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Merck Research Laboratories (G.A.H., A.B., C.S., P.K., B.Y., P.Z., K.S., D.H., M.T., A.Q.W., W.Z., M.J.D., W.T., K.M.G., J.A.W.), Rahway, New Jersey 07065; 3ClinicalResearch AG (B.D., G.G.), 16761 Berlin, Germany; Focus Clinical Drug Development GmBH (A.S.), 41460 Neuss, Germany; Free University of Brussels (B.K.), Brussels, 1050 Belgium; Clinical Pharmacology Associates (K.C.L.), Miami, Florida 33142; Diabetes and Glandular Disease Research Associates (M.S.K.), San Antonio, Texas 78229; MSD-Europe (C.C., M.D.S., I.d.L., K.V.D.), 1180 Brussels, Belgium; and University of Copenhagen (J.J.H., C.F.D.), DK-2200 Copenhagen, Denmark
Address all correspondence and requests for reprints to: Gary A. Herman, M.D., Merck Research Laboratories, Experimental Medicine, RY34-A4031, 126 East Lincoln Avenue, Rahway, New Jersey 07065. E-mail: gary_herman{at}merck.com.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: The objective of the study was to examine the pharmacodynamics, pharmacokinetics, and tolerability of sitagliptin.
Design: This was a randomized, double-blind, placebo-controlled, three-period, single-dose crossover study.
Setting: The study was conducted at six investigational sites.
Patients: The study population consisted of 58 patients with type 2 diabetes who were not on antihyperglycemic agents.
Interventions: Interventions included sitagliptin 25 mg, sitagliptin 200 mg, or placebo.
Main Outcome Measures: Measurements included plasma DPP-4 activity; post-OGTT glucose excursion; active and total incretin GIP levels; insulin, C-peptide, and glucagon concentrations; and sitagliptin pharmacokinetics.
Results: Sitagliptin dose-dependently inhibited plasma DPP-4 activity over 24 h, enhanced active GLP-1 and GIP levels, increased insulin/C-peptide, decreased glucagon, and reduced glycemic excursion after OGTTs administered at 2 and 24 h after single oral 25- or 200-mg doses of sitagliptin. Sitagliptin was generally well tolerated, with no hypoglycemic events.
Conclusions: In this study in patients with type 2 diabetes, near maximal glucose-lowering efficacy of sitagliptin after single oral doses was associated with inhibition of plasma DPP-4 activity of 80% or greater, corresponding to a plasma sitagliptin concentration of 100 nM or greater, and an augmentation of active GLP-1 and GIP levels of 2-fold or higher after an OGTT.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Sitagliptin is an oral and highly selective DPP-4 inhibitor (10). In sitagliptin-treated lean rodents, approximately 80% inhibition of plasma DPP-4 activity and 2- to 3-fold elevation in active GLP-1 levels were associated with near maximal reduction in glucose excursion after an oral glucose tolerance test (OGTT) (10). In healthy men with normal glucose concentrations, single doses of sitagliptin up to 600 mg were well tolerated without increased incidence of hypoglycemia or gastrointestinal adverse experiences, compared with placebo (11). Additionally, sitagliptin inhibited plasma DPP-4 enzyme activity and augmented active GLP-1 levels in a dose-dependent manner and had a pharmacokinetic (PK) profile consistent with once-daily dosing (11).
The degree of DPP-4 inhibition and level of active incretin augmentation required for near-maximal glucose lowering efficacy with a DPP4 inhibitor are not known. Therefore, the pharmacodynamics (PD), PK, and tolerability of sitagliptin were examined after administration of single oral doses of sitagliptin (25 or 200 mg) and OGTTs in patients with type 2 diabetes.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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The protocol was reviewed and approved by each study center. All patients provided written informed consent before enrollment. Eligible patients (age 21–60 yr) had type 2 diabetes and met all of the following criteria at the screening visit: FPG 126 mg/dl or greater and 250 mg/dl or less after an overnight fast of 8 h or longer; HbA1c 6.5–11.0% inclusive; C-peptide greater than 0.8 ng/ml; and not on an antihyperglycemic agent within 3 months of screening visit.
