catherine only
hsj
15.pdf
O R I G I N A L A R T I C L E doi: 10.1111/j.1463-1326.2007.00744.x
Efficacy and safety of the dipeptidyl peptidase-4 inhibitor,
sitagliptin, in patients with type 2 diabetes mellitus
inadequately controlled on glimepiride alone or on glimepiride
and metformin
K. Hermansen,1 M. Kipnes,2 E. Luo,3 D. Fanurik,3 H. Khatami3 and P. Stein,3
for the Sitagliptin Study 035 Group*
1 Aarhus University Hospital, Aarhus, Denmark
2 Diabetes and Glandular Disease Clinic, San Antonio, TX, USA
3Merck Research Laboratories, Rahway, NJ, USA
Aim: To assess the efficacy and safety of a 24-week treatment with sitagliptin, a highly selective once-daily oral
dipeptidyl peptidase-4 (DPP-4) inhibitor, in patients with type 2 diabetes who had inadequate glycaemic control
[glycosylated haemoglobin (HbA1c) �7.5% and �10.5%] while on glimepiride alone or in combination with metformin.
Methods: After a screening, diet/exercise run-in and drug wash-off period, a glimepiride � metformin dose titration/ stabilization period and a 2-week, single-blind placebo run-in, 441 patients (of ages 18–75 years) were randomized to
receive the addition of sitagliptin 100 mg once daily or placebo in a 1 : 1 ratio for 24 weeks. Of these patients, 212 were
on glimepiride (�4 mg/day) monotherapy and 229 were on glimepiride (�4 mg/day) plus metformin (�1500 mg/day) combination therapy. Patients exceeding pre-specified glycaemic thresholds during the double-blind treatment period
were provided open-label rescue therapy (pioglitazone) until study end. The primary efficacy analysis evaluated
the change in HbA1c from baseline to Week 24. Secondary efficacy endpoints included fasting plasma glucose (FPG),
2-h post-meal glucose and lipid measurements.
Results: Mean baseline HbA1c was 8.34% in the sitagliptin and placebo groups. After 24 weeks, sitagliptin reduced
HbA1c by 0.74% (p < 0.001) relative to placebo. In the subset of patients on glimepiride plus metformin, sitagliptin
reduced HbA1c by 0.89% relative to placebo, compared with a reduction of 0.57% in the subset of patients on gli-
mepiride alone. The addition of sitagliptin reduced FPG by 20.1 mg/dl (p < 0.001) and increased homeostasis
model assessment-b, a marker of b-cell function, by 12% (p < 0.05) relative to placebo. In patients who underwent a meal tolerance test (n ¼ 134), sitagliptin decreased 2-h post-prandial glucose (PPG) by 36.1 mg/dl (p < 0.001) rel- ative to placebo. The addition of sitagliptin was generally well tolerated, although there was a higher incidence of
overall (60 vs. 47%) and drug-related adverse experiences (AEs) (15 vs. 7%) in the sitagliptin group than in the pla-
cebo group. This was largely because of a higher incidence of hypoglycaemia AEs (12 vs. 2%, respectively) in the
sitagliptin group compared with the placebo group. Body weight modestly increased with sitagliptin relative to pla-
cebo (þ0.8 vs. �0.4 kg; p < 0.001). Conclusions: Sitagliptin 100 mg once daily significantly improved glycaemic control and b-cell function in patients with type 2 diabetes who had inadequate glycaemic control with glimepiride or glimepiride plus metformin therapy.
The addition of sitagliptin was generally well tolerated, with a modest increase in hypoglycaemia and body weight,
consistent with glimepiride therapy and the observed degree of glycaemic improvement.
Keywords: combination therapy, dipeptidyl peptidase-IV, DPP-IV, glimepiride, incretins, metformin, MK-0431, sitagliptin
Received 11 April 2007; returned for revision 11 May 2007; revised version accepted 14 May 2007
Correspondence:
Hootan Khatami, MD, Merck Research Laboratories, 126 East Lincoln Avenue, Mail Code: RY34-A256, Rahway, NJ 07065-0900, USA.
E-mail:
*See online appendix for list of Sitagliptin Study 035 investigators.
# 2007 The Authors
Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 9, 2007, 733–745 j 733
Introduction
Treatment with a single antihyperglycaemic agent is often
unsuccessful at achieving and/or maintaining long-term
glycaemic control in patients with type 2 diabetes, so
many patients require combination therapies [1]. Mono-
therapy with metformin or a sulphonylurea is the most
commonly used initial oral hypoglycaemic agent (OHA)
regimen to treat patients with type 2 diabetes. Sulpho-
nylureas improve blood glucose levels by stimulating
insulin secretion from pancreatic b-cells in a non-glucose– dependent manner [2]. Metformin, a biguanide, acts
primarily by lowering hepatic glucose production and
may also improve insulin resistance [3,4]. As with all
OHAs, monotherapy with a sulphonylurea may not ach-
ieve or maintain glycaemic control; therefore novel, effi-
cacious and well-tolerated therapies that can be added
to a sulphonylurea agent are needed. Similarly, dual-
combination therapy with a sulphonylurea agent and
metformin also may not achieve or maintain glycaemic
control [1]. In this setting, use of insulin is often the
next therapeutic step, although triple OHA therapy [e.g.
adding a thiazolidinedione, a peroxisome proliferator–
activated receptor g (PPARg) agent, to ongoing dual ther- apy with metformin and a sulphonylurea] is increasingly
being used in clinical practice. Insulin requires paren-
teral administration, which many patients find undesir-
able, and the addition of a thiazolidinedione can lead to
oedema and an increase in body weight. Hence, there is
a need for additional OHA options that can be added to
the dual combination of sulphonylurea and metformin to
avoid the need to switch to insulin.
Sitagliptin is a once-daily, orally active, potent and
highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor
approved in many countries for the treatment of patients
with type 2 diabetes [5]. DPP-4 is an enzyme involved in
the degradation of the intact (active) incretin hormones,
glucagon-like peptide-1 (GLP-1) and glucose-dependent
insulinotropic peptide (GIP) to inactive metabolites.
GLP-1 and GIP are released by the intestine into the cir-
culation in response to a meal, and both hormones
increase glucose-dependent insulin secretion; in addi-
tion, GLP-1 suppresses glucagon release. By inhibiting
the degradation of active incretins, sitagliptin increases
active incretin concentrations, thereby enhancing their
glucoregulatory effects [6–10]. Sitagliptin, administered
as monotherapy or as add-on therapy to metformin or to
a PPARg agent, has been shown to improve glycaemic control and is well tolerated in patients with type 2 dia-
betes [11–14].
Although both sitagliptin and sulphonylureas stimu-
late insulin secretion from pancreatic b-cells, the mode
by which these agents exert their effects differs [15,16].
Sitagliptin, acting through increases in active GLP-1
and GIP levels, increases insulin concentrations in
a glucose-dependent fashion through increased intra-
cellular levels of cyclic adenosine 3¢,5¢-monophosphate (cAMP), whereas sulphonylureas act in a non-glucose–
dependent fashion through the sulphonylurea receptor.
Sitagliptin has been shown to lower glucagon concen-
trations, which is likely to also contribute to the glucose
lowering obtained with this agent. The role of glucagon
in sulphonylurea action in patients with type 2 diabetes
mellitus is less well defined. Given the different mecha-
nisms of action of sitagliptin and sulphonylurea agents,
combination therapy with these two agents would seem
a rational approach to improving glycaemic control. Pre-
vious studies have shown that sitagliptin provides effec-
tive add-on combination treatment with metformin
[14,17]. If sitagliptin is effective in combination with
a sulphonylurea agent, then triple combination therapy
with metformin and a sulphonylurea agent would likely
be effective as well.
In this study, the efficacy and tolerability profile of add-
ing sitagliptin 100 mg or placebo to ongoing treatment
with glimepiride alone or glimepiride in combination
with metformin was assessed over a 24-week period. In
addition to assessment in the overall study population,
the efficacy and tolerability of sitagliptin relative to pla-
cebo in the individual subpopulations of patients on gli-
mepiride alone or on glimepiride and metformin were
examined separately.
