Selective Dipeptidyl Peptidase-4 Inhibitor Research Articles

Overview of saxagliptin efficacy and safety in patients with type 2 diabetes and cardiovascular disease or risk factors for cardiovascular disease.

Most individuals with type 2 diabetes mellitus have or will develop multiple independent risk factors for cardiovascular disease, particularly coronary artery disease (CAD). CAD is the leading cause of morbidity and mortality among individuals with type 2 diabetes mellitus, and treating these patients is challenging. The risk of hypoglycemia, weight gain, or fluid retention with some diabetes medications should be considered when developing a treatment plan for individuals with a history of CAD or at risk for CAD. Dipeptidyl peptidase-4 inhibitors are oral antihyperglycemic agents that inhibit the breakdown of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, resulting in increased glucose-dependent insulin secretion and suppression of glucagon secretion. Saxagliptin is a potent and selective dipeptidyl peptidase-4 inhibitor that improves glycemic control and is generally well tolerated when used as monotherapy and as add-on therapy to other antihyperglycemic medications. This review summarizes findings from recently published post hoc analyses of saxagliptin clinical trials that have been conducted in patients with and without a history of cardiovascular disease and in patients with and without various risk factors for cardiovascular disease. The results show that saxagliptin was generally well tolerated and consistently improved glycemic control, as assessed by reductions from baseline in glycated hemoglobin, fasting plasma glucose concentration, and postprandial glucose concentration, regardless of the presence or absence of baseline cardiovascular disease, hypertension, statin use, number of cardiovascular risk factors, or high Framingham 10-year cardiovascular risk score.

Gemigliptin, a novel dipeptidyl peptidase-4 inhibitor, exhibits potent anti-glycation properties in vitro and in vivo

This study evaluated the inhibitory effects of gemigliptin, a highly selective dipeptidyl peptidase-4 inhibitor, on the formation of advanced glycation end products (AGEs) and AGE cross-links with proteins in in vitro as well as in type 2 diabetic db/db mice. In in vitro assay, gemigliptin dose-dependently inhibited methylglyoxal-modified AGE-bovine serum albumin (BSA) formation (IC50=11.69mM). AGE-collagen cross-linking assays showed that gemigliptin had a potent inhibitory effect (IC50=1.39mM) on AGE-BSA cross-links to rat tail tendon collagen, and its activity was stronger than aminoguanidine (IC50=26.4mM). In addition, gemigliptin directly trapped methylglyoxal in a concentration-dependent manner in vitro. To determine whether gemigliptin inhibits the in vivo glycation processes, gemigliptin (100mg/kg/day) was orally administered into type 2 diabetic db/db mice for 12 weeks. Elevated serum levels of AGEs in db/db mice were suppressed by the administration of gemigliptin. These inhibitory effects of gemigliptin on the glycation process in both in vitro and in vivo suggest its therapeutic potential for ameliorating AGE-related diabetic complications.

Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors.

Dipeptidyl peptidase-4 (DPP4) is a widely expressed enzyme transducing actions through an anchored transmembrane molecule and a soluble circulating protein. Both membrane-associated and soluble DPP4 exert catalytic activity, cleaving proteins containing a position 2 alanine or proline. DPP4-mediated enzymatic cleavage alternatively inactivates peptides or generates new bioactive moieties that may exert competing or novel activities. The widespread use of selective DPP4 inhibitors for the treatment of type 2 diabetes has heightened interest in the molecular mechanisms through which DPP4 inhibitors exert their pleiotropic actions. Here we review the biology of DPP4 with a focus on: 1) identification of pharmacological vs physiological DPP4 substrates; and 2) elucidation of mechanisms of actions of DPP4 in studies employing genetic elimination or chemical reduction of DPP4 activity. We review data identifying the roles of key DPP4 substrates in transducing the glucoregulatory, anti-inflammatory, and cardiometabolic actions of DPP4 inhibitors in both preclinical and clinical studies. Finally, we highlight experimental pitfalls and technical challenges encountered in studies designed to understand the mechanisms of action and downstream targets activated by inhibition of DPP4.

