E m e r g i n g T r e a t m e n t s a n d T e c h n o l o g i e s
`O R I G I N A L
`A R T I C L E
`
`Efficacy and Safety of the Dipeptidyl
`Peptidase-4 Inhibitor Sitagliptin Added to
`Ongoing Metformin Therapy in Patients
`With Type 2 Diabetes Inadequately
`Controlled With Metformin Alone
`S itagliptin is an oral, once-daily, po-
`
`BERNARD CHARBONNEL, MD
`2
`AVRAHAM KARASIK, MD
`3
`JI LIU, MA
`
`1
`
`3
`MEI WU, MS
`3
`GARY MEININGER, MD
`FOR THE SITAGLIPTIN STUDY 020 GROUP*
`
`OBJECTIVE — The efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin,
`added to ongoing metformin therapy, were assessed in patients with type 2 diabetes who had
`inadequate glycemic control (HbA1c [A1C] ⱖ7 and ⱕ10%) with metformin alone.
`
`RESEARCH DESIGN AND METHODS — After a screening diet/exercise run-in period,
`a metformin dose titration/stabilization period, and a 2-week, single-blind, placebo run-in pe-
`riod, 701 patients, aged 19 –78 years, with mild to moderate hyperglycemia (mean A1C 8.0%)
`receiving ongoing metformin (ⱖ1,500 mg/day) were randomly assigned to receive the addition
`of placebo or sitagliptin 100 mg once-daily in a 1:2 ratio for 24 weeks. Patients exceeding specific
`glycemic limits were provided rescue therapy (pioglitazone) until the end of the study. The
`efficacy analyses were based on an all-patients-treated population using an ANCOVA and ex-
`cluded data obtained after glycemic rescue.
`
`RESULTS — At week 24, sitagliptin treatment led to significant reductions compared with
`placebo in A1C (⫺0.65%), fasting plasma glucose, and 2-h postmeal glucose. Fasting insulin,
`fasting C-peptide, fasting proinsulin-to-insulin ratio, postmeal insulin and C-peptide areas un-
`der the curve (AUCs), postmeal insulin AUC–to– glucose AUC ratio, homeostasis model assess-
`ment of ␤-cell function, and quantitative insulin sensitivity check index were significantly
`improved with sitagliptin relative to placebo. A significantly greater proportion of patients
`achieved an A1C ⬍7% with sitagliptin (47.0%) than with placebo (18.3%). There was no
`increased risk of hypoglycemia or gastrointestinal adverse experiences with sitagliptin compared
`with placebo. Body weight decreased similarly with sitagliptin and placebo.
`
`CONCLUSIONS — Sitagliptin 100 mg once-daily added to ongoing metformin therapy was
`efficacious and well tolerated in patients with type 2 diabetes who had inadequate glycemic
`control with metformin alone.
`
`Diabetes Care 29:2638 –2643, 2006
`
`● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●
`
`From the 1Centre Hospitalier Universitaire de Nantes, Nantes, France; the 2Chaim Sheba Medical Center, Tel
`Hashomer, Israel; and 3Merck Research Laboratories, Rahway, New Jersey.
`Address correspondence and reprint requests to Gary Meininger, MD, Director, Clinical Research, Merck
`Research Laboratories, 126 E. Lincoln Ave., RY34A-254, Rahway, NJ 07065. E-mail: gary_meininger@
`merck.com.
`Received for publication 31 March 2006 and accepted in revised form 28 August 2006.
`B.C. has acted as a consultant or speaker for GlaxoSmithKline, Merck, Sharpe & Dohme, Pfizer, Sanofi-
`Aventis, and Takeda. A.K. has acted as a consultant or speaker for Merck Research Laboratories.
`*A complete list of the Study 620 investigators can be found in the online appendix at http://care.
`diabetesjournals.org.
`Abbreviations: AUC, area under the curve; DPP-4, dipeptidyl peptidase-4; ECG, electrocardiogram;
`FPG, fasting plasma glucose; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like pep-
`tide-1; HOMA-␤, homeostasis model assessment of ␤-cell function; HOMA-IR, homeostasis model assess-
`ment of insulin resistance; OHA, oral antihyperglycemic agent; QUICKI, quantitative insulin sensitivity
`check index.
`A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion
`factors for many substances.
`DOI: 10.2337/dc06-0706. Clinical trial reg. no. NCT0086515, clinicaltrials.gov.
`© 2006 by the American Diabetes Association.
`The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby
`marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
`
`2638
`
`DIABETES CARE, VOLUME 29, NUMBER 12, DECEMBER 2006
`
`tent, and highly selective dipeptidyl
`peptidase-4 (DPP-4) inhibitor for
`the treatment of type 2 diabetes (1–5).
