To review additional
data on Sitagliptin/Januvia, see Sitagliptin
Beta-Cell Function in Patients with Type 2 Diabetes (T2DM): A Model-Based
Abstract Number: 2014-PO
LEI XU, CHIARA DALLA MAN, CLAUDIO COBELLI, DEBORA WILLIAMS-HERMAN, GARY
MEININGER, HOOTAN KHATAMI, PETER STEIN Institutions:
Rahway, NJ; Padova, Italy.
?-cell dysfunction occurs early in T2DM and is characterized by
abnormalities such as depressed ?-cell sensitivity to glucose with respect
to insulin release. Incretins have been shown to enhance ?-cell function in
patients with T2DM and in animal models of diabetes. Since sitagliptin (SIT; a
DPP-4 inhibitor) increases active incretin levels, ?-cell function was
assessed using frequently sampled (9-points) meal tolerance tests (MTT) in
sub-studies from 3 Phase III trials (2 monotherapy studies and an add-on to
metformin study) using a model-based analysis. For the MTT, blood was collected
at -10, 0, 10, 20, 30, 60, 90, 120, and 180 min relative to start of the meal.
Parameters for ?-cell function were assessed using the C-peptide minimal
model, which allows for the estimation of the insulin secretion rate and the
characterization of the insulin secretion response into basal (F?b; ?-cell
responsiveness to basal glucose concentrations), static (F?s; ?-cell responsiveness to above-basal glucose
concentrations following a meal), and dynamic (F?d; ?-cell
responsiveness to the rate of increase in above-basal glucose concentrations
following a meal) components. Insulin sensitivity was assessed with a validated
composite index (ISI). The disposition indices, which assess insulin secretion
in the context of changes in insulin sensitivity, were also assessed. When used
as monotherapy or added to on-going metformin therapy, SIT produced improvements
in F?s and in F?b and overall responsiveness
of the ?-cell to glucose (F). The parameter describing dynamic
sensitivity of the ?-cell to glucose (F?d) showed numerical, but not statistically significant,
improvements with SIT. Disposition indices were also broadly improved with SIT
treatment relative to placebo. Despite enhanced ?-cell sensitivity to
glucose, the very low rate of hypoglycemia observed in clinical trials with SIT
indicated that the increase in ?-cell function remained glucose-dependent.
In summary, SIT improved ?-cell function in both fasting and postprandial
Effects of Sitagliptin on the Pharmacokinetics (PK) of Rosiglitazone in
Abstract Number: 2001-PO
GOUTAM MISTRY, ARTHUR BERGMAN, WEN-LIN LUO, CAROLINE CILISSEN, WOUTER HAAZEN,
JOHN WAGNER, GARY HERMAN.
Rahway, NJ; Antwerp; Brussels, Belgium.
Sitagliptin an orally active, potent and selective dipeptidyl peptidase-4
inhibitor, is an incretin enhancer that is in development for the treatment of
type 2 diabetes. Sitagliptin is mainly renally eliminated and not a potent
inhibitor of CYP450 enzymes in vitro. Rosiglitazone, a thiazolidenedione, is an
insulin sensitizer and is mainly metabolized by CYP2C8. Since both agents may be
eventually coadministered in clinical practice, the purpose of this study was to
examine the effects of sitagliptin on rosiglitazone PK. In this open-label,
randomized, 2-period crossover study, 12 healthy subjects with normal glucose
concentrations, 21-44 years, received a single 4-mg dose of rosiglitazone alone
in one period and coadministered with sitagliptin on day 5 following a multiple
dose regimen for sitagliptin (200-mg qd x 5 days) in the other period.
Sitagliptin with or without rosiglitazone did not result in hypoglycemia or
serious adverse experiences in these healthy, normglycemic subjects. Sitagliptin
did not meaningfully alter the PK of rosiglitazone (see table).[table1]In
conclusion, sitagliptin does not meaningfully alter the PK of rosiglitazone in
healthy subjects. As rosiglitazone is a probe CYP2C8 substrate, these data
suggest that sitagliptin is not an inhibitor of CYP2C8-mediated metabolism.
Multiple doses of sitagliptin are generally well tolerated when administered
with or without a single dose of rosiglitazone.
