O R I G I N A L A R T I C L E
`
`doi: 10.1111/j.1463-1326.2006.00704.x
`
`Efficacy and safety of the dipeptidyl peptidase-4 inhibitor,
`sitagliptin, compared with the sulfonylurea, glipizide,
`in patients with type 2 diabetes inadequately controlled
`on metformin alone: a randomized, double-blind,
`non-inferiority trial
`
`M. A. Nauck,1 G. Meininger,2 D. Sheng,2 L. Terranella2 and P. P. Stein2 for the
`Sitagliptin Study 024 Group*
`
`1Diabeteszentrum Bad Lauterberg im Harz, Bad Lauterberg, Germany
`2Merck Research Laboratories, Rahway, NJ, USA
`
`Aim: To compare the efficacy and safety of sitagliptin vs. glipizide in patients with type 2 diabetes and inadequate
`glycaemic control [haemoglobin A1c (HbA1c)  6.5 and 10%] on metformin monotherapy.
`Methods: After a metformin dose titration/stabilization period (1500 mg/day), 1172 patients were randomized to the
`addition of sitagliptin 100 mg q.d. (N ¼ 588) or glipizide 5 mg/day (uptitrated to a potential maximum 20 mg/day) (N ¼
`584) for 52 weeks. The primary analysis assessed whether sitagliptin was non-inferior to glipizide regarding HbA1c
`changes from baseline at Week 52 using a per-protocol approach.
`Results: From a mean baseline of 7.5%, HbA1c changes from baseline were 0.67% at Week 52 in both groups,
`confirming non-inferiority. The proportions achieving an HbA1c < 7% were 63% (sitagliptin) and 59% (glipizide).
`Fasting plasma glucose changes from baseline were 0.56 mmol/l (10.0 mg/dl) and 0.42 mmol/l (7.5 mg/dl)
`for sitagliptin and glipizide, respectively. The proportion of patients experiencing hypoglycaemia episodes was
`significantly (p < 0.001) higher with glipizide (32%) than with sitagliptin (5%), with 657 events in glipizide-treated
`patients compared with 50 events in sitagliptin-treated patients. Sitagliptin led to weight loss (change from
`baseline ¼ 1.5 kg) compared with weight gain (þ1.1 kg) with glipizide [between-treatment difference (95%
`confidence interval) ¼ 2.5 kg (3.1, 2.0); p < 0.001].
`Conclusions: In this study, the addition of sitagliptin compared with glipizide provided similar HbA1c-lowering
`efficacy over 52 weeks in patients on ongoing metformin therapy. Sitagliptin was generally well tolerated, with
`a lower risk of hypoglycaemia relative to glipizide and with weight loss compared with weight gain with glipizide.
`
`Keywords: dipeptidyl peptidase-IV, DPP-IV, incretins, MK-0431, sulfonylureas
`Received 24 October 2006; returned for revision 15 December 2006; revised version accepted 18 December 2006
`
`Introduction
`
`Patients with type 2 diabetes have multiple defects con-
`tributing to hyperglycaemia including insulin resistance,
`inadequate insulin secretion and excessive hepatic glu-
`
`cose production. Oral antihyperglycaemic agents (OHA)
`that target any of these metabolic defects will improve
`glucose levels [1]. Metformin, the most commonly pre-
`scribed OHA, targets excessive hepatic glucose output
`and insulin resistance [2,3]. While defective at the time
`
`Correspondence:
`Peter P. Stein, MD, Merck Research Laboratories, 126 East Lincoln Avenue, Mail Code: RY34-A220, Rahway, NJ 07065-0900, USA.
`E-mail:
`peter_stein@merck.com
`*Study investigators are listed in Appendix 1
`
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`M. Nauck et al.
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`Efficacy and safety of sitagliptin vs. glipizide in type 2 diabetes
`
`j OA
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`of diagnosis, b-cell function continues to deteriorate
`over time in patients with type 2 diabetes, leading to
`progressive failure of insulin secretion. This progressive
`loss of b-cell function may explain why many patients
`who initially achieve glycaemic control fail to maintain
`control at levels consistent with current guidelines [e.g.
`haemoglobin A1c (HbA1c) < 7 or <6.5%] and hence
`require additional therapies [4]. Sulfonylureas, which
`act as insulin secretagogues, are the most common next
`therapeutic step when patients do not achieve or main-
`tain glycaemic control on metformin [5]. Glycaemic
`efficacy is similar across sulfonylurea agents [5,6].