Patients and Methods
Study Population
Men and women, �18 and �75 years of age, with type 2 diabetes were recruited for this study. Only the following
patients were eligible to be screened: (i) already taking
glimepiride alone (at any dose) or in combination with
metformin (at any dose), (ii) taking another OHA in mono-
therapy or in dual- or triple-combination therapy or (iii)
patients not taking any OHAs over the prior 8 weeks. At
the screening visit, patients were excluded if they had
a history of type 1 diabetes; were treated with insulin
within 8 weeks of the screening visit; had renal dysfunc-
tion (creatinine clearance <45 ml/min or <60 ml/min if
on metformin); or had a history of hypersensitivity, intol-
erance or a contraindication to the use of glimepiride,
sulphonylurea agents, metformin or pioglitazone (which
was included in this study as rescue therapy).
The study was conducted in accordance with the guide-
lines on good clinical practice and with ethical standards
OA j Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin K. Hermansen et al.
734 j Diabetes, Obesity and Metabolism, 9, 2007, 733–745 # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd
for human experimentation established by the Declara-
tion of Helsinki. Ethics review committee/institutional
review board approval was obtained for each study site.
Written informed consent was obtained from all patients
before any study procedure was performed.
Study Design
This was a multinational, randomized, double-blind,
parallel-group study with a single-blind placebo run-in
period followed by a double-blind placebo-controlled
treatment period. At the screening visit, patients were
instructed to receive glimepiride alone (Stratum 1) or gli-
mepiride plus metformin (Stratum 2) based upon their
OHA regimen at the screening visit and their baseline
glycosylated haemoglobin (HbA1c). An interactive voice
response system (IVRS) was used to monitor enrollment
and assign study drug and to ensure that approximately
50% of patients were assigned to each stratum. The
study was designed to detect a true difference of 0.5%
in the mean change from baseline in HbA1c between
sitagliptin and placebo for a two-tailed test at a ¼ 0.05 (two sided) with greater than 99% power for the entire
cohort and with greater than 90% power for each stratum.
Patients with HbA1c �7.5% and �10.5% who were already taking a stable dose of glimepiride (�4 mg/day up to a maximum daily dose of 8 mg/day) alone or in
combination with metformin (�1500 mg/day up to a maximum daily dose of 3000 mg/day) for at least
10 weeks directly entered a 2-week, single-blind pla-
cebo run-in period. Patients who were not on OHA with
HbA1c �9%, who were taking other OHAs in mono- therapy with HbA1c �7.5%, or who were taking other OHAs in dual or triple therapy with HbA1c �6.5% and �10.5%, discontinued their prior regimen and were switched to treatment with glimepiride alone or glime-
piride in combination with metformin. Following the
switch in treatments, these patients entered a dose titra-
tion period of up to 4 weeks and then a dose stabiliza-
tion run-in period of up to 10 weeks. If HbA1c was
�7.5% and �10.5% after this run-in period, patients entered a 2-week, single-blind placebo run-in period.
Patients with adequate compliance (�75%) during this placebo run-in period underwent baseline evaluations
and were randomized through an IVRS in a 1 : 1 ratio to
the addition of either once-daily sitagliptin 100 mg or
placebo to ongoing stable doses of glimepiride, alone or
in combination with metformin.
During the 24-week treatment period, patients not
meeting specific, progressively lower glycaemic goals
[fasting plasma glucose (FPG) >270 mg/dl between ran-
domization (Day 1) and Week 6, FPG >240 mg/dl after
Week 6 through Week 12, or FPG >200 mg/dl after Week
12 through Week 24] were provided open-label rescue
therapy (pioglitazone 30 mg/day) until the completion
of the study period. Patients receiving rescue therapy
remained in the study to provide additional safety expe-
rience with the combination of sitagliptin and glimepir-
ide � metformin. Patients were discontinued from the study if they were on rescue therapy for at least 4 weeks
and had an FPG consistently >200 mg/dl.
Study Assessments
The primary efficacy parameter was mean change from
baseline in HbA1c at Week 24. This endpoint was
assessed initially in the overall study population. If the
results for the overall study population were found to be
significant, then subsequent analyses were performed to
examine treatment effects within the two strata. Second-
ary efficacy endpoints included change from baseline in
FPG and per cent change from baseline in plasma lipids
[total cholesterol (TC), low-density lipoprotein choles-
terol (LDL-C), triglycerides (TG), high-density lipopro-
tein cholesterol (HDL-C) and non-HDL-C] at Week 24.
Homeostasis model assessment-b cell function (HOMA-b) and the proinsulin/insulin ratio were calculated to
assess b-cell function [18,19]. HOMA-insulin resistance (HOMA-IR) and the quantitative insulin sensitivity
check index (QUICKI) were calculated to assess changes
in insulin resistance [18,20].
Change from baseline in HbA1c was also evaluated
among several pre-specified subgroups including base-
line HbA1c level (greater than, or less than or equal to
median value; and by categories: <8%, �8% and <9%, �9%), prior OHA status (not taking OHA, taking OHA monotherapy or taking oral combination therapy), gen-
der, race, age (greater than or lesser than or equal to
median values at baseline), body mass index (BMI)
greater than or lesser than or equal to median value at
baseline), duration of diabetes (greater than or lesser
than or equal to median baseline duration of diabetes),
HOMA-IR (greater than or lesser than or equal to median
value at baseline), HOMA-b (greater than or lesser than or equal to median value at baseline) and metabolic syn-
drome status as defined by National Cholesterol Educa-
tion Program Adult Treatment Panel (NCEP ATP III)
criteria.
Safety and tolerability were assessed by physical exami-
nations, vital signs and 12-lead electrocardiograms (ECGs),
and safety laboratory measurements comprising haematol-
ogy (including complete blood count, differential and
absolute neutrophil count), serum chemistry (including
alanine aminotransferase, aspartate aminotransferase, total
K. Hermansen et al. Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin j OA
# 2007 The Authors
Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 9, 2007, 733–745 j 735
bilirubin and alkaline phosphatase) and urinalysis.
Adverse experiences (AEs) were monitored throughout
the study, and the severity and relationship to study drug
for any AE were determined by the investigator. AEs of
special interest included hypoglycaemia and selected gas-
trointestinal-related AEs (abdominal pain, nausea, vomit-
ing and diarrhoea).
All assays were performed by technicians blinded to
treatment sequence at PPD Global Central Labs, LLC
(Highland Heights, KY and Zaventem, Belgium). HbA1c
was determined by high-performance liquid chromatog-
raphy (Tosoh A1C 2.2; Tosoh Medics, Foster City, CA,
USA). Plasma glucose was determined with the hexoki-
nase method (Roche Diagnostics, Basel, Switzerland).
Serum insulin was determined by chemiluminescence
(Elecsys 2010; Roche Diagnostics). Serum proinsulin
was determined with an enzyme-linked immunosorbent
assay (Mercodia, Uppsala, Sweden). TG was measured
by enzymatic determination of glycerol (Roche Diag-
nostics). After selective removal of apo B–containing
lipoproteins by heparin and manganese chloride pre-
cipitation for HDL isolation, HDL-C and TC were quan-
tified enzymatically (Roche Diagnostics). LDL-C was
calculated using the Friedewald equation. Non-HDL-C
was calculated by subtracting HDL-C from TC.
Statistical Analyses
The primary efficacy endpoint, the change from baseline
in HbA1c at Week 24, was analysed using an analysis of
covariance (ANCOVA) model. Analyses were adjusted for
baseline HbA1c values and stratum (on metformin or not
on metformin at Visit 3). Efficacy analyses were based
on the all-patients-treated (APT) population that con-
sisted of all randomized patients who received at least
one dose of study drug and who had both baseline
and at least one post-baseline efficacy measurement.