Rosiglitazone + Sitagliptin
Rosiglitazone + Sitagliptin/Rosiglitazone
GMR (90% CI)
0.98 (0.93, 1.02)
0.99 (0.88, 1.12)
Geometric Least-Squares Mean; GMR= Geometric
Least-Squares Mean Ratio (Rosiglitazone + Sitagliptin/Rosiglitazone); CI=
Confidence Interval; § Median; ¦ Harmonic Least-Squares Mean; ¶
Between-treatment comparison p-value (Rosiglitazone + Sitagliptin versus
Sitagliptin Monotherapy Improved Glycemic Control and Beta-Cell Function after
18 Weeks in Patients with Type 2 Diabetes (T2DM)
Abstract Number: 1996-PO
ITAMAR RAZ, MARKOLF HANEFELD, LEI XU, CHRISTINE CARIA, MICHAEL DAVIES,
DEBORA WILLIAMS-HERMAN, HOOTAN KHATAMI.
Jerusalem, Israel; Dresden, Germany; Rahway, NJ.
The efficacy and safety of once-daily, sitagliptin (SIT), a DPP-4 inhibitor,
were assessed in a randomized, double-blind, placebo (PBO)-controlled study in
patients (pts) with T2DM. After a washout period for those on an
antihyperglycemic agent and a 2-week single-blind PBO run-in period, 521 pts
ages 27 - 76 yrs with HbA?1c =7.0% and =10.0% were randomized in a 1:2:2
ratio to PBO, SIT 100 mg q.d., or 200 mg q.d. for 18 wks. Mean baseline HbA?1c was 8.1%. The efficacy
analysis was based on an all-patients-treated population using an ANCOVA. After
18 wks, HbA1c was significantly reduced with SIT 100 mg and 200 mg compared with PBO (PBO-subtracted
HbA?1c (=9%) experienced
greater PBO-subtracted reductions in HbA1c with SIT treatment (-1.20% for 100 mg and -1.04% for
200 mg) than those with baseline HbA1c <8% (-0.44% and -0.33%, respectively) or 8% to 8.9%
(-0.61% and -0.39%, respectively). SIT significantly decreased FPG relative to
PBO (PBO-subtracted FPG: -19.7 mg/dL for 100 mg and -16.9 mg/dL for 200 mg). In
a subset of pts completing a meal tolerance test (n = 150), 2-hr post-meal
glucose (PPG) was significantly reduced with SIT 100 mg and 200 mg compared with
PBO (PBO-subtracted 2-hr PPG: -46.3 mg/dL and -52.7 mg/dL, respectively). There
were no significant differences between SIT doses for these glycemic parameters.
HOMA-?, an index of beta-cell function, was significantly increased for
both doses, and fasting proinsulin/insulin ratio was significantly decreased
with SIT 100 mg. SIT was overall well tolerated; there was no significant
increased incidence of hypoglycemia or GI AEs with SIT compared with PBO. Mean
body weight was similarly reduced with SIT 100 mg (-0.6 kg), SIT 200 mg (-0.2
kg) and PBO (-0.7 kg) after 18 wks. In this study, SIT monotherapy improved
glycemic control as well as measures of ?-cell function, and was
well-tolerated over 18 wks in pts with T2DM.
Use of Sitagliptin in Patients with Type 2 Diabetes (T2DM) and Renal
Abstract Number: 1997-PO
RUSSELL SCOTT, PAUL HARTLEY, EDMUND LUO, JACQUELINE YEE, MICHAEL DAVIES,
JUAN CAMILO ARJONA FERREIRA, DEBORA WILLIAMS-HERMAN.
Christchurch, New Zealand; Uniontown, PA; Rahway, NJ.
Sitagliptin (SIT), a dipeptidyl peptidase-4 inhibitor, is primarily renally
excreted, and SIT exposure (i.e., AUC0-8) is increased by approximately 2.3, 3.8, and
4.5-fold relative to healthy subjects for patients (pts) with moderate RI (creatinine
clearance [CrCl]=30 to <50 mL/min), severe RI (CrCl <30 mL/min), and ESRD
(on dialysis), respectively. The present study examined the safety of SIT in
T2DM pts with CrCl <50 mL/min. After diet/exercise and AHA washout period
(except pts on prior insulin therapy who remained on insulin), 91 pts ages 41-92
yrs (mean 68 yrs) with HbA?1c values of 6.2 - 10.3% (mean 7.7%) were randomized (2:1)
to SIT or placebo (PBO) for 12 wks. For pts randomized to SIT, pts with moderate
RI were dosed with 50 mg q.d. and those with severe RI or ESRD received 25 mg
q.d. in order to achieve drug exposure similar to that observed with 100 mg q.d.
