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PHARMACOKINETICS AND PHARMACODYNAMICS |
From Merck Research Laboratories, Rahway, New Jersey (Dr Herman, Dr Liu, Ms Stevens, Ms Snyder, Ms Hilliard, Mr Tanen, Dr Tanaka, Dr Meehan, Dr Wagner); Merck Research Laboratories, West Point, Pennsylvania (Dr Bergman, Dr Wang, Mr Zeng, Dr Chen); SFBC International, Miami, Florida (Dr Lasseter, Ms Dilzer); and Buffalo Clinical Research Center, Buffalo, New York (Dr Blum).
Address for reprints: Gary A. Herman, Merck Research Laboratories, RY34-A536, 126 East Lincoln Avenue, Rahway, NJ 07065-0900; phone: (732) 594-1893; fax: (732) 594-5405; e-mail: gary_herman{at}merck.com.
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONREFERENCES |
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90% inhibition of plasma DPP-4 activity, increased active glucagon-like peptide-1 (GLP-1) levels by 2.7-fold (P < .001), and decreased post–oral glucose tolerance test glucose excursion by 35% (P < .050) compared to placebo. In nondiabetic obese subjects, treatment with sitagliptin 200 mg bid was generally well tolerated without associated hypoglycemia and led to maximal inhibition of plasma DPP-4 activity, increased active GLP-1, and reduced glycemic excursion.
Key Words: Incretins • DPP-4 • MK-0431 • obesity • glycemic efficacy
DPP-4 inhibitors have a number of theoretical advantages over currently available insulin secretagogues. Because incretin-mediated effects on insulin biosynthesis and release are glucose dependent, DPP-4 inhibitors may pose less of a hypoglycemia risk than that observed with insulin, sulfonylureas, or meglitinides.8 In addition, in contrast to the weight gain typically associated with insulin, sulfonylurea, or thiazolidinedione therapy,9 52-week treatment with LAF-237, a DPP-4 inhibitor, led to no weight gain.10 Based on studies in animal models of diabetes, incretin-targeted therapies, such as DPP-4 inhibitors, may also have long-term beneficial effects on ß-cell function and mass.11 Moreover, DPP-4 inhibitors may have several potential advantages over long-acting GLP-1 analogs, which are also being investigated for the treatment of diabetes.12 Unlike GLP-1 analogs, DPP-4 inhibitors can be administered orally and are not expected to produce side effects such as nausea and vomiting that occur at high GLP-1 levels, which could limit the clinical utility of some GLP-1 analogs.13-15
Sitagliptin [MK-0431: (2R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine)] is an orally active, potent, and selective DPP-4 inhibitor currently under investigation in phase III trials for the treatment of patients with type 2 diabetes.16 Sitagliptin does not inhibit the closely related proteases, DPP8 and DPP9 (the margin for sitagliptin's activity against these enzymes relative to that for DPP-4 is at least 2600-fold). The inhibition of these enzymes, but not DPP-4, has been linked with multiorgan toxicity in preclinical studies,17 including T cell inhibitory effects.18 The clinical significance of DPP8/9 inhibition is unknown. Preclinical studies have demonstrated that sitagliptin inhibits DPP-4 activity, elevates GLP-1 levels, and markedly reduces glucose levels following an oral glucose load.16 These studies also demonstrated that 
80% inhibition of DPP-4 activity and/or a 2-fold augmentation of postprandial GLP-1 levels led to a maximal or near-maximal acute lowering of glucose levels.
Preclinical studies with DPP-4 inhibitors also show protective effects on the ß-cell and prevention or delayed progression of type 2 diabetes.11,19 Moreover, sitagliptin was well tolerated and increased active GLP-1 levels without causing hypoglycemia in phase I single-dose and multiple-dose studies in healthy subjects.20,21 Single oral doses of sitagliptin in patients with type 2 diabetes also reduce glycemic excursion, enhance insulin and c-peptide release, and reduce glucagon levels following an oral glucose tolerance test (OGTT).22
Because many patients with type 2 diabetes are also obese, the objective of the present study was to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple doses of sitagliptin in middle-aged, nondiabetic, obese men and women. A sitagliptin dose of 200 mg twice daily (bid) was chosen as it was predicted to provide maximal inhibition of DPP-4 activity throughout the day and was anticipated to be 2- to 4-fold higher than the clinical dose for use in patients with type 2 diabetes, thus providing additional reassurance about the tolerability of the drug.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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30 kg/m2 to 
40 kg/m2, were recruited for participation in this study. Subjects were excluded if they had a history of renal, hepatic, cardiovascular, gastrointestinal, or neurologic disease; symptomatic hypoglycemia; impaired glucose tolerance; or diabetes mellitus. Subjects were also excluded if they had donated blood, participated in another clinical study within 4 weeks prior to study start, anticipated needing any prescription or nonprescription drugs, or had an estimated creatinine clearance of <80 mL/min. All subjects gave written informed consent. The protocol was reviewed and approved by the following institutional review boards: Southern Institutional Review Board (Miami, Fla) and IntegReview (Austin, Tex). This study was conducted in accordance with the guidelines on good clinical practice and with ethical standards for human experimentation established by the Declaration of Helsinki.