Patients were excluded from participation for any of the following: history of type 1 diabetes; body mass index greater than 40 kg/m2; estimated creatinine clearance 60 ml/min or less; or history of symptomatic orthostatic hypotension.
Study design
This was a multicenter, randomized, double-blind, placebo-controlled, three-period, crossover study. At the screening visit, eligible patients were counseled to follow a dietary program for approximately 2 wk before randomization and throughout the study. This diet was based on American Diabetes Association recommendations (55–60% carbohydrate, 10–20% protein, and not more than 30% fat by kilocalorie). Patients were randomized using a computer-generated allocation schedule to one of six possible sequences during which they received single oral doses of sitagliptin 25 or 200 mg or placebo, separated by at least a 7-d washout interval. For each treatment period, patients were instructed to consume more than 150 g of carbohydrates/d for the 3 d before their visit. On the treatment day, patients who fasted overnight for at least 10 h were administered study drug and underwent an OGTT at 2 h postdose. At 24 h postdose, patients received either an OGTT or a standardized meal challenge. For the OGTT, a 75-g glucose solution was consumed within 5 min, and for the meal challenges, a mixed meal consisting of 578 kcal (70 g carbohydrate, 21 g fat, and 27 g protein) was ingested with 240 ml water within 10 min. Standardized meals at 6 and 12 h postdose and snacks at 8 and 15.5 h postdose were also provided during each treatment period.
Efficacy and tolerability parameters
The primary efficacy end point was the glucose excursion above the pre-OGTT glucose level over a 4-h interval [incremental area under the curve (AUC)0–240 min] after administration of an OGTT at 2 h postdose. Secondary efficacy end points included incremental glucose AUC0–120 min postadministration of either an OGTT or standardized meal at 24 h postdose and plasma sitagliptin PK data. Plasma DPP-4 activity was assessed over the 24-h period. Insulin, C-peptide, and glucagon levels were determined only for the 2 h after the OGTT at 2 h postdose. Active and total incretin levels were measured after the OGTT at 2 and 24 h postdose and the standardized meal at 6 and 24 h postdose.
Tolerability was assessed by clinical and statistical review of adverse experiences, laboratory values, vital signs, electrocardiograms, and physical exams. All adverse experiences were rated by the investigator for intensity and relationship to study drug. Specific adverse experiences of clinical interest included hypoglycemia and gastrointestinal-related adverse experiences.
Assay procedures
PK. Plasma sitagliptin concentration was determined predose and 1, 2, 4, 8, 12, and 24 h postdose. In addition, a subset of patients had additional sampling at 48 and 72 h postdose (n = 7) to determine apparent terminal half-life for sitagliptin. Details on PK assays and calculations were previously described (11).
PD. Plasma DPP-4 activity was measured as previously described (11) with blood collected at 0, 1, 2, 4, 8, 12, and 24 h postdose.
For the OGTT at 2 h postdose, blood was collected at 0, 0.5, 1, 2, and 4 h after glucose ingestion and used to measure plasma glucose, insulin, C-peptide, and glucagon levels. For meals or OGTTs at other time points, blood samples were obtained at 0, 0.5, 1, and 2 h, and only plasma glucose was determined. Glucose was measured with a glucose/hexokinase assay kit (Roche Molecular Biochemicals Corp., Indianapolis, IN). Insulin was assayed by the Elecsys insulin system (Roche Diagnostics, Indianapolis, IN). Glucagon was determined using a RIA kit using double-antibody methodology (Diagnostic Products Corp., Los Angeles, CA). C-peptide was assayed using an ELISA kit (American Laboratory Products, Co., Windham, NH).
For plasma active and total GLP-1 and GIP and glucose concentrations, blood was collected at 0, 2 (before OGTT), 2.5, 3, 4, 6, 6.5, 7, 8, 24 (before OGTT or standardized meal), 24.5, 25, and 26 h postdose. Active and total GLP-1 levels were measured with specific commercially available ELISA kits (Linco Research, Inc., St. Charles, MO) and as previously described (11). Active and total GIP levels were measured as previously described (12, 13, 14).