`Sulfonylurea stimulation of insulin secretion is not
`strictly glucose dependent [6]. Although generally well
`tolerated,
`these agents are associated with hypo-
`glycaemia because of continued stimulation of insulin
`secretion with falling glucose concentrations [7]. Weight
`gain is another common side effect of sulfonylurea treat-
`ment, potentially related to the sulfonylurea-induced
`increase in insulin concentrations [1]. An agent that can
`provide efficacy similar to a sulfonylurea but with a bet-
`ter safety profile could provide a useful alternative.
`Sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor,
`is a novel treatment for type 2 diabetes that improves gly-
`caemic control through a new mechanism, enhancement
`of the incretin axis [8–10]. Sitagliptin inhibits the enzy-
`matic degradation and inactivation of the incretins, glu-
`cagon-like peptide-1 (GLP-1) and glucose-dependent
`insulinotropic peptide (GIP) [11,12]. These incretins aug-
`ment glucose-induced insulin secretion after meals. In
`addition, GLP-1 suppresses glucagon release, delays gas-
`tric emptying and increases satiety [13–15]. Notably,
`incretin-induced stimulation of insulin release and the
`suppression of glucagon release by GLP-1 occur in a glu-
`cose-dependent fashion. Studies have shown, for exam-
`ple that at normal or elevated glucose levels, GLP-1
`potently stimulates insulin secretion and inhibits gluca-
`gon release – effects that disappear when glucose levels
`approach normal concentrations [16]. Single doses of sita-
`gliptin have been shown to increase active GLP-1 and GIP
`levels, enhance insulin secretion and suppress glucagon
`release in patients with type 2 diabetes [8]. In prior clin-
`ical studies, sitagliptin added to ongoing metformin
`monotherapy significantly improved fasting and post-
`prandial glycaemic control and measures of b-cell func-
`tion in patients with type 2 diabetes [17,18]. Moreover, in
`these trials, sitagliptin was well tolerated with a neutral
`effect on body weight and a low risk of hypoglycaemia
`and gastrointestinal adverse experiences. The present
`52-week study in patients with type 2 diabetes with inad-
`equate glycaemic control on metformin monotherapy was
`designed to compare the glycaemic efficacy and safety of
`
`the addition of sitagliptin with that of a standard sulfo-
`nylurea agent, glipizide.
`
`Patients and Methods
`
`Patients
`
`Patient Selection Criteria
`
`The screening/eligibility run-in period, described below,
`was designed to allow patients with type 2 diabetes on
`a variety of different regimens at screening to participate.
`Men and women (age 18–78 years) with type 2 diabetes
`who were not currently on an OHA, were taking any OHA
`in monotherapy or were taking metformin in combination
`with another OHA were potentially eligible to participate
`in the study if they all met screening criteria. Patients
`were excluded if they had a history of type 1 diabetes,
`insulin use within 8 weeks of screening, renal function
`impairment inconsistent with the use of metformin or
`a fasting plasma glucose (FPG) (or a fasting fingerstick
`glucose) at or just prior to randomization >15.0 mmol/l
`(270 mg/dl). Other treatments for hyperglycaemia were
`prohibited during the study. Concurrent lipid lowering
`and antihypertensive medications, thyroid medications,
`hormone replacement therapy and birth control medica-
`tions were allowed but were expected to remain at stable
`doses. Patients received counselling on exercise and a diet
`consistent with American Diabetes Association recom-
`mendations throughout the study.
`All patients provided written informed consent to par-
`ticipate, and the study protocol was reviewed and
`approved by the appropriate committees and authorities
`for each study site. The study was performed in accor-
`dance with the Declaration of Helsinki.
`
`Study Design
`
`This was a multinational, randomized, parallel-
`group, non-inferiority study with an active-controlled,
`double-blind treatment period (Sitagliptin Protocol
`024; Clinical Trials.gov NCT00094770). A non-inferiority
`design was chosen as a standard approach to assess sim-
`ilarity of a new agent to a standard therapy. Patients who
`were already on metformin 1500 mg/day and had an
`HbA1c  6.5 and 10% directly entered a 2-week pla-
`cebo run-in period and were eligible to be randomized.
`Patients not currently on an OHA, patients on an OHA
`other than metformin monotherapy at a dose 1500 mg/
`day or patients on metformin in combination with
`another OHA entered a metformin monotherapy treat-
`ment titration and dose-stable period of at least 8 weeks.
`
`# 2007 Merck & Co.
`Journal Compilation # 2007 Blackwell Publishing Ltd
`
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`j
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`Efficacy and safety of sitagliptin vs. glipizide in type 2 diabetes
`
`M. Nauck et al.