Alogliptin in combination with metformin and pioglitazone for the treatment of type 2 diabetes mellitus.

Alogliptin is a selective dipeptidyl peptidase-4 inhibitor recently marketed for once-daily administration in the treatment of type 2 diabetes mellitus (T2DM). Fixed-dose combinations of alogliptin with both metformin and pioglitazone are also commercially available, providing a measure of convenience in addition to an effective mode of delivering combination therapy to improve glycemic control. Alogliptin has been studied clinically as initial therapy in treatment-naïve patients with T2DM and as initial therapy or add-on in combination with other antidiabetic agents. Clinical trial data with alogliptin demonstrate clinical efficacy in terms of glycosylated hemoglobin A1c and fasting plasma glucose reductions when used both as monotherapy and as a component of two- or three-drug combination regimens for the treatment of T2DM. Extensive Phase II and Phase III clinical trial data support the use of alogliptin in combination with metformin and pioglitazone. Glycemic reduction with both combinations is similar to the sum of the respective monotherapies, with adverse event rates similar – or more moderate – than those observed with up-titration of monotherapy or the addition of other antihyperglycemic agents.

Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes

Inflammation and endothelial dysfunction are increasingly being recognized as key etiological factors in the development of atherosclerosis and subsequent cardiovascular disease. These pro-atherogenic factors are strongly correlated and are often found to co-segregate in patients with type 2 diabetes. The impact of sitagliptin, a selective inhibitor of dipeptidyl peptidase-4, on inflammation and markers of endothelial function remains to be fully characterized. ObjectiveThe objective of the present study was to examine the effects of treatment with sitagliptin on the plasma levels of various markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Methods and resultsThirty-six subjects with type 2 diabetes (30 men/6 postmenopausal women with a mean age of 58.1±6.4years and a body mass index of 30.7±4.9kg/m2) were recruited into this double-blind, cross-over study using sitagliptin (100mg/d) or placebo, each for a 6-week period, including a 4-week washout period between the two phases. Blood samples were taken at the end of each phase of treatment. Compared with placebo, treatment with sitagliptin significantly reduced the plasma levels of C-reactive protein (CRP) (44.9%, P=0.006), interleukin (IL)-6 (24.7%, P=0.04), IL-18 (7.3%, P=0.004), secreted phospholipase-A2 (sPLA2) (12.9%, P=0.04), soluble intercellular adhesion molecule-1 (5.3%, P=0.002), and E-selectin (5.9%, P=0.005). A significant inverse correlation was found between changes in glucagon-like peptide-1 (GLP-1) and changes in CRP levels (r=0.41, P=0.01) following sitagliptin therapy. Sitagliptin therapy had more pronounced effects in subjects with higher levels of inflammatory markers and cell adhesion molecules compared with subjects with lower levels. ConclusionsTreatment with sitagliptin for 6weeks reduced plasma markers of low-grade inflammation and cell adhesion molecules, most likely by increasing plasma GLP-1 levels and improving glucose-insulin homeostasis. These beneficial effects of sitagliptin might represent a further advantage in the management of diabetes and its proatherogenic comorbidities.

Abstract 411: Effect of Sitagliptin Therapy on Triglyceride-Rich Lipoprotein Kinetics in Patients With Type 2 Diabetes