Statistical methods
The incremental glucose AUC0–240 min after the OGTT at 2 h postdose was analyzed in the log scale using an appropriate ANOVA model for a complete three-period, crossover design. The ANOVA model included factors for subject, period, and treatment. Backtransformed summary statistics including geometric least-squares (LS) means, geometric mean ratio (GMR) for between-treatment comparisons (with 95% confidence interval), and P values for the between-treatment comparisons were provided. Similar analyses were performed on the incremental glucose AUC0–120 min after an OGTT at 24 h postdose and other metabolic parameters.
An ANOVA was used to compare the effect of sitagliptin vs. placebo on the weighted average inhibition of DPP-4 activity through 24 h relative to the baseline activity (area under DPP-4 inhibition time curve divided by 24 h). Predose measurements at each period were used as baseline. All analyses were carried out in the log-percent scale, and final results were reported as percent inhibition.
The active and total incretin concentrations and the active to total ratios after the OGTTs [i.e. area under the weighted average augmentation (WAA) of GLP-1 or GIP concentration time curve divided by 2 or 4 h] were compared between sitagliptin and placebo in the same manner as the weighted average inhibition in DPP-4 activity. All tests of significance were performed at alpha = 0.05, two-tailed.
PK/PD assessment
The relationship between PD parameters and plasma sitagliptin concentration was also explored. Individual values for plasma DPP-4 inhibition were pooled over all of the patients and doses and were plotted vs. plasma sitagliptin concentrations. A simple maximum response (Emax) model was used to describe the inhibition of plasma DPP-4 activity relative to plasma sitagliptin concentrations, in which Emax was set at 100%. EC50 (the concentration needed for 50% plasma DPP-4 inhibition) was estimated using the Gauss-Newton method (15). Because 80% or more inhibition of plasma DPP-4 activity was associated with maximal reductions in glycemic excursion after an OGTT in mice (10), EC80 was also estimated.
In a subset of patients who completed an OGTT at both 2 and 24 h postdose (n = 19), the relationship between plasma sitagliptin concentrations and the reduction of post-OGTT incremental glucose (i.e. GMR for incremental glucose AUC0–120 min after sitagliptin/incremental glucose AUC0–120 min after placebo) was explored, assuming that an empirical inhibitory Emax PK/PD model could describe the relationship. Use of the GMR provided a control for placebo effects. Similar analyses were conducted to explore treatment-related increases in the WAA GLP-1 and GIP GMR using Emax PK/PD models. In this model, Emax represents the maximal drug effect, and E0 represents the baseline effect. EC50 was calculated and represents the plasma concentration required to achieve 50% of the maximal effect. The predicted plasma concentration where 75% of the maximal effect would be observed (EC75) was also estimated to represent near-maximal effects.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Sixty-one patients were enrolled in the study, and 60 completed all three periods. Five patients were not included in the efficacy analysis: one patient was lost to follow-up after period 1; four patients were considered protocol violators (including three patients who were enrolled twice at different study centers). All patients were included in the safety assessment (n = 61). Of the 58 patients (excluding the three patients who enrolled twice), there were 42 men and 16 women with an average age of 50.0 yr (range 33–60 yr), weight of 87.6 kg (range 60.4–134.7 kg), and body mass index of 29.5 kg/m2 (range 26.0–38.1 kg/m2). The racial breakdown was 35 Caucasians, 2 blacks, and 21 Hispanics. At baseline, mean FPG was 182.2 mg/dl (range 116–291 mg/dl), and HbA1c was 8.3% (range 6.5–11.7%) in these patients.
PD
Mean percent inhibition of plasma DPP-4 activity from baseline (i.e. predose) to 24 h is shown in Fig. 1A
. Sitagliptin dose-dependently inhibited plasma DPP-4 activity. Plasma DPP-4 activity was inhibited by approximately 80 and 96% at 2 h postdose and 47 and 80% at 24 h postdose with sitagliptin 25 and 200 mg, respectively (Fig. 1A). The mean percent inhibition of DPP-4 activity over 24 h was significantly (P < 0.001) greater with both doses of sitagliptin [25 mg: 68.1% (95% confidence interval 66.6, 69.6) and 200 mg: 91.4% (90.9, 91.8)], compared with placebo [2.1% (–2.8, 6.7)], and the difference between sitagliptin doses was significant. For inhibition of plasma DPP-4 activity vs. plasma sitagliptin concentrations (Fig. 1B), approximately 50% inhibition was observed with a plasma sitagliptin concentration of 25.3 (0.5) nM [fitted EC50 value; mean (SE)], whereas EC80 was approximately 100 nM (EC80).
