Selective Dipeptidyl Peptidase-4 Inhibitor Research Articles

New dipeptidyl peptidase 4 inhibitors among adamantane derivatives

Fifteen adamantane derivatives were synthesized. Preliminary evaluation of their potential as dipeptidyl peptidase 4 (DPP-4) inhibitors was performed in silico by the Microcosm informational technology, PASS system, and docking in AutoDock Vina. The DPP-4 inhibition was studied in vitro. The selectivity of action of the most active compounds was studied by the direct inhibition of human plasma DPP-4 and recombinant human DPP-8. The highest activity was found for the compounds containing a nitrogen atom in the β-position of the side chain, namely, derivatives of adamantane carboxylic acid and N-(3-adamantyl-allyl) thiourea. We demonstrated that the most active compound of the series, 3,5-dimethyladamantane 1-carboxamide, was a selective DPP-4 inhibitor with IC50 53.94 μM.

Comparative effect of vildagliptin and teneligliptin on HbA1c, glycemic efficacy and insulin sensitivity

Background: Vildagliptin, a potent and selective dipeptidyl peptidase-4 (DPP-4) inhibitor, increases the availability of endogenous incretin hormones, glucagon-like peptide (GLP-1), and glucose-dependent insulinotropic polypeptide, thereby improving glycemic control. The objective of this study is to further investigate the insulin sensitizing properties of Vildagliptin in comparison to those of Teneligliptin.Methods: Naive subjects with T2DM were administered 50-100mg/day Vildagliptin monotherapy (n = 53). As a comparator, monotherapy, 20mg/day Teneligliptin monotherapy was performed in a non-randomized manner (n=58). No other drugs were administered. At 3 month, levels of diabetic parameters were compared with those at baseline.Results: At 3 months, while similar reductions of glycated hemoglobin (HbA1c) levels were observed with these two drugs, indexes for insulin sensitivity homeostasis model assessment (HOMA)-R ameliorated only with Vildagliptin. Then, the subjects were divided into two groups representing distinct degrees of insulin resistance; high HOMA-R (C4) and low HOMA-R (2) groups. With Vildagliptin, similar decreases of HbA1c levels were observed in high (10.85-8.66%, p\0.0005) and low (11.12-8.91%, p\0.01) HOMA-R groups. HOMA-R (-31.9%, p\0.05) and non-high density lipoprotein cholesterol (non-HDL-C, -7%, p\0.05) levels significantly decreased. HOMA-B levels increased in both groups with significant inter-group differences (102.1 % in low HOMA-R group vs. 53.4 % in high HOMA-R group). Group 2. With Teneligliptin similar decreases of HbA1c levels were observed from those of vildagliptin in either high or low HOMA-R group, but no changes of HOMA-R, non-HDL-C levels were noted. Increases of HOMA-B levels with teneligliptin were comparable to those with vildagliptin in either high or low HOMA-R group.Conclusions: These results indicate that vildagliptin ameliorates insulin sensitivity and non-HDL-C levels in subjects with high degrees of insulin resistance and vildagliptin also shows glycemic efficacy by decreasing HbA1c. This is not the case with teneligliptin though similar glycemic efficacies were observed.

Hepatoprotective effect of sitagliptin against methotrexate induced liver toxicity.

