XML Template (2009) [7.9.2009–9:27am] [1–14]
{TANDF_FPP}CMO/CMO_A_370737(NEW).3d (CMO) [First Proof]
Current Medical Research and Opinion
C213
Volume 25, Number 3 2008
Baseline HbA
1c
<8% >8% and <9%
>9% and <10% >10%
(mean 7.6%) (mean 8.4%)
(mean 9.4%) (mean 10.4%)
0.0 0.0
−0.5 −0.5
−1.0 −1.0
−1.5 −1.5
−2.0 −2.0
change from baseline at Week 54 (%)
1c
−2.5 −2.5
HbA
SITA 100 mg (n/n/n/n = 28/43/19/16)
MF 500 mg b.i.d. (32/39/30/16)
−3.0 −3.0
MF 1000 mg b.i.d. (40/53/33/8)
SITA 50 + MF 500 mg b.i.d. (39/49/38/21)
SITA 50 + MF 1000 mg b.i.d. (33/60/43/17)
−3.5 −3.5
Figure 2. Mean change (SE) from baseline in HbA
1c
by baseline HbA
1c
subgroup (n per subgroup for continuation APT population within legend).
SITA, sitagliptin; MF, metformin.
210
responses were observed in all treatment groups compared
Phase A Continuation Phase
200
with the CAPT analyses. Consistent with the finding that
190
baseline HbA
1c
impacts treatment response
25
, changes
from a baseline at week 54 ranged from C02.0% in the
180
sitagliptin group to C03.1% in the high-dose combination
170
group in a subgroup of patients with baseline HbA
1c
160
C2110%. The substantial reduction in HbA
1c
enabled two-
FPG (mg/dL)
150
thirds of the continuation patients in the high-dose com-
140 binationgrouptoreachtheHbA
1c
targetof57.0%atweek
130
54. Furthermore, among CAPT patients in the high-dose
120
combination group who had an HbA
1c
57.0% at week 24,
110
86% had an HbA
1c
57.0% at week 54. Importantly, treat-
0 3 6 12 18 24 30 38 46 54 ment with initial combination therapy was durable, as
Weeks
demonstrated by the HbA
Sitagliptin 100 mg q.d. (
1c
and FPG curves over time.
n = 105)
MF 500 mg b.i.d. (n = 117)
Although the combination treatments have greater effects
MF 1000 mg b.i.d. (n = 134)
Sitagliptin 50 mg + MF 500 mg b.i.d. (n = 146)
on HbA
1c
, the curves over time have similar shapes, sug-
Sitagliptin 50 mg + MF 1000 mg b.i.d. (n = 153)
gesting similar durability among treatments.
Figure 3. Fasting plasma glucose (FPG) over time (meanC6standard error;
Substantial reductions in glucose in the fasting and
continuation APT population). postprandial state were observed at week 54 in all groups
with the largest reductions in the combination groups.
Furthermore, the combination of sitagliptin and metfor-
well-tolerated and produced additive and substantial minimprovedmeasuresofC12-cellfunction(e.g.,HOMA-C12;
improvement in overall glycemic control
15
. P/I ratio) and insulin resistance. The ratio of insulin
The 24-week study, previously reported
15
, was contin- secreted per unit glucose following a standard meal was
ued for an additional 30 weeks to provide information also increased with combined treatment, suggesting
about the longer-term efficacy and safety results for the enhanced C12-cell responsiveness. Collectively, these
initial combination therapy of sitagliptin and metformin. improvements demonstrate the complementary mechan-
In this 54-week study, the combinations of sitagliptin and ismsofactionofsitagliptinandmetformin,whichtogether
metformin provided substantial reductions (1.4% and target the three core pathophysiologic defects of type 2
1.8% for the low and high doses, respectively) in HbA
1c
. diabetes: declining C12-cell function, increased insulin resis-
In the completers analyses, numerically greater glycemic tance, and excess hepatic glucose output
26,27
.
!
2009 Informa UK Ltd
www.cmrojournal.com 54-week efficacy and safety of sitagliptin/metformin Williams-Herman et al.
9
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