Missing data were handled using the last-observation-
carried-forward method. The differences between sitaglip-
tin and placebo for HbA1c and other efficacy endpoints
were assessed by testing the difference in the least
squares (LS) mean change (or per cent change) from
baseline at Week 24. The entire cohort (with both strata
combined) was analysed as the primary efficacy pop-
ulation; however, additional key analyses included the
full range of primary and secondary efficacy endpoints
in each stratum individually. The proportion of patients
meeting HbA1c goal of <7.0% at Week 24 was compared
between treatment groups. An ANCOVA model similar to
that described above was utilized to evaluate the consis-
tency of the HbA1c-lowering effect of sitagliptin relative
to placebo across pre-defined subgroups (see Study
Assessment section) by examining the between-group
LS mean differences and 95% confidence intervals.
For each subgroup factor, the ANCOVA model included
terms for treatment, stratum, subgroup, treatment-by-
subgroup interaction and baseline HbA1c. For the sub-
group factor of prior antihyperglycemia therapy status,
the stratum was not included in the ANOVA model. No
formal treatment-by-subgroup interaction testing was
performed to evaluate the statistical significance of
these findings. A time-to-glycaemic-rescue analysis was
performed using the Kaplan–Meier estimator and the
log-rank test. The proportion of patients who received
glycaemic rescue therapy was compared between treat-
ment groups. To avoid the confounding influence of res-
cue therapy on efficacy comparisons in this 24-week
study, data were treated as missing after the initiation of
pioglitazone rescue therapy in the efficacy analyses. For
data presented in conventional units, the following SI
conversion factors may be used: to convert glucose val-
ues to mmol/l, multiply by 0.0551; to convert insulin
values to pmol/l, multiply by 6; and to convert C-pep-
tide values to nmol/l, multiply by 0.331. The same con-
version factors can be utilized for the conversion of the
area under curve (AUC) values of glucose, insulin and
C-peptide.
Safety and tolerability analyses were performed in the
all-patients-as-treated (APaT) population, which included
randomized patients who received at least one dose of
double-blind study medication. Safety parameters assessed
included AEs, laboratory safety analytes, body weight, vital
signs and ECGs. Safety analyses excluded data after initiat-
ing rescue therapy. Inferential testing was performed on the
between-group differences for hypoglycaemia, selected
gastrointestinal AEs and change in body weight.
Results
Patients
Of 1098 patients screened, a total of 441 patients (441/
1098; 40%) were randomized, which consisted of Stra-
tum 1 [glimepiride alone (n ¼ 212/441; 48%)] and Stra- tum 2 [glimepiride plus metformin combination therapy
(n ¼ 229/441; 52%)] at entry into the run-in period (fig- ure 1). A total of 657 patients (657/1098; 60%) were
excluded from participating in the study, with 548 of
these (548/657; 83%) not meeting protocol eligibility
criteria and 57 (57/657; 9%) withdrawing consent. Of
the 441 randomized patients, 222 received sitagliptin
100 mg once daily (n ¼ 106 in Stratum 1 and n ¼ 116 in Stratum 2) and 219 received placebo (n ¼ 106 in
OA j Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin K. Hermansen et al.
736 j Diabetes, Obesity and Metabolism, 9, 2007, 733–745 # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd
Stratum 1 and n ¼ 113 in Stratum 2). In total, 185 patients (185/222; 83%) in the sitagliptin arm and 179
patients (179/219; 82%) in the placebo arm completed
the 24-week double-blind treatment period. A total of
425 patients (217 patients in the sitagliptin 100 mg group
and 208 in the placebo group) with baseline and at least
one valid on-treatment measurement comprised the APT
population for the HbA1c efficacy analysis (primary end-
point). All randomized patients were included in the
APaT population for the safety and tolerability analyses.
There were no clinically meaningful differences in
baseline demographic or anthropometric characteristics
between treatment groups for the entire study population
and across strata based on assigned OHA therapy (table 1).
For the entire study population, the average duration of
diabetes was 8.8 years, and the average baseline HbA1c
was 8.34%, with about 35% of patients having an HbA1c
<8%. The HbA1c range at randomization was 6.7–10.6%
(note: baseline HbA1c values <7.5% were observed since
inclusion criteria were assessed at Week -2). The average
baseline FPG was 181.2 mg/dl. The baseline disease char-
acteristics for the entire study population were similar
between treatment groups. Patients on glimepiride plus
metformin combination therapy (Stratum 2) had slightly
lower HbA1c values and longer duration of type 2 diabetes
at baseline than patients on glimepiride alone (Stratum 1).
Note that Stratum 2 included more patients on dual ther-
apy, who typically have a longer mean duration of disease,
because, per protocol, such patients were generally
entered into Stratum 2 rather than Stratum 1 (table 1).
Efficacy
In the overall randomized cohort of patients (i.e. com-
bined strata), treatment with sitagliptin 100 mg once
daily significantly (p < 0.001) decreased HbA1c from
baseline relative to placebo, with a �0.74% (95% CI �0.90 to �0.57) between-treatment difference in LS mean change from baseline at Week 24 (table 2, figure 2
A). Sitagliptin also led to significant improvements in
HbA1c in each stratum. In patients receiving glimepiride
alone (Stratum 1), sitagliptin led to a �0.57% (95% CI �0.82 to �0.32) placebo-subtracted reduction in HbA1c at Week 24, while a placebo-subtracted decrease in
HbA1c of �0.89% (�1.10 to �0.68) was observed in patients on glimepiride plus metformin (table 2, fig-
ure 2B). Formal treatment by subgroup interaction test-
ing was not performed in this study (see Patients and
Methods); however, subgroups were assessed for consis-
tency of the response in HbA1c lowering. For the overall
study population and in the two strata, the magnitudes
of the placebo-subtracted HbA1c reduction with sitagliptin
Excluded n = 657
Reasons for exclusions: Did not meet inclusion or met exclusion criteria n = 548 Patient withdrew consent Lost to follow-up Clinical/laboratory adverse experience Patient moved Protocol deviation Trial enrollment closed at site Unknown reason
n = 57 n = 12 n = 18 n = 1 n = 11 n = 8 n = 2
Reasons for discontinuation: Clinical adverse experience
Patient withdrew consent Protocol deviation
n = 5 n = 8 n = 4
Protocol-specific discontinuation criteria Site Terminated
Screened n = 1098
Randomized n = 441
Glimepiride n = 106 Glimepiride + Metformin n = 116
Reasons for discontinuation: Clinical adverse experience
n = 5 Lost to follow-up n = 4 Patient discontinued for other n = 3 Patient withdrew consent n = 5 Protocol deviation n = 2
Reasons for discontinuation: Exceeded prespecified glycaemic criteria
Exceeded prespecified glycaemic criteria
Exceeded prespecified glycaemic criteria
Lost to follow-up Patient withdrew consent n = 5 Protocol deviation
n = 10 n = 2
n =2
Reasons for discontinuation: Clinical adverse experience Laboratory adverse experience
Patient withdrew consent n = 3 Protocol deviation n = 1
Placebo n = 219 Sitagliptin 100 mg q.d., n = 222
Glimepiride + Metformin n = 113Glimepiride n = 106
Completed n = 87 Completed n = 92 Completed n = 83 Completed n = 102
n = 1
n = 2 n = 4 n = 2 n = 1
n = 1 n = 7
Exceeded prespecified glycaemic criteria
Fig. 1 Disposition of patients in the study.
K. Hermansen et al. Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin j OA
# 2007 The Authors
Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 9, 2007, 733–745 j 737
were generally consistent across the pre-specified
subgroups defined by demographic (e.g. age, gender,
race/ethnic group, duration of diabetes) and anthropo-
metric characteristics (e.g. BMI) (data not shown). In the
entire cohort, moderately greater placebo-subtracted
HbA1c reductions from baseline were observed with
progressively higher baseline HbA1c values (i.e. patients
with HbA1c <8%, �8% to <9% and �9%). This pattern appeared to be driven entirely by the progressively
greater change by baseline in HbA1c that occurred in
Stratum 2 [HbA1c reductions of �0.55% (95% CI: �0.91 to �0.20), �0.97% (90% CI: �1.27 to �0.66) and �1.34% (95% CI: �1.88 to �0.80) in patients with baseline HbA1c <8%, �8% to <9% and �9% respectively], with essentially no differences in change from baseline by
baseline HbA1c observed in Stratum 1.