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, A and B. After an OGTT at 2 h postdose, both sitagliptin doses significantly (P < 0.001) increased WAA active GLP-1 levels by approximately 2-fold relative to placebo (Fig. 2C). After an OGTT at 24 h postdose, sitagliptin 25 and 200 mg significantly (P < 0.001) increased WAA active GLP-1 levels by approximately 1.3- and 1.9-fold, respectively, compared with placebo; the difference between doses was also significant (Fig. 2C). Weighted average total GLP-1 was significantly reduced by 10–17% with sitagliptin, compared with placebo, after the OGTTs at 2 and 24 h postdose (Fig. 2C). The ratios of active to total GLP-1 levels, compared with placebo, were increased to a similar extent as the active GLP-1 results (data not shown).
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, A and B. Relative to placebo, WAA active GIP levels were significantly (P < 0.001) increased by approximately 2-fold with both sitagliptin doses after the OGTT at 2 h postdose and 1.4-fold with 25 mg and 2-fold with 200 mg after the OGTT at 24 h postdose (Fig. 3C). The difference between sitagliptin doses was also significant (P < 0.001) at 24 h postdose. After the OGTT at 2 and 24 h postdose, weighted average total GIP levels were significantly reduced by 16–29% after treatment with sitagliptin, compared with placebo (Fig. 3C). The ratio of active to total GIP levels was increased by approximately 1.7-fold with both doses after the OGTT at 2 h and approximately 1.5-fold with 25 mg and 2-fold with 200 mg after the OGTT at 24 h relative to placebo. Comparable effects on active and total GLP-1 and GIP levels were observed after meals administered at 6 and 24 h postdose (data not shown).
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0.001) reduced mean incremental glucose AUC0–240 min by 22 and 26%, respectively, compared with placebo (Fig. 4A and Table 1). Both sitagliptin doses significantly increased insulin (21–22%) and C-peptide concentrations (13–21%) and decreased glucagon concentrations (7–14%) after the OGTT at 2 h postdose relative to placebo (Fig. 4, B–D, and Table 1).
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0.001) reduced by 18% with the 200-mg dose and was numerically but not significantly lower by 9% with the 25-mg dose, compared with placebo (Table 1
). In the subset of patients administered a standardized meal at 24 h postdose, sitagliptin did not significantly reduce postmeal glucose, although the level of glucose excursion after placebo administration was modest. PK
Plasma sitagliptin AUC0–24 h [geometric LS mean (SD) = 1.55 (0.29) and 14.10 (3.13) µM·h], Cmax [140.0 (35.1) and 1923 (661.0) nM], C2 h [106 (43) and 1627 (791) nM], and C24 h [22.2 (7.5) and 96.3 (41.3) nM] were increased dose dependently, and median Tmax was 4 and 2 h with sitagliptin 25 and 200 mg, respectively. In a subset of patients with plasma sampling up to 72 h postdose (n = 7), the apparent terminal half-life [harmonic mean (jackknife SD)] for sitagliptin averaged 13.1 (2.6) h for 25 mg and 11.0 (1.8) h for 200 mg.
PK/PD relationships
Sitagliptin PK/PD data were modeled in a subset of patients (n = 19) who completed an OGTT at both 2 and 24 h postdose. In this subset of patients, both doses of sitagliptin were associated with incretin effects and glucose-lowering after the OGTT at 2 h postdose that were similar to the results shown in Figs. 3C and 4C and Table 1 for the entire cohort. The relationship between plasma sitagliptin concentrations and the change in post-OGTT incremental glucose or active GLP-1 and GIP concentrations was explored with an empirical inhibitory Emax PK/PD model. For the purpose of this analysis, near-maximal effects were arbitrarily defined as 75% of the theoretical maximal effect (EC75). In Table 2, the results are provided for the model that fit sitagliptin concentration vs. post-OGTT incremental glucose AUC0–120 min GMR (sitagliptin/placebo) and the WAA active GLP-1 and GIP GMR (sitagliptin/placebo) along with EC75 results. The predicted EC75 values for reduction of post-OGTT incremental glucose and increases in active GLP-1 levels were both approximately 100 nM, which was similar to the EC80 described above for inhibition of plasma DPP-4 activity. The predicted EC75 for effects on active GIP levels was lower at approximately 65 nM.