in pts with normal to mildly impaired renal function. At baseline, 10% were on
insulin therapy, and 43% had CrCl <30 mL/min. The overall incidence of
adverse experiences (AEs) was similar between groups. The incidences of
drug-related AEs, serious AEs, and discontinuations due to AEs were modestly
higher with SIT than with PBO. These differences did not reflect any particular
AEs with meaningfully higher incidences. No differences in the proportion of pts
experiencing hypoglycemia or GI AEs were observed between groups. Two pts died
of sudden death: 1 prior to randomization and 1 on SIT during the treatment
period. Three (4.6%) of 65 pts on SIT, and 0 of 25 pts on PBO had AEs of heart
failure; all 3 pts with heart failure had pre-existing CAD and heart failure.
After 12 wks, mean HbA?1c and FPG were reduced by 0.59% and 25.5 mg/dL,
respectively, with SIT (doses pooled) and 0.18% and 3.0 mg/dL with PBO. Body
weight was unchanged with SIT and decreased 0.6 kg with PBO at wk 12. In this
study, dose-adjusted SIT was generally well tolerated and appeared to be
effective in pts with T2DM and moderate to severe RI including ESRD.
Improved Glycemic Control in the Fasting and Postprandial States and Beta-Cell
Function after 24 Weeks in Patients with Type 2 Diabetes (T2DM)
Abstract Number: 1995-PO
PABLO ASCHNER, MARK KIPNES, JARED LUNCEFORD, CAROLYN MICKEL, MICHAEL DAVIES,
BogotÁ, Colombia; San Antonio, TX; Rahway, NJ.
The efficacy and safety of once-daily sitagliptin (SIT), a DPP-4 inhibitor,
were assessed in a 24-wk, randomized, double-blind, placebo (PBO)-controlled
study in patients (pts) with T2DM. After drug washout period for those on an
AHA, and a 2-wk single-blind PBO run-in period, 741 pts ages 18-75 yrs with HbA1c =7.0% and
=10.0% were randomized (1:1:1) to PBO, SIT 100 mg q.d., or SIT 200 mg q.d.
Mean baseline HbA?1c
was 8.0%. The efficacy analysis was based on an all-patients-treated population
using an ANCOVA. After 24 wks, SIT 100 mg and 200 mg produced significant (p
< 0.001) PBO-subtracted reductions in HbA1c (-0.79% and -0.94%,
respectively) and FPG (-17.1 mg/dL and -21.3 mg/dL, respectively). Pts with
higher baseline HbA?1c (=9%) had greater reductions in PBO-subtracted HbA1c with SIT (-1.52% for 100
mg and -1.50% for 200 mg) than those with baseline HbA?1c, FPG, or PPG reductions between SIT doses. Post-meal
insulin and C-peptide AUC, ratio of insulin AUC/glucose AUC, and HOMA-?, an
index of ?-cell function, were significantly increased with SIT relative to
PBO. Fasting insulin, C-peptide, and proinsulin were not different between SIT
and PBO. Proinsulin/insulin ratio was significantly reduced with SIT compared to
PBO. There was no increased rate of hypoglycemia or GI AEs with SIT compared
with PBO. Minimal reductions from baseline in body weight were observed with SIT
100 mg (-0.2 kg) and 200 mg (-0.1 kg); body weight was significantly reduced
with PBO (-1.1 kg). In this 24-wk study, SIT monotherapy improved glycemic
control in the fasting and postprandial states, improved measures of ?-cell
function and was well tolerated in pts with T2DM.
Sitagliptin, a DPP-4
Inhibitor, Does Not Inhibit the Pharmacokinetics of the Sulfonylurea,
Abstract Number: 558-P
MARCELLA K. RUDDY, ARTHUR J. BERGMAN, WEI ZHENG, DAVID HRENIUK, MIGUEL ZINNY,
JOHN A. WAGNER, GARY A. HERMAN.
Boston, MA; West Point, PA; Rahway, NJ.
