SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 7 NUMBER 2 • JUNE 2010
71
receiving the higher liraglutide doses.
Antibodies to liraglutide developed in 9 to 13% of subjects but
had no effect on HbA
1c
. It was reassuring that plasma concentrations
of calcitonin were no different in the three groups treated with
liraglutide compared to rosiglitazone and placebo.
In conclusion, liraglutide once daily was an effective and well-
tolerated GLP-1 analogue used in combination with a sulphonylurea
for the management of type 2 diabetes.
The efficacy and safety of liraglutide in combination
with metformin (LEAD-2 study)
4
In this study, overweight (BMI
≤
40 kg/m
2
), recently diagnosed
type 2 diabetics who had been treated with either metformin or
a combination of oral agents including metformin, for a period of
three months, were randomly assigned to liraglutide treatment as
a once-daily injection at dosages of 0.6, 1.2 or 1.8 mg/day, or to
glimepiride (4 mg once daily), or to a placebo, thereby creating
a metformin-only treated group. In the oral combination group,
liraglutide replaced one of the oral agents but not metformin.
The study set out to determine whether glycaemic control,
measured as HbA
1c
concentrations, was better with liraglutide
added to metformin than with metformin monotherapy, and as
good as that achieved with combination therapy of metformin and
glimepiride. Baseline HbA
1c
levels were between 7 and 11%. The
study design was a double-blind multi-centre study conducted in
21 countries; 1 091 patients were evaluated for a period of 26
weeks.
At study end, the mean HbA
1c
values for the overall population
decreased by 0.7
±
0.1% for the 0.6-mg/day liraglutide group
and by 1.0
±
0.1% for both the 1.2- and 1.8-mg/day liraglutide
groups and for the glimepiride group, and increased by 0.1
±
0.1%
for the placebo group (all values means
±
SEM). The estimated
treatment differences of all three liraglutide groups compared with
the placebo group and the resulting 95% confidence intervals
demonstrated that liraglutide-treated subjects had superior
glycaemic control compared with those in the placebo group [0.6
mg liraglutide versus placebo –0.8% (95% CI: –1.0 to –0.6); 1.2
mg liraglutide versus placebo –1.1% (–1.3 to –0.9); and 1.8 mg
liraglutide versus placebo –1.1% (–1.3 to –0.9)]. Analysis of the
estimated treatment difference in HbA
1C
levels between liraglutide
and glimepiride demonstrated that 1.2- and 1.8-mg/day liraglutide
treatments were non-inferior to treatment with glimepiride [1.2
mg/day liraglutide versus glimepiride 0.0% (–0.2 to 0.2) and 1.8
mg/day liraglutide versus glimepiride –0.0% (–0.2 to 0.2)].
In the patients receiving doses of liraglutide more than 1.2 mg/
day, significant reductions in systolic blood pressure occurred,
perhaps beyond the weight-reduction effect.
Side effects were most commonly nausea, vomiting and
diarrhoea, which led to liraglutide withdrawal in 5% of all
liraglutide-treated subjects. The extent of the gastrointestinal
disorders was dose-dependent and occurred mainly during the first
month of treatment.
Minor hypoglycaemia occurred at low incidence (
~
3% of
subjects in the placebo and liraglutide groups and 17% in the
glimepiride group), resulting in a relatively low rate of reported
minor hypoglycaemia (0.03–0.14 events/year for the placebo and
liraglutide groups and 1.23 events/year for the glimepiride group),
which was significantly less for all three liraglutide groups than for
the glimepiride group (
p
<
0.001). No major hypoglycaemic events
were reported. Patients treated with glimepiride and metformin
had greater weight gain and significantly more hypoglycaemia than
the liraglutide-treated group.
This study showed that liraglutide could be used with metformin
and was superior to metformin monotherapy and non-inferior to
glimepiride and metformin.
Comparison of liraglutide to glimepiride monotherapy
in early type 2 diabetes (LEAD-3 Mono)
5
In this trial comparing liraglutide (1.2 or 1.8 mg/day) to glimepiride
(8 mg/day), a traditional first-line sulphonylurea therapy for type 2
diabetes, patients were included who were thought to be in the
early stages of disease because they were drug-naïve, were treated
with lifestyle modification, or had failed to achieve control with
a single oral drug at less than 50% of maximum approved dose.
Previous treatment had to be for a period shorter than two months
and patients were switched to glimepiride or liraglutide on study
entry. The study was double-blind and conducted over 52 weeks in
a multi-centre trial in the United States and Mexico; 745 patients
participated in the trial in the three active treatment arms, with
similar demographic and baseline characteristics – equal numbers
of men and women, average BMI of 33 kg/m
2
and likely duration
of diabetes of five years.
The primary outcome was change in value of HbA
1c
from
baseline to 52 weeks. Secondary outcomes included changes in
body weight, fasting plasma glucose levels, self-measured eight-
point plasma glucose profiles (measured before each meal, 90
min after the start of each meal, at bedtime, and at 03:00), blood
pressure,
β
-cell function [pro-insulin to insulin ratio and two models
of
β
-cell function; homoeostasis model assessment (HOMA)-B and
HOMA-IR (insulin resistance)], fasting glucagon, and patients’
reported assessment of quality of life.
Treatment with liraglutide provided better glycaemic control
over the 52-week period than with glimepiride. Liraglutide reduced
both fasting and post-prandial glucose in its once-daily dosage
regimen. Importantly, at the dosage of 1.8 mg/day of liraglutide,
no tailing off of HbA
1c
reduction was seen over the 52-week period,
supporting the concept of a longer duration effect on HbA
1c
levels
with liraglutide.
At the end of the study, 28% of participants treated with the
lower dose of liraglutide and 38% treated with the higher dose
achieved HbA
1c
levels below 6.5%, compared with 16% on
glimepiride (6.5% is the target level of the American Association
of Clinical Endocrinologists). In those patients who were oral drug
treatment-naïve, the treatment success rates were even higher,
with 43 and 51% in the two dosage formats reaching target levels
of less than 7%.
HOMA-IR and fasting glucagon showed significant decreases
with liraglutide but mean increases with glimepiride treatment.
Insulin resistance decreased in both liraglutide groups but increased
on glimepiride therapy.
Participants in the liraglutide groups lost weight whereas those
on glimepiride gained weight. There was no relationship between
duration of nausea with liraglutide and achieved weight loss.
Importantly, patients randomly assigned to liraglutide 1.8 mg/day
reported improved quality of life with regard to both physical and
emotional factors.
No major hypoglycaemic events requiring third-party assistance
occurred in any of the treatment groups. Minor hypoglycaemic
