DRUG TRENDS
SA JOURNAL OF DIABETES & VASCULAR DISEASE
142
VOLUME 8 NUMBER 3 • SEPTEMBER 2011
A
meeting hosted by Novo Nordisk at
Zimbali Lodge near Durban in late May
2011 spotlighted the promise of incretin-
based therapies for type 2 diabetes, par-
ticularly the glucagon-like peptide-1 (GLP-1)
analogue, liraglutide.
The science behind the molecule
Dr Anne Mette Rosenfalck, endocrinologist
and vice-president, Novo Nordisk, Denmark
The development of liraglutide, which was
patented in 1997, marked the culmina-
tion of a long journey – several decades of
research, in fact. Over the past decade and
a half, the number of articles evaluating the
role of GLP-1 in diabetes has increased dra-
matically, reflecting an explosion of interest
in the subject. Much research and develop-
ment effort at Novo Nordisk led to liraglu-
tide being approved in Europe in 2009 and
in the USA in 2010. It is currently approved
in 58 countries worldwide and has been
launched in 32, most recently in China in
March 2011.
GLP-1 is a gut hormone, a member of the
incretin family, which is secreted in response
to meal ingestion. It, in turn, stimulates
the secretion of endogenous insulin – the
so-called ‘incretin effect’, which is severely
impaired in individuals with type 2 diabetes.
This suggests that introducing GLP-1 from
outside can address this impairment. The
infusion of a GLP-1 analogue is associated
with increased secretion of insulin.
As the blood glucose levels normalise,
the incretin effect wears off, which means
that incretin therapy does not carry the
risk of hypoglycaemia that comes with
insulin therapy. ‘Because GLP-1 is glucose-
dependent, the secretion thereof declines
to normal levels as the glucose levels go
down, minimising the risk of hypoglycae-
mia. Treatment with GLP-1 therefore does
not impair the hypoglycaemic counter-regu-
latory response.’
‘Much of the research has focused on the
pancreas’, said Dr Rosenfalck. ‘GLP-1 has an
impact on all functional pancreatic cells and
is responsible for an increase in both early-
and late-stage insulin secretion and synthe-
sis. But it also has important effects on the
brain, liver, heart and gastrointestinal tract.’
The first proof of the benefit of GLP-1
infusion came in a 1997 study by Rachman
et al.
1
that was published in
Diabetologia
.
A 17-hour infusion of a GLP-1 analogue
improved diabetic blood glucose to levels
similar to those of healthy controls. In 2001,
Toft-Nielsen
et al.
2
showed safe and effec-
tive blood glucose lowering with a four-
hour GLP-1 infusion. There was no decrease
to hypoglycaemic levels and there were no
non-responders. Subsequent studies have
shown that in addition to its blood glucose-
lowering effects, GLP-1 stimulates beta-cell
regeneration and reduces beta-cell apopto-
sis in animal models.
Zander
et al.
,
3
in a study published 2002,
showed that GLP-1 improved beta-cell func-
tion in humans, controlling blood glucose
levels and body weight in type 2 diabetes.
Dr Rosenfalck underscored that this was an
important finding, as improving blood glu-
cose control with currently available thera-
pies usually leads to increase in weight.
The indications are therefore clear that
pharmacological doses of GLP-1 can restore
insulin responses to normal physiological
levels in those with type 2 diabetes. Addi-
tional beneficial effects include improved
learning and memory function, neuropro-
tection, improved cardiac function and the
promotion of greater feelings of satiety and
hence reduced food intake. ‘GLP-1 was ini-
tially shown to reduce both the number and
size of meals in animal models’, she said,
‘findings that were repeated in human sub-
jects. GLP-1 leads to reduced energy intake,
proving that liraglutide provides dose-de-
pendent weight reduction.’
Where cardiac benefits are concerned,
GLP-1 reduces systolic blood pressure. ‘In a
mouse model of myocardial infarction (MI), it
was also associated with better survival and
improved cardiac output. A human study
confirmed that it improved left ventricular
function. ‘That it improves biomarkers of
cardiovascular risk adds to its importance in
type 2 diabetes’, said Dr Rosenfalck.
To use GLP-1 pharmacologically required
some structural changes to the molecule,
because native GLP-1 has a very short half-
life and is quickly degraded in the body by
dipeptidyl-peptidase-4 (DPP-4). ‘Much work
was done to get around this, resulting in two
kinds of incretin therapies, namely DPP-4
inhibitors and GLP-1 receptor agonists.
Liraglutide belongs to the latter class
and is a once-daily human GLP-1 ana-
logue, which is 97% similar to native GLP-1,
having undergone only two small molecu-
lar changes. The latter ensured that it is
absorbed more slowly and remains longer
in the blood. Its half-life has been increased
to 13 hours and its susceptibility to DPP-4
degradation has been reduced.
Exenatide, the other GLP-1 receptor
agonist on the market, requires twice-daily
administration and is only 53% similar to
native GLP-1. ‘Liraglutide’s greater similar-
ity to native GLP-1 means it produces fewer
antibodies than exenatide’, observed Dr
Rosenfalck.
Summing up, Dr Rosenfalck concluded
that liraglutide is a very interesting mol-
ecule. ‘It offers efficacious glucose lowering,
reduces body weight and has the potential
to halt disease progression.’
Getting to the root of the LEAD
study results
Wolfgang Schmidt, professor of Medicine,
Gastroenterology and Diabetology, Ruhr
University Bochum, Germany
Liraglutide’s promise was confirmed in a
series of trials collectively known as the LEAD
studies. Prof Schmidt reviewed some of the
key findings and what they have taught in
respect of how type 2 diabetes should be
treated in 2011.
‘We know that beta-cell dysfunction is
critical to the development of type 2 diabe-
tes, but we’ve learned that alpha-cell dys-
function plays a role too, with hypertrophy
of those cells producing hyperglucagonae-
mia. Previously, we were only able to “inter-
fere” with the beta-cell dysfunction, but
the inhibitory effect of incretin therapy on
alpha-cells opens up new treatment possi-
bilities.’
Key to the evaluation of new treatment
paradigms is the need to avoid hypoglycae-
mic episodes and treatment-related weight
gain. Stringent and safe glycaemic control
Getting to the root of diabetes: the promise of liraglutide