Treatment with sitagliptin 100 mg once daily signifi-
cantly increased the proportion of patients attaining an
HbA1c of <7.0% compared with placebo for the over-
all study population [17.1% (37/217) vs. 4.8% (10/
208) respectively; p < 0.001]. For patients on glime-
piride plus metformin (Stratum 2), 22.6% (26/115) of
patients in the sitagliptin group attained an HbA1c of
<7.0% compared with 1.0% (1/105) of patients in the
placebo group (p < 0.001). In patients receiving glime-
piride alone (Stratum 1), there was no significant
between-group difference in the proportion of pa-
tients reaching HbA1c levels <7.0% [10.8% (11/102)
for sitagliptin compared with 8.7% (9/103) for placebo;
p ¼ 0.638]. After 24 weeks of treatment, the addition of sitagliptin
led to a significant (p < 0.001) reduction from baseline in
FPG relative to placebo (table 2) for the overall study
population as well as in each stratum. For the overall
study population, the between-treatment difference in
LS mean change from baseline (95% CI) in FPG was
�20.1 mg/dl (�28.4 to �11.8). The between-treatment dif- ferences in LS mean change from baseline (95% CI) in
FPG at Week 24 were �19.3 mg/dl (�31.9 to �6.7) for patients on glimepiride alone (Stratum 1) and �20.7 mg/dl
Table 1 Baseline demographics and characteristics of randomized patients
Characteristic
Sitagliptin 100 mg q.d. Placebo
Entire cohort
(n 5 222)
Glimepiride
(n 5 106)
Glimepiride 1
metformin
(n 5 116)
Entire cohort
(n 5 219)
Glimepiride
(n 5 106)
Glimepiride 1
metformin
(n 5 113)
Age, mean � s.d. (years) 55.6 � 9.6 54.4 � 10.3 56.6 � 8.8 56.5 � 9.6 55.2 � 10.2 57.7 � 8.9 Age, range (years) 32–73 32–72 33–73 28–75 28–75 33–75
Sex, n (%)
Male 117 (52.7) 56 (52.8) 61 (52.6) 117 (53.4) 58 (54.7) 59 (52.2)
Female 105 (47.3) 50 (47.2) 55 (47.4) 102 (46.6) 48 (45.3) 54 (47.8)
Race, n (%)
Caucasian 136 (61.3) 61 (57.5) 75 (64.7) 140 (63.9) 59 (55.7) 81 (71.7)
Black 10 (4.5) 7 (6.6) 3 (2.6) 12 (5.5) 3 (2.8) 9 (8.0)
Hispanic 39 (17.6) 26 (24.5) 13 (11.2) 32 (14.6) 25 (23.6) 7 (6.2)
Asian 22 (9.9) 6 (5.7) 16 (13.8) 25 (11.4) 12 (11.3) 13 (11.5)
Other 15 (6.8) 6 (5.7) 9 (7.8) 10 (4.6) 7 (6.6) 3 (2.7)
Body weight, kg 86.5 � 21.1 85.8 � 22.5 87.2 � 19.7 85.9 � 21.8 85.1 � 22.6 86.7 � 21.1 Body mass index, kg/m2 31.2 � 6.3 31.0 � 6.7 31.3 � 5.9 30.7 � 6.3 30.7 � 6.4 30.7 � 6.2 Duration of diabetes mellitus, years 8.3 � 5.5 7.2 � 5.0 9.3 � 5.7 9.3 � 6.8 8.0 � 6.5 10.6 � 6.8 Use of OHA at screening, n (%)
Combination therapy 140 (63.1) 29 (27.4) 111 (95.7) 136 (62.1) 29 (27.4) 107 (94.7)
Monotherapy 71 (32.0) 66 (62.3) 5 (4.3) 72 (32.9) 69 (65.1) 3 (2.7)
Absence 11 (5.0) 11 (10.4) 0 11 (5.0) 8 (7.5) 3 (2.7)
HbA1c, % (range) 8.34 � 0.76 (6.70–10.50)
8.42 � 0.79 (7.00–10.30)
8.27 � 0.73 (6.70–10.50)
8.34 � 0.74 (6.90–10.60)
8.43 � 0.80 (6.90–10.40)
8.26 � 0.68 (7.20–10.60)
HbA1c distribution at baseline, n (%)
HbA1c <8% 81 (36.5) 36 (34.0) 45 (38.8) 73 (33.8) 34 (32.1) 39 (35.5)
HbA1c �8% and <9% 95 (42.8) 44 (41.5) 51 (44.0) 101 (46.8) 45 (42.5) 56 (50.9) HbA1c �9% 46 (20.7) 26 (24.5) 20 (17.2) 42 (19.4) 27 (25.5) 15 (13.6)
Fasting plasma glucose, mg/dl 180.9 � 37.7 182.6 � 33.1 179.4 � 41.6 181.6 � 42.5 184.9 � 42.3 178.4 � 42.6 Post-prandial glucose, mg/dl 267.0 � 58.4 279.6 � 60.8 251.7 � 52.2 271.1 � 62.6 289.3 � 65.4 257.4 � 57.5 Fasting insulin, mIU/ml 14.5 � 13.2 16.2 � 16.0 12.9 � 9.7 12.3 � 9.7 13.1 � 11.1 11.6 � 8.1
HbA1c, glycosylated haemoglobin; OHA, oral antihyperglycaemic agent; s.d., standard deviation.
Data are expressed as mean � s.d. or frequency [n (%)], unless otherwise indicated.
OA j Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin K. Hermansen et al.
738 j Diabetes, Obesity and Metabolism, 9, 2007, 733–745 # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd
(�31.7 to �9.7) for those on glimepiride plus metformin (Stratum 2).
Treatment with sitagliptin 100 mg once daily led to
significant (p ¼ 0.020) increases in fasting insulin and in HOMA-b at Week 24 for the overall study population (table 3). No statistically significant between-treatment
differences were detected for fasting proinsulin, pro-
insulin/insulin ratio, fasting C-peptide, HOMA-IR or
QUICKI (data not shown). Sitagliptin had neutral effects
on plasma lipids relative to placebo (data not shown).
The baseline demographic, anthropometric and disease
characteristics for the cohort of patients (n ¼ 184) who participated in a nine-point meal tolerance test were gen-
erally similar to the overall study population (data not
shown). Treatment with sitagliptin 100 mg led to signifi-
cant (p � 0.001) reductions in 2-h post-prandial glucose (PPG) (36.1 mg/dl placebo-subtracted reduction) com-
pared with placebo for the overall study population; a sim-
ilar effect on PPG was observed in the two strata (table 2).
For the entire study cohort, treatment with sitagliptin
also significantly improved 2-h post-meal glucose AUC
(p < 0.001), 2-h post-meal insulin AUC (p ¼ 0.007), 2-h post-meal C-peptide AUC (p < 0.001), C-peptide total
AUC (p ¼ 0.005), glucose total AUC (p < 0.001) and insulin/glucose total AUC ratio (p ¼ 0.013) relative to placebo (table 3).
Twice as many patients in the placebo group required
rescue glycaemic therapy during the 24-week study
compared with those in the sitagliptin group [24.7%
(54/219) vs. 11.3% (25/222), respectively]. Time to ini-
tiation of rescue therapy, as assessed by Kaplan–Meier
time-to-event analysis, was significantly (p < 0.001)
later in the sitagliptin group compared with the placebo
group.
Safety and Tolerability
The addition of sitagliptin 100 mg to ongoing therapy
with glimepiride alone or in combination with metfor-
min was generally well tolerated. In the entire cohort,
prior to the initiation of glycaemic rescue therapy, the
overall incidences of clinical AEs [132 (59.5%) vs. 103
(47.0%); between-treatment difference ¼ 12.4% (95% CI: 3.1–21.4)] and drug-related clinical AEs [12
(14.9%) vs. 15 (6.8%); between-treatment difference
¼ 8.0% (95% CI: 2.2–13.9)] were higher in the sitagliptin group as compared with the placebo group (table 4). The
higher incidence of overall AEs observed in the sita-
gliptin group was accounted for by a higher incidence
of the AE of hypoglycaemia (see table 4) and small dif-
ferences in other AEs. The between-group differenceT a b le
2 L
S m
e a n
c h
a n
g e
fr o m
b a s e li
n e
to W
e e k
2 4
in g ly
c a e m
ic a n
d m
e a l
to le
ra n
c e
te st
e n
d p
o in
ts fo
r th
e e n
ti re
s tu
d y
p o p
u la
ti o n
(e n
ti re
c o h
o rt
) a n
d s u
b s e t
o f
p a ti
e n
ts
re c e iv
in g
g li
m e p
ir id
e a lo
n e
(S tr
a tu
m 1 )
o r
g li
m e p
ir id
e in
c o m
b in
a ti
o n
w it
h m
e tf
o rm
in th
e ra
p y
(S tr
a tu
m 2 ).