Sitagliptin is selective dipeptidyl peptidase-4 inhibitor (DPP4-I), used clinically as a new oral anti-diabetic agent. This study explored the underlying mechanisms of the hepatoprotective role of sitagliptin pretreatment against methotrexate (MTX) induced hepatotoxicity in mice. Forty mice were divided into four groups (10 mice each); control, MTX, and two sitagliptin groups (pretreated with sitagliptin 10 and 20 mg/kg/day, respectively) for five consecutive days prior to MTX injection. Results showed that MTX induced marked hepatic injury in the form of cloudy swelling, hydropic degeneration, apoptosis and focal necrosis in all hepatic zones. Biochemical analysis revealed significant increase in the serum transaminases, alkaline phosphatase and lactate dehydrogenase in MTX group. Oxidative stress and depressed antioxidant system of the hepatic tissues were evident in MTX group. MTX down-regulated nuclear factor erythroid 2-related factor 2 (Nrf2) expression and reduced its binding capacity. Additionally, MTX increased the activation and the expression of nuclear factor kappa-B (NF-κB) and downstream inflammatory mediators. MTX induced the activation of inducible nitric oxide synthase (iNOS) and increased nitrite/nitrate level. Finally, hepatic cellular apoptosis was clearly obvious in MTX-intoxicated animals using TUNEL staining. Also, there was increase in the immunoexpression of pro-apoptotic protein Bax, increase in Bax and caspase-3 levels and decrease in the level of anti-apoptotic Bcl2 in liver. On the other hand, sitagliptin pretreatment significantly ameliorated all of the above mentioned biochemical, histopathological, immunohistochemical changes induced by MTX. These results provide new evidences that the hepatoprotective effect of sitagliptin is possibly mediated through modulation of Nrf2 and NF-κB signaling pathways with subsequent suppression of inflammatory and apoptotic processes.

Comparative Effectiveness of Adding Alogliptin to Metformin Plus Sulfonylurea with Other DPP-4 Inhibitors in Type 2 Diabetes: A Systematic Review and Network Meta-Analysis.

IntroductionAlogliptin is an oral antihyperglycemic agent that is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4), approved for the treatment of type 2 diabetes mellitus (T2DM). There currently exists no comparative data to support the use of alogliptin in combination with metformin (met) and sulfonylurea (SU). A decision-focused network meta-analysis (NMA) was performed to compare the relative efficacy and safety of alogliptin 25 mg once daily to other DPP-4 inhibitors as part of a triple therapy regimen for patients inadequately controlled on metformin and SU dual therapy.MethodsA systematic literature review was conducted to identify published papers of randomized controlled trials (RCTs) that compared alogliptin with other DPP-4 inhibitors (linagliptin, saxagliptin, sitagliptin, and vildagliptin) at their Summary of Product Characteristics (SmPC) recommended daily doses, added on to metformin and SU. Comprehensive comparative analysis involving frequentist meta-analysis and Bayesian NMA compared alogliptin to each DPP-4 inhibitor separately and collectively as a group. Quasi-random effect models were introduced when random effect models could not be estimated.ResultsThe review identified 2186 articles, and 94 full-text articles were assessed for eligibility. Eight RCTs contained appropriate data for inclusion in the NMA. All analyses over all trial population sets produced very similar results, and show that alogliptin 25 mg is as least as effective (as measured by change in HbA1c from baseline, but supported by other outcome measures: change in body weight and FPG from baseline) and safe (as measured by incidence of hypoglycemia and adverse events leading to study discontinuation) as all the other DPP-4 inhibitors in triple therapy.ConclusionThis decision-focused systematic review and NMA demonstrated alogliptin 25 mg daily to have similar efficacy and safety compared to other DPP-4 inhibitors, for the treatment of T2DM in adults inadequately controlled on metformin and SU. (Funded by Takeda Development Centre Americas; EXAMINE ClinicalTrials.gov number, NCT00968708).Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-017-0245-8) contains supplementary material, which is available to authorized users.

Synthesis of phenylpyridine derivatives and their biological evaluation toward dipeptidyl peptidase-4

A novel series of pyridine-based derivatives was synthesized and evaluated for their inhibitory activity against dipeptidyl peptidase-4 (DPP4). 5-Aminomethyl-6-(2,4-dichlorophenyl)-4-[(1H-1,2,4-triazol-1-yl)methyl]pyridine-2-carboxylic acid was identified as a potent (IC50 0.57 nM) and selective DPP4 inhibitor (DPP8/DPP4 = 238). A docking study of this compound revealed a hydrogen-bonding interaction with the Arg125 residue of the enzyme providing a potential target residue for further structural optimization.