`DPP-4 inhibitors enhance levels of active
`incretin hormones, gut-derived pep-
`tides that are released into the circulation
`after ingestion of a meal (6 – 8). Glucagon-
`like peptide-1 (GLP-1) and glucose-
`dependent insulinotropic peptide (GIP)
`account for the majority of incretin action
`(9). In the presence of elevated glucose
`concentrations, GLP-1 and GIP increase
`insulin release and GLP-1 lowers gluca-
`gon secretion, thereby decreasing the
`postmeal rise in glucose concentration
`and reducing fasting glucose concentra-
`tions (9). Both GLP-1 and GIP are rapidly
`inactivated by the enzyme DPP-4 (10,11).
`By blocking this inactivation, DPP-4 in-
`hibitors increase active incretin levels, en-
`hancing incretin effects, and thereby offer
`a new therapeutic approach for the man-
`agement of patients with type 2 diabetes.
`Treatment with a single antihypergly-
`cemic agent is often unsuccessful in
`achieving and/or maintaining glycemic
`control in patients with type 2 diabetes,
`and many patients require combinations
`of antihyperglycemic agents (12). Met-
`formin, a biguanide, is one of the most
`commonly used first-line antihyperglyce-
`mic agents in the treatment of type 2 dia-
`betes, which acts primarily by lowering
`hepatic glucose production and may also
`improve insulin resistance (12). Because
`sitagliptin and metformin target poten-
`tially complementary pathways, the addi-
`tion of sitagliptin for patients with type 2
`diabetes who do not have adequate glyce-
`mic control with metformin mono-
`therapy may provide improved glycemic
`control. In an earlier, short-term study
`(13) of sitagliptin added to ongoing met-
`formin therapy in patients with type 2 di-
`abetes with inadequate glycemic control
`with metformin alone, a sustained 24-h
`reduction in glucose compared with pla-
`cebo was observed after 28 days of treat-
`
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`
`ment. In light of these findings, the
`present placebo-controlled study as-
`sessed the efficacy and safety of sitagliptin
`100 mg once-daily added to ongoing met-
`formin therapy in patients with type 2 di-
`abetes who were inadequately controlled
`on metformin alone. The 100 mg once-
`daily dose of sitagliptin was selected
`based on the results of two previous, 12-
`week, dose-range-finding studies in pa-
`tients with type 2 diabetes in which
`treatment at this dose produced the great-
`est improvement in glycemic control
`(4,5).
`
`RESEARCH DESIGN AND
`METHODS — Men and women (aged
`18 –78 years) with type 2 diabetes and
`inadequate glycemic control (defined by
`an HbA1c [A1C] level ⱖ7 and ⱕ10%)
`while taking metformin monotherapy at a
`stable dose of at least 1,500 mg/day, either
`at entry into the study or after a met-
`formin dose-stable run-in period, were el-
`igible to be randomized. Patients who
`were not currently taking an oral antihy-
`perglycemic agent (OHA), were taking
`any OHA in monotherapy, or were taking
`metformin in combination with another
`OHA were potentially eligible to partici-
`pate in the study if their A1C level met the
`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 finger-
`stick glucose) at, or just before, random-
`ization ⬎14.4 mmol/l (260 mg/dl). A
`history of hypoglycemia was not an ex-
`clusion criterion. Other OHAs were
`prohibited during the study. Concurrent
`lipid-lowering and antihypertensive med-
`ications, thyroid medications, hormone
`replacement therapy, and birth control
`medications were allowed but were ex-
`pected to remain at stable doses.
`This was a multinational, random-
`ized, parallel-group study with a placebo-
`controlled, double-blind treatment
`period. The screening/eligibility run-in
`period was designed to allow patients
`with type 2 diabetes being treated with a
`variety of different regimens, as described
`in the prior section, to participate. Pa-
`tients who were already taking metformin
`at a dose of at least 1,500 mg/day whose
`A1C level was ⱖ7 and ⱕ10% directly en-
`tered a 2-week placebo run-in period and
`were eligible to be randomized. Patients
`not currently taking an OHA, patients
`taking any OHA in monotherapy (other
`
`than metformin ⱖ1,500 mg/day), or pa-
`tients taking metformin in combination
`with another OHA entered a metformin
`monotherapy treatment titration and
`dose-stable period of up to 19 weeks (the
`duration was variable, on the basis of
`prior therapy, to ensure sufficient time to
`respond to metformin monotherapy). Af-
`ter the dose-stable run-in period of met-
`formin monotherapy, patients with A1C
`ⱖ7 and ⱕ10% entered a 2-week placebo
`run-in period and were eligible to be
`randomized. Patients were randomly as-
`signed to receive the addition of placebo
`or sitagliptin 100 mg once-daily in a 1:2
`ratio. The double-blind treatment period
`was 24 weeks. Patients exceeding specific
`glycemic limits during the 24-week treat-
`ment period were provided rescue ther-
`apy (pioglitazone, administered in
`accordance with the product label) until
`the completion of the placebo-controlled
`study period. Rescue therapy was initi-
`ated if FPG was ⬎15.0 mmol/l (270 mg/
`dl) from baseline through week 6, ⬎13.3
`mmol/l (240 mg/dl) after week 6 through
`week 12, and ⬎11.1 mmol/l (200 mg/dl)
`after week 12. An ongoing active-
`comparator treatment phase for patients
`who completed the placebo-controlled
`period will be the subject of a subsequent
`report.