E ff ic a c y
p a ra m e te r
E n ti re
c o h o rt
S u b s e t o f p a ti e n ts
o n g li m e p ir id e
m o n o th e ra p y (S tr a tu m
1 )
S u b s e t o f p a ti e n ts
o n g li m e p ir id e 1
m e tf o rm
in (S tr a tu m
2 )
L S m e a n c h a n g e fr o m
b a s e li n e (9 5 %
C I)
D if fe re n c e in
L S
m e a n s (9 5 %
C I)
L S m e a n c h a n g e fr o m
b a s e li n e (9 5 %
C I)
D if fe re n c e in
L S
m e a n s (9 5 %
C I)
L S m e a n c h a n g e fr o m
b a s e li n e (9 5 %
C I)
D if fe re n c e in
L S
m e a n s (9 5 %
C I)
S it a g li p ti n
n 5
2 1 7 – 2 1 9 *
P la c e b o
n 5
2 0 8 – 2 1 3 y
S it a g li p ti n
n 5
1 0 2 – 1 0 4 *
P la c e b o
n 5
1 0 3 – 1 0 4 y
S it a g li p ti n
n 5
1 1 5 *
P la c e b o
n 5
1 0 5 – 1 0 9 y
H b A 1 c , %
� 0 .4 5 (�
0 .5 7 to
� 0 .3 4 )z
0 .2 8 (0 .1 7 to
0 .4 0 )z
� 0 .7 4 (�
0 .9 0 to
� 0 .5 7 )x
� 0 .3 0 (�
0 .4 8 to
� 0 .1 2 )z
0 .2 7 (0 .0 9 to
0 .4 5 )k
� 0 .5 7 (�
0 .8 2 to
� 0 .3 2 )x
� 0 .5 9 (�
0 .7 4 to
� 0 .4 4 )z
0 .3 0 (0 .1 4 to
0 .4 5 )z
� 0 .8 9 (�
1 .1 0 to
� 0 .6 8 )x
F a s ti n g p la s m a
g lu c o s e , m g /d l
� 4 .4
(� 1 0 .2
to 1 .4 )
1 5 .7
(9 .8
to 2 1 .6 )z
� 2 0 .1
(� 2 8 .4
to � 1 1 .8 )x
� 0 .8 8 (�
9 .8
to 8 .0 )
1 8 .4
(9 .5
to 2 7 .3 )z
� 1 9 .3
(� 3 1 .9
to � 6 .7 ){
� 7 .8
(� 1 5 .5
to � 0 .2 )k
1 2 .9
(5 .0
to 2 0 .8 )z
� 2 0 .7
(� 3 1 .7
to � 9 .7 )x
2 -h
p o s t- m e a l
g lu c o s e , m m o l/ l
� 2 2 .7
(� 3 5 .5
to � 9 .9 )z
1 3 .5
(0 .3
to 2 6 .7 )k
� 3 6 .1
(� 5 4 .6
to � 1 7 .7 )x
� 2 4 .4
(� 4 2 .3
to � 6 .4 )k
1 0 .7
(� 1 0 .2
to 3 1 .6 ) � 3 5 .1
(� 6 2 .6
to � 7 .5 ){
� 2 1 .3
(� 4 0 .1
to � 2 .5 )k
1 5 .8
(� 1 .4
to 3 3 .1 )
� 3 7 .1
(� 6 2 .7
to � 1 1 .6 ){
C I,
c o n
fi d
e n
c e
in te
rv a l;
H b A
1 c , g ly
c o s y la
te d
h a e m
o g lo
b in
; L
S , le
a s t
s q u
a re
s .
* F
o r
2 -h
p o s t-
m e a l
g lu
c o s e , n ¼
6 9
fo r
e n
ti re
c o h
o rt
, n ¼
3 8
fo r
s u
b s e t
o f
p a ti
e n
ts o n
g li
m e p
ir id
e a n
d 3 1
fo r
s u
b s e t
o f
p a ti
e n
ts o n
g li
m e p
ir id
e þ
m e tf
o rm
in .
yF o r
2 -h
p o s t-
m e a l
g lu
c o s e , n ¼
6 5
fo r
e n
ti re
c o h
o rt
, n ¼
2 8
fo r
s u
b s e t
o f
p a ti
e n
ts o n
g li
m e p
ir id
e a n
d 3 7
fo r
s u
b s e t
o f
p a ti
e n
ts o n
g li
m e p
ir id
e þ
m e tf
o rm
in .
zp <
0 .0
0 1
fo r
th e
w it
h in
-t re
a tm
e n
t d
if fe
re n
c e .
xp <
0 .0
0 1
fo r
th e
b e tw
e e n
-t re
a tm
e n
t d
if fe
re n
c e .
kp <
0 .0
5 0
fo r
th e
w it
h in
-t re
a tm
e n
t d
if fe
re n
c e .
{p <
0 .0
5 0
fo r
th e
b e tw
e e n
-t re
a tm
e n
t d
if fe
re n
c e .
K. Hermansen et al. Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin j OA
# 2007 The Authors
Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 9, 2007, 733–745 j 739
observed in drug-related AEs was a result of the differ-
ence in hypoglycaemia AEs. No meaningful differences
were observed between the two groups in the inci-
dence of serious AEs, AEs leading to discontinuation
(as a result of non-serious or serious AEs) or other sum-
mary measures of clinical AEs. One patient in the sita-
gliptin group (in Stratum 2) with a medical history of
chronic obstructive pulmonary disease, interstitial lung
disease, obesity and chronic smoking died from intersti-
tial lung disease during the course of this study. The
investigator deemed this serious adverse event to be def-
initely not related to study medication.
An analysis of safety results by stratum showed gener-
ally similar findings to that observed for the overall study
population, with a slightly greater difference in the inci-
dence of overall clinical AEs seen in Stratum 1 patients
[15.1% (95% CI: 1.7–27.8) between-group difference]
than in Stratum 2 patients [between-group difference
9.8% (95% CI: �2.9 to 22.1)]. Additionally, a higher inci- dence of drug-related AEs was observed with sitagliptin
treatment relative to placebo in the subset of patients on
glimepiride plus metformin (Stratum 2) [21 (18.1%) vs. 8
(7.1%); between-treatment difference ¼ 11.0% (95% CI: 2.4–19.7)] but not in patients receiving glimepiride alone
(Stratum 1) [12 (11.3%) vs. 7 (6.6%); between-treatment
difference ¼ 4.7% (95% CI: �3.2 to 12.9)]. Similar to what was seen for the entire cohort, the increased inci-
dence of overall and drug-related clinical AEs with sita-
gliptin treatment in Stratum 2 was related to the increased
incidence of hypoglycaemia adverse events and small dif-
ferences in other AEs (see table 4). There were no clini-
cally meaningful differences in incidence of serious
Weeks
H bA
1c (%
) H
bA 1c
(% )
6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0 Sitagliptin 100 mg q.d. + Glimepiride ± Metformin (n = 222–216) Placebo + Glimepiride ± Metformin (n = 219–207)
Weeks
0 6 12 18 24
0 6 12 18 24 6.0
6.5
7.0
7.5
8.0
8.5
9.0
9.5
10.0 Stratum 1
Stratum 2 Sitagliptin 100 mg q.d. + Glimepiride + Metformin (n = 116–114) Placebo + Glimepiride + Metformin (n = 113–105)
Placebo + Glimepiride (n = 106–103) Sitagliptin 100 mg q.d. + Glimepiride (n = 106–102)
A
B
Fig. 2 Mean (SE) HbA1c over time for sitagliptin 100 mg once daily vs. placebo in the entire study cohort (A) and in the
subset of patients taking glimepiride monotherapy (Stratum 1) or glimepiride plus metformin combination therapy
(Stratum 2) (B). HbA1c, glycosylated haemoglobin.