The Vildagliptin Experience - 25 Years Since the Initiation of the Novartis Glucagon-like Peptide-1 Based Therapy Programme and 10 Years Since the First Vildagliptin Registration.

The discovery of the incretin hormone glucagon like peptide-1 (GLP-1), and its usefulness in the treatment of type 2 diabetes mellitus (T2DM) followed by the finding that dipeptidyl peptidase-4 (DPP-4) inhibition prevents GLP-1 inactivation, led to the discovery of DPP-728. In 1999, studies with DPP-728 established the first proof-of-concept that DPP-4 inhibition improves glycaemic control in patients with T2DM. Further efforts to improve the binding kinetics of DPP-728 resulted in the discovery of vildagliptin (LAF237). In the last 20 years, a plethora of studies conducted by Novartis in collaboration with external investigators has demonstrated the mechanism of action of vildagliptin and its efficacy as monotherapy and as an add-on therapy for patients with T2DM. The studies establish that vildagliptin is a selective DPP-4 inhibitor that blocks GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) inactivation, thereby prolonging their action, resulting in improved glycaemic control. This review aims to discuss the discovery and development of vildagliptin, with an emphasis on mechanism of action and clinical efficacy.

A concise review of the bioanalytical methods for the quantitation of sitagliptin, an important dipeptidyl peptidase-4 (DPP4) inhibitor, utilized for the characterization of the drug.

Inhibition of dipeptidyl peptidase-4 (DPP4) is an emerging therapeutic approach for treating type 2 diabetes and has revolutionized the concept of diabetes management. Sitagliptin is the first approved orally active, potent, selective and nonpeptidomimetic DPP4 inhibitor. Incidence of hypoglycemia and weight gain is negligible with sitagliptin treatment. It is used as monotherapy or in combination with other anti-diabetic drugs to treat type 2 diabetes. There are numerous bioanalytical methods published for the analysis of sitagliptin in preclinical and clinical samples. This review focuses on the various HPLC and LC-MS/MS methods that have been used to analyze sitagliptin in various biological matrices. A small section is devoted to the bioanalysis of other DPP4 inhibitors such as vildagliptin, saxagliptin and linagliptin. This review provides key information in a concise manner regarding sample processing options, chromatographic/detection conditions and validation parameters of the chosen methods for sitagliptin and other DPP4 inhibitors.

Teneligliptin in type 2 diabetes: a guide to its use in Argentina

Oral teneligliptin [Teneglucon® (Argentina)], a potent, selective dipeptidyl peptidase-4 (DPP-4) inhibitor, is a useful option to improve glycaemic control in patients with type 2 diabetes who have not responded adequately to treatment with diet and exercise, or the addition of biguanides, sulfonylureas or thiazolidinediones. In clinical trials, teneligliptin (20 or 40 mg once daily) monotherapy or combination therapy with metformin, glimepiride or pioglitazone, improved glycaemic control, including in patients with end-stage renal disease receiving haemodialysis. Improvements in glycaemic control were sustained after 52 weeks’ treatment. Teneligliptin is generally well tolerated, does not increase the risk of hypoglycaemia and is bodyweight neutral.

Inhibition of Dipeptidyl Peptidase-4 Impairs Ventricular Function and Promotes Cardiac Fibrosis in High Fat-Fed Diabetic Mice.