Study Design
This was a multicenter, double-blind, randomized, placebo-controlled, multiple-dose study in which subjects were randomized to receive sitagliptin 200 mg or placebo (3:1) bid for 28 days. A baseline OGTT was administered on day –1. Intensive sampling for plasma sitagliptin concentrations occurred on days 1 and 28, and trough measurements were taken on days 2, 3, 4, 5, 7, 10, 14, 17, 21, and 24. Urine for sitagliptin concentrations and for measurement of creatinine clearance was obtained on day 28. An OGTT was administered 2 hours predose on day 14 and 2 hours postdose on day 28. Blood for determination of plasma DPP-4 activity was collected for each subject at the following time points: predose on day 1 and predose and 0.5, 1, 2, 4, 6, 8, 10, 12, 16, and 24 hours postdose on day 28. Blood for active and total GLP-1 levels was collected for each subject at the following time points: day –1, pre-OGTT and 30 minutes, 1, 2, 3, and 4 hours post-OGTT; day 1, predose; and day 28, predose and 2 (pre-OGTT), 2.5, 3, 4, 5, and 6 hours postdose (30 minutes, 1, 2, 3, and 4 hours following OGTT). Blood for glucose, insulin, C-peptide, and glucagon levels was collected for each subject at the following time points: day –1, pre-OGTT and 30 minutes, 1, 2, 3, and 4 hours post-OGTT; day 1, predose; day 14, pre-OGTT and 30 minutes, 1 hour, and 2 hours following OGTT (predose); and day 28, predose, then pre-OGTT and 2.5, 3, 4, 5, and 6 hours postdose (30 minutes, 1, 2, 3, and 4 hours following OGTT). Measurements for insulin-like growth factor-1 (IGF-1)/IGF binding protein-3 (IGF-bp3) and fructosamine were obtained on day –1 (baseline) and predose on day 28. Body weight was measured using a calibrated digital scale on days –1, 1, 7, 14, 21, and 28.
Safety Assessments
Adverse experiences were assessed throughout the study. Investigators evaluated all clinical adverse experiences in terms of intensity (mild, moderate, or severe), duration, severity, outcome, and relationship to study drug. Physical examinations, vital signs, 12-lead electrocardiogram (ECG; including assessment for QTc and PR-interval prolongation), and safety laboratory analyses comprising routine hematology, serum chemistry (including liver transaminase and muscle creatine phosphokinase measurements), and urinalysis were performed prestudy, at various time points postdose, and at poststudy. The IGF-1 and IGF-bp3 levels were also obtained predose on days 1 and 10. Serum IGF-1 and IGF-bp3 levels were measured by enzyme-linked immunosorbent assay (ELISA; Diagnostic Systems Laboratories, Webster, Tex).
Pharmacokinetic and Pharmacodynamic Assessments
The detailed methods for the assay of sitagliptin have been published previously.23 Briefly, sitagliptin was assayed in plasma and urine using a high-turbulence liquid chromatography (2300 HTLC system, Cohesive Technologies, Inc, Franklin, Mass) online extraction method. Sitagliptin and internal standard were detected by mass spectroscopy (API 4000, Applied Biosystems, Toronto, Canada) using selected reaction monitoring with turbo-ionspray interface in the positive ion mode. The assay for sitagliptin in plasma was linear over a range of concentrations from 1.23 to 2350 nmol/L and had a lower limit of quantitation of 1.23 nmol/L. Corresponding values for sitagliptin in urine were 0.246 to 123 µmol/L and 0.246 µmol/L, respectively. Plasma and urine quality control (QC) samples were prepared before the clinical study. The concentrations were 1.5, 100, and 800 ng/mL for plasma QCs and 0.3, 5, and 40 µg/mL for urine QCs. Two to 7 QCs (at least 5% of the number of clinical samples) at each concentration were analyzed in each analytical run with clinical samples to assess the accuracy of the assay. The interday precision of 15 sets of plasma QCs from 3 analytical runs varied from 4.7% to 9.2%, and the accuracy was from 97.5% to 108.6% of the nominal value. The interday precision of 9 sets of urine QCs from 2 analytical runs varied from 3.3% to 4.4%, and the accuracy was from 104.2% to 111.0% of the nominal value.