OA j Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin K. Hermansen et al.
740 j Diabetes, Obesity and Metabolism, 9, 2007, 733–745 # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd
AEs, AEs leading to discontinuation and other summary
measures of clinical AEs between the sitagliptin and
placebo groups within each stratum. There also were no
statistically significant differences between the treat-
ment groups, or within each stratum, in the incidence of
pre-specified gastrointestinal adverse events (abdominal
pain, nausea, vomiting and diarrhoea) (table 4).
In the entire study cohort, 31 patients reported AEs of
hypoglycaemia [27 (12.2%) in the sitagliptin group vs. 4
(1.8%) in the placebo group; between-group difference
(95% CI) ¼ 10.3 (5.7–15.4); p < 0.001] (table 4). None of the reported hypoglycaemia episodes was considered by
the study investigator to be severe or required medical
attention, and the majority of the episodes (55/75 epi-
sodes; 73%) had precipitating factors, such as skipped
meals or increased physical activity. A higher incidence
of hypoglycaemia was seen when sitagliptin was added
to patients in Stratum 2 than in Stratum 1: in Stratum 2,
19 patients (16.4%) and 1 patient (0.9%) had hypo-
glycaemia episodes reported in the sitagliptin 100 mg
q.d. and placebo groups, respectively (p < 0.001). In
Stratum 1, 8 (7.5%) and 3 (2.8%) patients had hypo-
glycaemia episodes reported in the sitagliptin 100 mg
q.d. and placebo groups, respectively (p ¼ 0.214). In the entire study cohort, there was a low, generally
similar incidence of specific laboratory AEs in the sita-
gliptin and placebo groups. Laboratory AEs in patients
who had at least one laboratory test performed post-
baseline were reported by 13 of 220 (5.9%) patients in
the sitagliptin group and 9 of 217 (4.1%) patients in the
placebo group. Drug-related laboratory AEs were reported
in one patient in the sitagliptin group and four patients in
Table 3 LS mean change from baseline to Week 24 in glycaemic and meal tolerance test endpoints for the entire study cohort
n
Week 0 (baseline)
mean (s.d.)
Week 24
mean (s.d.)
LS mean change from
baseline (95% CI)
Difference in LS mean
change (95% CI)
Glycaemic parameters
Fasting serum insulin, mIU/ml Sitagliptin þ G � M 188 14.8 (13.8) 16.2 (12.9) 1.8 (0.8 to 2.9)* 1.8 (0.2 to 3.4)y Placebo þ G � M 162 12.4 (10.4) 12.9 (9.1) 0.1 (�1.1 to 1.2)
HOMA-b (%) Sitagliptin þ G � M 186 50.7 (47.8) 61.4 (57.3) 11.3 (4.4 to 18.1)* 12.0 (1.8 to 22.1)y Placebo þ G � M 156 47.4 (47.7) 47.4 (55.2) �0.7 (�8.2 to 6.8)
Proinsulin/insulin ratio
Sitagliptin þ G � M 180 0.517 (0.363) 0.452 (0.271) �0.057 (�0.091 to �0.022)z �0.028 (�0.080 to 0.025) Placebo þ G � M 144 0.491 (0.286) 0.473 (0.269) �0.029 (�0.068 to 0.010)
Meal tolerance test parameters
2-hr post-meal insulin, mIU/ml Sitagliptin þ G � M 63 55.6 (46.7) 65.7 (53.5) 10.6 (3.4 to 17.9)z 14.4 (3.9 to 24.9)y Placebo þ G � M 59 46.3 (27.1) 43.3 (32.1) �3.8 (�11.3 to 3.7)
2-hr post-meal C-peptide, ng/ml
Sitagliptin þ G � M 70 7.1 (3.2) 7.6 (2.7) 0.6 (0.2 to 0.9)* 1.1 (0.6 to 1.6)x Placebo þ G � M 65 6.5 (2.9) 6.1 (2.5) �0.5 (�0.9 to �0.2)z
Glucose total AUC, mg � h/dl Sitagliptin þ G � M 67 497.1 (84.1) 465.1 (95.6) �33.4 (�54.5 to �12.2)z �61.2 (�91.5 to �30.8)x Placebo þ G � M 64 499.9 (97.9) 526.3 (103.8) 27.8 (6.2 to 49.4)z
Insulin total AUC, mIU � h/ml Sitagliptin þ G � M 51 92.8 (68.6) 98.9 (73.7) 6.5 (�3.1 to 16.2) 7.6 (�6.3 to 21.4) Placebo þ G � M 50 69.4 (39.0) 68.8 (50.9) �1.0 (�10.8 to 8.7)
C-peptide total AUC, ng � h/ml Sitagliptin þ G � M 68 10.9 (4.7) 11.5 (4.6) 0.7 (0.2 to 1.1)z 1.0 (0.3 to 1.7)y Placebo þ G � M 65 9.7 (3.9) 9.5 (3.5) �0.4 (�0.9 to 0.1)
Insulin total AUC/glucose total AUC ratio
Sitagliptin þ G � M 47 0.200 (0.150) 0.226 (0.164) 0.029 (0.003 to 0.054)z 0.045 (0.010 to 0.081)y Placebo þ G � M 48 0.151 (0.103) 0.137 (0.114) �0.017 (�0.041 to 0.008)
LS, least squares; s.d., standard deviation; CI, confidence interval; G, glimepiride; M, metformin; HOMA–b, homeostasis model assessment–b; AUC, area under curve.
*p < 0.001 for the within-treatment difference.
yp < 0.050 for the between-treatment difference. zp < 0.050 for the within-treatment difference. xp < 0.001 for the between-treatment difference.
K. Hermansen et al. Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin j OA
# 2007 The Authors
Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 9, 2007, 733–745 j 741
the placebo group. The sitagliptin-treated patient had
a slight creatine phosphokinase (CK) elevation from a
baseline level of 127 mU/ml (normal <120 mU/ml) to
200 mU/ml at Day 62 and was subsequently discontinued
from the study because of meeting protocol-specified dis-
continuation criteria. This patient’s final CK measure-
ment returned to baseline levels while still on treatment.
Minimal between-treatment differences were observed
in mean concentrations of safety laboratory tests in the
entire study cohort and across treatment strata. Small
mean changes over time were observed for alkaline phos-
phatase (�2.1 vs. 0.9 IU/l respectively) and bilirubin (�0.011 vs. 0.014 mg/dl respectively) between the sita- gliptin and placebo groups. The time courses of mean
change from baseline for alkaline phosphatase and biliru-
bin were similar, with both analytes reaching maximal
reductions at the first post-randomization visit (Week 6)
and remaining stable through Week 24. There were no
meaningful differences between the groups with regard
to mean changes from baseline in liver transaminase lev-
els or in the incidence of episodes of elevations in liver
transaminases. Small increases in mean changes from
baseline in white blood cell count (357.7 vs. 63.9 cells/
ml) and absolute neutrophil count (354.1 vs. 73.0 cells/ml) were observed in patients treated with sitagliptin com-
pared with placebo respectively. No notable changes in
other serum chemistry and haematology analyses were
observed during the course of this study.