Dipeptidyl peptidase-4 (DPP4) inhibitors used for the treatment of type 2 diabetes are cardioprotective in preclinical studies; however, some cardiovascular outcome studies revealed increased hospitalization rates for heart failure (HF) among a subset of DPP4 inhibitor-treated subjects with diabetes. We evaluated cardiovascular function in young euglycemic Dpp4(-/-) mice and in older, high fat-fed, diabetic C57BL/6J mice treated with either the glucagon-like peptide 1 receptor (GLP-1R) agonist liraglutide or the highly selective DPP4 inhibitor MK-0626. We assessed glucose metabolism, ventricular function and remodeling, and cardiac gene expression profiles linked to inflammation and fibrosis after transverse aortic constriction (TAC) surgery, a pressure-volume overload model of HF. Young euglycemic Dpp4(-/-) mice exhibited a cardioprotective response after TAC surgery or doxorubicin administration, with reduced fibrosis; however, cardiac mRNA analysis revealed increased expression of inflammation-related transcripts. Older, diabetic, high fat-fed mice treated with the GLP-1R agonist liraglutide exhibited preservation of cardiac function. In contrast, diabetic mice treated with MK-0626 exhibited modest cardiac hypertrophy, impairment of cardiac function, and dysregulated expression of genes and proteins controlling inflammation and cardiac fibrosis. These findings provide a model for the analysis of mechanisms linking fibrosis, inflammation, and impaired ventricular function to DPP4 inhibition in preclinical studies.

Abstract 14911: Dipeptidyl Peptidase-4 Deteriorates Cardiac Function During Autoimmune Myocarditis by Facilitating Cathepsin-G Activity

Post-myocarditis dilated cardiomyopathy is the most common cause of non-hereditary heart failure developing at a young age. Our colleagues have shown previously that dipeptidyl peptidase-4 (DPP-4) worsens the development of experimental autoimmune myocarditis (EAM) by promoting expression of inflammatory cytokines and cardiac fibrosis in mice. In order to clarify how DPP-4 mediates this detrimental effect in the EAM heart, mouse EAM model generated by immunizing with α-MHC peptide in BALB/c mice were given a diet mixed with linagliptin, a selective DPP-4 inhibitor (83 mg/kg chow corresponding to around 3 mg/kg oral dosing) (LINA group, N = 6), or normal diet (CONT group, N = 6). After 21 days of EAM induction, lung weight / body weight were significantly smaller in LINA group than in CONT group (7.7 ± 0.1 mg/g* vs. 8.3 ± 0.1 mg/g, *P < 0.05). Left ventricular ejection fraction after induction of EAM was significantly higher in LINA group than in CONT group (72.6 ± 6.6%* vs. 60.1 ± 9.2%, *P < 0.05). Immunostaining demonstrated that the number of RORγt-positive Th17 cells infiltrated to inflamed myocardium was significantly smaller in LINA group than in CONT group. Consistent with this result and the previous finding that Th17 cells express high level of enzymatically active DPP-4, the DPP-4 activity in inflamed myocardium was significantly lower in LINA group than in CONT group (46.9 ± 2.4 RFU* vs. 116.8 ± 8.6 RFU, *P < 0.05). Mass spectrometry analysis using lysates from inflamed myocardium co-immunoprecipitated with Flag-DPP-4 recombinant protein revealed that DPP-4 bound to cathepsin-G (CTSG), a plasma membrane-bound serine protease, in the EAM heart. Co-immunoprecipitation - western blot analysis verified the physical interaction between DPP-4 and CTSG. The activity of CTSG in inflamed myocardium was significantly higher in EAM mice compared to those in untreated mice, and CTSG activity in the EAM heart was significantly lower in LINA group than in CONT group. The amount of angiotensin II, a major product catalyzed by CTSG, in the EAM heart was also significantly lower in LINA group than in CONT group. Collectively, these results suggest that DPP-4 derived from Th17 cells aggravates cardiac dysfunction during EAM, possibly through enhancing CTSG activity in the heart.

Evogliptin: First Global Approval.

Evogliptin (Suganon) is an orally bioavailable, selective dipeptidyl peptidase-4 (DPP-4; CD26 antigen) inhibitor being developed by Dong-A ST for the treatment of type 2 diabetes mellitus. DPP-4 inhibitors control glucose levels by preventing the breakdown of the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), which stimulate insulin secretion in response to the increased levels of glucose in the period following meals. In October 2015, evogliptin received its first global approval in South Korea for blood glucose control in patients with type 2 diabetes mellitus. This article summarizes the milestones in the development of evogliptin leading to this first approval for type 2 diabetes mellitus.