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Sitagliptin doses were well tolerated, with an adverse experience profile that was generally similar to that observed with placebo. There were no serious adverse experiences during the sitagliptin treatment periods. One patient experienced a myocardial infarction 24 h postdose after receiving placebo, and the investigator did not consider this serious adverse experience to be related to study drug. No clinical or laboratory adverse experiences of hypoglycemia were reported. The incidence of gastrointestinal-related adverse experiences including nausea and vomiting was similar across the three treatments. No clinically significant, treatment-related changes from baseline were noted in routine blood and urine chemistry panels, complete blood count, electrocardiogram, vital signs, and physical examinations.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In the present study, sitagliptin produced approximately 2-fold elevations in weighted average active GLP-1 and GIP levels during an OGTT 2 h postdose. At 24 h postdose, the 2-fold increases in active GLP-1 and GIP were still present for the 200-mg dose during either an OGTT or meal tolerance test. In agreement, vildagliptin 100 mg twice a day increased the mean GLP-1 and GIP levels (i.e. AUC/time) over the 13.5-h period after dosing by approximately 2-fold relative to placebo after 1 d of treatment (16). Sitagliptin enhanced incretin levels by inhibiting degradation of the active form rather than increasing secretion because the ratios of active to total GLP-1 and GIP were increased, and total GLP-1 or GIP levels were reduced. Augmentation in active GLP-1 and GIP levels and reduction in total GLP-1 and GIP levels were observed in dogs with the DPP-4 inhibitor, NVP-DPP728, suggesting a possible feedback mechanism with increased secretion of intact peptides (17).
Treatment with DPP-4 inhibitors in the double incretin (GLP-1 and GIP) receptor knockout mice did not lower plasma glucose levels after an OGTT (18), suggesting that GLP-1 and GIP are major mediators of the glucoregulatory effects of DPP-4 inhibitors. These incretins lower glucose via multiple mechanisms including glucose-dependent increases in insulin (GLP-1 and GIP) and decreases in glucagon (GLP-1) release (19). In the present study, both insulin and C-peptide levels were significantly increased, and glucagon levels were significantly reduced with sitagliptin during an OGTT at 2 h postdose. These changes in glucoregulatory hormones were associated with 22–26% reduction in glucose excursion with sitagliptin treatment after an OGTT at 2 h postdose. The effectiveness of sitagliptin 200 mg was observed 24 h postdose with an 18% reduction in glucose observed during an OGTT. Effects on post-OGTT glucose were less apparent at 24 h postdose after the 25-mg dose. Treatment with other DPP-4 inhibitors has demonstrated similar effects of postprandial glucose, insulin, and/or glucagon concentrations after a meal (7, 8, 16).