Postprandial hyperlipemia is a key metabolic feature of insulin-resistant states and an important risk factor for cardiovascular disease, due to the accumulation of atherogenic triglyceride (TG)-rich lipoproteins (TRL) from both hepatic and intestinal origin. Sitagliptin is a selective inhibitor of dipeptidyl peptidase-4 that has been shown to reduce fasting and postprandial glucose levels in patients with type 2 diabetes (T2D) presumably through incretin hormone-mediated improvements in islet function. The objective of the present study was to investigate the effects of sitagliptin therapy on the kinetics of TRL apolipoprotein (apo) B-48, VLDL apoB-100, apoE and apoC-III in patients with type 2 diabetes. Twenty two subjects with T2D (18 men and 4 postmenopausal women, mean age of 58.2±3.8 y) were recruited in this double-blind crossover study using sitagliptin 100 mg/d or placebo for a 6-week period each, with a 4-week washout period between the two phases. At the end of each phase of treatment, the in vivo kinetics of the different apolipoproteins were assessed using a primed-constant infusion of L-[5,5,5-D3]leucine for 12 h with the participants in a constantly fed state. Sitagliptin therapy vs. placebo significantly reduced concentrations of fasting plasma TG (-15.4%, 0.03), apoB-48 (-16.3%, P=0.03), free fatty acids (-9.5%, P= 0.04), HbA1C (placebo: 7.0%±0.8 vs sitagliptin: 6.6%±0.7, P<0.0001), and plasma glucose (-13.5%, P=0.001) without any significant effect on insulin level. Treatment with sitagliptin significantly reduced the pool size of TRL apoB-48 by -20.8% (P=0.03), due to a reduction in the production rate of these particles (-16.0%, P=0.03). VLDL apoB-100 pool size was also significantly decreased by sitagliptin therapy (-9.3%, P=0.03), mainly due to a reduction in the hepatic secretion of these lipoproteins (-9.2%, P=0.06). Finally, sitagliptin treatment had no effect on VLDL apoC-III and apoE levels, but reduced both fractional catabolic and production rates of VLDL apoE (-10.6%, P=0.05 and -12.7%, P=0.04). In conclusion, treatment with sitagliptin for 6 weeks reduces TG-rich apoB-containing lipoproteins levels through a reduction in the synthesis of these particles in patients with T2D.

Separation of alogliptin enantiomers in cyclodextrin‐modified capillary electrophoresis: A validated method

The single enantiomer drug, alogliptin (Alo, Nesina®) is a novel, orally available and selective dipeptidyl peptidase-4 inhibitor used for the treatment of type II diabetes. Following its pKa determination by CE-pH titration, a validated chiral CE method has been developed to separate Alo enantiomers. Preliminary screening of the native CDs and their ten derivatives revealed that sulfopropylated-γ-CD, sulfopropylated-β-CD and sulfopropylated-γ-CD, sulfobutyl-ether-β-CD (SBE-β-CD) and sulfobutyl-ether-γ-CD enabled enantioresolution. Furthermore, cavity size dependent enantiomer migration order reversal was observed between γ- and β-CD derivatives. To improve enantioseparation, buffer composition and pH, CD concentration, applied voltage, temperature, and injection parameters were optimized for the Alo/ SBE-β-CD system, yielding a resolution of 8.34. RSD percentage of the resolution value, migration times, and corrected peak areas were below 3 and 5% during testing repeatability and intermediate precision. LOD and LOQ values were found to be 2 and 6 μg/mL, respectively, for each enantiomer. Calibration lines ranging from 6 to 250 μg/mL were constructed with r(2) > 0.9997. Robustness could be successfully verified by using the Plackett-Burman statistical experimental design. The optimized system containing 5mM SBE-β-CD in a 25mM acetate buffer at pH 4.75 was found promising to detect 0.1% distomer in the presence of the API.

Population pharmacokinetic analysis of dutogliptin, a selective dipeptidyl peptidase‐4 inhibitor

Dutogliptin is a selective dipeptidyl peptidase-4 inhibitor shown to be efficacious and safe in patients with type 2 diabetes mellitus (T2DM). Population pharmacokinetic (PK) analysis of dutogliptin was performed based on data collected in 561 healthy subjects and patients with T2DM enrolled in Phase I and II studies to assess sources of variability and support dosing rationale. The effect of extrinsic (formulations, fed/fasting conditions, potential drug-drug interaction with metformin) and intrinsic (baseline characteristics, markers of renal function, renal impairment category, and disease status) covariates was evaluated using non-linear mixed effect modeling. Plasma concentrations of dutogliptin were best fitted with a two-compartment model with a first-order rate constant of absorption (Ka) and a lag time. No differences were observed between healthy subjects and patients with T2DM. Apparent clearance (CL/F) and terminal elimination half-life of dutogliptin were 176 L/h and 12.2 hours, respectively. Typical CL/F values in patients with mild and moderate renal impairment were 121 and 79 L/h, respectively. No drug-drug interaction was observed with metformin. These results suggest that a reduction in dosing from 400 to 200 mg daily is warranted in T2DM patients with moderate renal impairment. No dose adjustments were deemed necessary for other evaluated patient characteristics and coadministration with metformin.