After 24 weeks, sitagliptin 100 mg led to a modest
increase in mean body weight from baseline [LS mean
change from baseline ¼ 0.8 kg (95% CI: 0.4–1.2)] com- pared with a slight decrease in the placebo group (LS
mean change from baseline ¼ �0.4 kg (95% CI: �0.8 to 0.1)]. This resulted in a placebo-adjusted body weight
gain of 1.1 kg (95% CI: 0.5–1.7) for the entire study pop-
ulation at Week 24. Similar changes in body weight with
sitagliptin treatment relative to placebo were observed
within each stratum. In Stratum 1, sitagliptin 100 mg also
led to a significant increase in mean body weight [LS
mean change from baseline ¼ 1.1 kg (95% CI: 0.5–1.8)] compared with no change in placebo group [LS mean
change from baseline ¼ 0.0 kg (95% CI: �0.6 to 0.7)]. In Stratum 2, a small numerical increase in mean body
weight [LS mean change from baseline ¼ 0.4 kg (95%
Table 4 Summary of clinical AEs*
n (%)
Sitagliptin 100 mg q.d. Placebo
Entire cohort
(n 5 222)
Glimepiride
(n 5 106)
Glimepiride 1
metformin
(n 5 116)
Entire cohort
(n 5 219)
Glimepiride
(n 5 106)
Glimepiride 1
metformin
(n 5 113)
One or more AEs 132 (59.5) 59 (55.7) 73 (62.9) 103 (47.0) 43 (40.6) 60 (53.1)
Drug-related AEsy 33 (14.9) 12 (11.3) 21 (18.1) 15 (6.8) 7 (6.6) 8 (7.1) Serious AEs (SAEs) 12 (5.4) 5 (4.7) 7 (6.0) 8 (3.7) 6 (5.7) 2 (1.8)
Drug-related SAEsy 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) Death 1 (0.5)z 0 (0.0) 1 (0.9)z 0 (0.0) 0 (0.0) 0 (0.0) Discontinuations because
of AEs
5 (2.3) 3 (2.8) 2 (1.7) 3 (1.4) 1 (0.9) 2 (1.8)
Discontinuations because
of drug-related AEsy 1 (0.5) 1 (0.9) 0 (0.0) 1 (0.5) 0 (0.0) 1 (0.9)
Discontinuations because
of SAEs
3 (1.4) 2 (1.9) 1 (0.9) 1 (0.5) 1 (0.9) 0 (0.0)
Discontinuations because
of drug-related SAEsy 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0)
Clinical AEs of special interest
Hypoglycaemia 27 (12.2) 8 (7.5) 19 (16.4) 4 (1.8) 3 (2.8) 1 (0.9)
Overall gastrointestinal AEs 11 (5.0) 6 (5.7) 5 (4.3) 10 (4.6) 2 (1.9) 8 (7.1)
Selected gastrointestinal AEs
Abdominal pain 5 (2.3) 3 (2.8) 2 (1.7) 2 (0.9) 0 (0.0) 2 (1.8)
Diarrhoea 3 (1.4) 2 (1.9) 1 (0.9) 6 (2.7) 2 (1.9) 4 (3.5)
Nausea 1 (0.5) 0 (0.0) 1 (0.9) 1 (0.5) 0 (0.0) 1 (0.9)
Vomiting 3 (1.4) 1 (0.9) 2 (1.7) 1 (0.5) 0 (0.0) 1 (0.9)
AE, adverse experience.
*Excludes AEs after initiating glycaemic rescue therapy (pioglitazone).
yConsidered by the investigator as possibly, probably or definitely related to study drug. zOne patient receiving triple-combination therapy died from interstitial lung disease during the course of the study.
OA j Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin K. Hermansen et al.
742 j Diabetes, Obesity and Metabolism, 9, 2007, 733–745 # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd
CI: �0.1 to 0.9)] was observed with sitagliptin compared with a significant decrease in the placebo group [LS mean
change from baseline ¼ �0.7 kg (95% CI: �1.4 to �0.1)]. In both strata, a significant placebo-adjusted body weight
gain of 1.1 kg was observed at Week 24.
Discussion
The efficacy and safety of sitagliptin 100 mg once daily
were assessed in this 24-week, placebo-controlled ran-
domized study in patients with type 2 diabetes with inad-
equate glycaemic control on glimepiride, either alone or
in combination with metformin. Because this study was
designed to evaluate the efficacy and safety of the addition
of sitagliptin compared with placebo for the entire study
cohort and within each stratum, no formal comparisons
between the two strata were performed. For the entire
patient cohort, sitagliptin provided substantial, statisti-
cally significant improvements in HbA1c at Week 24 rela-
tive to placebo. For patients in each stratum, the addition
of sitagliptin provided meaningful HbA1c-lowering effi-
cacy, with numerically greater reductions observed in
patients on glimepiride and metformin (Stratum 2) rela-
tive to patients on glimepiride alone. The efficacy of sita-
gliptin was generally consistent across subgroups defined
by demographic, anthropometric or disease character-
istics. In addition to substantial HbA1c-lowering efficacy,
treatment with sitagliptin led to significant and clinically
important improvements in FPG and 2-h PPG in the
entire cohort and in each stratum. Sitagliptin treatment
also led to an increase in a marker of fasting insulin
secretion (i.e. HOMA-b). Overall, more patients treated with sitagliptin achieved
the American Diabetes Association recommended HbA1c
goal of <7.0% [21] at 24 weeks compared with patients
treated with placebo, with the effect observed in Stra-
tum 2 (patients on glimepiride and metformin), consis-
tent with the numerically greater HbA1c-lowering
observed in this stratum.
As noted above, the addition of sitagliptin to the com-
bination of glimepiride and metformin provided numer-
ically greater improvement in HbA1c than the addition of
sitagliptin to glimepiride alone. In a recent study, both
metformin and sitagliptin increased active GLP-1
levels in healthy volunteers – metformin likely operated
through increased GLP-1 release and sitagliptin by
inhibiting degradation – and the combination provided
at least additive effects on intact GLP-1 (unpublished
data; submitted for presentation). This complementary
effect of sitagliptin and metformin on increasing intact
GLP-1 levels could provide a basis for explaining the
enhanced efficacy observed in the present study when
sitagliptin was added to a background of glimepiride
and metformin (Stratum 2) relative to when sitagliptin
was added to glimepiride alone (Stratum 1).
Sitagliptin was generally well tolerated in the entire
patient cohort and in each stratum. The higher percen-
tages of patients in the sitagliptin 100 mg group compared
with patients in the placebo group who had one or more
clinical AEs and drug-related clinical AEs appeared to
be related, at least in part, to a higher incidence of hypo-
glycaemia (see below). A modest but statistically signifi-
cant body weight increase was observed with sitagliptin
treatment in the entire patient cohort and in each treat-
ment stratum, consistent with glycaemic improvement
greater than placebo, and treatment with a sulphonylurea
in this study. In previous clinical trials of add-on combi-
nation use (including add-on to metformin use and add-
on to a PPARg agent use), sitagliptin had a neutral effect on body weight [13,14]. The different effect of sitagliptin
on body weight observed in this add-on combination
use study compared to these previous studies may be
attributable to the present study using background treat-
ment with the sulphonylurea agent, glimepiride.
When added to glimepiride alone or glimepiride in
combination with metformin, sitagliptin was associated
with a higher incidence of hypoglycaemia, although none
of the episodes was considered to be severe by the inves-
tigators and most were associated with precipitating fac-
tors, such as skipped meals or increased physical activity.
Of note, the incidence of hypoglycaemia observed in this
study is consistent with that observed with other antihy-
perglycaemic agents that are themselves not associated
with hypoglycaemia (e.g. metformin, exenatide, thiazoli-
dinediones) but do result in increased hypoglycaemia
when added to ongoing therapy with a sulphonylurea agent
[22,23]. Prior studies have shown that sitagliptin is asso-
ciated with an incidence of hypoglycaemia that is similar
to placebo when used in monotherapy or in combination
therapy with other agents (i.e. metformin, PPARg agonists) [9,12–14]. Hence, the incidence of hypoglycaemia ob-
served in the current study is consistent with observations
in other studies using similar treatment regimens.
In summary, this study showed that treatment with
sitagliptin 100 mg once daily led to clinically meaningful
reductions in HbA1c, fasting glucose and PPG in dual
combination with glimepiride alone and in triple com-
bination with glimepiride plus metformin over a 24-
week period. Overall, treatment with sitagliptin was
well tolerated with a modest increase in weight, consis-
tent with the achieved degree of glycaemic improve-
ment. The higher incidence of hypoglycaemia events
seen with sitagliptin in this study was similar to that
K. Hermansen et al. Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin j OA
# 2007 The Authors
Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 9, 2007, 733–745 j 743
previously reported in other studies of sulphonylurea-
containing dual and triple OHA combination therapies.