`
`Study end points
`The primary efficacy end point was
`change from baseline at week 24 in A1C.
`Secondary efficacy end points included
`change from baseline at week 24 in FPG
`as well as in glucose, insulin, and C-
`peptide concentrations, measured imme-
`diately before and at 60 and 120 min after
`a standard meal, and a lipid panel (total
`cholesterol, triglycerides, LDL choles-
`terol, HDL cholesterol, non-HDL choles-
`terol, and triglyceride-to-HDL cholesterol
`ratio). Exploratory end points included
`mean glucose, insulin, and C-peptide
`concentrations, as well as area under the
`curve (AUC) for glucose, insulin, and C-
`peptide, and insulin AUC–to– glucose
`AUC ratio, after a standardized morning
`meal. All assays were performed by tech-
`nicians blinded to the treatment sequence
`at PPD Global Central Labs (Lexington,
`KY).
`Safety and tolerability were assessed
`throughout the study. Monitoring for ad-
`verse experiences, physical examinations,
`vital signs, body weight, 12-lead electro-
`cardiograms (ECGs) (read at a central
`reading laboratory), and safety laboratory
`measurements comprising routine hema-
`
`Charbonnel and Associates
`
`tology, serum chemistry, and urinalysis
`were performed. Investigators evaluated
`each clinical adverse experience for inten-
`sity (mild, moderate, or severe), duration,
`outcome, and relationship to study drug.
`Adverse experiences of special interest in-
`cluded hypoglycemia and gastrointestinal
`adverse experiences.
`
`Statistical analysis
`Efficacy analyses were based on the all-
`patients-treated population, which con-
`sisted of randomly assigned patients who
`had received at least one dose of study
`treatment and had both a baseline and at
`least one postbaseline measurement. An
`ANCOVA model was used to analyze the
`treatment groups for the continuous effi-
`cacy parameters, comparing change from
`baseline (day 1/randomization) at week
`24. Analyses were adjusted for baseline
`values and the presence/absence of prior
`antihyperglycemic therapy. Missing data
`were handled using the last observation
`carried forward method. To avoid the
`confounding influence of rescue therapy
`on efficacy comparisons, in efficacy anal-
`yses we treated data obtained after initia-
`tion of rescue therapy as missing data.
`The primary efficacy hypothesis for this
`study was that the addition of sitagliptin
`100 mg compared with placebo would
`lead to a greater reduction in A1C at week
`24 and was assessed by testing the statis-
`tical significance of the difference in the
`least-squares mean change from baseline
`at week 24 in A1C for the sitagliptin
`group versus the placebo group. The test-
`ing procedures for the secondary efficacy
`end points proceeded in a conditional
`manner and were prioritized in the order
`of FPG and then 2-h postmeal glucose,
`provided the primary efficacy hypothesis
`for A1C was met. The proportion of pa-
`tients in each group achieving an A1C
`goal ⬍7% at week 24 was also assessed. A
`time-to-glycemic-rescue analysis was per-
`formed using the Kaplan-Meier estimator
`and the log-rank test. The proportion of
`patients in each treatment group who had
`received glycemic rescue therapy during
`the study was also determined.
`Safety analyses were performed using
`the all-patients-as-treated population,
`which included all randomly assigned pa-
`tients who received at least one dose of
`double-blind study therapy. For hypogly-
`cemia as well as prespecified selected
`gastrointestinal adverse experiences
`(abdominal pain, diarrhea, nausea, and
`vomiting) and change in body weight, in-
`ferential testing was done to determine
`
`DIABETES CARE, VOLUME 29, NUMBER 12, DECEMBER 2006
`
`2639
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`
`Sitagliptin added to metformin in diabetes
`
`Table 1—Glycemic efficacy end points
`
`Parameter
`
`n
`
`Baseline
`
`Week 24
`
`Least-squares change from baseline
`
`A1C (%)
`Placebo
`Sitagliptin 100 mg q.d.