Alogliptin: A new dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus

The pharmacology, pharmacodynamics, pharmacokinetics, safety, efficacy, and place in therapy of alogliptin and its combinations for managing type 2 diabetes mellitus are reviewed. Alogliptin is a selective, orally bioavailable inhibitor of the enzymatic activity of dipeptidyl peptidase-4 (DPP-4). It works by slowing the inactivation of the incretin hormones, thereby increasing their concentrations in the bloodstream and reducing fasting and postprandial glucose concentrations in a glucose-dependent manner in patients with type 2 diabetes mellitus. Alogliptin has a moderate degree of absorption, estimated to exceed 75%, and its absorption is not affected by food. No drug interactions are known to be associated with alogliptin monotherapy. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The clinical efficacy and safety of alogliptin have been demonstrated in several clinical trials, reducing patients' glycosylated hemoglobin level by 0.4-1.0% in 26 weeks. Alogliptin does not require any dosage adjustment when coadministered with ketoconazole, fluconazole, gemfibrozil, warfarin, metformin, glyburide, and pioglitazone. Alogliptin selectively binds to and inhibits DPP-4 in vitro at concentrations approximating therapeutic exposures. The most common adverse events associated with alogliptin are nasopharyngitis, headache, and upper respiratory tract infection. As with the other DPP-4 inhibitors, use of alogliptin may be associated with the development of pancreatitis during therapy. Alogliptin, a selective DPP-4 inhibitor, does not differ greatly from the other DPP-4 inhibitors currently available. It can be used as monotherapy or in combination with metformin for the management of type 2 diabetes.

Sitagliptin: A Review of Its Use in Patients with Type 2 Diabetes Mellitus

Sitagliptin (Januvia(®), Xelevia™, Glactiv(®), Tesavel(®)) is an orally administered, potent and highly selective inhibitor of dipeptidyl peptidase-4 (DPP-4) and was the first agent of its class to be approved for use in the management of adults with type 2 diabetes. Numerous randomized placebo- or active comparator-controlled trials have demonstrated the efficacy of sitagliptin in terms of improving glycaemic control in patients with type 2 diabetes, including its use as monotherapy, initial combination therapy (usually with fixed-dose combinations of sitagliptin/metformin), or add-on therapy to metformin or to other antihyperglycaemic drugs, with or without metformin. The primary endpoint of the clinical trials was the reduction from baseline in glycosylated haemoglobin (HbA1c), although sitagliptin also showed beneficial effects for other endpoints, such as the proportion of patients who achieved target HbA1c, and reductions from baseline in fasting plasma glucose (FPG) levels and 2-h postprandial glucose (PPG) levels. Sitagliptin was generally well tolerated in clinical trials, had a low risk of hypoglycaemia (although this depends on background therapy) and had a neutral effect on body weight. Despite concerns regarding a possible increased risk of rare pancreatic adverse events (e.g. pancreatitis) with glucagon-like peptide-1 (GLP-1)-based therapies, such as GLP-1 receptor agonists and DPP-4 inhibitors, no causal association has been found; regulators in Europe recently conducted a review of available data, concluding that there is little evidence that these drugs could cause pancreatic inflammation or pancreatic cancer. A similar review is planned in the USA and postmarketing surveillance will continue. Thus, oral sitagliptin is an effective and generally well tolerated treatment option for the management of patients with type 2 diabetes.

Liraglutide suppresses obesity and hyperglycemia associated with increases in hepatic fibroblast growth factor 21 production in KKAy mice.