Area under the plasma concentration-time curve over the dosing interval (AUC0-12 h for twice daily dosing) was calculated using the linear trapezoidal method for ascending concentrations and the log trapezoidal method for descending concentrations. Cmax, C12 h, and tmax were obtained by inspection of the plasma concentration data. The day 28 MK-0431 apparent terminal rate constant (
) was estimated by regression of the terminal log-linear portion of the plasma concentration-time profile; t1/2 was calculated as the quotient of ln(2) and .
The AUC accumulation ratios (R) following multiple dosing were calculated from the ratio of AUC0-12 h values from the last dose to the first dose. Accumulation ratios for Cmax and trough concentrations (C12 h) were calculated in the same manner. AUC accumulation t1/2 was calculated from the AUC accumulation ratio (R), where
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= the dosing interval. The amount of sitagliptin excreted unchanged in urine in each collection interval was determined by the product of the urine concentrations and the urine volume. The fraction of the sitagliptin dose that was excreted unchanged in urine over the dosing intervals (fe,0-12 h) was determined by the quotient of the sum of sitagliptin collected over all dosing intervals and the dose administered. Renal clearance (ClR) was determined as the quotient of the amount of sitagliptin excreted and AUC0-12 h.
For plasma DPP-4 and glucagon assays, blood was collected into tubes containing EDTA. For active and total GLP-1 assays, blood was collected into tubes containing EDTA, DPP-4 inhibitor, and aprotinin. Blood for serum glucose, insulin, and C-peptide assays was collected in serum tubes containing clot activator (Sarstedt, Inc, Newton, NC). Blood for serum IGF-1 and IGF-BP3 was collected into vacuum tubes (Vacutainer; Becton, Dickinson and Company, Franklin Lakes, NJ). Plasma and serum samples were stored at –70°C until assayed.
DPP-4 enzyme activity was measured by incubating 4 µL EDTA human plasma (2.5-fold dilution in assay) with the substrate glycyl-prolyl-paranitroaniline (400 µM in assay Gly-Pro-pNA) at 30°C and measuring the release of pNA by an increase in absorbance at 390 nm over time. The change in absorbance between each 30-second interval was averaged over 10 minutes to calculate the slope for each sample. Enzyme activity was defined as the slope (in mOD/min) from 4 to 14 minutes. The lower limit of reliable quantitation (ie, 20% interassay coefficient of variation [CV]) was a slope of 0.6 mOD/min based on an analysis of an extra-low QC that reads near this lower limit. For each subject, the percentage inhibition of plasma DPP-4 activity was plotted against the plasma sitagliptin concentration, and a simple correct as written maximal response (Emax) model was used to determine the median effective concentration (EC50) by the Gauss-Newton method. The DPP-4 assay was conducted in the Clinical Development Laboratory at Merck Research Laboratories (Rahway, NJ).
Active GLP-1 (GLP-1-[7-36] amide and GLP-1-[7-37]) was assayed using an ELISA kit according to the manufacturer's specifications (Linco Research, Inc, St. Charles, Mo). Lot-to-lot variability was noted between different ELISA kits. The lower limit of reliable quantitation was estimated to be 2.0 pmol/L. Total GLP-1 was assayed with a radioimmunoassay (RIA) kit (Linco Research, Inc) using a modified assay procedure. For the RIA, plasma (300 µL) was mixed with 0.03% N-octyl BD-glucopyranoside and 0.5% bovine serum albumin (final concentrations), and GLP-1 was extracted with 1.0 mL of 95% ethanol. The resulting precipitate was reextracted with 500 µL of 95% ethanol. The supernatants were then pooled and dried under a stream of nitrogen for 3 hours at room temperature (20°C). Dried extract was rehydrated in 300 µL of sample hydrating solution and assayed in the RIA in 96-well plates. Free and bound radioactive ligand was separated by filtration onto a 96-well glass-fiber filter plate and counted. The lower limit of reliable quantitation was estimated to be 4.45 pmol/L, which was based on day-to-day precision for the low total GLP-1 QC provided with the assay. Both assays were conducted in the Clinical Development Laboratory at Merck Research Laboratories (Rahway, NJ).