The levels of DPP-4 inhibition and active GLP-1 and GIP augmentation required for maximal postprandial glucose lowering in humans has not been completely elucidated with DPP-4 inhibitors. In contrast to therapy with GLP-1 analogs, DPP-4 inhibitor-related effects on incretin levels are episodic and meal related, making extrapolations from results with exogenously administered GLP-1 analogs problematic. Therefore, sitagliptin PK and PD data were evaluated in the 19 patients who completed an OGTT at both 2 and 24 h postdose. Before the OGTT at 2 h postdose, plasma sitagliptin levels were greater than 100 nM, and inhibition of plasma DPP-4 activity was greater than 80% with both sitagliptin doses. In response to an OGTT at 2 h postdose, active GLP-1 and GIP levels increased greater than 2-fold with both doses. At 24 h postdose, plasma sitagliptin concentration was approximately 100 nM with the 200-mg dose, providing about 80% plasma DPP-4 inhibition and was associated with nearly 2-fold augmentation of active GLP-1 and GIP levels after an OGTT. In contrast, at 24-h after the 25-mg dose, plasma sitagliptin concentration was less than 25 nM, DPP-4 inhibition was less than 50%, and 1.4-fold or less increases in active GLP-1 and GIP levels were observed after the OGTT. Based on these observations, near-maximal post-OGTT glucose-lowering effect with DPP-4 inhibition was associated with plasma sitagliptin concentrations of 100 nM or greater, inhibition of plasma DPP-4 activity of 80% or greater, and 2-fold or greater enhancement of active GLP-1 and GIP levels. Similarly, in sitagliptin-treated lean C57BL/6N mice, near-maximal glucose lowering efficacy during an OGTT was observed with approximately 80% DPP-4 inhibition and 2- to 3-fold increases in active GLP-1 levels (10).
These observations were corroborated by examining the relationship between sitagliptin plasma concentrations and stabilization of active GLP-1 and GIP levels or post-OGTT glucose lowering using Emax models. Based on this modeling, 80% inhibition of plasma DPP-4 activity (EC80) was predicted to be associated with a plasma sitagliptin concentration of approximately 100 nM. Similarly, the predicted plasma concentration was approximately 100 nM for 75% of the maximal effects (EC75) on reduction in post-OGTT incremental glucose levels, whereas the EC75 was approximately 110 nM and 65 nM for active GLP-1 and GIP levels, respectively.
Treatment with single doses of sitagliptin was generally well tolerated in this study. There were no treatment-related clinically relevant changes in vital signs and laboratory measurements with any treatment. Due to the effect of DPP-4 on the gut peptides, GLP-1 and GIP (20, 21), gastrointestinal-related adverse experiences including nausea and vomiting were of special clinical interest, and the incidence was similar among treatments in this study. Hypoglycemia was not observed, either by clinical or laboratory assessment. This result was not unexpected considering that glucose-lowering effects of incretins are glucose dependent (22).
In the present study in patients with type 2 diabetes, the PK/PD results predicted that sitagliptin doses that produced plasma sitagliptin concentrations of 100 nM or greater over 24 h would provide the necessary inhibition of plasma DPP-4 activity (80% or greater) and enhancement of active GLP-1 and GIP (2-fold or greater) to receive the near-maximal post-OGTT glucose lowering effect with DPP-4 inhibition. In healthy adults, single doses of sitagliptin of 100 mg or more were associated with plasma sitagliptin concentrations of at least 100 nM over 24 h (11). Longer-term studies are underway to assess the chronic efficacy of once-daily sitagliptin.
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Footnotes |
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Summary of disclosure information: G.A.H., A.B., C.S., K.S., D.H., M.T., C.C., M.D.S., I.d.L., K.V.D., A.Q.W., W.Z., M.J.D., W.T., K.M.G., and J.A.W. are Merck & Co., Inc. or MSD employees and hold equity interests in the company. P.K., B.Y., and P.Z. were previously employed by Merck & Co., Inc. B.D., G.G., A.S., B.K., K.C.L., and M.S.K. have nothing to declare. J.J.H. consults for Merck & Co., Inc. and has received lecture fees from Merck & Co., Inc. C.F.D. consults for Novartis, Bristol Myers Squibb, and Takeda and has received lecture fees from Merck & Co., Inc.
First Published Online August 23, 2006
Abbreviations: AUC, Area under the curve; DPP-4, dipeptidyl peptidase-4; Emax, maximum response; FPG, fasting plasma glucose; GIP, glucose-dependent insulinotropic peptide; GLP, glucagon-like peptide; GMR, geometric mean ratio; HbA1c, hemoglobin A1c; LS, least squares; OGTT, oral glucose tolerance test; PD, pharmacodynamic; PK, pharmacokinetic; WAA, weighted average augmentation.
Received May 10, 2006.
Accepted August 3, 2006.
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, P < 0.05 for sitagliptin vs. placebo; 
, P < 0.001 for sitagliptin 200 vs. 25 mg.