`
`Patients with an HbA1c 6.5 and 10% after the metfor-
`min dose-stable period entered a 2-week single-blind
`placebo run-in period. Following this 2-week period,
`eligible patients had baseline measurements and then
`were randomized in a 1 : 1 ratio to the addition of sita-
`gliptin 100 mg once daily or glipizide (at an initial dose
`of 5 mg/day). After the starting dose of 5 mg/day, glipi-
`zide was uptitrated according to protocol-specified
`criteria to a potential maximum dose of 20 mg/day. In 3-
`week intervals during the first 18 weeks of treatment,
`glipizide was uptitrated if premeal fingerstick glucose
`values were >6.1 mmol/l (110 mg/dl). At the inves-
`tigator’s discretion, uptitration of glipizide was with-
`held if
`the investigator considered that uptitration
`would place the patient at risk for hypoglycaemia. At
`any time during the study, glipizide could be down-
`titrated to prevent recurrent hypoglycaemic events.
`
`Study Evaluations
`
`Efficacy Assessments
`
`After an overnight fast, blood was collected for the
`assessment of HbA1c, FPG,
`insulin, proinsulin and
`lipid parameters [total cholesterol (TC),
`low-density
`lipoprotein–cholesterol
`(LDL-C),
`triglycerides (TGs),
`high-density lipoprotein–cholesterol (HDL-C) and non-
`HDL-C] at baseline and at various time points during the
`study. Homeostasis model assessment-b cell function
`(HOMA-b) and the proinsulin/insulin ratio were used to
`assess aspects of b-cell function [19,20]. HOMA-insulin
`resistance (HOMA-IR) and the quantitative insulin sen-
`sitivity check index (QUICKI) were calculated to assess
`changes in insulin resistance [20,21]. As a prespecified
`analysis, durability of
`treatments was evaluated by
`comparing the rate of rise in HbA1c from Week 24 to
`Week 52.
`
`Safety Assessments
`
`Data on adverse experiences, physical examinations, vital
`signs, ECGs and body weight were collected throughout
`the study. All adverse experiences were rated by the study
`site investigators for intensity and relationship to study
`drug. Laboratory safety evaluations included blood chem-
`istry, haematology and urinalysis. Patients experiencing
`symptoms of hypoglycaemia were instructed to obtain
`a fingerstick glucose, record the value in a log book and
`contact their study site. Patients were discontinued for
`lack of efficacy based on progressively stricter glycaemic
`criteria: from randomization through Week 6 for patients
`on two tablets (5-mg tablets) of glipizide/glipizide pla-
`
`cebo for at least 2 weeks, FPG > 14.4 mmol/l (270 mg/
`dl); from Week 6 through Week 12 for patients on maximal
`dose (four 5-mg tablets) of glipizide/glipizide placebo for
`at least 2 weeks, FPG > 13.3 mmol/l (240 mg/dl); from
`Week 12 through Week 18 for patients on maximal dose
`of glipizide/glipizide placebo for at least 2 weeks, FPG >
`12.2 mmol/l (220 mg/dl); from Week 18 through Week 30,
`FPG > 11.1 mmol/l (220 mg/dl) and from Week 30 to Week
`52, HbA1c > 8.0%.
`All laboratory efficacy and safety measurements and
`ECGs were performed at central laboratories (PPD Global
`Central Labs, LLC, Highland Heights, KY, USA, and
`Zaventem, Belgium; Covance Central Diagnostics, Inc.,
`Reno, NV, USA). HbA1c was determined by high-perfor-
`mance liquid chromatography (Tosoh A1c 2.2; Tosoh
`Medics, Foster City, CA, USA). Plasma glucose was
`determined by the hexokinase method (Roche Diag-
`nostics, Basel, Switzerland). Serum insulin was deter-
`mined using chemiluminescence assay (Elecsys 2010;
`Roche Diagnostics). Serum proinsulin was determined
`using an enzyme-linked immunosorbent assay (Merco-
`dia, Uppsala, Sweden). TG was measured by enzymatic
`determination of glycerol
`(Roche Diagnostics). After
`selective removal of apolipoprotein B–containing lip-
`oproteins by heparin and manganese chloride pre-
`cipitation for HDL isolation, HDL-C and TC were
`quantified enzymatically (Roche Diagnostics). LDL-C
`level was calculated using the Friedewald equation [22].
`Non-HDL-C level was calculated by subtracting HDL-C
`level from TC.
`
`Statistical Analyses
`
`The primary efficacy analysis assessed whether the study
`treatments were non-inferior with regard to the HbA1c
`change from baseline at Week 52 using a per-protocol
`(PP) approach [23]. The PP population consists of
`patients who completed all 52 weeks of treatment and
`did not have any reasons for exclusion from this pop-
`ulation, including no baseline data, no treatment data at
`Week 52 or major protocol violations (e.g. drug compli-
`ance <75%, change in metformin dose, addition of non-
`study OHA, incorrect double-blind study medication).