`FPG (mmol/l)
`Placebo
`Sitagliptin 100 mg q.d.
`Insulin (pmol/l)
`Placebo
`Sitagliptin 100 mg q.d.
`Proinsulin-to-insulin ratio
`Placebo
`Sitagliptin 100 mg q.d.
`C-peptide (nmol/l)
`Placebo
`Sitagliptin 100 mg q.d.
`HOMA-␤
`Placebo
`Sitagliptin 100 mg q.d.
`QUICKI
`⫺0.002 (⫺0.007 to 0.003)
`0.312 ⫾ 0.028
`0.314 ⫾ 0.031
`196
`Placebo
`0.003 (⫺0.000 to 0.007)†
`0.318 ⫾ 0.036
`0.315 ⫾ 0.032
`418
`Sitagliptin 100 mg q.d.
`Data are means ⫾ SD or mean (95% CI). To convert glucose from millimoles per liter to milligrams per deciliter, divide by 0.05551.*P ⬍ 0.001 vs. placebo; †P ⬍
`0.050 vs. placebo; ‡P ⬍ 0.010 vs. placebo.
`
`⫺0.02 (⫺0.15 to 0.10)
`⫺0.67 (⫺0.77 to ⫺0.57)*
`
`0.5 (0.2 to 0.8)
`⫺0.9 (⫺1.2 to ⫺0.7)*
`
`⫺1.2 (⫺10.2 to 8.4)
`7.8 (0.6–15.0)†
`
`0.02 (⫺0.02 to 0.05)
`⫺0.03 (⫺0.05 to 0.00)‡
`
`0.03 (⫺0.03 to 0.01)
`0.10 (0.03–0.13)‡
`
`3.5 (⫺4.9 to 11.8)
`19.5 (12.9–26.2)*
`
`224
`453
`
`226
`454
`
`197
`419
`
`169
`397
`
`186
`390
`
`196
`418
`
`8.03 ⫾ 0.82
`7.96 ⫾ 0.81
`
`9.6 ⫾ 2.3
`9.4 ⫾ 2.3
`
`72.0 ⫾ 45.6
`72.6 ⫾ 58.2
`
`0.37 ⫾ 0.20
`0.36 ⫾ 0.21
`
`0.83 ⫾ 0.40
`0.83 ⫾ 0.43
`
`45.1 ⫾ 34.2
`46.4 ⫾ 38.9
`
`7.95 ⫾ 1.10
`7.26 ⫾ 0.97
`
`9.9 ⫾ 2.8
`8.4 ⫾ 2.2
`
`72.0 ⫾ 40.8
`81.6 ⫾ 76.2
`
`0.37 ⫾ 0.21
`0.33 ⫾ 0.21
`
`0.87 ⫾ 0.40
`0.93 ⫾ 0.43
`
`47.6 ⫾ 37.5
`65.2 ⫾ 68.9
`
`statistical significance levels for between-
`group comparisons.
`
`RESULTS
`
`Demographics and baseline
`characteristics
`The overall disposition of patients who
`were screened and randomly assigned in
`the placebo-controlled period of the
`study is shown in Fig. 1 of the online ap-
`pendix (available at http://care.diabetes
`journals.org). Of the 1,464 patients who
`were screened, 701 were randomly as-
`signed to study treatment. The demo-
`graphic and baseline anthropometric and
`disease characteristics of the randomly as-
`signed patients were similar between the
`treatment groups (see Fig. 1 of the online
`appendix). For the entire study popula-
`tion, the average duration of diabetes was
`6.2 years, average baseline A1C was 8%
`(range 6.4 –11.0%; 55% of patients had a
`baseline A1C ⬍8%), and the average
`baseline FPG was 9.5 mmol/l (171.5 mg/
`dl). A greater percentage of patients in the
`placebo group discontinued the study
`compared with patients in the sitagliptin
`group (19 vs. 10%) (see Fig. 1 of the on-
`line appendix). The most common rea-
`sons for discontinuation were lack of
`efficacy (placebo 5.5 vs. sitagliptin 1.5%),
`withdrawal of consent (placebo 4.2 vs.
`
`sitagliptin 2.2%), clinical adverse experi-
`ences (placebo 2.1 vs. sitagliptin 2.4%),
`and lost to follow-up (placebo 2.1 vs. sita-
`gliptin 0.9%).
`
`Efficacy
`At week 24, treatment with sitagliptin
`100 mg once-daily led to a significant
`(P ⬍ 0.001) reduction from baseline in
`A1C compared with placebo (Table 1).
