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Liraglutide Treatment for Type 2 Diabetes
addition of a fatty acid side chain linked via a glutamoyl spacer at position Figure: 1 The Effect of Liraglutide Addition at Various
26. From a therapeutic perspective, the modification of the amino acid
Stages of Oral Antidiabetes Therapy Intensification
sequence and the addition of a fatty acid side chain substantially
improves the pharmacokinetics and pharmacodynamics of liraglutide
Add a third oral
Liraglutide + MET + TZDagent or start insulin
compared with human GLP-1, increasing the versus MET + TZDin vivo half-life from
approximately two minutes to 13 hours. This increase in the half-life of
liraglutide is related to increased self-association (heptamer formation)
Liraglutide + MET + SU
versus glargine + MET
and albumin binding and reduced susceptibility to DPP-4.
Therapeutic + SU (LEAD 5)
levels of liraglutide are sustained over 24 hours following a single dose,
Liraglutide + MET versus
SU + MET
which means that liraglutide can be administered once daily. In addition,
Liraglutide + MET and/or
liraglutide has a glucose-dependent mechanism of action,
SU versus exenatide +
Liraglutide + SU versus
MET and/or SU
that it lowers blood glucose only when plasma glucose levels are high.
TZD + SU
Start an oral agent
There is no evidence that liraglutide exhibits clinically relevant alteration
in drug metabolism in individuals with renal and hepatic insufficiency, so
these data suggest that liraglutide could be used without dose
adjustment in these populations.
By contrast, exenatide is not
recommended for patients with renal insufficiency.
sitagliptin is not recommended for patients with moderate or severe
From the Liraglutide Effect and Action in Diabetes (LEAD) trials.
renal impairment in Europe, while in the US it is recommended that MET = metformin; SU = sulphonylurea; TZD = thiazolidinedione.
sitagliptin dosing be adjusted in individuals with renal insufficiency.
study of atorvastatin, lisinopril, digoxin and griseofulvin, drugs with liraglutide 1.8mg compared with placebo, rosiglitazone and
differing solubility and permeability properties, demonstrated that glimepiride.
Liraglutide was associated with significantly greater
liraglutide does not induce clinically significant alterations in the HbA
reductions (-1.12%) compared with exenatide (-0.79%) in the
pharmacokinetics of concomitantly administered oral drugs.
Other LEAD 6 study (p<0.0001).
reduction observed with exenatide
drug interaction studies have demonstrated that liraglutide has no in LEAD 6 was similar to previously reported HbA
clinically significant interactions with paracetamol or a low-dose oral FPG concentrations were reduced by a maximum of 0.6mmol/l with
exenatide compared with a gain of 0.8mmol/l in the placebo group
Sitagliptin monotherapy with 100 or 200mg once daily
Clinical Data produced reductions in HbA
of -0.6 and -0.8%, respectively (p<0.001
In a 14-week phase II study of adult patients with type 2 diabetes, versus placebo), and reductions in FPG of -0.7 and -0.9 mmol/l versus
liraglutide demonstrated an average glycated haemoglobin (HbA
) placebo, respectively.
reduction of 1.74% versus placebo from a baseline of 8.5%, and
approximately 50% of patients met the American Diabetes Association Low Risk of Hypoglycaemia
(ADA) target of <10mmol/l for post-prandial hyperglycaemia (PPG) with Liraglutide is associated with a low risk of hypoglycaemia. In total, only
1.9 and 1.25mg/day liraglutide monotherapy.
In addition, liraglutide was six patients in all of the LEAD trials treated with liraglutide reported
associated with dose-dependent weight reduction (-2.99kg in the 1.9mg major hypoglycaemic episodes.
Significantly lower rates of minor
group; p=0.039 versus placebo), improvements in pancreatic hypoglycaemia were reported with liraglutide versus glimepiride in the
β-cell function (p<0.0001 for all liraglutide doses versus placebo) and LEAD 2 and LEAD 3 trials (p<0.0001) and versus exenatide in the LEAD 6
reductions in systolic blood pressure of 5.02–7.9mmHg versus placebo.
trial (1.9 versus 2.6 events per patient-year; p=0.01). In LEAD 4, minor
The 1.9mg dose was used in the phase II studies; however, in the phase hypoglycaemia was low in all groups but was significantly higher in the
III studies liraglutide was dosed at 1.2 or 1.8mg daily. liraglutide group than in the metformin + rosiglitazone group (0.64
versus 0.17 events per patient-year; p=0.004). Higher rates of
The six phase III Liraglutide Effect and Action in Diabetes (LEAD) trials hypoglycaemia were observed in trials where liraglutide or exenatide
examined the effect of liraglutide in patients with type 2 diabetes at were combined with SUs, suggesting that SU dosing may need to be
various stages of the disease (see Figure 1). The LEAD studies reduced when it is used in combination with GLP-1 receptor agonists.
demonstrated that liraglutide was effective as a monotherapy (LEAD 3)
Low rates of hypoglycaemia were also observed in trials of exenatide
in combination with one oral antidiabetic agent (OAD), such as and the DPP-4 inhibitor sitagliptin.
metformin (LEAD 2),
or a sulphonylurea (SU) (LEAD 1
and LEAD 6
with two OADs such as metfomin and thiazolidinediones (TZD) in LEAD Safety
or metformin and an SU in LEAD 5
and LEAD 6.
reductions Liraglutide is generally well tolerated: across the six LEAD trials
of between 1 and 1.5% were observed across the trials with the 1.8mg approximately 22% of patients in the liraglutide 1.8mg/day dosage group
once daily dose of liraglutide (see Table 1), and half of all LEAD patients experienced nausea.
The feelings of nausea may relate to the action
who received this dose achieved HbA
levels of <7%. LEAD 3, which of GLP-1 on delaying gastric emptying. Most cases of nausea were mild
compared liraglutide and glimepiride monotherapy, demonstrated the and transient in nature. Furthermore, studies with both liraglutide and
maintenance of HbA
reductions (1.14% for the 1.8mg dose) over exenatide have indicated that nausea can be largely avoided by
the 52-week study length,
while the other LEAD trials demonstrated gradually escalating the dose following initiation.
Lower rates of
sustained reductions over 26 weeks. Significant fasting plasma glucose gastrointestinal (GI) adverse events were observed with the DPP-4
(FPG) reductions of -1.4 to -2.4mmol/l and significant post-prandial inhibitors such as sitagliptin compared with the GLP-1 receptor agonists,
glucose (PPG) reductions of -1.8 to -2.7mmol/l were observed with which may reflect the differing levels of GLP-1 receptor stimulation with
EUROPEAN ENDOCRINOLOGY 39