Acknowledgements
This study was funded by Merck & Co., Inc., Whitehouse
Station, NJ, USA. The authors thank Amy O. Johnson-
Levonas (Merck Research Laboratories) for her contribu-
tions to the writing of the manuscript. Principal investi-
gators in the Sitagliptin Study 035 Group included
L. Alder, J. P. Antunes, R. Aronson, B. Bahadori, A. Basdevant,
P. Bavenholm, R. Benediktsson, R. Bernstein, R. Brazg,
M. Carvalheiro, J. Castilleja, S. Cerdas, M. Chien,
C. Christiansen, X. Clar Guevara, J. Cooper, T. Davis,
M. Davidson, K. Dawson, R. DeGarmo, P. Denker, A. Dextre,
G. Fulcher, K. Furuseth, S. Gambardella, G. Ghirlanda,
J. Glassman, G. Gonzalez Galvez, A. Graff, D. Helton,
E. Hermansen, K. Hermansen, H, Hoivik, Y. Hung, S. Islas,
M. Kipnes, Z. Krejsova, M. Kvapil, K. Lam, C. Le Devehat,
H. Lee, R. Lipetz, T. Littlejohn III, L. Loman, S. Mather,
S. Mayeda, C. McKeown-Biagas, N. Misra, J. Mitchell,
C. Montjoy, R. Moses, S. Narejos Perez, K. W. Ng, R. Noble,
A. Norrby, B. Pogue, E. Racicka, L. Ramı́rez, D. Schmeidler,
W. So, H. Y. Son, J. Soufer, S. Sriussadaporn, B. St-Pierre,
R. Tamayo, G. Tan, H. Toplak, D. Torpy, J. Wainstein, M.
Weerasinghe, R. Weinstein, F. Winkler and E. Zahumensky.
References
1 Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control
with diet, sulfonylurea, metformin, or insulin in patients
with type 2 diabetes mellitus: progressive requirement for
multiple therapies (UKPDS 49). UK Prospective Diabetes
Study (UKPDS) Group. JAMA 1999; 281: 2005–2012.
2 Doar JW, Thompson ME, Wilde CE, Sewell PF. Diet and
oral antidiabetic drugs and plasma sugar and insulin
levels in patients with maturity-onset diabetes mellitus.
Br Med J 1976; 1: 498–500.
3 Hundal RS, Krssak M, Dufour S et al. Mechanism by
which metformin reduces glucose production in type 2
diabetes. Diabetes 2000; 49: 2063–2069.
4 Inzucchi SE, Maggs DG, Spollett GR et al. Efficacy and
metabolic effects of metformin and troglitazone in
type II diabetes mellitus. N Engl J Med 1998; 338:
867–872.
5 Product Information. JANUVIA (sitagliptin). White-
house Station: Merck & Co., Inc.October 2006.
6 Holst JJ, Deacon CF. Inhibition of the activity of di-
peptidyl-peptidase IV as a treatment for type 2 diabetes.
Diabetes 1998; 47: 1663–1670.
7 Deacon CF, Ahren B, Holst JJ. Inhibitors of dipeptidyl
peptidase IV: a novel approach for the prevention and
treatment of Type 2 diabetes? Expert Opin Investig
Drugs 2004; 13: 1091–1102.
8 Herman GA, Stevens C, Van Dyck K et al. Pharmacoki-
netics and pharmacodynamics of sitagliptin, an inhibi-
tor of dipeptidyl peptidase IV, in healthy subjects:
results from two randomized, double-blind, placebo-
controlled studies with single oral doses. Clin Pharma-
col Ther 2005; 78: 675–688.
9 Bergman AJ, Stevens C, Zhou Y et al. Pharmacokinetic
and pharmacodynamic properties of multiple oral doses of
sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-
blind, randomized, placebo-controlled study in healthy
male volunteers. Clin Ther 2006; 28: 55–72.
10 Herman GA, Bergman A, Stevens C et al. Effect of sin-
gle oral doses of sitagliptin, a dipeptidyl peptidase-4
inhibitor, on incretin and plasma glucose levels after an
oral glucose tolerance test in patients with type 2 dia-
betes. J Clin Endocrinol Metab 2006; 91: 4612–4619.
11 Aschner P, Kipnes MS, Lunceford JK, Sanchez M,
Mickel C, Williams-Herman DE. Effect of the dipeptidyl
peptidase-4 inhibitor sitagliptin as monotherapy on gly-
cemic control in patients with type 2 diabetes. Diabetes
Care 2006; 29: 2632–2637.
12 Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D,
Khatami H. Efficacy and safety of the dipeptidyl peptidase-
4 inhibitor sitagliptin as monotherapy in patients with
type 2 diabetes mellitus. Diabetologia 2006; 49: 2564–2571.
13 Rosenstock J, Brazg R, Andryuk P, Lu K, Stein P. Effi-
cacy and safety of the dipeptidyl peptidase-4 inhibitor
sitagliptin added to ongoing pioglitazone therapy in
patients with type 2 diabetes: a 24-week, multicenter,
randomized, double-Blind, placebo-controlled parallel
group study. Clin Ther 2006; 28: 1556–1568.
14 Charbonnel B, Karasik A, Liu J, Wu M, Meininger G.
Efficacy and safety of the dipeptidyl peptidase-4 inhibi-
tor sitagliptin added to ongoing metformin therapy in
patients with type 2 diabetes inadequately controlled on
metformin alone. Diabetes Care 2006; 29: 2638–2643.
15 Idris I, Donnelly R. Dipeptidyl peptidase-IV inhibitors:
a major new class of oral antidiabetic drug. Diabetes
Obes Metab 2007; 9: 153–165.
16 Del Prato S, Pulizzi N. The place of sulfonylureas in
the therapy for type 2 diabetes mellitus. Metabolism
2006; 55: S20–S27.
17 Brazg R, Thomas K, Zhao PL, Xu L, Chen X, Stein PP.
Effect of adding MK-0431 to on-going metformin therapy
in type 2 diabetic patients who have inadequate glycemic
control on metformin (abstract). Diabetes 2005; 54: A3.
18 Matthews DR, Hosker JP, Rudenski AS, Naylor BA,
Treacher DF, Turner RC. Homeostasis model assess-
ment: insulin resistance and beta-cell function from
fasting plasma glucose and insulin concentrations in
man. Diabetologia 1985; 28: 412–419.
19 Tura A, Pacini G, Kautzky-Willer A, Ludvik B, Prager
R, Thomaseth K. Basal and dynamic proinsulin-insulin
relationship to assess beta-cell function during OGTT
in metabolic disorders. Am J Physiol Endocrinol Metab
2003; 285: E155–E162.
OA j Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin K. Hermansen et al.
744 j Diabetes, Obesity and Metabolism, 9, 2007, 733–745 # 2007 The Authors Journal Compilation # 2007 Blackwell Publishing Ltd
20 Katz A, Nambi SS, Mather K et al. Quantitative insulin
sensitivity check index: a simple, accurate method for
assessing insulin sensitivity in humans. J Clin Endo-
crinol Metab 2000; 85: 2402–2410.
21 Standards of medical care for patients with diabetes
mellitus. Diabetes Care 2003; 26 (Suppl. 1): S33–S50.
22 Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron
AD. Effects of exenatide (exendin-4) on glycemic con-
trol over 30 weeks in sulfonylurea-treated patients with
type 2 diabetes. Diabetes Care 2004; 27: 2628–2635.
23 Roberts VL, Stewart J, Issa M, Lake B, Melis R. Triple
therapy with glimepiride in patients with type 2 diabe-
tes mellitus inadequately controlled by metformin and
a thiazolidinedione: results of a 30-week, randomized,
double-blind, placebo-controlled, parallel-group study.
Clin Ther 2005; 27: 1535–1547.
K. Hermansen et al. Addition of sitagliptin to glimepiride alone or glimepiride in combination with metformin j OA
# 2007 The Authors
Journal Compilation # 2007 Blackwell Publishing Ltd Diabetes, Obesity and Metabolism, 9, 2007, 733–745 j 745