Sitagliptin (MK-0431) is an oral, potent and highly selective DPP-4
inhibitor. Glyburide (glibenclamide), a CYP2C9 substrate, is a second generation
oral sulfonylurea drug. It is anticipated that a subset of patients who have
inadequate glycemic control on monotherapy may benefit from the coadministration
of sitagliptin and a sulfonylurea. The purpose of this study was to demonstrate
that steady-state concentrations of sitagliptin do not meaningfully alter the
pharmacokinetics of glyburide. This randomized, open-label, 2-period, crossover
study examined the effects of oral multiple dose administration of sitagliptin
on the single dose pharmacokinetics of glyburide in healthy adults. Subjects
were randomized to the sequence of 2 treatment periods separated by a minimum
washout of 7 days between doses of glyburide. In Treatment A, subjects received
200 mg sitagliptin once daily for 6 days (Days 1 to 6) and a single open-label
1.25-mg dose of glyburide on Day 5. In Treatment B, subjects received a single
1.25-mg dose of glyburide on Day 1.
results of this study indicate that steady state concentrations of sitagliptin
(obtained after 5 days of administration of once-daily dosing) have no
meaningful effect on the pharmacokinetics of a single dose of glyburide. The AUC?0-8 GMR for (glyburide+sitagliptin/ glyburide) was 1.09 with a
corresponding 90% CI of (0.96, 1.24) which was contained within the
pre-specified bounds of (0.70, 1.43) and supported the study's primary
hypothesis. The C?max
GMR for glyburide+sitagliptin/ glyburide was 1.01 with a corresponding 90% CI of
(0.84, 1.23). There were also no statistically significant differences in those
subjects treated with coadministered sitagliptin and glyburide vs. glyburide
alone in either AUC?0-8 or C?max.
In addition, there were no meaningful differences in T?max
nor apparent t?1/2 values between treatments.
conclusion, sitaglitpin does not meaningfully alter the pharmacokinetics of
glyburide and therefore is not an inhibitor of CYP 2C9.
Direct Comparison of Efficacy and Durability of DPP-4 Inhibitor, PPARG
Agonist and Sulfonylurea on Glycemic Control and ?-Cell Function in a
Rodent Model of Type 2 Diabetes
Abstract Number: 588-P
JAMES MU, YUN-PING ZHOU, JOHN WOODS, ZHIHUA LI, YUE FENG, EMANUEL ZYCBAND,
ANDREW HOWARD, CAI LI, NANCY A. THORNBERRY, BEI B. ZHANG.
Dipeptidyl peptidase-4 (DPP-4) is a key regulator of actions of incretin
hormones. We have previously shown that DPP-4 inhibition improves glycemic
control in streptozotocin-treated high-fat fed (HFD/STZ) ICR mouse model with
defects in insulin sensitivity and secretion. Here, we examined the effects of
des-fluoro-sitagliptin (a DPP-4 inhibitor; an analog of sitagliptin) on glycemic
control and pancreatic islet function in ICR HFD/STZ mice in comparison with
rosiglitazone (a PPARG agonist; Rosi) and glipizide (a sulfonylurea).
Significant correction of postprandial and fasting hyperglycemia, HbA1c,
circulating insulin, triglyceride and free fatty acid levels were observed in
mice following a 10-week treatment with des-F-sitagliptin. The improved glucose
homeostasis in the des-F-sitagliptin treated mice was linked to significant
increased ?-cell mass, ?/? cell ratio, and improved
glucose-stimulated insulin secretion (GSIS). Compared to DPP-4 inhibition, Rosi
treatment led to comparable improvement in plasma glucose and islet function,
but less favorable effects on glucose tolerance and liver triglyceride, likely
due to significant body weight gain and fat accumulation associated with chronic
Rosi treatment. Glipizide administration in the same paradigm resulted in
glucose (but not HbA1c) lowering only in the first weeks, but its efficacy
diminished afterwards possibly due to exhaustion of insulin-producing capacity
of ?-cells. Furthermore, greater reductions in circulating and pancreatic
glucagon levels and in glucagon positive ?-cell/total islet area were
observed in des-F-sitagliptin treated mice. These findings suggest that DPP-4
inhibition with des-F-sitagliptin provides superior disease-modifying potential
and better durability of glucose lowering compared to glipizide and better
improvement in glucose tolerance and less body weight gain than observed with
PPARG agonist therapy.
Twelve-Week Efficacy and
Tolerability of Sitagliptin, a Dipeptidyl Peptidase-IV (DPP-4) Inhibitor, in
Japanese Patients with T2DM
Abstract Number: 537-P
KENJI NONAKA, TARO KAKIKAWA, ASAKO SATO, KOTOBA OKUYAMA, GO FUJIMOTO, NAOKI
HAYASHI, HIDEYO SUZUKI, YUKIO HIRAYAMA, PETER STEIN.
Tokyo, Japan; Rahway, NJ.