Mosapride, a selective serotonin 5-HT4 receptor agonist, and alogliptin, a selective dipeptidyl peptidase-4 inhibitor, exert synergic effects on plasma active GLP-1 levels and glucose tolerance in mice

Pharmacologic stimulation of serotonin 5-HT4 receptors increased plasma active glucagon-like-peptide-1 (GLP-1) levels independent of feeding, and that pharmacologic stimulation of 5-HT4 receptors and pharmacologic inhibition of dipeptidyl peptidase-4 exerted synergic effects on plasma active GLP-1 levels and glucose tolerance in mice.

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a class of oral antidiabetic drugs that improve glycaemic control without causing weight gain or increasing hypoglycaemic risk in patients with type 2 diabetes mellitus (T2DM). The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with identical mechanism of action and similar safety profiles in patients with T2DM. DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose-lowering agents such as metformin, thiazolidinediones, or sulfonylureas. Although DPP-4 inhibitors have the same mode of action, they differ by some important pharmacokinetic and pharmacodynamic properties that may be clinically relevant in some patients. The main differences between the eight gliptins include: potency, target selectivity, oral bioavailability, elimination half-life, binding to plasma proteins, metabolic pathways, formation of active metabolite(s), main excretion routes, dosage adjustment for renal and liver insufficiency, and potential drug-drug interactions. The off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. As a drug class, the DPP-4 inhibitors have become accepted in clinical practice due to their excellent tolerability profile, with a low risk of hypoglycaemia, a neutral effect on body weight, and once-daily dosing. It is unknown if DPP-4 inhibitors can prevent disease progression. More clinical studies are needed to validate the optimal regimens of DPP-4 inhibitors for the management of T2DM when their potential toxicities are closely monitored.

Synergism in Pharmacokinetics of Retagliptin and Metformin Observed during Clinical Trials of their Combination Therapy

Purpose: To investigate the safety and potential pharmacokinetic (PK) interaction between retagliptin, a selective inhibitor of dipeptidyl peptidase-4, and metformin in healthy subjects.Methods: In open-label, randomized, three-period, three-treatment crossover studies, 15 subjects received 100 mg retagliptin, 1500 mg metformin or the combination. The area under the curve from the time of dosing to infinity (AUCinf) and the maximum observed plasma concentration (Cmax) of each drug were measured.Results: The combination of retagliptin and metformin did not result in clinically significant alterations in the pharmacokinetics of SP2086 or metformin. The AUCinf and Cmax of retagliptin co-administered with metformin were 16.49 and 25.88 % higher than for retagliptin alone, respectively, while the AUCinf of metformin co-administered with retagliptin was 22.06 % higher than for metformin alone. The 90 % confidence interval of both glucose-lowering drugs’ AUCinf and Cmax of the geometric mean ratios of SP2086 + metformin fell within the pre-specified interval of 80 - 125 %. No laboratory adverse conditions occurred during the study. Retagliptin appeared generally safe and well-tolerated when administered alone or in combination with metformin.Conclusion: The results may be an indication that no dose adjustments are likely to be required when retagliptin is given in combination with metformin.

Pharmacological stimulation of serotonin 5-HT1B receptors enhances increases in plasma active glucagon-like peptide-1 levels induced by dipeptidyl peptidase-4 inhibition independently of feeding in mice