`For change from baseline in HbA1c, sitagliptin was con-
`sidered non-inferior to glipizide if the upper boundary
`of the two-sided 95% confidence interval (CI) for the
`mean difference between sitagliptin and glipizide was
`less than the margin, d ¼ 0.3%. This margin was
`selected so that for non-inferiority to be declared (i.e. for
`the upper boundary of the confidence interval to be less
`than the selected margin), the between-group difference
`observed would be small. An analysis of covariance
`
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`M. Nauck et al.
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`Efficacy and safety of sitagliptin vs. glipizide in type 2 diabetes
`
`j OA
`
`model was used to compare the treatment groups for
`efficacy endpoints, focusing on change from baseline at
`Week 52, with baseline values and prior OHA status as
`covariates. The difference between sitagliptin and glipi-
`zide for efficacy endpoints was assessed by testing the
`difference in the least squares (LS) mean change (or
`mean per cent change) from baseline at Week 52. Addi-
`tional efficacy analyses were based on the all patients–
`treated (APT) population that consisted of all random-
`ized patients who received at least one dose of study
`treatment and who had both a baseline and at least one
`post-baseline measurement; missing values in the APT
`analysis were handled by the last observation carried
`forward approach.
`The durability of HbA1c lowering was compared
`between treatments by evaluating the coefficient of
`durability (COD), defined as the rate of rise in HbA1c
`from Week 24 to Week 52. The proportion of patients
`achieving an HbA1c < 7 or <6.5% was compared
`between treatments using a logistic regression analysis.
`Subgroup analyses for the primary efficacy endpoint
`(i.e. change from baseline in HbA1c at Week 52) were
`performed in subgroups defined by baseline HbA1c cate-
`gories (<7, 7% to <8, 8% to <9, 9%).
`Safety and tolerability were evaluated by a review of
`safety parameters including adverse experiences, labora-
`tory safety parameters, body weight, vital signs and ECG
`data from the all-patients-as-treated population, which
`was defined as all randomized patients who received at
`least one dose of study medication. For body weight
`change and the prespecified clinical adverse experiences
`of hypoglycaemia and specific gastrointestinal adverse
`experiences (abdominal pain, nausea, vomiting and diar-
`rhoea), inferential testing was performed for between-
`group comparisons. Compliance was assessed by
`tablet count.
`
`Results
`
`Patient Disposition and Characteristics
`
`Of the 1172 randomized patients, 793 were included
`in the PP analysis (sitagliptin, n ¼ 382 and glipizide,
`n ¼ 411) (figure 1). Of the 379 patients excluded from
`the PP analysis, 96% were excluded because of missing
`treatment data at Week 52. More patients in the sitagliptin
`group discontinued treatment compared with those in the
`glipizide group (figure 1); this difference was mainly
`because of a higher number of sitagliptin-treated patients
`discontinuing for lack of efficacy, which was based on
`prespecified FPG and/or HbA1c criteria throughout the
`
`treatment period. Patients who discontinued because
`of lack of efficacy had more severe hyperglycaemia at
`baseline than those who completed the study (baseline
`respectively); discontinued
`HbA1c: 8.6 vs. 7.5%,
`patients also tended to be slightly older than patients
`who completed the study (57 vs. 55 years, respectively)
`and had a slightly more body weight (93 vs. 90 kg,
`respectively).
`The mean dose of glipizide was 10.3 mg/day in the PP
`population. Approximately 58% of patients reached
`a final dose of at least 10 mg/day (22% reached a final
`dose of 20 mg/day), while because downtitration was per-
`mitted for recurrent hypoglycaemia, 10% of patients were
`not taking glipizide at study end. For the APT population,
`the mean dose of glipizide was 10.6 mg/day. For all
`patients, the mean duration of exposure to study drug
`was slightly greater in the sitagliptin group [297.1 days
`(42.4 weeks)] than in the glipizide group [287.5 days (41.1
`weeks)]. The mean (s.d.) compliance rates were 98.6%
`(3.8) and 98.3% (3.6) in the sitagliptin and glipizide
`groups, respectively.
`Treatment groups were generally well balanced for
`baseline demographics and efficacy variables for all ran-
`domized patients (table 1). In the PP population, the base-
`line demographics and efficacy variables were similar to
`those of the randomized population results, with an aver-
`age duration of known diabetes of 5.8 years, 70% on an
`OHA monotherapy at screening, and a mild-to-moderate
`degree of hyperglycaemia with a mean HbA1c of 7.5%
`(range ¼ 5.8–10.1%; 73% of patients with an HbA1c <
`8.0%) and mean FPG of 8.8 mmol/l (158 mg/dl).