`The placebo-subtracted least-squares
`mean (95% CI) reduction from baseline
`in A1C for the sitagliptin 100 mg group
`was ⫺0.65% (⫺0.77 to ⫺0.53). A1C de-
`creased in the sitagliptin group relative to
`the placebo group during the first 12
`weeks of treatment and then remained
`generally stable, with a slight trend to-
`ward further reduction, over the subse-
`quent double-blind treatment period
`(Fig. 1A). No significant treatment-by-
`baseline A1C or treatment-by-prior dia-
`betes pharmacotherapy interaction was
`observed. Treatment with sitagliptin led
`to a significant increase in the proportion
`of patients achieving an A1C ⬍7% com-
`pared with placebo (213 of 453 patients
`[47.0%] in the sitagliptin group versus 41
`of 224 patients [18.3%] in the placebo
`group; P ⬍ 0.001 for between-group
`comparison).
`Treatment with sitagliptin 100 mg
`also led to a significant (P ⬍ 0.001) re-
`
`duction from baseline at week 24 in FPG
`compared with placebo (Table 1). The
`placebo-subtracted least-squares mean
`(95% CI) reduction from baseline in FPG
`for the sitagliptin 100 mg group was ⫺1.4
`mmol/l (⫺1.7 to ⫺1.1) (⫺25.4 mg/dl
`[⫺31.0 to ⫺19.8]). The mean reduction
`from baseline in FPG in the sitagliptin
`group was near maximal for the study by
`week 6, with a trend toward a progressive
`further decrease in FPG through the re-
`mainder of the double-blind treatment
`period (Fig. 1B). In contrast, there was a
`generally sustained mean increase from
`baseline in FPG levels in the placebo
`group from weeks 6 through 24 (Fig. 1B).
`In addition to the significant de-
`creases in A1C and FPG, treatment with
`sitagliptin 100 mg also led to significant
`increases relative to placebo in fasting in-
`sulin (P ⬍ 0.050), fasting C-peptide (P ⬍
`0.010), homeostasis model assessment of
`␤-cell function (HOMA-␤) (P ⬍ 0.001),
`and quantitative insulin sensitivity check
`index (QUICKI) (P ⬍ 0.050) and a signif-
`icant decrease in fasting proinsulin-to-
`insulin ratio (P ⬍ 0.010) at week 24
`(Table 1). Sitagliptin 100 mg had no sig-
`nificant effect on fasting proinsulin levels
`or homeostasis model assessment of insu-
`lin resistance (HOMA-IR) (see Table 1 of
`the online appendix).
`Treatment with sitagliptin 100 mg led
`
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`Charbonnel and Associates
`
`to a significant decrease in 2-h postmeal
`glucose (P ⬍ 0.001) (see Table 1 of the
`online appendix and Fig. 1C) and signif-
`icant increases in 2-h postmeal insulin
`(P ⬍ 0.050) (see Table 1 of the online
`appendix) and 2-h postmeal C-peptide
`(P ⬍ 0.001) relative to placebo at week 24
`(see Table 1 of the online appendix).
`Treatment with sitagliptin also led to a
`significant decrease in 2-h postmeal glu-
`cose total AUC (P ⬍ 0.001) and signifi-
`cant increases in 2-h postmeal insulin
`total AUC (P ⬍ 0.010), 2-h postmeal C-
`peptide AUC (P ⬍ 0.001), and 2-h post-
`meal insulin-to-glucose AUC ratio (P ⬍
`0.001) relative to placebo at week 24 (see
`Table 1 of the online appendix).
`A significantly smaller proportion of
`patients in the sitagliptin group required
`glycemic rescue therapy during the 24-
`week study compared with the placebo
`group (21 of 464 patients [4.5%] receiv-
`ing sitagliptin required rescue therapy
`during the study compared with 32 of
`237 patients [13.5%] in the placebo
`group; P ⬍ 0.001). Additionally, the time
`to initiation of rescue therapy was signif-
`icantly (P ⬍ 0.001) later in the sitagliptin
`group than in the placebo group.
`Treatment with sitagliptin 100 mg led
`to statistically significant, albeit generally
`small, decreases in total cholesterol, tri-
`glycerides, non-HDL cholesterol, and tri-
`glyceride-to-HDL cholesterol ratio, as
`well as a small, statistically significant, in-
`crease in HDL cholesterol relative to pla-
`cebo at week 24. However, no significant
`between-group difference in LDL choles-
`terol was observed (placebo-subtracted
`least-squares mean [95% CI] percent
`changes from baseline at week 24: total
`cholesterol ⫺2.8% [⫺5.3 to ⫺0.4]; tri-
`glycerides ⫺16.9% [⫺24.3 to ⫺9.4];
`HDL cholesterol 2.0% [0.0 – 4.0]; non-
`HDL cholesterol ⫺4.8% [⫺8.3 to ⫺1.3];
`triglyceride-to-HDL cholesterol ratio
`⫺19.4% [⫺27.9 to ⫺10.8]; LDL choles-
`terol ⫺0.8% [⫺5.4 to 3.8]) (see Table 1 of
`the online appendix).