AimGlucagon-like peptide-1 (GLP-1), an incretin hormone, is released from intestinal L cells in response to nutrient ingestion. Dipeptidyl peptidase-4 (DPP-4) rapidly degrades the active form of GLP-1 to an inactive form in the bloodstream. The present study aimed to investigate the role of serotonin (5-HT)1B receptors in the regulation of plasma active GLP-1 levels and glucose tolerance under DPP-4 inhibition. MethodsC57BL6J mice treated with or without alogliptin, a highly selective DPP-4 inhibitor, for 4 days were intraperitoneally injected with either saline, the 5-HT1B/2C receptor agonist meta-chlorophenylpiperazine (mCPP) at 2.5mg/kg and 5mg/kg or the selective 5-HT1B receptor agonist CP94253 at 2.5mg/kg and 5mg/kg, and food-deprived after treatment. An hour later, plasma active GLP-1 levels were determined. Also, a glucose tolerance test was done by injecting d-glucose (2g/kg) following the injection of saline or CP94253 (5mg/kg) in mice treated with alogliptin. ResultsIntraperitoneal injection of mCPP (2.5 and 5mg/kg) or CP94253 (2.5 and 5mg/kg) in mice treated with alogliptin for 4 days significantly increased plasma active GLP-1 levels compared with saline controls in mice that were food-deprived after the injections. While intraperitoneal injection of either mCPP or CP94253 alone had no significant effect on plasma active GLP-1 levels, the injection of CP94253 improved glucose tolerance in mice treated with alogliptin compared with saline. ConclusionThese findings suggest that pharmacological stimulation of 5-HT1B receptors enhances the increases in plasma active GLP-1 induced by DPP-4 inhibition independently of feeding and also improves glucose tolerance in mice.

Important species differences regarding lymph contribution to gut hormone responses

IntroductionGLP-1 is secreted from the gut upon nutrient intake and stimulates insulin secretion. The lymph draining the intestine may transport high levels of GLP-1 to the systemic circulation before it is metabolized by DPP-4. The aims of this study were to investigate to what extent the lymphatic system might contribute to the final level(s) of systemic circulating intact GLP-1 and, in addition, whether secretory profiles in intestinal lymph might reflect lamina propria levels of GLP-1 i.e. before capillary uptake and degradation by endothelial dipeptidyl peptidase-4 (DPP-4). Method7 pigs of the YDL-strain were catheterized in the portal vein, carotid artery and cisterna chyli (lymph). Neuromedin C (NC) was infused through an ear vein catheter, before and after injection of a selective DPP-4 inhibitor (vildagliptin). Total and intact GLP-1 levels were measured throughout the 150min experiments using specific sandwich ELISAs. DPP-4 activity was measured spectrophotometrically. ResultsConcentrations of both total and intact GLP-1 were markedly lower in lymph compared to plasma samples, and did not increase significantly in response to stimulation with NC in the absence/presence of vildagliptin. In contrast, total and intact GLP-1 levels increased significantly in the portal vein and carotid artery. DPP-4 activity was lower in lymph than plasma, and was reduced further by vildagliptin. ConclusionOur observations indicate that the lymphatic system does not transport high levels of intact GLP-1 to the systemic circulation, and that GLP-1 levels in cisternal lymph do not reflect the hormone levels in the intestinal lamina propria.

Alogliptin benzoate for management of type 2 diabetes.

Dipeptidyl peptidase-4 (DPP-4) inhibitors, a new class of oral hypoglycemic agents, augment glucose-dependent insulin secretion and suppress glucagon levels through enhancement of the action of endogenous incretin by inhibiting DPP-4, an incretin-degrading enzyme. DPP-4 inhibitors are generally well tolerated because of their low risk of hypoglycemia and other adverse events. Moreover, with their potential to improve beta cell function, a core defect of type 2 diabetes, DPP-4 inhibitors are becoming a major component of treatment of type 2 diabetes. Alogliptin benzoate is a newly developed, highly selective DPP-4 inhibitor which has been approved in many countries throughout the world. Once-daily administration of alogliptin as either monotherapy or combination therapy with other oral antidiabetic drugs or insulin has a potent glucose-lowering effect which is similar to that of other DPP-4 inhibitors, with a low risk of hypoglycemia and weight gain. The cardiovascular safety of this drug has been confirmed in a recent randomized controlled trial. This review summarizes the efficacy and safety of alogliptin, and discusses the role of DPP-4 inhibitors in the treatment of type 2 diabetes.