`
`Efficacy
`
`In the PP population, the LS mean HbA1c change from
`baseline at Week 52 was 0.67% in both the sitagliptin
`and the glipizide treatment groups (table 2). The upper
`limit of the two-sided 95% CI for the between-group LS
`mean difference (0.08%) was less than the prespecified
`non-inferiority margin of 0.3%, satisfying the primary
`hypothesis of non-inferiority of sitagliptin to glipizide
`in lowering HbA1c when co-administered with metfor-
`min. In the APT population, LS mean HbA1c change
`from baseline at Week 52 was similar in the two treat-
`ment groups: 0.51% (95% CI: 0.60, 0.43) with sita-
`gliptin and 0.56% (0.64, 0.47) with glipizide
`[between-group difference in LS mean change from
`baseline (95% CI) ¼ 0.04% (0.04, 0.13)]. This minimal
`between-group difference supported the PP results
`regarding non-inferiority of sitagliptin to glipizide.
`Although treatment with glipizide provided greater ini-
`tial HbA1c lowering, with the maximum between-group
`
`# 2007 Merck & Co.
`Journal Compilation # 2007 Blackwell Publishing Ltd
`
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`Efficacy and safety of sitagliptin vs. glipizide in type 2 diabetes
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`M. Nauck et al.
`
`Screened, N=2141
`
`Randomized, n=1172
`
`Excluded, n=969
`
`Did not meet inclusion or met exclusion criteria, n=784
`Patient withdrew consent, n=114
`Lost to follow-up, n=23
`Clinical adverse experience, n=21
`Laboratory adverse experience, n=3
`Patient moved, n=5
`Protocol deviation, n=12
`Trial enrollment closed at site, n=7
`
`Sitagliptin 100mg q.d., n=588
`
`Glipizide, n=584
`
`Discontinued, n=202
`
`Clinical adverse experience, n=17
`Laboratory adverse experience, n=8
`Lack of efficacy, n=86
`Lost to follow-up, n=19
`Patient discontinued for other
`reasons: (n=10)
` Excluded medications, (n=4)
` Non-compliance, (n=1)
` Extended vacation, (n=1)
` Surgery, (n=1)
` Drug accounting, (n=1)
` Pre-randomization lab value, (n=1)
` Increased glucose values, (n=1)
`Patient moved, n=6
`Patient withdrew consent, n=25
`Prespecified discontinuation
` criteria, n=19
`Protocol deviation, n=10
`Site terminated, n=2
`
`APT cohorta, n=576
`PP cohortb, n=382
`Completedc, n=386
`
`Discontinued, n=172
`
`Clinical adverse experience, n=20
`Laboratory adverse experience, n=6
`Lack of efficacy, n=58
`Lost to follow-up, n=10
`Patient discontinued for other
`reasons: (n=11)
` Excluded medications, (n=3)
` Non-compliance, (n=2)
` Extended vacation, (n=2)
` Surgery, (n=1)
` Death, (n=2)
` Prerandomization lab value, (n=1)
`
`Patient moved, n=2
`Patient withdrew consent, n=28
`Prespecified discontinuation
` criteria, n=25
`Protocol deviation, n=10
`Site terminated, n=2
`
`APT cohorta, n=559
`PP cohortb, n=411
`Completedc, n=412
`
`Fig. 1 Patient disposition at each stage of the study.aAll patients–treated (APT) cohort includes randomized patients who
`received at least one dose of study treatment and who had both a baseline and at least one post-baseline measurement.
`bPer-protocol (PP) cohort includes randomized patients who completed all 52 weeks of treatment and did not have any
`reasons for exclusion from this population, including no baseline data, no treatment data at Week 52 or major protocol
`violations. cCompleter population includes randomized patients who completed all 52 weeks of treatment.
`
`difference observed at Week 24 (figure 2A), treatment
`with sitagliptin was significantly more durable (i.e.
`smaller rise in HbA1c from Week 24 to Week 54) than
`that with glipizide [COD (95% CI): 0.008%/week (0.005,
`0.010) vs. 0.011%/week (0.008, 0.013), respectively;
`between-group difference in COD (95% CI) ¼ 0.003
`(0.005, 0.001)].