`
`Safety
`Treatment with sitagliptin 100 mg once-
`daily added to ongoing metformin ther-
`apy was generally well tolerated. The
`overall incidence of clinical adverse expe-
`riences, drug-related clinical adverse ex-
`periences, serious clinical adverse
`experiences, and drug-related serious
`clinical adverse experiences was similar in
`the two treatment groups (Table 2). The
`incidence of discontinuation due to ad-
`verse experiences was also similar between
`
`Figure 1—Key glycemic efficacy end points: A: Mean (SE) A1C (percentage) over time for
`sitagliptin 100 mg once-daily (q.d.) versus placebo added to ongoing metformin therapy in patients
`with type 2 diabetes who had inadequate glycemic control with metformin alone. B: Mean (SE)
`FPG (millimoles per liter) over time for sitagliptin 100 mg once-daily versus placebo added to
`ongoing metformin therapy in patients with type 2 diabetes who had inadequate glycemic control
`with metformin alone. C: Mean (SE) plasma glucose concentrations (millimoles per liter) over 2 h
`after a standard meal at baseline (week 0) and week 24 for sitagliptin 100 mg once-daily or
`placebo added to ongoing metformin therapy in patients with type 2 diabetes who had inadequate
`glycemic control with metformin alone.
`
`DIABETES CARE, VOLUME 29, NUMBER 12, DECEMBER 2006
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`Sitagliptin added to metformin in diabetes
`
`Table 2—Safety summary
`
`Safety parameter
`
`Placebo
`
`Sitagliptin 100 mg q.d.
`
`n
`Patients with one or more clinical adverse experience
`Patients with drug-related clinical adverse experiences*
`Patients with serious clinical adverse experiences
`Patients with drug-related serious clinical adverse experiences
`Patients who discontinued due to clinical adverse experiences
`Patients who discontinued due to drug-related clinical adverse experiences
`Patients who discontinued due to serious clinical adverse experiences
`Patients who discontinued due to serious drug-related clinical adverse experiences
`Hypoglycemia
`Overall gastrointestinal adverse experiences
`Selected gastrointestinal adverse experiences
`10 (2.2)
`9 (3.8)
`Abdominal pain
`12 (2.6)
`6 (2.5)
`Diarrhea
`6 (1.3)
`2 (0.8)
`Nausea
`5 (1.1)
`2 (0.8)
`Vomiting
`Data are n (%). *Determined by the investigator to be possibly, probably, or definitely drug related. †Includes five patients who discontinued during the initial
`placebo-controlled phase and two patients who discontinued after completing this phase because of adverse experiences that had an onset during the placebo-
`controlled phase.
`
`464
`262 (56.5)
`45 (9.7)
`13 (2.8)
`0
`11 (2.4)
`4 (0.9)
`6 (1.3)
`0
`6 (1.3)
`55 (11.9)
`
`237
`128 (54.0)
`25 (10.5)
`7 (3.0)
`0
`7 (3.0)†
`0
`1 (0.4)
`0
`5 (2.1)
`25 (10.5)
`
`the two treatment groups (Table 2). There
`were no statistically significant differences
`in the incidence of either hypoglycemia or
`predefined gastrointestinal adverse experi-
`ences between the sitagliptin and placebo
`groups (Table 2).
`For most specific clinical adverse ex-
`periences, the incidences were generally
`similar in the sitagliptin and placebo
`groups. Only a few adverse experiences
`occurred at a higher incidence with sita-
`gliptin compared with placebo, and for
`these, which included nasopharyngitis,
`urinary tract infection, arthralgia, back
`pain, and cough, the differences were
`generally small (see Table 2 of the online
`appendix). The incidence of other ad-
`verse experiences classified by body sys-
`tem, including the incidence of cardiac-
`related adverse experiences, infections,
`and musculoskeletal adverse experiences,
`was generally comparable between the
`two treatment groups.