Dipeptidyl peptidase-4 greatly contributes to the hydrolysis of vildagliptin in human liver.

The major metabolic pathway of vildagliptin in mice, rats, dogs, and humans is hydrolysis at the cyano group to produce a carboxylic acid metabolite M20.7 (LAY151), whereas the major metabolic enzyme of vildagliptin has not been identified. In the present study, we determined the contribution rate of dipeptidyl peptidase-4 (DPP-4) to the hydrolysis of vildagliptin in the liver. We performed hydrolysis assay of the cyano group of vildagliptin using mouse, rat, and human liver samples. Additionally, DPP-4 activities in each liver sample were assessed by DPP-4 activity assay using the synthetic substrate H-glycyl-prolyl-7-amino-4-methylcoumarin (Gly-Pro-AMC). M20.7 formation rates in liver microsomes were higher than those in liver cytosol. M20.7 formation rate was significantly positively correlated with the DPP-4 activity using Gly-Pro-AMC in liver samples (r = 0.917, P < 0.01). The formation of M20.7 in mouse, rat, and human liver S9 fraction was inhibited by sitagliptin, a selective DPP-4 inhibitor. These findings indicate that DPP-4 is greatly involved in vildagliptin hydrolysis in the liver. Additionally, we established stable single expression systems of human DPP-4 and its R623Q mutant, which is the nonsynonymous single-nucleotide polymorphism of human DPP-4, in human embryonic kidney 293 (HEK293) cells to investigate the effect of R623Q mutant on vildagliptin-hydrolyzing activity. M20.7 formation rate in HEK293 cells expressing human DPP-4 was significantly higher than that in control HEK293 cells. Interestingly, R623Q mutation resulted in a decrease of the vildagliptin-hydrolyzing activity. Our findings might be useful for the prediction of interindividual variability in vildagliptin pharmacokinetics.

Comparative evaluation of combination of metformin and glimepiride with that of metformin and sitagliptin in type 2 diabetes mellitus with respect to glycemic targets

Background: Sitagliptin, an oral and selective dipeptidyl peptidase-4 inhibitor, represents a novel therapeutic approach for the treatment of type 2 diabetes mellitus. Metformin and glimepiride are most commonly used oral hypoglycemic agents. Objective: To compare combination of metformin and glimepiride with that of metformin and sitagliptin in patients with type 2 diabetes mellitus. Materials and Methods: The study was conducted by Department of Pharmacology, Shri Guru Ram Rai Institute of Medical and Health Sciences, Dehradun, Uttarakhand, India, in Medicine OPD for 1 year. Total 60 patients with type 2 diabetes mellitus were included in the study. The patients were divided into two groups: Group I (n = 30), patients were put on metformin 500 mg + glimepiride 1 mg once daily and Group II, (n = 30), patients were put on metformin 500 + sitagliptin 50 mg once daily. The patients were stabilized for 2 weeks and followed up every 6 weeks for 24 weeks. Fasting blood sugar (FBS) and postprandial blood sugar (PPBS) were measured at every follow-up; glycosylated hemoglobin (HbA1c) was measured at 0 and 24 weeks. Analysis was done using t-test, and a p-value of 0.05), PPBS (p 0.05) was done. Most common adverse drug reactions were hypoglycemia, abdominal discomfort, weight loss, and nausea/vomiting. Conclusion: Both groups showed significant improvement in FBS, PPBS, and HbA1c at the end of the study period. Intergroup comparison showed significant improvement in PPG in group II (with a combination of metformin and sitagliptin) at the end of the study.

Effects of Sitagliptin on Insulin and Glucagon Levels in Type 2 Diabetes Mellitus.

Effects of Sitagliptin on Insulin and Glucagon Levels in Type 2 Diabetes Mellitus.