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Diabetes Management Incretin Mimetics
Table 1: The LEAD Trials Examined the Role of Liraglutide
Beta-cell Effects
Therapy Across a Range of Treatment Intensities
Studies in animal and in vitro models suggested that GLP-1 receptor
agonists may promote pancreatic beta-cell neogenesis and preservation.
Study Liraglutide Group Active Comparator Placebo and These initial observations have been supported by data from the LEAD
Background Therapy
trials showing improvements in beta-cell function by a homoeostatic
LEAD 1
34
Liraglutide + Rosiglitazone + Glimepiride
model assessment (HOMA) index of beta-cell function (HOMA-B) of
glimepiride glimepiride
27–35% from baseline following liraglutide treatment.
34–39
Similar
LEAD 2
35
Liraglutide + Glimepiride + Metformin
metformin metformin
improvements in HOMA-B were observed with exenatide.
40,41
Liraglutide
LEAD 3
36
Liraglutide Glimepiride No placebo group
and exenatide also improved other measures of beta-cell function, such
monotherapy monotherapy
as the pro-insulin to insulin ratio, as well as other non-beta-cell-related
LEAD 4
37
Liraglutide + No active Metformin + improvements in glycemic measures, such as the HOMA-index of insulin
metformin and comparator group rosiglitazone resistance. These results suggest that GLP-1 receptor agonists have the
rosiglitazone
potential to improve beta-cell function, a key underlying pathology in
LEAD 5
38
Liraglutide + Insulin glargine + Metformin +
type 2 diabetes. Whether this is reflected in improved durability of
metformin and metformin + glimepiride
glycemic control needs to be tested in long-term clinical trials.
glimepiride glimepiride
LEAD 6
39
Liraglutide + Exenatide + No placebo group
Adverse Side Effects
metformin and/ metformin and/
As expected from the glucose-dependent glucose lowering of GLP-1, the
or glimepiride or glimepiride
GLP-1 receptor agonists are associated with low hypoglycemia rates
Appropriate placebos for both liraglutide injections plus active comparators were included in all
in clinical studies. Hypoglycemia was most commonly reported when
treatment groups.
GLP-1 receptor agonists were combined with SUs, so prescribing
Figure 3: Systolic Blood Pressure Reduction with
information for exenatide and liraglutide both include a recommendation
Liraglutide 1.8mg Once Daily
34–39
to reduce SU dosing when adding a GLP-1 receptor agonist. Individuals
may also experience nausea when therapy is initiated, which in most
cases ceases within four weeks. This probably relates to delayed gastric
emptying. Gradual dose titration of both exenatide and liraglutide mayLEAD-3 LEAD-2 LEAD-1 LEAD-4 LEAD-5 LEAD-6
Baseline
help to avoid this potential side effect.
41,42
SBP (mmHg) 128 130 131 135 132 132 131 133 126 135 133 133 132 134
128
1.0
0.5
0.4
The Dipeptidyl Peptidase-4 Inhibitors
0
DPP-4 inhibitors act by increasing endogenous GLP-1 and GIP activity.
However, only GLP-1 retains insulinotrophic activity in individuals with
-1.0
type 2 diabetes. There is evidence that DPP-4 inhibitors induce lower
-0.7
-0.9
-1.1
placebo-corrected HbA
1c
reductions (0.7–1.0%) compared with GLP-1
-1.4-2.0
receptor agonists (1.0–1.5%),
32,34–38,43
but this needs to be confirmed in-1.8
-2.0
-2.3-2.3
head-to-head trials. There are a number of DPP-4 inhibitors in
-3.0
-2.5
-2.8
development, including alogliptin and linagliptin; however, this section
SBP reduction (mmHg)
-4.0
will concentrate on sitagliptin and saxagliptin, as these agents have
-3.6
-4.0
received regulatory approval in the US.
-5.0
Sitagliptin
-6.0
-5.6
Sitagliptin is approved for use at a dose of 100mg/day as either
Liraglutide Active comparator Placebo
monotherapy or in combination with metformin or TZDs in the US.
44
In
patients with moderate or severe renal insufficiency the dose ofActive comparator: LEAD-1 rosiglitazone 4mg; LEAD-2 and LEAD-3, glimepiride 8mg;
LEAD-5, insulin glargine; LEAD-6, exenatide 10μg BID
sitagliptin should be reduced to 50 and 25mg/day, respectively.
44
In the
EU, sitagliptin is approved for use as dual or triple combination therapy
SBP = systolic blood pressure.
with metformin, SUs, or TZDs and as monotherapy where metformin is
hypoglycemia was also less frequent with liraglutide than with exenatide contraindicated or not tolerated. In addition, sitagliptin is indicated as
(1.93 versus 2.60 events per patient per year; p=0.01).
39
With the an add-on to insulin (± metformin) when diet and exercise plus insulin
exception of LEAD 1, in which liraglutide plus glimepiride treatment do not achieve adequate glycemic control. At doses ≥100mg,
was weight-neutral,
34
in the other studies liraglutide treatment was sitagliptin inhibits ≥80% of DPP-4 activity over 24 hours.
45
This results
associated with weight reductions of approximately 2–3kg (see Figure in at least a two-fold increase in post-meal levels of endogenous GLP-
2).
35–39
Systolic blood pressure reductions of between 2.3 and 5.6mmHg 1 compared with placebo.
45–47
The greatest HbA
1c
reductions reported
were also observed with liraglutide treatment (see Figure 3). In the head- with sitagliptin have been observed when it has been used in
to-head comparison of liraglutide and exenatide (LEAD 6), the decrease combination with metformin in previously OAD-naïve patients
in systolic blood pressure by 2.5 and 2.0mmHg, respectively, was not (placebo-adjusted reductions of -0.83 and -1.57% for sitagliptin 100mg
significantly different between the groups.
39
and sitagliptin 100mg plus metformin 1,000mg, respectively).
48
This
60 US ENDOCRINOLOGY
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