Serum glucose level was measured with a hexokinase enzymatic assay on an automated analyzer (Hitachi 747, Roche Diagnostics, Indianapolis, Ind). This assay was linear in the range of 0 to 750 mg/dL, and the interassay CV was 1.3%. Serum insulin level was measured using electrochemiluminescence on the ELECSYS automated analyzer (Roche Diagnostics). This assay had a working range of 0.2 to 100 µIU/mL and an interassay CV of 5.5%. Plasma glucagon level was measured using a double-antibody RIA kit (Diagnostic Products Corporation, Los Angeles, Calif). The lower limit of detection was 13 pg/mL, and the interassay CV was 9%. Serum C-peptide level was measured using a double-antibody RIA kit (Diagnostics Products Corp). The lower limit of detection was 0.22 ng/mL, and the interassay CV was 7.1%. The glucose, insulin, glucagons, and C-peptide assays were conducted by Medical Research Laboratories, LLC (Highland Heights, Ky).
Serum IGF-1 and IGF-BP3 levels were measured by respective ELISA kits at Medical Research Laboratories, LLC (Highland Heights, Ky), according to the manufacturer's specifications (Diagnostic Systems Laboratories, Webster, Tex). The sensitivity of the IGF-1 assay was 0.03 ng/mL, and the interassay CV was 6.7%. The sensitivity of the IGF-BP3 assay was 0.04 ng/mL, and the interassay CV was 9.5%.
Serum fructosamine levels were quantitated by a nitroblue tetrazolium reduction assay on a Hitachi 747 automated analyzer (Roche Diagnostics).
Statistical Analysis
Safety
The safety and tolerability of sitagliptin 200 mg bid was determined by review and assessment of adverse experiences observed as well as summary statistics for laboratory, vital sign, and ECG parameters. Summary statistics were also provided for the percent change from baseline over time in IGF-1 and IGF-bp3.
Body Weight
Summary statistics were provided for mean body weight over time. An analysis of variance (ANOVA) model (with factors for treatment, subject within treatment, and day) was used to compare the mean change from baseline (day –1) at day 28 in body weight for sitagliptin compared to placebo.
Pharmacokinetics
Summary statistics were provided for day 1 and day 28 (steady-state) sitagliptin plasma and urine pharmacokinetic parameters (area under the concentrationtime curve over the dosing interval [AUC0-12 h], maximum plasma concentration [Cmax], trough concentration [C12 h], time to maximum plasma concentration [tmax], apparent terminal t1/2, the fraction of dose excreted unchanged in urine over the dosing interval [fe,0-12 h], and renal clearance [ClR]) and for accumulation parameters (effective t1/2 and AUC0-12 h accumulation ratio, Cmax accumulation ratio, and C12 h accumulation ratio). Natural logarithmic transformation was performed on the data of AUC0-12 h,Cmax, C12 h, ClR, and of AUC0-12 h,Cmax, C12 h accumulation ratios; reciprocal transformation was applied to the data of apparent terminal t1/2 and effective t1/2. Results were presented on the raw scale after back-transformation.
Pharmacodynamics
Summary statistics were provided for the weighted average inhibition (WAI) of DPP-4 activity over 24 hours on day 28 over baseline (predose day 1). The difference in the WAI of DPP-4 activity on day 28 between sitagliptin and placebo was assessed by a 1-way ANOVA model, and a 2-sided 95% confidence interval (CI) for the between-treatment difference in WAI of DPP-4 was calculated.24 Summary statistics on post-OGTT time-weighted average (TWA) active and total GLP-1 levels and the active/total GLP-1 ratio on days –1 (baseline) and 28 were provided. The comparison between sitagliptin and placebo on the TWA of GLP-1 was fulfilled via a repeated-measures ANOVA model (with factors for treatment, subject within treatment, and day). Two-sided 95% CIs for the between-treatment differences were calculated respectively for active and total GLP-1 levels and for the active/total GLP-1 ratio. The same statistical model for the TWA of GLP-1 was used to analyze the post-OGTT incremental glucose AUC over a 2-hour post-OGTT interval on days –1, 14, and 28. For all the ANOVA analyses, assumptions of normality and homogeneity of variances were tested using the Shapiro-Wilk's test and Levene's test, respectively, and found to be reasonable assumptions. The above analyses on DPP-4 activity, GLP-1 levels, and glucose excursion were performed on a natural logarithmic scale, and the final results were presented on raw scales after back-transformation.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Pharmacodynamics
Plasma DPP-4 Activity
Treatment with sitagliptin 200 mg bid led to a mean inhibition on day 28 from baseline (predose day 1) in plasma DPP-4 of approximately 90.0% throughout the 24-hour sampling period (Figure 2). The mean difference in the weighted average inhibition of plasma DPP-4 activity over 24 hours between sitagliptin and placebo was 90.0% (P < .001; Table II) with the 95% CI of (81.5%, 99.3%).