Social isolation contributes to the development of obesity and insulin-independent diabetes in KKAy mice. Here we show that systemic administration of liraglutide, a long-acting human glucagon-like peptide-1 (GLP-1) analog, significantly decreased food intake, body weight, and blood glucose levels at 24 h after its administration while having no significant effects on plasma insulin and glucagon levels in individually housed KKAy mice. In addition, the systemic administration of liraglutide significantly increased plasma fibroblast growth factor (Fgf) 21 levels (1.8-fold increase) associated with increases in the expression of hepatic Fgf21 (1.9-fold increase) and Pparγ (1.8-fold increase), while having no effects on the expression of hepatic Pparα and Fgf21 in white adipose tissue. Moreover, systemic administration of liraglutide over 3 days significantly suppressed food intake, body weight gain, and hyperglycemia in KKAy mice. On the other hand, despite remarkably increased plasma active GLP-1 levels (4.2-fold increase), the ingestion of alogliptin, a selective dipeptidyl peptidase-4 inhibitor, over 3 days had no effects on food intake, body weight, blood glucose levels, and plasma Fgf21 levels in KKAy mice. These findings suggest that systemic administration of liraglutide induces hepatic Fgf21 production and suppresses the social isolation-induced obesity and diabetes independently of insulin, glucagon, and active GLP-1 in KKAy mice.

Teneligliptin as an initial therapy for newly diagnosed, drug naive subjects with type 2 diabetes.

BackgroundTeneligliptin is a novel, highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor. The aim of this study is to explore the glycemic and non-glycemic efficacies of teneligliptin as an initial therapy.MethodsNewly diagnosed, drug naive Japanese subjects with type 2 diabetes (T2DM) were assigned to 20 mg/day teneligliptin monotherapy (n = 31). At 3 months, levels of glycemic and other parameters were compared with those at baseline.ResultsSignificant reductions of HbA1c (from 10.34 ± 2.06 to 8.38 ± 2.23%) and fasting blood glucose (FGB, from 211.3 ± 68.4 to 167.3 ± 70.2 mg/dL) levels were observed without any clinically significant adverse events. However, significant increases of uric acids (UA) levels were observed and two subjects reported mild hypoglycemic events. Homeostasis model assessment-B (HOMA-B) levels significantly increased, while high HOMA-R levels significantly decreased. Significant correlations were observed between the changes (Δ) of HbA1c and those of HOMA-B, and between ΔFBG and ΔHOMA-R. No changes in lipid and body weight were noted.ConclusionsTeneligliptin might be effectively and safely used as an initial therapy for newly diagnosed T2DM. Glycemic efficacy of teneligliptin is obtained through activating beta-cell function as well as decreasing insulin resistance.

Alogliptin

To review the pharmacology, pharmacokinetics, safety, and efficacy of alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor in the management of type 2 diabetes mellitus (T2DM). Searches were conducted in MEDLINE (1946-August 2013) and Embase (1974-August 2013) for English language articles using key words alogliptin, SYR-332, Nesina, Oseni, and Kazano. References of articles were reviewed to identify any additional sources. Articles with adequate sample sizes, evaluating clinically relevant end points were included. Alogliptin is a highly selective and potent competitive inhibitor of DPP-4. The DPP-4 enzyme rapidly inactivates the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. GLP-1, which releases postprandial insulin in response to meals, is thought to be deficient in patients with T2DM. Studies evaluating the role of alogliptin in T2DM have shown significant reductions in blood glucose and hemoglobin A1C (A1C) levels. Alogliptin doses of 12.5 to 25 mg once daily reduced A1C by 0.56% to 0.59% as monotherapy. Patients given alogliptin in addition to other antidiabetic agentsexperienced additional A1C lowering of 0.4% to 0.8%. Side effects of alogliptin include nasopharyngitis, upper-respiratory tract infections, and headache. Alogliptin demonstrates a neutral effect on weight. A large trial evaluating the cardiovascular safety of alogliptin is currently being conducted. Alogliptin is the fourth DDP-4 inhibitor approved in the US for the treatment of T2DM. It is available alone (Nesina) and in fixed-dose combinations with metformin (Kazano) and pioglitazone (Oseni). It has no demonstrable advantages over other agents in its class.

Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes

A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC50=0.017μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4=1324; DPP-9/DPP-4=1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague–Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent.

