REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
70
VOLUME 7 NUMBER 2 • JUNE 2010
Focus on liraglutide: the LEAD studies
JL AALBERS, WF MOLLENTZE
L
iraglutide is a very close analogue of the human glucagon-
like peptide-1 (GLP-1), with a 97% sequence identity to the
physiological GLP-1 gut hormone
1
and a plasma half-life of 13
hours.
2
The close identity of liraglutide to the human GLP-1 hormone
has advantages in achieving reduced antibody production,
1
which
may well translate into a longer effective period of use for this
agent in the glycaemic control of type 2 diabetic patients.
Both the European Medicines Evaluation Agency (EMEA) and
the Federal Drug Agency (FDA) have approved liraglutide for the
treatment of type 2 diabetic patients.
In this issue of the
Journal
, an editorial deals with these new
entities as a class and provides data related mainly to exenatide,
as it is currently available on the South African market
3
(see page
x). The clinical usefulness of these agents is likely to lead to the
registration of liraglutide in South Africa, and review of this novel
agent is pertinent for local physicians. In addition, South African
specialist groups will seek to place these GLP-1 analogues into
their protocols, and data on the value and clinical experience with
liraglutide is pertinent to these developments.
As is advocated in evidence-led clinical practice, the overall long-
term use of all GLP analogues awaits outcome data and ongoing
post-marketing surveillance will bring further clarity to their
sustained use.
Liraglutide in the LEAD studies
The LEAD (Liraglutide Effect and Action in Diabetes) studies
1,4-7
constitute a well-constructed series of phase III trials which were
undertaken to determine the efficacy and safety of liraglutide
across the continuum from early type 2 diabetes management as
monotherapy to combined use with available oral anti-diabetic
agents. The most recent LEAD study investigated the value
of liraglutide compared to insulin glargine therapy in type 2
diabetes.
7
Rationale for liraglutide use in type 2 diabetes with
special reference to the pharmacokinetics
The development of GLP-1 analogues is based on providing a
longer-acting molecule to extend the physiological actions of the
native GLP-1, which has a very short half-life of approximately one
hour in humans after subcutaneous administration, because of its
rapid degradation by the dipeptidyl peptidase IV (DPP-IV) enzyme.
Liraglutide is a humanGLP-1 analoguewith 97%homology to native
GLP-1.
4
By the addition of a fatty acid side chain (that promotes
binding to albumin) and a single amino acid substitution, the
resulting molecules self-associate and thus prolong its absorption
after subcutaneous injection.
4
The albumin-bound portion of the
molecule is also resistant to DPP-IV degradation.
4
The resistance to GLP-1 inactivation allows liraglutide to reach
maximum concentrations within 10 to 14 hours, with a half-life of
13 hours.
2
This longer plasma half-life makes liraglutide very suitable
as a once-a-day treatment for people with type 2 diabetes.
In the developmental phase II clinical trials in healthy male
volunteers, headache and dizziness occurred in 47 and 53% of
subjects, respectively, while gastrointestinal side effects including
abdominal pain, loss of appetite and nausea were reported in 27 to
33% of subjects, most likely due to delayed gastric emptying.
2
Liraglutide added to a sulphonylurea compared to
adding rosiglitazone or placebo (LEAD-1 SU)
1
In this 26-week, double-blind, double-dummy, active control trial
of 1 041 subjects randomised into five arms, all subjects received
glimeperide 2–4 mg/day in conjunction with:
one of three liraglutide doses (0.6, 1.2 or 1.8 mg/day injected
•
subcutaneously) and rosiglitazone placebo (therefore two active
substances: liraglutide and glimeride)
liraglutide placebo and rosiglitazone placebo (therefore
•
glimeperide as the only active substance)
liraglutide placebo and rosiglitazone 4 mg/day (therefore two
•
active compounds: glimeperide and rosiglitazone).
All three doses of liraglutide added to glimeperide significantly
reduced HbA
1c
concentrations after 26 weeks. Both liraglutide doses
of 1.2 and 1.8 mg/day decreased HbA
1c
by 1.1% from baseline.
Liraglutide 0.6 mg/day as well as rosiglitazone resulted in a decrease
in HbA
1c
of approximately 0.4%. More subjects (42%) treated with
liraglutide 1.8 mg/day reached an HbA
1c
target of
<
7.0%, while
21% reached a target HbA
1c
of
<
6.5% after 26 weeks.
The average BMI of subjects in each of the five arms was
approximately 30 kg/m
2
. Liraglutide 1.8 mg/day resulted in a
decrease in body weight of 0.2 kg after 26 weeks. Liraglutide 1.2
and 0.6 mg/day resulted in a weight increase of 0.3 and 0.7 kg,
respectively, whereas rosiglitazone resulted in a weight increase
of 2.1 kg. Nausea was more common in patients treated with
liraglutide, especially during the first four weeks, where after it
dissipated.
One patient without a history of previous pancreatic disease
developed chronic pancreatitis while taking liraglutide 0.6 mg/day.
Five more patients with a previous diagnosis of pancreatitis were
enrolled in the trial. All six patients completed the trial without
reporting any symptoms related to pancreatitis. One major episode
of hypoglycaemia was reported in one patient taking liraglutide 1.8
mg/day in conjunction with glimeperide. The dose of glimeperide
was reduced in this patient. Minor episodes of hypoglycaemia
occurred in 10% of patients and it was more common in patients
Correspondence to: JL Aalbers
Special Assignments Editor,
South African Journal of Diabetes & Vascular
Disease
Tel: +27 (0)21 976-4378
Fax: 086 610 3395
e-mail:
Correspondence to: WF Mollentze
Department of Internal Medicine, University of the Free State, Bloemfontein
Tel: +27 (0)51 405-3154
Fax: +27 (0)51 444-3138
e-mail:
S Afr J Diabetes Vasc Dis
2010;
7
: 70–73.