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Plasma GLP-1 Levels
Treatment with sitagliptin led to an approximately 2- to 3-fold increase in active GLP-1 levels following an OGTT at 2 hours postdose on day 28 compared to placebo and compared to pretreatment baseline levels relative to placebo (Figure 3A, Table III). The geometric mean ratio (GMR; sitagliptin/placebo) of the post-OGTT time-weighted average active GLP-1 level on day 28 was 2.74 (P < .001; Table III) with the 95% CI of (1.87, 4.00). There was also a significant fold increase on day 28 over baseline in post-OGTT time-weighted average active GLP-1 levels in the sitagliptin group relative to placebo, with the GMR of sitagliptin/placebo and corresponding 95% CI estimated to be 2.18 and (1.54, 3.10); (P < .001; Table III).
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Total (ie, active plus inactivated) GLP-1 levels were not meaningfully altered by 28 days of sitagliptin treatment when compared to placebo or to pretreatment baseline levels (Figure 3B, Table III).
The ratio of active to total GLP-1 levels also increased approximately 2- to 3-fold following sitagliptin treatment compared to placebo or to pretreatment baseline levels, relative to placebo (Figure 3C). Increases were apparent after overnight fasting as well as following an OGTT. On day 28, the post-OGTT time-weighted average ratio of active to total GLP-1 ratio GMR (sitagliptin/placebo) was 2.90 (P < .001; Table III) with the 95% CI of (1.92, 4.36). In addition, the post-OGTT time-weighted average active to total GLP-1 ratio GMR (sitagliptin/placebo) in the fold increase on day 28 over baseline was 2.41 (P < .001; Table III) with the 95% CI of (1.91, 3.03).
Glycemic Parameters
The time course after an OGTT of mean plasma glucose concentrations at baseline (day –1) and following multiple doses of sitagliptin on days 14 and 28 is shown in Figure 4 (the OGTT was administered predose on day 14 and 2 hours postdose on day 28). Sitagliptin treatment led to a significant reduction in post-OGTT glycemic excursion on both day 14 and day 28 (Figure 4, Table IV). The post-OGTT incremental glucose AUC GMR (sitagliptin/placebo) was 0.65 on day 14 with the 95% CI of (0.43, 0.99) and 0.65 on day 28 with the 95% CI of (0.43, 0.99); (P < .050 for both between-group comparisons; Table IV). Post-OGTT mean incremental glucose AUC was numerically lower after sitagliptin treatment compared to the pretreatment baseline relative to placebo, but the results were not statistically significant (Table IV).
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No mean changes in post-OGTT insulin or C-peptide concentrations or in glucagon levels were observed with sitagliptin compared to placebo treatment (data not shown). In these nondiabetic patients, plasma fructosamine levels were also not lowered with sitagliptin treatment (data not shown).
Safety
Sitagliptin was generally well tolerated. No serious clinical adverse experiences were reported during the study, and no subject discontinued because of an adverse experience. All clinical adverse experiences were transient and rated mild in intensity. No clinical or laboratory adverse experiences of hypoglycemia were reported. Compared to placebo, no clinically meaningful changes were observed for IGF-1 or IGF-bp3 levels after 28 days of sitagliptin treatment (Table V; P > .200 for between-group comparisons). There was no evidence of any treatment-related changes in laboratory, vital signs, or ECG safety parameters over 28 days of treatment with sitagliptin.
