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{TANDF_FPP}CMO/CMO_A_370737(NEW).3d (CMO) [First Proof]
Current Medical Research and Opinion
C213
Volume 25, Number 3 2008
(A)
9.0
Phase A Continuation Phase
co-administration and the metformin monotherapy
groups, with the lowest incidence observed in the sitaglip-
8.5
tin group. The incidences of serious adverse experiences
were slightly higher in the placebo/metformin switch
8.0
group compared with the other groups. A single serious
(%)
drug-related adverse experience was reported over the
1c 7.5
54 weeks: ketoacidosis in a placebo-treated patient who
HbA
discontinued treatment, reported in phase A
15
. Over the
7.0
54 weeks, two patients died: one patient in the placebo
6.5
group died of sudden cardiac death during the initial
24 weeks of thisstudy and the other patient in the high-
6.0
dose co-administration group died of an electrical shock
016 2182430384654
during the continuation phase. One patient who discon-
Weeks
Sitagliptin 100 mg q.d. (
tinued from the low-dose metformin group during phase A
n = 106)
MF 500 mg b.i.d. (n = 117) due to esophageal carcinoma was subsequently reported to
MF 1000 mg b.i.d. (n = 134)
Sitagliptin 50 mg + MF 500 mg b.i.d. (n = 147)
have died during the study period. An additional patient
Sitagliptin 50 mg + MF 1000 mg b.i.d. (n = 153)
died of a cerebral hemorrhage prior to randomization. The
(B) 9.0
proportions of patients discontinuing treatment due to an
Phase A Continuation Phase
adverse experience or a drug-related adverse experience
8.5
were low and similar across groups (Table 7).
The incidences of hypoglycemia were low (1–3%) and
8.0 similar across groups (Table 7). Two patients in the met-
(%)
formin500mgb.i.d.grouphadhypoglycemiaepisodesthat
1c 7.5
required non-medical assistance. No episode of hypoglyce-
HbA mia exhibited marked severity (i.e., altered consciousness
7.0
or the requirement for medical assistance). The propor-
tions of patients reporting gastrointestinal adverse experi-
6.5
ences were similar between the co-administration and
metformin monotherapy groups (Table 7). Similar find-
6.0
016 2182430384654
ingswerenotedfortheprespecified,select,gastrointestinal
Weeks adverse experiences (Table 7).
Sitagliptin 100 mg q.d. (n = 58)
MF 500 mg b.i.d. (n = 77)
MF 1000 mg b.i.d. (n = 101)
Sitagliptin 50 mg + MF 500 mg b.i.d. (n = 106)
Sitagliptin 50 mg + MF 1000 mg b.i.d. (n = 124)
Discussion
Figure 1. HbA
1c
over time (meanC6standard error). A. continuation APT
population, B. week 54 completers population.
Sitagliptin inhibits the enzymatic degradation and inacti-
vation of glucagon-like peptide-1 (GLP-1) and glucose-
dependent insulinotropic polypeptide (GIP)
16
, the incre-
groups (low-dose group (n¼143): C00.7kg [95% CI: C01.3,
tin hormones involved in glucose homeostasis
17
.
C00.0]; high-dose group (n¼153): C01.7kg [C02.4, C01.1])
Sitagliptin lowers blood glucose through its effects on
and in the metformin monotherapy groups (500mg b.i.d.
incretins by enhancing insulin release and reducing gluca-
group (n¼116): C01.0kg [95% CI: C01.7, C00.3]; 1000mg
gon secretion following a meal in patients with type 2
b.i.d. group (n¼132): C01.5kg [C02.2, C00.8]). There was
diabetes
18
.Inadditiontoimprovingglycemiccontrol,sita-
no change from baseline for patients in the sitagliptin
gliptin has been shown to improve C12-cell function using
group (n¼100; 0.6kg [95% CI: C00.2, 1.4]).
surrogate markers (HOMA-C12 and proinsulin/insulin ratio)
and a model-based approach
4,19–21
. Metformin suppresses
Safety/tolerability
hepatic glucose output and improves insulin resistance
22
.
There is also evidence that metformin may increase total
After 54 weeks of treatment, the incidences of adverse GLP-1 release
23,24
. Based on these complementary effects
experiences were generally similar in the co-administra- on glucoregulation and the safety profiles of each agent,
tion groups and their respective metformin monotherapy initial combination therapy with sitagliptin and metfor-
groups (Table 7). Lower incidences were observed in the min might be considered a useful clinical therapy for
sitagliptin and placebo/metformin groups relative to the patients with type 2 diabetes. This was confirmed in a
other groups (Table 7). The incidences of drug-related 24-week placebo-controlled trial demonstrating that the
adverse experiences were generally similar between the combination of sitagliptin and metformin was generally
8
54-week efficacy and safety of sitagliptin/metformin Williams-Herman et al. www.cmrojournal.com
!
2009 Informa UK Ltd
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