REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
72
VOLUME 7 NUMBER 2 • JUNE 2010
events were fewer with liraglutide (12 and 8% in the lower and
higher dosages, respectively) than with glimepiride (24%).
In terms of adverse events, a weak association between
development of pancreatitis and liraglutide treatment could not be
excluded as only two participants experienced pancreatitis – one
after 197 days of treatment and one after 133 days. Both patients
recovered and one continued in the study.
This study is important, as traditional first-line therapy is not
appropriate for all patients. Metformin is frequently not well
tolerated and clinicians may avoid using metformin in patients with
renal impairment. A study of liraglutide reported no need for dose
adjustments in patients with severe renal impairment.
8
The LEAD-3 study is being continued for a further four years
in order to assess the durability of liraglutide therapy and the
prevalence of antibodies, and to identify sub-populations that may
best respond to this therapy.
Eefficacy and safety of liraglutide in combination
with metformin and rosiglitazone (LEAD-4 Met+TZD)
6
In this 26-week, double-blind, parallel-group, placebo-controlled
trial, 533 subjects with type 2 diabetes of a mean duration of
nine years and a mean HbA
1c
concentration of 7 to 11% were
randomised into three groups. All three groups received metformin
1 g twice daily and rosiglitazone 4 mg twice daily. In addition, one
group received once-daily liraglutide 1.2 mg subcutaneously (sc),
another group once-daily liraglutide 1.8 mg sc, and the last group
placebo sc once daily.
At the end of the study, HbA
1c
levels decreased significantly by
1.5% for both the 1.2- and 1.8-mg/day liraglutide groups compared
to a decrease of 0.5% in the placebo group. At study end, 58 and
54% of the subjects in the 1.2- and 1.8-mg/day liraglutide groups,
respectively, attained an HbA
1c
concentration
<
7.0% compared
with 28% of subjects in the placebo group, whereas 37 and
36% of subjects, respectively, reached an HbA
1c
level of
<
6.5%
compared to 14% of subjects in the placebo group. Fasting as
well as post-prandial glucose levels were also significantly reduced
in both liraglutide groups compared with placebo. Improved
glycaemic control occurred against a background of a significant
improvement in
β
-cell function.
Weight loss of 1.0 and 2.0 kg occurred in the 1.2- and 1.8-mg/
day liraglutide groups, respectively, during the study period,
whereas the placebo group gained 0.6 kg in weight. Systolic blood
pressure decreased by 6.7 and 5.6 mmHg in the liraglutide 1.2- and
1.8-mg/day groups, respectively, compared to a decrease of 1.1
mmHg in the placebo group. This phenomenon may be related to
reduced renal sodium reabsorption.
Nausea, vomiting and diarrhoea were collectively reported by
45% of subjects in the 1.2-mg/day liraglutide group, and by 56%
of subjects in the 1.8-mg/day group, compared to 19% of the
placebo group. The majority of nausea was transient, as it occurred
in the first four weeks. There were no episodes of pancreatitis
and no deaths occurred. Minor hypoglycaemia occurred at a low
incidence and there was no significant treatment effect of 1.8 mg/
day liraglutide on calcitonin compared to placebo.
Liraglutide versus insulin glargin and placebo in
combination with metformin and sulfonylurea
therapy in type 2 diabetes (LEAD-5 met+SU)
7
Of more interest to clinicians is whether liraglutide could
be effectively utilised in combination with metformin and a
sulphonylurea (glimepiride) and how this GLP-1 agonist compares
to basal insulin with regard to glycaemic control in type 2
diabetes.
In this careful 26-week study, type 2 diabetic patients 18 to 80
years old were randomised into parallel groups receiving liraglutide
1.8 mg/day (blinded) injection, or a placebo (blinded) injection, or
open-label insulin glargine; 581 patients were randomised in this
multi-centre and multi-country study and 522 patients completed
the study. At baseline, the HbA
1c
was between 7.5 and 10% on
multi-oral therapy. Patients were excluded if they had impaired
hepatic or renal function, clinically significant cardiovascular
or extensive microvascular disease (proliferative retinopathy or
maculopathy) or were hypertensive (
≥
180/100 mmHg).
During a six-week run-in period, participants were placed on
a standard combination therapy with metformin and glimepiride
up-titrated to maximum doses of 2 g/day metformin and 4 mg/day
glimepiride. If fasting plasma glucose (FPG) was between 7.5 and
12.8 mmol/l following the run-in period, patients were randomised
to the three arms. Insulin glargine was self-titrated by patients
according to a dosing algorithm for insulin glargine, based on
fasting blood glucose levels.
9
The primary-efficacy outcome measure was change in whole
blood HbA
1c
concentrations after 26 weeks of treatment. The
secondary outcome measures included changes in body weight,
waist circumference, fasting plasma glucose, eight-point plasma
glucose (PG) profiles, beta-cell function (pro-insulin to C-peptide
ratio) and blood pressure.
The reduction in HbA
1c
concentration was significantly greater
with liraglutide (1.33%) (final mean HbA
1c
7.0%) than with insulin
glargine (1.09%) (final mean HbA
1c
7.2%) and placebo (0.24%)
(final mean HbA
1c
8.1%). Also significantly more patients reached
HbA
1c
levels below 6.5% (AACE target) and below 7.0% (ADA
target) on liraglutide compared to insulin glargine. This difference
in HbA
1c
was within the predefined non-inferiority margin of 0.4
percentage points.
The mean weight loss of 1.8 kg from baseline achieved with
liraglutide was significantly superior to the reduction in the
placebo group. Weight increased by 1.6 kg with insulin glargine.
Waist circumference decreased by 1.5 cm in the liraglutide group
and increased by 0.89 cm in the insulin glargine group. Overall,
weight loss with liraglutide was independent of nausea, although
weight loss in eight patients with sustained nausea was on average
3.2 kg.
Beta-cell function improved in the liraglutide group as measured
by the pro-insulin to C-peptide ratio. Systolic blood pressure
dropped by 4 mmHg on liraglutide and was unchanged with insulin
glargine. This drop in systolic blood pressure occurred before
substantial weight loss.
The proportion of patients experiencing minor hypoglycaemia
(FPG
<
3.1 mmol/l) during the treatment period in the liraglutide
group (27.4% patients) was not different from that in the insulin
glargine group (28.9%) but higher compared with the placebo
group (16.7%). The rate of hypoglycaemic episodes (major, minor
and symptoms only) was, respectively, 0.06, 1.2 and 1.0 events/
patient/year in the liraglutide group; 0, 1.3 and 1.8 events/patient/
year in the glargine group; and 0, 1.0 and 0.5 events/patient/
year in the placebo group. Five patients (2.2%) in the liraglutide
group reported major hypoglycaemic events, one required medical
assistance, and none resulted in coma or seizures. None of the
