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PubMed2020

Glucocorticoids mobilize macrophages by transcriptionally up-regulating the exopeptidase DPP4.

Glucocorticoids are potent endogenous anti-inflammatory molecules, and their cognate receptor, glucocorticoid receptor (GR), is expressed in nearly all immune cells. Macrophages are heterogeneous immune cells having a central role in both tissue homeostasis and inflammation and also play a role in the pathogenesis of some inflammatory diseases. Paradoxically, glucocorticoids have only a limited efficacy in controlling the resolution of these macrophage-related diseases. Here, we report that the transcriptomes of monocyte-like THP-1 cells and macrophage-like THP-1 cells (THP1-MΦ) have largely conserved gene expression patterns. In contrast, the differentiation to THP1-MΦ significantly altered the sensitivity of gene transcription to glucocorticoids. Among glucocorticoid-regulated genes, we identified the exopeptidase dipeptidyl peptidase-4 (DPP4) as a critical glucocorticoid-responsive gene in THP1-MΦ. We found that GR directly induces DPP4 gene expression by binding to two glucocorticoid-responsive elements (GREs) within the DPP4 promoter. Additionally, we show that glucocorticoid-induced DPP4 expression is blocked by the GR antagonist RU-486 and by GR siRNA transfection and that DPP4 enzyme activity is reduced by DPP4 inhibitors. Of note, glucocorticoids highly stimulated macrophage mobility; unexpectedly, DPP4 mediated the glucocorticoid-induced macrophage migration, and siRNA-mediated knockdowns of GR and DPP4 blocked dexamethasone-induced THP1-MΦ migration. Moreover, glucocorticoid-induced DPP4 activation was also observed in proinflammatory M1-polarized murine macrophages, as well as peritoneal macrophages, and was associated with increased macrophage migration. Our results indicate that glucocorticoids directly up-regulate DPP4 expression and thereby induce migration in macrophages, potentially explaining why glucocorticoid therapy is less effective in controlling macrophage-dominated inflammatory disorders.

Animals↗

PubMed2005

(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: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (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 (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.

Administration, Oral↗

PubMed2006

Determination of MK-0431 in human plasma using high turbulence liquid chromatography online extraction and tandem mass spectrometry.

A robust and sensitive method using high turbulence liquid chromatography (HTLC) online extraction with tandem mass spectrometry (MS/MS) for the determination of MK-0431 in human plasma was developed and validated to support the clinical studies. This HTLC online extraction method eliminated the time-consuming offline sample extraction procedures and significantly increased productivity. A narrow bore large particle size reversed-phase column (Cyclone, 50 x 1.0 mm, 60 microm) and a BDS Hypersil C18 column (30 x 2.1 mm, 3 microm) were used as extraction and analytical columns, respectively. The linear dynamic range of the calibration curve was 0.5 to 1000 ng/mL. Intraday validation was conducted using five calibration curves prepared in five lots of human control plasma, and the intraday precision (RSD%) was from 2.4 to 9.0% and the accuracy was from 98.0 to 103% of the nominal value. The intraday precision (RSD%, n = 5) for plasma quality control (QC) samples varied from 2.0 to 5.3% and accuracy from 103 to 105% of the nominal value. The interday precision (RSD%) for 100 sets of plasma QC samples in 29 analytical runs varied from 6.3 to 9.0% and the accuracy from 98.8 to 104% of the nominal value. No significant difference was observed between the interday and intraday precision and accuracy of the QC samples.

Chromatography, High Pressure Liquid↗

PubMed2006

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: The aim of this study was to assess the efficacy and safety of sitagliptin (MK-0431) as monotherapy in patients with type 2 diabetes mellitus and inadequate glycaemic control (HbA(1c) > or =7% and < or =10%) on exercise and diet. METHODS: A total of 521 patients aged 27-76 years with a mean baseline HbA(1c) of 8.1% were randomised in a 1:2:2 ratio to treatment with placebo, sitagliptin 100 mg once daily, or sitagliptin 200 mg once daily, for 18 weeks. The efficacy analysis was based on an all-patients-treated population using an analysis of covariance, excluding data obtained after glycaemic rescue. RESULTS: After 18 weeks, HbA(1c) was significantly reduced with sitagliptin 100 mg and 200 mg compared with placebo (placebo-subtracted HbA(1c) reduction: -0.60% and -0.48%, respectively). Sitagliptin also significantly decreased fasting plasma glucose relative to placebo. Patients with higher baseline HbA(1c) (> or =9%) experienced greater placebo-subtracted HbA(1c) reductions with sitagliptin (-1.20% for 100 mg and -1.04% for 200 mg) than those with HbA(1c) <8% (-0.44% and -0.33%, respectively) or > or =8% to 8.9% (-0.61% and -0.39%, respectively). Homeostasis model assessment beta cell function index and fasting proinsulin:insulin ratio, markers of insulin secretion and beta cell function, were significantly improved with sitagliptin. The incidence of hypoglycaemia and gastrointestinal adverse experiences was not significantly different between sitagliptin and placebo. Sitagliptin had a neutral effect on body weight. CONCLUSIONS/INTERPRETATION: Sitagliptin significantly improved glycaemic control and was well tolerated in patients with type 2 diabetes mellitus who had inadequate glycaemic control on exercise and diet.