`In the PP population, the percentage of patients with an
`HbA1c < 7% at Week 52 was similar between the sita-
`gliptin (63%; n/N ¼ 240/382) and the glipizide (59%;
`242/411) groups [difference in proportion (95% CI) ¼
`j Diabetes, Obesity and Metabolism, 9, 2007, 194–205
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`198
`
`3.9% (2.8, 10.7)]. In both groups, 29% of the patients
`reached an HbA1c < 6.5% [difference in proportion
`(95% CI) ¼ 0.1% (6.4, 6.2)]. In the APT population at
`Week 52, 52 and 51% of patients had an HbA1c < 7%
`[difference in proportion (95% CI) ¼ 0.9% (4.9, 6.7)],
`and 24 and 25% had an HbA1c < 6.5% [difference in
`proportion (95% CI) ¼ 0.7% (5.7, 4.3)] in the sita-
`gliptin and glipizide groups, respectively.
`A subgroup analysis of HbA1c response by baseline
`HbA1c levels showed an increase in treatment effects for
`both treatment groups, with increasing baseline HbA1c
`
`# 2007 Merck & Co.
`Journal Compilation # 2007 Blackwell Publishing Ltd
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`
`M. Nauck et al.
`
`Efficacy and safety of sitagliptin vs. glipizide in type 2 diabetes
`
`j OA
`
`Table 1 Baseline demographics and efficacy endpoint data
`for all randomized patients*
`
`Characteristic
`
`Sitagliptin 100 mg
`q.d. 1 metformin
`(N 5 588)
`
`Glipizide 1 metformin
`(N 5 584)
`
`56.8 (9.3)
`
`336 (57.1)
`252 (42.9)
`
`432 (73.5)
`41 (7.0)
`43 (7.3)
`50 (8.5)
`22 (3.7)
`89.5 (17.4)
`31.2 (5.0)
`
`Age (years)
`Sex, n (%)
`Male
`Female
`Race, n (%)
`Caucasian
`Black
`Hispanic
`Asian
`Other
`Body weight (kg)
`Body mass
`index (kg/m2)
`Duration of diabetes
`mellitus (years)
`Use of OHA at screening, n (%)
`Dual therapy
`177 (30.1)
`Monotherapy
`386 (65.6)
`Absence
`25 (4.3)
`HbA1c, % (range)
`7.7 (0.9) (6.1–11.0)
`HbA1c distribution at baseline, n (%)
`375 (64.0)
`HbA1c < 8%
`HbA1c  8 to <9% 151 (25.8)
`HbA1c  9%
`60 (10.2)
`FPG (mmol/l)
`9.2 (2.3)
`
`6.5 (6.1)
`
`56.6 (9.8)
`
`358 (61.3)
`226 (38.7)
`
`434 (74.3)
`35 (6.0)
`46 (7.9)
`49 (8.4)
`20 (3.4)
`89.7 (17.5)
`31.3 (5.2)
`
`6.2 (5.4)
`
`159 (27.2)
`397 (68.0)
`28 (4.8)
`7.6 (0.9) (5.8–10.5)
`
`381 (65.5)
`141 (24.2)
`60 (10.3)
`9.1 (2.3)
`
`line in fasting insulin compared with the glipizide group
`(table 2). There was a decrease from baseline in fasting
`proinsulin and the proinsulin/insulin ratio at Week 52
`in the sitagliptin group; however, the glipizide group
`had an increase from baseline in these two endpoints at
`Week 52 (table 2). The sitagliptin group had a smaller
`increase in HOMA-b than the glipizide group. No mean-
`ingful changes in HOMA-IR were found at Week 52,
`although QUICKI was significantly increased from base-
`line with sitagliptin relative to glipizide (table 2). No
`between-group differences were observed for any mea-
`sured lipid parameter, except for HDL-C, in which a sig-
`nificant increase from baseline was found with sitagliptin
`(3.7%) compared with glipizide (1.2%) [between-group
`difference in LS mean per cent change from baseline
`(95% CI) ¼ 2.5% (0.6, 4.3)].
`
`Safety and Tolerability
`
`When added to ongoing metformin therapy, there were no
`meaningful differences between groups in the incidence
`of overall clinical adverse experiences or clinical adverse
`experiences that were assessed as serious or leading to
`discontinuation (table 3). The proportion of patients
`experiencing adverse experiences considered related to
`study drug by the investigator was higher with glipizide
`than with sitagliptin (30.3 vs. 14.5%, respectively),
`related to a higher incidence of hypoglycaemia observed
`with glipizide treatment. There were two serious adverse
`experiences considered related to study drug by the
`investigator in the glipizide group (myocardial infarction
`and spontaneous abortion) and none in the sitagliptin
`group. Three deaths occurred in this 52-week study, two
`in the glipizide group (sudden cardiac death and myocar-
`dial infarction) and one in the sitagliptin group (because
`of trauma) (table 3); none was considered related to study
`drug. The incidence of adverse experiences by body sys-
`tems was comparable between the sitagliptin and the gli-
`pizide treatment groups. There was a slightly higher
`incidence of adverse experiences in the sitagliptin group
`than in the glipizide group for fatigue (3.1 vs. 0.9%), diz-
`ziness (3.7 vs. 2.1%), nasopharyngitis (10.5 vs. 7.5%),
`sinusitis (3.2 vs. 1.9%), urinary tract infection (5.4 vs.