`There were no laboratory adverse ex-
`periences that had a notably greater inci-
`dence in the sitagliptin group compared
`with the placebo group (see Table 2 of the
`online appendix). No meaningful differ-
`ences between treatment groups were ob-
`served in mean changes from baseline or
`in the occurrence of elevations in alanine
`aminotransferase or aspartate amino-
`transferase. A small mean increase
`(ⱕ10%) was observed in white blood cell
`count related to an increase in absolute
`neutrophil count in the sitagliptin 100 mg
`group compared with placebo. These
`changes appeared to remain stable over
`
`the course of the treatment period. A
`small mean increase (⬃10 ␮mol/l) from
`baseline in uric acid was observed in the
`sitagliptin group relative to the placebo
`group at week 24 (baseline uric acid lev-
`els: 330.7 ␮mol/l for sitagliptin 100 mg
`once-daily vs. 335.5 ␮mol/l for placebo);
`no laboratory adverse experiences of hy-
`peruricemia or clinical adverse experi-
`ences of gout were reported. A small mean
`decrease (⬃4%) from baseline in alkaline
`phosphatase was also detected in the sita-
`gliptin group compared with placebo at
`week 24. There was a slightly greater, al-
`beit not statistically significant, incidence
`of hemoglobin values that met the pre-
`defined limit of change criteria for at least
`one decrease of ⱖ1.5 g/l in the sitagliptin
`100 mg group (5.7%) compared with the
`placebo group (3.5%). There was no
`meaningful difference between the two
`treatment groups in mean change from
`baseline for hemoglobin. No meaningful
`differences were observed between treat-
`ment groups in the mean changes from
`baseline or in changes meeting predefined
`limits of change criteria for other labora-
`tory assessments.
`There were no clinically meaningful
`changes in ECGs or vital signs with sita-
`gliptin treatment. Small (0.6 – 0.7 kg), but
`statistically significant (P ⬍ 0.05), mean
`decreases from baseline in body weight
`were observed in both treatment groups;
`however, the mean between-group differ-
`ence was not significant (P ⫽ 0.835 for
`between-group comparison for change
`from baseline at Week 24).
`
`CONCLUSIONS — In this study,
`sitagliptin 100 mg once-daily provided
`statistically significant and clinically
`meaningful reductions in A1C compared
`with placebo when added to ongoing
`metformin therapy in patients with type 2
`diabetes and mild to moderate hypergly-
`cemia who had inadequate glycemic
`control with metformin monotherapy.
`Secondary glycemic end points including
`FPG and 2-h postmeal glucose also
`showed clinically important and statisti-
`cally significant improvements with sita-
`gliptin 100 mg compared with placebo.
`The A1C- and FPG-lowering responses to
`sitagliptin treatment were sustained dur-
`ing the 24-week treatment period, with a
`trend of continuing reductions in both
`end points throughout the treatment pe-
`riod. Nearly half of the patients receiving
`sitagliptin 100 mg once-daily achieved
`the current American Diabetes Associa-
`tion glycemic goal of A1C ⬍7% (14) com-
`pared with less than one-fifth of placebo-
`treated patients.
`Consistent with its mechanism of ac-
`tion, treatment with sitagliptin 100 mg
`led to a statistically significant increase
`compared with placebo in HOMA-␤, a
`surrogate end point that has been used to
`assess the ability of pancreatic ␤-cells to
`secrete insulin under fasting conditions.
`In addition, improvement in the fasting
`proinsulin-to-insulin ratio, consistent
`with improved ␤-cell function, was also
`observed with sitagliptin treatment. Pre-
`clinical studies have shown that GLP-1
`can stimulate ␤-cell differentiation and
`
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`Mylan EX 1004, Page 5
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`
`proliferation; additionally, GLP-1 has
`been shown to inhibit apoptosis of
`␤-cells, including that of human ␤-cells in
`vitro (8,9). Moreover, DPP-4 inhibitors
`have been shown to stimulate ␤-cell neo-
`genesis and survival in streptozotocin-
`treated rats (15). The implications of such
`effects of DPP-4 inhibition on ␤-cell mass
`and function in humans still need to be
`determined with additional clinical stud-
`ies. End points reflecting changes in insu-
`lin sensitivity (QUICKI and HOMA-IR)
`showed a mixed response with a small,
`but statistically significant, increase in
`QUICKI and no significant change in
`HOMA-IR.
`During this study, patients under-
`went a standard 2-h meal tolerance test,
`enabling an assessment of the effect of
`treatment on postmeal glucose, insulin,
`and C-peptide concentrations and the ra-
`tio of insulin to glucose. Treatment with
`sitagliptin led to clinically important and
`statistically significant improvements in
`all of these end points compared with
`placebo.