Adenosine Deaminase Inhibitors↗

PubMed2006

(3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.

Animals↗

PubMed2006

Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers.

BACKGROUND: Dipeptidyl peptidase-IV (DPP-IV) inhibitors represent a new class of oral antihyperglycemic agents. Sitagliptin is an orally active and selective DPP-IV inhibitor currently in Phase III development for the treatment of type 2 diabetes mellitus. OBJECTIVE: The aim of this study was to assess the pharmacokinetic and pharmacodynamic (PK/PD) properties and tolerability of multiple oral once-daily or twice-daily doses of sitagliptin. METHODS: This double-blind, randomized, placebo-controlled,incremental oral-dose study was conducted at SGS Biopharma, Antwerp, Belgium. Healthy, nonsmoking male volunteers aged 18 to 45 years with a creatinine clearance rate of >80 mL/min and normoglycemia and weighing within 15% of their ideal height/weight range were randomly assigned to 1 of 8 treatment groups: sitagliptin 25, 50, 100, 200, or 400 mg or placebo, QD for 10 days; a single dose of sitagliptin 800 mg administered on day 1 followed by 600 mg QD on days 3 to 10; or sitagliptin 300 mg BID for 10 days. For analysis of PK properties, plasma and urine samples were obtained before study drug administration on day 1 and at 0.5, 1, 2, 4, 6, 8, 10, 12, and 16 hours after study drug administration on day 1; before study drug administration on days 2 to 9; and every 24 hours for 96 hours after the last dose on day 10, and analyzed for sitagliptin concentrations. Assays were used to measure inhibition of plasma DPP-IV activity and plasma concentrations of active and total glucagon-like peptide-1 (GLP-1), glucose, and glucagon, and serum concentrations of insulin, C-peptide, insulin-like growth factor-1, and insulin like growth factor binding protein-3. Tolerability was assessed throughout the study using physical examination, including vital sign measurements; 12-lead electrocardiography; and laboratory analysis, including hematology, biochemistry (hepatic aminotransferase and creatine phosphokinase), and urinalysis. RESULTS: Seventy subjects were enrolled (mean age, 32.9 years [range, 18-45 years]; mean weight, 79.7 kg [range, 63.4-97.7 kg]; 8 patients per sitagliptin study group and 14 patients in the control group). In the sitagliptin groups, the plasma concentration-time profiles and principal PK parameters (T(max), C(max), and t((1/2))) were statistically similar at days 1 (single dose) and 10 (steady state). In the groups receiving sitagliptin QD doses, accumulation of sitagliptin was modest (AUC accumulation ratio [day 10/day 1] range, 1.05-1.29), and the apparent terminal elimination t((1/2)) was 11.8 to 14.4 hours. At steady state in the sitagliptin QD groups, the mean proportion of drug excreted unchanged in the urine was approximately 70.6%. Dose-dependent inhibition of plasma DPP-IV activity was apparent, and the pattern of inhibition at steady state (day 10) was statistically similar to that observed on day 1. Day-10 weighted mean inhibition of plasma DPP-IV activity over 24 hours was > or = 80% for doses of > or = 50 mg QD. After a standard meal, active GLP-1 concentrations were significantly increased in the sitagliptin groups by approximately 2-fold compared with that in the control group, a finding consistent with near-maximal acute glucose lowering in preclinical studies. Across doses, no apparent adverse effects, including hypoglycemia, were found or reported. CONCLUSIONS: The results from this study in a select population of healthy male volunteers suggest that multiple oral doses of sitagliptin inhibited plasma DPP-IV activity and affected active GLP-1 concentrations in a dose-dependent manner, without producing hypoglycemia. Multiple dosing of sitagliptin exhibited a PK/PD profile consistent with that of a QD regimen and was well tolerated.