`2.7%), osteoarthritis (2.6 vs. 0.7%) and pain in extremity
`(3.4 vs. 1.4%). In general, most of these events were rated
`as mild in intensity, not related to study drug, and
`resolved while patients continued in the study. The inci-
`dence of overall gastrointestinal events was similar in the
`sitagliptin and glipizide groups (20.4 vs. 19.3%, respec-
`tively) and the incidence of prespecified gastrointestinal
`events [abdominal pain, diarrhoea, nausea and vomiting
`(table 3)] was not significantly different between groups.
`
`FPG, fasting plasma glucose; HbA1c, glycosylated haemoglobin A1c;
`OHA, oral antihyperglycaemic agent.
`*Data are expressed as mean (s.d.) or frequency [n (%)], unless
`otherwise indicated. To convert FPG in mmol/l to mg/dl, multiply
`by 18.
`
`levels. In the PP population, the change in HbA1c from
`baseline was similar between treatments within each
`baseline HbA1c stratum with the greatest effect observed
`in patients with baseline HbA1c 9.0% [mean change
`from baseline (s.e.) ¼ 1.68% (0.16) with sitagliptin and
`1.76 (0.13) with glipizide; figure 2B]. In the APT pop-
`ulation, the mean change in HbA1c from baseline was
`also similar between treatments within each baseline
`HbA1c stratum, except for the results in the highest
`baseline HbA1c stratum (9%). In this stratum, the
`change from baseline was numerically greater in the gli-
`pizide group (1.31%) than in the sitagliptin group
`(0.94%).
`In the PP population, the maximal FPG effect was
`observed at Week 24 for both treatments, followed by a rise
`in FPG through Week 52 (figure 3). The LS mean FPG
`change from baseline at Week 52 was not different
`between groups (table 2). At Week 52, the sitagliptin
`group showed a numerically smaller increase from base-
`
`# 2007 Merck & Co.
`Journal Compilation # 2007 Blackwell Publishing Ltd
`
`Diabetes, Obesity and Metabolism, 9, 2007, 194–205
`
`j
`
`199
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`j
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`OA
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`Efficacy and safety of sitagliptin vs. glipizide in type 2 diabetes
`
`M. Nauck et al.
`
`Table 2 Key efficacy results in the per-protocol population*
`
`HbA1c (%)
`Glipizide þ metformin
`Sitagliptin þ metformin
`Fasting plasma glucose (mmol/l)
`Glipizide þ metformin
`Sitagliptin þ metformin
`Fasting serum insulin (pmol/l)
`Glipizide þ metformin
`Sitagliptin þ metformin
`Fasting serum proinsulin (pmol/l)
`Glipizide þ metformin
`Sitagliptin þ metformin
`Proinsulin/insulin ratio
`Glipizide þ metformin
`Sitagliptin þ metformin
`HOMA-b (%)
`Glipizide þ metformin
`Sitagliptin þ metformin
`HOMA-IR
`Glipizide þ metformin
`Sitagliptin þ metformin
`QUICKI (insulin sensitivity)
`Glipizide þ metformin
`Sitagliptin þ metformin
`
`n
`
`411
`382
`
`407
`382
`
`393
`374
`
`400
`371
`
`388
`365
`
`387
`368
`
`388
`368
`
`388
`368
`
`Week 0
`(baseline),
`mean (s.d.)
`
`7.52 (0.85)
`7.48 (0.76)
`
`8.84 (2.14)
`8.75 (1.87)
`
`80.4 (63.0)
`79.8 (72.6)
`
`26.3 (26.5)
`25.5 (24.1)
`
`Week 52,
`mean (s.d.)