`Sitagliptin 100 mg was well tolerated
`in this clinical trial. No clinically mean-
`ingful differences in the overall incidence
`of clinical adverse experiences, clinical
`adverse experiences leading to discontin-
`uation, serious clinical adverse experi-
`ences, or laboratory adverse experiences
`were observed in the sitagliptin group
`compared with the placebo group. The
`addition of sitagliptin to ongoing met-
`formin therapy did not lead to an increase
`in the incidence of gastrointestinal side
`effects, which are typically associated
`with metformin treatment alone. Sitaglip-
`tin treatment was associated with a very
`low incidence of hypoglycemia adverse
`experiences, with a rate similar to that
`seen in the placebo group. Furthermore,
`none of the hypoglycemia episodes exhib-
`ited marked severity. Treatment with sita-
`gliptin led to a small, but statistically
`significant, mean decrease from baseline
`in body weight, with no significant differ-
`ence in weight change compared with
`placebo. Sitagliptin treatment also led to
`slight, statistically significant improve-
`ments in lipid parameters. No clinically
`meaningful differences were observed in
`the sitagliptin group compared with pla-
`cebo with respect to mean changes in se-
`rum chemistry and hematology analytes,
`and there were no clinically meaningful
`changes in vital signs or ECGs with sita-
`gliptin treatment.
`
`In summary, in patients with type 2
`diabetes who had inadequate glycemic
`control with metformin alone, the addi-
`tion of sitagliptin 100 mg once-daily was
`well tolerated and provided effective and
`sustained improvement in A1C, FPG, and
`2-h postmeal glucose, as well as signifi-
`cant improvements in indexes of insulin
`secretion and ␤-cell function, including
`HOMA-␤ and the fasting proinsulin-to-
`insulin ratio. Treatment with sitagliptin
`was associated with a low rate of hypogly-
`cemia that was similar to that seen with
`placebo, as well as a neutral effect on body
`weight.
`
`Acknowledgments— Funding for this study
`was provided by Merck Research Laboratories.
`The authors thank Dr. Alan G. Meehan (Merck
`Research Laboratories) for his contribution in
`writing this article.
`A list of author contributions regarding the
`work performed in this study can be found in
`the online appendix.
`
`References
`1. Kim D, Wang L, Beconi M, Eiermann GJ,
`Fisher MH, He H, Hickey GJ, Kowalchick
`JE, Leiting B, Lyons K, Marsilio F, Mc-
`Cann ME, Patel RA, Petrov A, Scapin G,
`Patel SB, Roy RS, Wu JK, Wyvratt MJ,
`Zhang BB, Zhu L, Thornberry NA, Weber
`AE: (2R)-4-Oxo-4-[3-(trifluoromethyl)-
`5 , 6 - d i h y d r o [ 1 , 2 , 4 ] t r i a z o l o [ 4 , 3 -
`a ] p y r a z i n - 7 ( 8 H ) - y l ] - 1 - ( 2 , 4 , 5 -
`trifluorophenyl)butan-2-amine: a po-
`tent, orally active dipeptidyl peptidase
`IV inhibitor for the treatment of type 2
`diabetes. J Med Chem 48:141–151, 2005
`2. Herman GA, Stevens C, Van Dyck K,
`Bergman A, Yi B, DeSmet M, Snyder K,
`Hilliard D, Tanen M, Tanaka W, Wang
`AQ, Chen L, Zeng W, Musson D, Laethem
`M, Zhou YY, Winchell G, Davies MJ, Ra-
`mael S, Gottesdiener KM, Wagner JA:
`Pharmacokinetics and pharmacodynam-
`ics of single doses of sitagliptin, an inhib-
`itor of dipeptidyl peptidase-IV, in healthy
`subjects. Clin Pharm Ther 78:675– 688,
`2005
`3. Herman GA, Bergman A, Stevens C, Kotey
`P, Yi B, Zhao P, Dietrich B, Golor G,
`Schrodter A, Keymeulen B, Lasseter KC,
`Kipnes MS, Snyder K, Hilliard D, Tanen
`M, Cilissen C, De Smet M, de Lepeleire I,
`Van Dyck K, Wang AQ, Zeng W, Davies
`MJ, Tanaka W, Holst JJ, Deacon CF,
`Gottesdiener KM, Wagner JA: Effect of
`single oral doses of sitagliptin, a dipepti-
`dyl peptidase-4 inhibitor, on incretin and
`plasma glucose levels following an oral
`glucose tolerance test in patients with
`type 2 diabetes. J Clin Endocrinol Metab.
`
`Charbonnel and Associates
`
`91:4612⫺4619, 2006
`4. Scott R, Herman GA, Zhao PL, Chen X,
`Wu M, Stein PP: Twelve-week efficacy
`and tolerability of MK-0431, a dipeptidyl
`peptidase IV (DPP-IV) inhibitor, in the
`treatment of type 2 diabetes (Abstract).
`Diabetes 54:A10, 2005
`5. Herman GA, Hanef