Administration, Oral↗

PubMed2006

Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: The efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy were assessed in patients with type 2 diabetes and inadequate glycemic control (glycosylated hemoglobin [HbA(1c)] > or =7% and < or =10%) while receiving a stable dose of pioglitazone. METHODS: This was a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel group study in patients aged > or =18 years (ClinicalTrials. gov NCT00086502). At screening, all patients began a diet/exercise program that continued throughout the study period. Patients taking antihyperglycemic therapy other than pioglitazone underwent a washout of this therapy and entered an 8- to 14-week open-label pioglitazone dose-titration/stabilization period. Patients with an HbA(1c) > or =7% and < or =10% at the end of this period entered a 2-week, single-blind, placebo run-in period (total duration of run-in period, up to 21 weeks). Patients who had been receiving pioglitazone monotherapy (30 or 45 mg/d) and had an HbA(1c) > or =7% and < or =10% entered the 2-week, single-blind, placebo run-in period directly. Thus, at the time of randomization, all patients were receiving ongoing pioglitazone (30 or 45 mg/d). Patients were randomized in a 1:1 ratio to receive sitagliptin 100 mg once daily or placebo for 24 weeks. The primary efficacy end point was the change from baseline in HbA(1c) at week 24. Secondary efficacy end points included the change from baseline in fasting plasma glucose (FPG), insulin, and proinsulin; the Homeostasis Model Assessment beta-cell function and insulin-resistance indexes; the proinsulin/ insulin ratio; the Quantitative Insulin Sensitivity Check Index; the percent changes from baseline in selected lipid parameters; the proportion of patients meeting the American Diabetes Association HbA(1c), goal of <7.0%; the proportion of patients requiring metformin rescue therapy; and the time to the initiation of rescue therapy. RESULTS: One hundred seventy-five patients were randomized to receive sitagliptin, and 178 were randomized to receive placebo. The mean (SD) baseline HbAlc value was 8.1% (0.8) in the sitagliptin group and 8.0% (0.8) in the placebo group. After 24 weeks, sitagliptin added to pioglitazone therapy was associated with significant reductions compared with placebo in HbA(1c) (between-treatment difference in least squares [LS] mean change from baseline. -0.70 %; 95 % CI, -0.85 to -0.54; P < 0.001) and FPG (-17.7 mg/dL; 95% CI, -24.3 to -11.0; P < 0.001). Mean HbA(1c) values at end point were 7.2% (0.9) and 7.8% (1.1) in the respective treatment groups, and the proportions of patients reaching a target HbA(1c) of <7.0% were 45.4% and 23.0% (P < 0.001). Significant reductions in fasting serum proinsulin levels and the proinsulin/insulin ratio were seen with sitagliptin treatment compared with placebo (both, P < 0.01). Sitagliptin was generally well tolerated, with no increased risk of hypoglycemia compared with placebo (2 vs 0 patients, respectively).

Aged↗

PubMed2005

Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses.

BACKGROUND: 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 inhibitor of dipeptidyl peptidase IV (DPP-IV) currently in phase III development for the treatment of type 2 diabetes. METHODS: Two double-blind, randomized, placebo-controlled, alternating-panel studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of sitagliptin (1.5-600 mg) in healthy male volunteers. RESULTS: Sitagliptin was well absorbed (approximately 80% excreted unchanged in the urine) with an apparent terminal half-life ranging from 8 to 14 hours. Renal clearance of sitagliptin averaged 388 mL/min and was largely uninfluenced by the dose administered. The area under the plasma concentration-time curve for sitagliptin increased in an approximately dose-dependent manner and was not meaningfully influenced by food. Single doses of sitagliptin markedly and dose-dependently inhibited plasma DPP-IV activity, with approximately 80% or greater inhibition of DPP-IV activity occurring at 50 mg or greater over a 12-hour period and at 100 mg or greater over a 24-hour period. Compared with placebo, sitagliptin produced an approximately 2-fold increase in postmeal active glucagon-like peptide 1 levels. Sitagliptin was well tolerated and was not associated with hypoglycemia. CONCLUSIONS: This study provides proof of pharmacologic characteristics for sitagliptin in humans. By inhibiting plasma DPP-IV activity, sitagliptin increases the postprandial rise in active glucagon-like peptide 1 concentrations without causing hypoglycemia in normoglycemic healthy male volunteers. Sitagliptin possesses pharmacokinetic and pharmacodynamic characteristics that support a once-daily dosing regimen.