`
`LS mean change from
`baseline (95% CI)
`
`Difference in LS mean
`change (95% CI)
`
`6.86 (0.69)
`6.84 (0.66)
`
`8.22 (2.20)
`8.04 (1.84)
`
`83.4 (51.6)
`78.0 (54.0)
`
`29.7 (24.2)
`22.9 (21.1)
`
`0.67 (0.75, 0.59)
`0.67 (0.75, 0.59)
`
`0.42 (0.67, 0.17)
`0.56 (0.81, 0.30)
`
`6.6 (0.6, 12.6)
`1.8 (4.8, 7.8)
`
`3.8 (1.3, 6.2)
`2.5 (5.1, 0.1)
`
`0.01 (0.09, 0.08)
`
`0.14 (0.38, 0.11)
`
`5.4 (11.4, 0.6)
`
`6.3 (8.7, 3.8)
`
`0.341 (0.193)
`0.334 (0.198)
`
`0.364 (0.201)
`0.310 (0.218)
`
`0.033 (0.009, 0.057)
`0.016 (0.040, 0.009)
`
`0.048 (0.072, 0.025)
`
`57.0 (48.5)
`57.6 (51.9)
`
`5.3 (4.6)
`5.2 (5.4)
`
`74.3 (75.8)
`64.4 (46.3)
`
`5.1 (3.5)
`4.8 (3.8)
`
`14.0 (6.5, 21.5)
`3.6 (4.1, 11.3)
`
`0.2 (0.3, 0.6)
`0.1 (0.5, 0.4)
`
`0.314 (0.033)
`0.313 (0.029)
`
`0.313 (0.028)
`0.317 (0.031)
`
`0.003 (0.006, 0.000)
`0.002 (0.001, 0.005)
`
`10.4 (18.0, 2.8)
`
`0.3 (0.7, 0.2)
`
`0.005 (0.002, 0.008)
`
`CI, confidence interval; FPG, fasting plasma glucose; HOMA-b, homeostasis model assessment-b cell function; HOMA-IR, HOMA-insulin resis-
`tance; LS, least squares.
`*To convert FPG in mmol/l to mg/dl, multiply by 18.
`[correction added after online publication 23 January 2007: column 4, values were rearranged; column 5, value was corrected]
`
`There were 187 (32.0%) glipizide-treated patients who
`reported 657 episodes of hypoglycaemia compared
`with 29 (4.9%) sitagliptin-treated patients who reported
`50 episodes of hypoglycaemia (table 3). Patients were
`instructed to collect fingerstick glucose values if possible
`when hypoglycaemia symptoms occurred. In 598 epi-
`sodes in the glipizide group, fingerstick values were
`obtained, of which 435 (73%) were <3.9 mmol/l (70 mg/
`dl). For sitagliptin, 43 episodes had fingerstick glucose
`values, and 31 (72%) of these episodes had values <3.9
`mmol/l (70 mg/dl). Eight patients (1.4%) on glipizide had
`a hypoglycaemic episode that required non-medical
`assistance but did not exhibit marked severity (i.e. mark-
`edly depressed level of consciousness, loss of conscious-
`ness or seizure) compared with one patient (0.2%) on
`sitagliptin, while seven patients (1.2%) in the glipizide
`group had an episode that required medical assistance or
`exhibited marked severity compared with one patient
`(0.2%) in the sitagliptin group.
`At 52 weeks, body weight was significantly reduced
`with sitagliptin [LS mean change from baseline (95%
`CI) ¼ 1.5 kg (2.0, 0.9)] and significantly increased
`j Diabetes, Obesity and Metabolism, 9, 2007, 194–205
`
`with glipizide [1.1 kg (0.5, 1.6)] relative to baseline, with
`a between-treatment difference of2.5 kg (3.1,2.0; p <
`0.001) (figure 4). The changes in body weight for each
`group were consistent with changes in waist circumfer-
`ence: a mean (s.d.) decrease from baseline of 1.4 cm
`(5.8) was measured for the sitagliptin group compared
`with a mean (s.d.) increase from baseline of 0.7 cm
`(6.0) in the glipizide group [between-group difference
`in LS mean change from baseline (95% CI) ¼ 2.1 cm
`(2.8, 1.3)].
`There were no clinically meaningful differences in
`the proportion of patients with values meeting prede-
`fined limits of change criteria for any of the measured
`chemistry and haematology analytes. A slight mean
`decrease from baseline in ALT was observed with sita-
`gliptin; from a baseline ALT value of approximately 20
`IU/l in both groups, the mean changes (s.d.) from base-
`line of 1.3 IU/l (11.9) in the sitagliptin group com-
`pared with a slight increase of 0.9 IU/l (8.2) in the
`glipizide group at Week 52. A similar pattern was
`observed for AST, with mean changes (s.d.) from base-
`line at Week 52 of 0.4 IU/l (6.1) in the sitagliptin
`
`# 2007 Merck & Co.
`Journal Compilation # 2007 Blackwell Publishing Ltd
`
`200
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`M. Nauck et al.
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`Efficacy and safety of sit