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Body Weight
Patients treated with sitagliptin had a numerically, but not statistically significant, greater mean decrease in body weight compared to placebo-treated patients: on day 28, the sitagliptin 200-mg bid group had a mean decrease from baseline (day –1) in body weight of 0.6 kg compared to a mean increase from baseline of 0.2 kg in the placebo group (Figure 5).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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Sitagliptin pharmacokinetics after 200 mg bid over 28 days was assessed. Examination of trough concentrations revealed that steady-state plasma levels were reached within 2 days of starting dosing, and the trough concentrations did not change appreciably over the 28 days of the study, suggesting that the clearance of sitagliptin was generally time independent. Renal clearance and the fraction of sitagliptin excreted intact in urine were generally similar to that observed after single and multiple oral doses in healthy male subjects.20,21 Similarly, the AUC0- exposures observed in this study were generally comparable to those reported for healthy young male subjects after only 10 days of treatment.21
Inhibition of plasma DPP-4 activity was assessed to determine the pharmacologic activity of chronic multiple dosing with sitagliptin. Treatment with sitagliptin 200 mg bid for 28 days led to near-maximal inhibition of plasma DPP-4 activity, measured over a 24-hour period. On day 28, the mean WAI of plasma DPP-4 activity over 24 hours with sitagliptin relative to placebo was approximately 90%. This pattern of DPP-4 inhibition was consistent with that observed in healthy male subjects following single or multiple oral sitagliptin doses of lesser duration.20,21
Evidence of the sustained pharmacologic activity of sitagliptin after chronic administration was demonstrated by showing a treatment-related increase in active GLP-1 levels. Sitagliptin treatment led to an increase in active GLP-1 levels following an OGTT of approximately 2- to 3-fold as compared to placebo and to pretreatment baseline active GLP-1 levels. Similar increases in active GLP-1 levels also appeared to be present after overnight fasting, prior to administration of the OGTT. Sitagliptin also increased the ratio of active to total GLP-1 levels by a similar degree, relative to placebo and compared to pretreatment baseline levels. In this study, sitagliptin treatment had no significant effect on total GLP-1 levels versus placebo or compared to pretreatment baseline levels.
In this study in obese, nondiabetic subjects, sitagliptin treatment reduced glycemic excursion following an oral glucose load. An OGTT was administered at baseline, at trough after 14 days of treatment, and at peak after 28 days of treatment. Treatment with sitagliptin led to a similar, statistically significant reduction in post-OGTT glucose excursion at both day 14 and day 28, as compared to placebo. Post-OGTT incremental glucose AUC was reduced by approximately 35% on days 14 and 28. Although DPP-4 inhibitors are thought to reduce glycemic excursion by enhancing glucose-dependent insulin release and/or suppressing glucagon,1-8 mean changes in insulin, C-peptide, or glucagon levels were not detected in this study. Lack of a decrease in C-peptide levels, despite lower glucose levels, does suggest that insulin secretion was modestly enhanced relative to plasma glucose levels. Because subjects were randomized in a 3:1 ratio (active to placebo), the absence of a detectable increase here may also be related to limitations in study design and subject numbers rather than suggesting that glucose levels were reduced by another mechanism.
Treatment with sitagliptin was generally well tolerated without associated hypoglycemia. All adverse experiences were rated mild in intensity, and there were no discontinuations due to an adverse experience. There were no consistent treatment-related clinically significant changes in laboratory, ECG, and vital signs safety parameters. Growth hormone-releasing hormone (GHRH) has been proposed to be a potential substrate of DPP-4, but it is unknown whether this hormone is a physiologically relevant substrate of DPP-4 in vivo. If meaningful stabilization of GHRH were achieved by DPP-4 inhibition, one might expect to see increases in IGF-1 or IGF-bp3 levels. In this study, however, at dosages of sitagliptin that provided near-maximal inhibition of DPP-4, no increases in serum IGF-1 and IGF-bp3 levels compared to predose baseline levels were observed.
Glucagon-like peptide-1 has been hypothesized to play a role in the regulation of appetite and satiety.25 Based on preclinical studies in DPP-4 deficient mice, and analogous to what is observed in clinical studies with other GLP-1-based therapies, little or no weight gain is expected with DPP-4 inhibitors, a potential advantage over currently available insulin secretagogues. In this study, no weight gain was observed after 28 days of treatment with sitagliptin in obese individuals. A nonstatistically significant trend toward a mean reduction in body weight compared to placebo was seen—it will require larger studies to determine if this modest weight reduction can be demonstrated.
In summary, this study in middle-aged, nondiabetic, obese men and women demonstrated that chronic (28 days) treatment with sitagliptin 200 mg bid was generally well tolerated and exhibited plasma concentration-time profiles and principal pharmacokinetic parameters after 28 days of dosing that were similar to those observed on the first day of dosing. Treatment with sitagliptin 200 mg bid also led to sustained inhibition of DPP-4 over a 24-hour dosing interval, which was associated with an approximately 2- to 3-fold increase in post-OGTT active GLP-1 levels relative to placebo and a reduction in post-OGTT glucose excursion.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONREFERENCES |
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