Administration, Oral↗

PubMed2006

The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.

Glucagon-like peptide 1 (GLP-1) is a gut-derived incretin hormone that stimulates insulin and suppresses glucagon secretion, inhibits gastric emptying, and reduces appetite and food intake. Therapeutic approaches for enhancing incretin action include degradation-resistant GLP-1 receptor agonists (incretin mimetics), and inhibitors of dipeptidyl peptidase-4 (DPP-4) activity (incretin enhancers). Clinical trials with the incretin mimetic exenatide (two injections per day or long-acting release form once weekly) and liraglutide (one injection per day) show reductions in fasting and postprandial glucose concentrations, and haemoglobin A1c (HbA1c) (1-2%), associated with weight loss (2-5 kg). The most common adverse event associated with GLP-1 receptor agonists is mild nausea, which lessens over time. Orally administered DPP-4 inhibitors, such as sitagliptin and vildagliptin, reduce HbA1c by 0.5-1.0%, with few adverse events and no weight gain. These new classes of antidiabetic agents, and incretin mimetics and enhancers, also expand beta-cell mass in preclinical studies. However, long-term clinical studies are needed to determine the benefits of targeting the incretin axis for the treatment of type 2 diabetes.

Adamantane↗

PubMed2006

The development of a stable, coated pellet formulation of a water-sensitive drug, a case study: development of a stable core formulation.

A development program has been carried out to provide a stable extrusion/spheronisation pellet formulation for a highly water-soluble drug, sitagliptin, which undergoes a change in physical form on processing and is subject to hydrolytic decomposition. A conventional extrusion/spheronization formulation resulted in significant degradation of the drug. The inclusion of glyceryl monostearate into the formulation was found to reduce the water levels required to such a level that there was no significant degradation of the drug during processing to form pellets. The use of a ram extruder to screen formulations with small quantities minimizes the need for the drug in the formulation-screening process, and the results from this method of extrusion were found to be translatable to the use of a screen extruder, which allowed scale-up of the process.

Chemistry, Pharmaceutical↗

PubMed2006

DPP-4 inhibitors and their potential role in the management of type 2 diabetes.

The dipeptidyl peptidase 4 (DPP-4) inhibitors enhance the body's own ability to control blood glucose by increasing the active levels of incretin hormones in the body. Their mechanism of action is distinct from any existing class of oral glucose-lowering agents. They control elevated blood glucose by triggering pancreatic insulin secretion, suppressing pancreatic glucagon secretion, and signalling the liver to reduce glucose production. The leading DPP-4 inhibitors have shown clinically significant HbA1c reductions up to 1 year of treatment and offer many potential advantages over existing diabetes therapies including a low risk of hypoglycaemia, no effect on body weight, and the potential, based on animal and in vitro studies, for the regeneration and differentiation of pancreatic beta-cells. They are efficacious as monotherapy and also in combination with commonly prescribed antidiabetic agents and are suitable for once-daily oral dosing. Consequently, many DPP-4 inhibitors such as vildagliptin (Galvus; LAF-237), sitagliptin (Januvia; MK-0431), and saxagliptin (BMS-477118) have advanced into late-stage human clinical trials. Search strategy and selection criteria This review was built on a systematic MEDLINE search for publications on the subject with the key words: DPP-4 inhibitor; vildagliptin (LAF-237); sitagliptin (MK-0431); saxagliptin (BMS-477118); and type 2 diabetes; up to August 2006. Meeting abstracts were also searched, as much of the data currently only exists in abstract form. Take home message for clinician The DPP-4 inhibitors appear to have great potential for the treatment of type 2 diabetes, but time will tell if this will be realized. While they do not lower glucose to a greater extent than existing therapies, they offer many potential advantages, including the ability to achieve sustainable reductions in HbA1c with a well-tolerated agent that has a low risk of hypoglycaemia and no weight gain, and which can be administered as a once-daily oral dose.

Adamantane↗

PubMed2006

Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes.