The Relationship between Anagliptin Concentration Showing Over 80% Inhibition of Plasma Dipeptidyl Peptidase-4 Activity and its Protective Effect against Glucagon-like Peptide-1 Degradation

In dipeptidyl peptidase-4 (DPP-4) inhibitors, the inhibition of plasma DPP-4 activity by 80% is considered sufficient to have an effect on glycemic control improvement through the elevation of intact glucagon-like peptide-1 (GLP-1). To clarify whether or not the 80% inhibition is sufficient to protect against GLP-1 degradation, we investigated rats with a continuous infusion of exogenous GLP-1. When GLP-1 was infused into the femoral or portal vein, the steady state active GLP-1 levels in plasma significantly increased (P<0.05) at the 80% inhibitory concentration (IC80) of anagliptin (a highly selective DPP-4 inhibitor) against plasma DPP-4 activity, compared with control. In addition, the peptide levels increased in a concentration-dependent manner at drug concentrations from IC80 to 10-fold IC80, and the levels at the 10-fold IC80 were significantly higher (P<0.05) than those at IC80. The concentration dependency on GLP-1 increment was also confirmed based on the experiment in which the endogenous active GLP-1 levels were measured after an oral carbohydrate load. These findings suggest that an almost complete inhibition (80%) of plasma DPP-4 activity was insufficient to protect GLP-1 degradation, and much higher drug concentrations such as 10-fold IC80 are necessary to potently protect GLP-1 from degradation by DPP-4 commonly present in blood and tissues.

Mo1035 Amelioration of Hepatic Steatosis in Obese Mice by Mk-0626, a Selective α-Amino Amide Dipeptidyl Peptidase-4 Inhibitor

Mo1035 Amelioration of Hepatic Steatosis in Obese Mice by Mk-0626, a Selective α-Amino Amide Dipeptidyl Peptidase-4 Inhibitor

Alogliptin, a dipeptidylpeptidase-4 inhibitor, for patients with diabetes mellitus type 2, induces tolerance to focal cerebral ischemia in non-diabetic, normal mice

Effective interventions that provide obvious neuroprotection are currently fairly limited. Glucagon-like peptide-1 (GLP-1), an enhancer of insulin production with a trophic effect on β cells in the islets, has been found to be trophic for neuronal cells. Alogliptin benzoate (AGL), a selective inhibitor of dipeptidylpeptidase-4 (DPP-4) functioning as a long-acting agonist of GLP-1, is in clinical use worldwide for patients with diabetes mellitus type 2. To clarify whether administration of AGL, independent of the insulinotropic effect, protects the brain against focal ischemia, we investigated the effect of AGL on the development of cerebral infarction in non-diabetic normal mice. Male C57BL/6J mice were administered AGL (7.5, 15, or 30μg) once a day for three weeks by intragastric gavage. After the induction of temporary focal ischemia, volumes of infarcted lesions and neurological deficits were analyzed at 24h (acute phase) and seven days (chronic phase). In the acute phase, significant reductions were observed in the volumes of infarcted lesions (p=0.009), and in the severity of neurological deficits (p=0.004), in the group treated with 15μg of alogliptin benzoate, but not the 7.5 or 30μg-treated groups. This significant reduction in volumes of infarcted lesions persisted into the chronic phase. At the end of the AGL treatment; before the induction of ischemia, the levels of brain-derived neurotrophic factor (BDNF), a potent neuroprotectant in the brain, were elevated in the cortex (p=0.008), or in the whole forebrain (p=0.023). AGL could be used as a daily neuroprotectant or an enhancer of BDNF production aiming to attenuate cerebral injuries, for the growing number of people who have the risk of ischemic stroke.

