-
•
tin, liraglutide was superior in respect
of both reduction of HbA
1c
levels and
weight loss.
When insulin detemir was added to
•
a combination of liraglutide and met-
formin, it showed additional benefit, with
no negative effects on weight loss and
no significant additional hypoglycaemia.
An additional 17% of patients reached
target, over and above the 61% who had
already reached target on liraglutide and
metformin.
‘When one looks at the triple endpoints
•
of HbA
1c
control, weight loss and the
avoidance of hypoglycaemia, the whole
LEAD programme showed liraglutide to
be the most active choice to achieve it.
Exenatide came in second; all other treat-
ments were less effective’, observed Prof
Schmidt.
So who will benefit most from incretin-
based treatment? Prof Schmidt cited patients
not achieving goal HbA
1c
levels on metformin
monotherapy; patients who are metformin
intolerant; patients on sulphonylureas who
experience recurrent hypoglycaemia; and
patients who really want/need to lose weight.
‘Therapy needs to be individualised accord-
ing to patient needs’, he concluded. ‘GLP-1
analogues have great potential, because the
important limitations of other treatments are
avoided.’
Liraglutide in clinical practice,
and preliminary results of the
DURATION-6 study
Wolfgang Schmidt, professor of Medicine,
Gastroenterology and Diabetology, Ruhr
University Bochum, Germany
Spotlighting the use of liraglutide in clinical
practice, Prof Schmidt once again under-
scored the problems and limitations of
current treatment, notably therapy-induced
hypoglycaemia, which was significant in the
ACCORD, VADT and ADVANCE studies.
‘In ACCORD, intensive treatment was
associated with severe hypoglycaemia and
grotesque weight gain’, he said. ‘The VADT
study emphasised that severe hypoglycae-
mia is a predictor of cardiovascular death
– not a risk factor as such, but certainly an
important risk indicator.’
Hypoglycaemic episodes impair brain
function. Even one severe episode increases
the relative risk of dementia later in life.
Treatment-related weight gain (high-
lighted in the UKPDS and ADOPT studies)
was shown to be an important risk factor
for various diseases. It is also associated with
increased all-cause, cardiovascular, diabetes
and cancer mortality. Another major limita-
tion of current treatments is that they do not
address progressive beta-cell loss.
Prof Schmidt went on to cite three
case studies, which showed the benefit of
liraglutide in specific patients. The first was
a 45-year-old man, who had had type 2 dia-
betes for 3.5 years. He had a fasting plasma
glucose (FPG) level of 9.4 mmol/l and a BMI
of 48.2 kg/m
2
.
Lifestyle modification was not working
in the long term and he had subsequently
been put onto metformin, ramipril and
simvastatin. After initiation of liraglutide,
his FPG dropped to 7.2 mmol/l at week two
and 6.2 mmol/l at week eight. After eight
weeks he had lost 6 kg and had near-normal
blood pressure. By three months, he had
lost 10 kg; this had reached 18 kg by six
months, at which time his HbA
1c
level was
6.9%.
The second patient was a 63-year-old
woman. She had been diabetic for eight
years and had had a previous MI. She had
elevated plasma lipid levels and blood pres-
sure, and gradually deteriorating glycaemia.
The introduction of pioglitazone decreased
her HbA
1c
levels, but at the expense of dra-
matic weight gain. It was discontinued and
liraglutide introduced. After three months,
she had lost 6 kg and her HbA
1c
level was
7.2%. At six months she had lost 12 kg and
her HbA
1c
level was 6%.
The third case was one where exenatide
was switched for liraglutide. The patient
was a 58-year-old woman who had been
diabetic for 14 years. Initial good control
had gradually deteriorated over the past six