Sitagliptin (MK-0431) is an orally active, potent, selective DPP-4 inhibitor
in development for the treatment of T2DM. This randomized, double-blind,
placebo-controlled, parallel group study evaluated the efficacy and tolerability
of sitagliptin in Japanese patients with T2DM.
with T2DM either not on an antihyperglycemic agent or on an antihyperglycemic
agent in monotherapy (discontinued at entry into the run-in period), entered an
8 week diet and exercise run-in period. Patients with an A1C of 6.5 to 10.0%
after the run-in period were eligible to be randomized to sitagliptin 100 mg q.d.
or placebo for a 12-week treatment period. The efficacy analysis was based on a
modified intention-to-treat population with last observation carried forward.
(N = 151), ages 27-69 years, were randomized 1:1 to sitagliptin (n=75) or to
placebo (n=76). Mean baseline A1C was 7.5% in the sitagliptin and 7.7% in the
placebo. At Week 12, A1C decreased by -0.65% in the sitagliptin compared with an
increase of 0.41% in the placebo, for a between-treatment group difference in
A1C of -1.05% (95% CI: -1.27, -0.84%; p<0.001). In an analysis of patients
achieving A1C goal, 58.1% of patients on sitagliptin achieved an A1C of <7%
compared with 14.5% on placebo. In a subset that underwent a meal tolerance
test, 2-hour postprandial glucose decreased by -69.2 mg/dL in the sitagliptin
group compared with an increase of 11.7 mg/dL on placebo at week 12. Treatment
with sitagliptin was well tolerated with no reported adverse experiences of
hypoglycemia. The overall incidence of adverse experiences reported was similar
between treatment groups. Although body weight was unchanged in the sitagliptin
after 12 weeks (-0.1 kg), the reduction was significantly (p=0.003) greater in
the placebo(-0.7 kg).
mg q.d. in monotherapy was efficacious and well tolerated in Japanese patients
with T2DM, with no reports of hypoglycemia.
Multiple Dose Administration
of Sitagliptin, a Dipeptidyl Peptide IV (DPP-4) Inhibitor, in Healthy Japanese
Abstract Number: 533-P
HIROHISA NARITA, KENJI NONAKA, CATHY STEVENS, KOTOBA OKUYAMA, GO FUJIMOTO,
KAREN SNYDER, DEBORAH HILLIARD, WES TANAKA, TAKATOSHI TAKUBO, KENICHI HARA,
YASUYUKI ISHII, JOHN A. WAGNER, GARY A. HERMAN.
Tokyo, Tsukuba, Japan; Rahway, NJ.
Sitagliptin (MK-0431) is an orally active, potent, selective DPP-4 inhibitor
in development for the treatment of type 2 diabetes. The safety, tolerability,
pharmacokinetics, and pharmacodynamics of multiple oral doses (25 to 400 mg q.d.
and 50 mg b.i.d. for 10 days) of sitagliptin were examined
double-blind, randomized, placebo-controlled, incremental dose, parallel-group
study in healthy, normoglycemic, Japanese male subjects (8 subjects on
sitagliptin, 2 on placebo per dose level).
doses of sitagliptin were generally well tolerated with no observed episodes of
hypoglycemia. Examination of sitagliptin trough concentrations over time
indicated that steady-state plasma concentrations of sitagliptin were generally
achieved by Day 2. Sitagliptin plasma Day 10 AUC increased approximately
dose-proportionally over all q.d. doses studied. C?max increased in a slightly greater than dose proportional manner and C?24 hr increased in a less than dose proportional manner. Sitagliptin was
primarily renally eliminated with an apparent terminal elimination half-life of
10.8 to 12.4 hrs over the dose range of 25 to 200 mg q.d. Plasma DPP-4 enzyme
activity was significantly inhibited by sitagliptin at all dose levels compared
to placebo. Multiple dose administration (sitagliptin =50 mg q.d.) was
associated with a weighted average inhibition of plasma DPP-4 activity over 24
hrs of approximately 80% or higher on Day 10. Following the administration of
standardized meals at various times postdose, sitagliptin at doses =25 mg
q.d. was associated with approximately 2-fold or greater increases in post-meal
weighted average augumentation of active GLP-1 levels as compared to placebo.
Sitagliptin was generally well tolerated and exhibited a pharmacokinetic and
pharmacodynamic profile consistent with a once-daily dosing regimen
Sitagliptin Added to Ongoing
Metformin Therapy Enhanced Glycemic Control and Beta-Cell Function in Patients
with Type 2 Diabetes
Abstract Number: 501-P
AVRAHAM KARASIK, BERNARD CHARBONNEL, JI LIU, MEI WU, ALAN MEEHAN, GARY
Tel Hashomer, Israel; Nantes Cedex, France; Rahway, NJ.
