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The Incretin System and Type 2 Diabetes
Figure 1: HbA
1c
Reductions with Exenatide 10µg Twice Figure 2: Weight Reductions with Exenatide 10µg Twice
Daily (A)
26–31
and Liraglutide 1.8mg Once Daily (B)
34–39
Daily (A)
26–28
and Liraglutide 1.8mg Once Daily (B)
34–39
A A
AMIGO AMIGO AMIGO Heine Barnett Nauck
AMIGO 1 AMIGO 2 AMIGO 3
Baseline1 2 3 2005 2007 2007
101 100 95 99 98 99
Baseline
weight (kg)
8.2 8.2 8.6 8.7 8.5 8.5 8.2 8.0 8.9 9.0 8.6 8.6
HbA (%)
1c
3.0
0.5
0.2
0.1 0.1
2.0
0
1.0
-0.5
0
-1.0
-0.3 reduction (%)
1c -0.6
-1.0-0.8 -0.9 -0.8
-0.9-1.0
-0.9
**
**-1.1 -1.1
HbA ight reduction (kg)
-1.5
e
-1.6 -1.6
W
-2.0
-1.4 -1.4
**
-2.0
-3.0 -2.8
Exenatide Placebo Insulin glargine Insulin aspart
-4.0
*Significantly greater HbA reduction with experience versus placebo (p<0.002)
1c
**Significantly greater HbA reductions from baseline for exenatide and comparator (p<0.001)
1c
Exenatide Placebo
B
B
LEAD-3 LEAD-2 LEAD-1 LEAD-4 LEAD-5 LEAD-6
LEAD-3 LEAD-2 LEAD-1 LEAD-4 LEAD-5 LEAD-6
Baseline
8.3 8.4 8.4 8.4 8.4 8.5 8.4 8.4 8.6 8.4 9.1 9.1 9.4 8.2 8.1
HbA (%)
1c
Baseline
92.8 93.4 88.0 91.0 89.0 83.0 81.9 80.6 94.9 85.5 85.7 85.0 93.1 93.0
98.50.5 weight (kg)
0.2
3.0
0.1
0
2.1
2.0
1.6
-0.2
-0.5 1.1
1.0
1.5
-0.4
-0.5
-0.5 0.5
-1.0
-0.8
reduction 9%)
0
1c
-1.0-1.0
-1.1
*-1.1 -0.1*-1.1 *-1.1HbA
-1.5
-0.2
-0.4-1.0-1.3
*-1.5 ight reduction (kg)
e
-2.0
W
-2.0 -1.5
-1.8
Liraglutide Active comparator Placebo
-2.0
-2.5
-3.0*Significantly greater HbA reduction with liraglutide versus active comparator (p<0.0001)
1c -2.8
Active comparators: LEAD-1, rosigliazone 4mg; LEAD-2 and LEAD-3, glimepiride 8mg;
-2.9
LEAD-5, insulin glargine; LEAD-6, exenatide 10μg BID
-3.2
-4.0
Liraglutide Active comparator Placebo
reductions of 0.80–0.86% were observed in the three AMIGO trials where
Active comparator: LEAD-3 and LEAD-2, glimepiride 8 mg; LEAD-1, rosiglitazone 4mg;
exenatide treatment was added to various OAD combinations (see LEAD-5, insulin glargine; LEAD-6, exenatide 10μg BIDFigure
1).
26–28
Other trials have demonstrated that exenatide offers HbA
1c
reductions that are non-inferior to insulin glargine
29–30
or insulin aspart
31
Liraglutide has been studied in the LEAD (Liraglutide Effect and Action in
(see Figure 1). Exenatide treatment was associated with weight reductions Diabetes) trials,
34–39
which were designed to investigate liraglutide as
of 1.6–2.8kg (see Figure 2).
26–28
These data are in agreement with a meta- either monotherapy or in combination with one or two OADs and
analysis of trials involving exenatide, which indicated an average reduction compare them against some commonly used therapies for type 2
in HbA
1c
of approximately 1.0%, a reduction in fasting blood glucose of diabetes (see Table 1).
34–39
Liraglutide treatment was associated with
approximately 25mg/dl, and weight reductions of 2–3kg over 30 weeks.
32
reductions in HbA
1c
of between 1–1.5% in the LEAD trials (see Figure
Exenatide was associated with weight benefits versus insulin glargine 1).
34–39
Liraglutide induced significantly greater reductions in HbA
1c
than
(between-group difference -2.2kg; p<0.001)
29
and insulin aspart (-5.4kg; comparator treatment in all but the LEAD 2 trial,
35
in which it was similar.
p<0.001).
31
Higher rates of gastrointestinal adverse events were observed The LEAD 6 study compared liraglutide 1.8mg once daily and exenatide
with exenatide than with insulins.
29–31
A long-term evaluation of patients 10µg twice daily as add-ons to metformin and/or SU therapy.
39
In
who continued exenatide treatment following the AMIGO studies has LEAD 6, mean HbA
1c
reduction was significantly greater with liraglutide
suggested that initial improvements in glycemic control and weight loss treatment than with exenatide (-1.12 versus -0.79%; p<0.0001) and
continued over a two-year period.
33
Of 1,446 individuals included in the mean fasting plasma glucose was significantly lower with liraglutide
original intention-to-treat population, however, only 283 completed the (-29mg/dl) compared with exenatide (-10.8mg/dl; p<0.0001).
39
Both
two-year extension, so loss of approximately 80% of the original study liraglutide and exenatide were well tolerated. Nausea was less
population may have introduced some bias in the study findings.
33
persistent with liraglutide than with exenatide (p<0·0001). Minor
US ENDOCRINOLOGY 59
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