Pharmacokinetic disposition of anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in rats and dogs

The pharmacokinetic disposition of anagliptin, an orally active and highly selective dipeptidyl peptidase-4 (DPP-4) inhibitor was evaluated in male rats and dogs. Anagliptin was well absorbed in dogs (70.4%) and moderately to well absorbed in rats ranging from 38.1 to 85.5% depending on the dose. In situ testing indicated that anagliptin absorption from rat intestine was apparently limited by P-glycoprotein. The absorbed radioactivity was distributed rapidly throughout the body, and high levels of radioactivity were found in the tissues expressing DPP-4 at high levels, especially small intestine, kidney and liver. In both species, the major circulating component was unchanged anagliptin; major circulating metabolites were M1 resulting from hydrolysis of the cyano group and M6 and M7, both of which resulting from the oxidation-cleavage of the methylene function adjacent to the amine. After intravenous dosing, urinary excretion of radioactivity was the major route of elimination for rats (64.6%) and dogs (66.2%), and biliary excretion was demonstrated to be an important pathway in rats (25.2%). The total recovery was good (97.5-99.5%) and most of the radioactivity was excreted by 24h in both species. The renal clearance of unbound anagliptin in rats (91.7ml/min/kg) was much higher than the glomerular filtration rate, indicative of active renal elimination.

The dipeptidyl peptidase-4 inhibitor alogliptin improves glycemic control in type 2 diabetic patients undergoing hemodialysis

Objectives: The potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor alogliptin improves glycemic control in patients with type 2 diabetes through incretin hormone-mediated increases in both α- and β-cell responsiveness to glucose. In this study, the efficacy and safety of alogliptin in type 2 diabetic patients undergoing hemodialysis (HD) were evaluated.Methods: A prospective, open-label study of 30 patients (male/female: 24/6; mean age: 69.7 ± 1.7 years) with type 2 diabetes who were undergoing HD without insulin injection therapy was conducted. Patients were administered 6.25 mg/day alogliptin and efficacy and safety were determined by monitoring clinical and laboratory parameters during the 48-week study period.Results: After 48 weeks, alogliptin had decreased postprandial plasma glucose levels from 212 ± 8 mg/dL baseline to 156 ± 7 mg/dL, hemoglobin A1c levels from 7.1 ± 0.2% baseline to 6.3 ± 0.2% and glycated albumin (GA) levels from 25.6 ± 0.6% baseline to 20.7 ± 0.4% (all p < 0.0001). Alogliptin efficacy did not differ according to median age or body mass index, but the GA reduction was significantly greater in the antidiabetic agents-naïve group. The magnitude of GA reduction was baseline GA-dependent, being greater at higher baseline GA levels. No serious adverse effects, such as hypoglycemia or liver impairment, were observed in any patient.Conclusion: Alogliptin as monotherapy or in combination with other oral antidiabetic agents improved glycemic control and was generally well tolerated in patients with HD over a 48-week period.

Addition of sitagliptin to ongoing metformin monotherapy improves glycemic control in Japanese patients with type 2 diabetes over 52 weeks

The efficacy and safety of sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, when added to metformin monotherapy was examined in Japanese patients with type 2 diabetes. In this 52-week, add-on to metformin study, 149 patients were randomly assigned to receive sitagliptin 50mg or placebo once daily in a double-blind fashion for 12weeks. Thereafter, all patients who completed the double-blind period of the study received open-label sitagliptin 50mg once daily for 40weeks, with the investigator option of increasing sitagliptin to 100mg once daily for patients who met predefined glycemic thresholds. After 12weeks of treatment, the mean change from baseline in glycated hemoglobin (HbA1c) significantly decreased with sitagliptin relative to placebo (between-group difference [95% confidence interval]=-0.7% [-0.9 to -0.5] P<0.001). At week 12, the mean changes in 2-h post-meal glucose (-2.6mmol/L [-3.5 to -1.7]) and fasting plasma glucose (-1.0mmol/L [-1.3 to -0.6]) also decreased significantly with sitagliptin relative to placebo (P<0.001 for both). Significant improvements from baseline in glycemic control were also observed in the open-label period through to week 52. There were no differences between treatment groups in the incidence of adverse events (AEs), including hypoglycemia and predefined gastrointestinal AEs (nausea, vomiting and diarrhea) during the double-blind period, with similar findings in the open-label period. Over a period of 52weeks, the addition of sitagliptin once-daily to ongoing metformin therapy was efficacious and generally well tolerated in Japanese patients with type 2 diabetes. This trial was registered with ClinicalTrials.gov (no. NCT00363948).