The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin,
added to ongoing metformin therapy, were assessed in patients with type 2
diabetes and inadequate glycemic control (HbA?1c =7% and =10%)
on metformin (=1500 mg/day) alone. After a metformin
titration/stabilization period, and a 2-week, single-blind, placebo run-in, 701
patients ages 19 - 78 years (mean baseline HbA?1c = 8.0%) were randomized in a 1:2 ratio to receive the
addition of placebo or sitagliptin 100 mg q.d. for 24 weeks. The efficacy
analysis was based on an all-patients-treated population using an ANCOVA. After
24 weeks, the addition of sitagliptin to ongoing metformin therapy led to a
significant (p<0.001) placebo-subtracted reduction in HbA?1c (-0.65%), fasting plasma
glucose (-25.4 mg/dL), and 2-hour post-meal plasma glucose (-50.6 mg/dL).
Fasting insulin and C-peptide, post-meal insulin and C-peptide AUCs, and
post-meal insulin AUC to glucose AUC ratio were all significantly increased with
sitagliptin relative to placebo. HOMA-?, an index of beta-cell function,
was also significantly increased with sitagliptin compared to placebo. In
addition, there was a significant decrease in the proinsulin to insulin ratio
with sitagliptin relative to placebo, reflecting improved beta-cell function.
Sitagliptin was generally well tolerated, with no increased incidence of
hypoglycemia or gastrointestinal adverse events compared with placebo. Mean body
weight change was not different between sitagliptin (-0.7 kg) and placebo (-0.6
kg) when added to ongoing metformin treatment. In this 24-week study, the
addition of sitagliptin 100 mg q.d. to ongoing metformin therapy led to
significant improvements in glycemic control and measures of beta-cell function,
and was well tolerated in patients with type 2 diabetes and inadequate glycemic
control on metformin alone.
Addition of Sitagliptin to
Pioglitazone Improved Glycemic Control with Neutral Weight Effect over 24
Weeks in Inadequately Controlled Type 2 Diabetes (T2DM)
Abstract Number: 556-P
JULIO ROSENSTOCK, RONALD BRAZG, PAULA J. ANDRYUK, CHRISTINE MCCRARY SISK,
KAIFENG LU, PETER STEIN.
Dallas, TX; Renton, WA; Rahway, NJ.
Thiazolidinediones are increasingly used in T2DM but may not provide
sufficient glycemic control in monotherapy. This 24-wk, randomized,
double-blind, placebo (PBO)-controlled study assessed the efficacy and safety of
adding once-daily sitagliptin (SIT), a DPP-4 inhibitor, to patients (pts) with
T2DM treated with pioglitazone (PIO) monotherapy. After a diet/exercise run-in
and an 8-14 wk dose-stable period on PIO (duration according to previous
therapy) and a 2-wk single-blind PBO run-in period, pts with HbA1c =7% and =10% were randomized (1:1) to
addition of PBO or SIT 100 mg q.d. to ongoing PIO. Mean baseline characteristics
of randomized pts (N = 353) including age 56 yrs (range 24-87 yrs); diabetes
duration 6.1 yrs; HbA?1c 8.0%, FPG 167 mg/dL; BMI
31.5 kg/m2 were similar between groups. Efficacy analysis was based on an
all-patients-treated population using ANCOVA. After 24 wks, addition of SIT to
PIO produced significant PBO-subtracted reductions in HbA1c (-0.70%, p<0.001) and FPG (-17.7 mg/dL, p<0.001). SIT effects on
glycemic control were maintained over the 24-wk study. Endpoint HbA?1c was 7.2% and 7.8% for SIT and PBO and the % of
pts reaching target HbA?1c <7% was 45% and 23%
(p<0.001), respectively. Proinsulin levels and proinsulin/insulin ratio were
significantly reduced with SIT compared with PBO, suggesting improvements in
?-cell function. Sitagliptin was well tolerated with an overall incidence
of AEs and of hypoglycemia similar to PBO. A slightly higher incidence of
abdominal pain was observed with SIT, with no significant differences in other
specific GI AEs compared to PBO. Mean body weight change was not different
between SIT and PBO when added to PIO. In conclusion, in pts with T2DM with
inadequate glycemic control on PIO, the addition of sitagliptin 100 mg once
daily led to significant lowering of HbA?1c and FPG while improving some measures of ?-cell function without
additional weight gain and with good tolerance over a 24-wk period