The aim of this study was to assess the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes who have inadequate glycaemic control on diet and exercise. In a randomised, double-blind, placebo- and active-controlled study, 743 patients with type 2 diabetes and a mean baseline HbA(1c) of 7.9% were randomised to receive one of six treatments for 12 weeks: placebo, sitagliptin 5, 12.5, 25 or 50 mg b.i.d., or glipizide 5 mg/day (electively titrated up to 20 mg/day). At week 12, treatment with sitagliptin at all doses tested led to a significant (p < 0.001) reduction in HbA(1c) relative to placebo, with the largest reductions occurring in the 50-mg b.i.d. group. The placebo-subtracted differences in HbA(1c) for the sitagliptin dose groups ranged from -0.38% to -0.77% in a dose-dependent manner, and -1.00% in the glipizide group. Sitagliptin also produced significant reductions in fasting plasma glucose and mean daily glucose across the dose range studied. Sitagliptin treatment was well tolerated and resulted in no significant weight change relative to placebo. There was a modest weight gain observed with glipizide treatment relative to placebo. Hypoglycaemia adverse experiences were reported with the highest incidence in the glipizide group (17%) compared with the placebo (2%) or sitagliptin groups (0-4%, not dose-dependent). In summary, in this study sitagliptin improved glycaemic control, with 50 mg b.i.d. being the most effective dose, and was generally well-tolerated in patients with type 2 diabetes.

Adult↗

PubMed2007

Characterization of two cyclic metabolites of sitagliptin.

Two novel metabolites of the dipeptidyl peptidase inhibitor 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), were identified after purification from dog urine. The metabolites (referred to as M2 and M5) were characterized by hydrogen/deuterium exchange tandem mass spectrometry and NMR spectroscopy nuclear Overhauser effect experiments as the cis and trans stereoisomers formed by cyclization of the primary amino group with the alpha carbon of the piperazine ring, following oxidative desaturation.

Animals↗

PubMed2007

Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C]sitagliptin in humans.

The metabolism and excretion of [(14)C]sitagliptin, an orally active, potent and selective dipeptidyl peptidase 4 inhibitor, were investigated in humans after a single oral dose of 83 mg/193 muCi. Urine, feces, and plasma were collected at regular intervals for up to 7 days. The primary route of excretion of radioactivity was via the kidneys, with a mean value of 87% of the administered dose recovered in urine. Mean fecal excretion was 13% of the administered dose. Parent drug was the major radioactive component in plasma, urine, and feces, with only 16% of the dose excreted as metabolites (13% in urine and 3% in feces), indicating that sitagliptin was eliminated primarily by renal excretion. Approximately 74% of plasma AUC of total radioactivity was accounted for by parent drug. Six metabolites were detected at trace levels, each representing <1 to 7% of the radioactivity in plasma. These metabolites were the N-sulfate and N-carbamoyl glucuronic acid conjugates of parent drug, a mixture of hydroxylated derivatives, an ether glucuronide of a hydroxylated metabolite, and two metabolites formed by oxidative desaturation of the piperazine ring followed by cyclization. These metabolites were detected also in urine, at low levels. Metabolite profiles in feces were similar to those in urine and plasma, except that the glucuronides were not detected in feces. CYP3A4 was the major cytochrome P450 isozyme responsible for the limited oxidative metabolism of sitagliptin, with some minor contribution from CYP2C8.

Adenosine Deaminase↗

PubMed2006

Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects.

Sitagliptin (MK-0431) is an oral, potent, and selective dipeptidyl peptidase-IV (DPP-4) inhibitor developed for the treatment of type 2 diabetes. This multicenter, randomized, double-blind, placebo-controlled study examined the pharmacokinetic and pharmacodynamic effects of sitagliptin in obese subjects. Middle-aged (45-63 years), nondiabetic, obese (body mass index: 30-40 kg/m2) men and women were randomized to sitagliptin 200 mg bid (n = 24) or placebo (n = 8) for 28 days. Steady-state plasma concentrations of sitagliptin were achieved within 2 days of starting treatment, and >90% of the dose was excreted unchanged in urine. Sitagliptin treatment led to approximately 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.

Adenosine Deaminase↗

PubMed2006

Inhibition of dipeptidyl-peptidase IV does not increase circulating IGF-1 concentrations in growing pigs.

The enzyme dipeptidyl peptidase-IV (DPP-IV) inactivates a variety of bioactive peptides, including glucagon-like peptide-1 (GLP-1) and growth hormone releasing hormone (GHRH). Inhibiting DPP-IV in order to increase circulating GLP-1 is of interest as a treatment for Type II diabetes. Inactivation of DPP-IV may also increase circulating GHRH, potentially enhancing growth in domestic animals. To test the hypothesis that inhibition of DPP-IV activity will influence the growth hormone/ IGF-1 axis, growing pigs (Sus scrofa domesticus, 78 kg) were treated with a DPP-IV inhibitor (Compound 1, the 2,5-difluor-ophenyl analog of the triazolopiperazine MK0431, sitagliptin), and plasma concentrations of IGF-1 were monitored. Pigs were administered either sterile saline (0.11 ml/kg followed by a continuous infusion at 2 ml/hr for 72 hrs, controls, n = 2), Compound 1 (2.78 mg/kg followed by a continuous infusion at 0.327 mg/kg x hr for 72 hrs, n = 4) or GHRH (0.11 ml/kg sterile saline, followed by a continuous infusion of GHRH at 2.5 microg/ kg x hr for 48 hrs, n = 4). Plasma concentrations of Compound 1 were maintained at 1 microM, which resulted in a 90% inhibition of circulating DPP-IV activity. Relative to the predose 24-hr period, area under the IGF-1 concentration curve (AUC) tended to be lower (P = 0.062) with Compound 1 (.79 +/- 130 ng/ml x hr) than controls (543 +/- 330 ng/ml x hr). GHRH treatment increased the IGF-1 AUC (1210 +/- 160 ng/ml x hr, P = 0.049 vs. controls and P = 0.001 vs. Compound 1). We conclude that inhibition of DPP-IV does not alter the circulating levels of IGF-1 in the growing pig.

Animals↗

PubMed2006

Tolerability and pharmacokinetics of metformin and the dipeptidyl peptidase-4 inhibitor sitagliptin when co-administered in patients with type 2 diabetes.

OBJECTIVE: As part of the clinical development of sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of type 2 diabetes, the potential for pharmacokinetic interactions with other antihyperglycemic agents used in managing patients with type 2 diabetes are being carefully evaluated. The purposes of this study were to evaluate the tolerability of co-administered sitagliptin and metformin and effects of sitagliptin on metformin pharmacokinetics as well as metformin on sitagliptin pharmacokinetics under steady-state conditions. METHODS: This placebo-controlled, multiple-dose, crossover study in patients with type 2 diabetes assessed the tolerability of co-administered sitagliptin (50 mg b.i.d.) with metformin (1000 mg b.i.d.). Patients received, in a randomized crossover manner, three treatments (each of 7 days duration): 50 mg sitagliptin twice daily and placebo to metformin twice daily; 1000 mg of metformin twice daily and placebo to sitagliptin twice daily; concomitant administration of 50 mg of sitagliptin twice daily and 1000 mg of metformin twice daily. Following dosing on Day 7 of each treatment period, these pharmacokinetic parameters were determined for plasma sitagliptin and metformin: area under the plasma concentrations-time curve over the dosing interval (AUC(0-12h)), maximum observed plasma concentrations (C(max)), and time of occurrence of maximum observed plasma concentrations (T(max)). Renal clearance was also determined for sitagliptin. RESULTS: In this study, no adverse experiences were reported by 11 of 13 patients. Two patients had adverse experiences, which were not related to study drugs as determined by the investigators. The mean metformin plasma concentration-time profiles were nearly identical with or without sitagliptin co-administration [metformin AUC(0-12h) geometric mean ratio (GMR; [metformin + sitagliptin]/metformin)] was 1.02 (90% CI 0.95, 1.09). Similarly metformin administration did not alter the plasma sitagliptin pharmacokinetics [sitagliptin AUC(0-12 h) GMR ([sitagliptin + metformin]/sitagliptin)] was 1.02 (90% CI 0.97, 1.08) or renal clearance of sitagliptin. No efficacy measurements (glycosylated hemoglobin or fasting plasma glucose) were obtained during this study. Urinary pharmacokinetics for metformin were not determined due to the lack of effect of sitagliptin on plasma metformin pharmacokinetics. CONCLUSIONS: In this study, co-administration of sitagliptin and metformin was generally well tolerated in patients with type 2 diabetes and did not meaningfully alter the steady-state pharmacokinetics of either agent.

Adenosine Deaminase Inhibitors↗

PubMed2006

Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes.

CONTEXT: In response to a meal, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are released and modulate glycemic control. Normally these incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). DPP-4 inhibitors are a novel class of oral antihyperglycemic agents in development for the treatment of type 2 diabetes. The degree of DPP-4 inhibition and the level of active incretin augmentation required for glucose lowering efficacy after an oral glucose tolerance test (OGTT) were evaluated. 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.

Administration, Oral↗