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Type 2 diabetes (T2DM) is a progressive disease, and pharmacotherapy with a single agent does not generally provide durable glycaemic control over the long term. Sulphonylurea (SU) drugs have a history stretching back over 60 years, and have traditionally been the mainstay choice as second-line agents to be added to metformin once glycaemic control with metformin monotherapy deteriorates; however, they are associated with undesirable side effects, including increased hypoglycaemia risk and weight gain. Dipeptidyl peptidase (DPP)-4 inhibitors are, by comparison, more recent, with the first compound being launched in 2006, but the class now globally encompasses at least 11 different compounds. DPP-4 inhibitors improve glycaemic control with similar efficacy to SUs, but do not usually provoke hypoglycaemia or weight gain, are relatively free from adverse side effects, and have recently been shown not to increase cardiovascular risk in large prospective safety trials. Because of these factors, DPP-4 inhibitors have become an established therapy for T2DM and are increasingly being positioned earlier in treatment algorithms. The present article reviews these two classes of oral antidiabetic drugs (DPP-4 inhibitors and SUs), highlighting differences and similarities between members of the same class, as well as discussing the potential advantages and disadvantages of the two drug classes. While both classes have their merits, the choice of which to use depends on the characteristics of each individual patient; however, for the majority of patients, DPP-4 inhibitors are now the preferred choice.

Recent studies suggested that reduced hepatic insulin clearance (HIC) after mixed meal ingestion was associated with amelioration of postprandial hyperglycemia by supplying sufficient insulin throughout the body and that HIC might be regulated by increases in serum incretins. Despite broad use in practice, the effects of DPP-4i on HIC are little known. Thus, we aimed to clarify the effect of a DPP-4i, anagliptin (ANA), on HIC in type 2 diabetes mellitus (T2DM) patients. Analyzed were 977 T2DM patients (72% male, mean age: 58 y, HbA1c: 8.0%, BMI: 25 kg/m2, HOMA-β: 26.4, HOMA-IR: 2.7) on diet and exercise therapy who received ANA or a placebo as initial monotherapy and add-on therapy in five phase 2 and 3 randomized controlled trials (ANA: 706, placebo: 271). Postprandial HIC (P-HIC) from the meal tolerance test was calculated as the ratio: C-peptide AUC0-120min to insulin AUC0-120min. Differences in variables between ANA and placebo were analyzed by an ANCOVA model, with the treatment group as a fixed effect and the baseline value as a covariate. Multivariate analysis was done to clarify possible independent factors associated with HbA1c. After taking ANA for 12 weeks, HbA1c was significantly reduced (-0.65%, p Disclosure Y. Matsubayashi: None. T. Abe: None. S. Muragishi: Employee; Self; Kowa Pharmaceutical Co., Ltd. A. Yoshida: Employee; Self; Kowa Pharmaceutical Co. Ltd. H. Suganami: Employee; Self; Kowa Company, Ltd. K. Furusawa: Employee; Self; Sanwakagakukenkyusho Co.,LTD. T. Yamada: None. K. Fujihara: None. S. Tanaka: None. K. Kaku: Speaker's Bureau; Self; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim GmbH. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation, MSD K.K.. Advisory Panel; Self; Novo Nordisk A/S. Speaker's Bureau; Self; Ono Pharmaceutical Co., Ltd.. Advisory Panel; Self; Sanwa Kagaku Kenkyusho Co., Ltd.. Speaker's Bureau; Self; Taisho Pharmaceutical Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceuticals, Japan Inc., Kowa Pharmaceuticals, Japan Inc.. Advisory Panel; Self; Astellas, Japan Inc. H. Sone: Research Support; Self; Novo Nordisk Inc., Eli Lilly and Company, MSD K.K., Chugai Pharmaceutical Co., Ltd., Taisho Pharmaceutical Co., Ltd., Takeda Development Center Asia, Pte. Ltd., Daiichi Sankyo Company, Limited, Ono Pharmaceutical Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Sanofi, Kowa Pharmaceuticals America, Inc., Eisai Inc..

Background: We have found that anagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4) significantly ameliorates arterial stiffness in Type 2 Diabetes Mellitus (T2DM) patients compared with an equivalent hypoglycaemic agent, glimepiride. However, it remains unclear whether switching DPP-4 inhibitors to tofogliflozin, a selective inhibitor of Sodium-Glucose Cotransporter 2 (SGLT2) improves arterial stiffness in T2DM patients. Methods: Nineteen T2DM patients who had received DPP-4 inhibitors for at least 1 year were enrolled in this study. Clinical parameters and arterial stiffness evaluated by cardio-ankle vascular index (CAVI) were measured at baseline and after 6-months treatment with tofogliflozin. Results: At 6 months after switching to tofogliflozin, CAVI, waist circumference, body weight, body mass index, subcutaneous and visceral fat volume, white blood cell number, fasting plasma insulin, uric acid, aspartate transaminase (AST), γ-glutamyl transferase (GTP), and advanced glycation end products (AGEs) were significantly reduced, while red blood cell number, haemoglobin, and HbA1c values were increased. When stratified by median values of change in CAVI after switching to tofogliflozin (ΔCAVI), baseline serum levels of AGEs were significantly higher in the low ΔCAVI group (high responder) than in the high one (low responder). ΔAST and ΔGTP were positively correlated with ΔCAVI. Conclusion: The present study suggests that switching DPP-4 inhibitors to tofogliflozin ameliorates arterial stiffness in T2DM patients partly via improvement of liver function. Baseline serum levels of AGEs may identify patients who improve arterial stiffness more after treatment with tofogliflozin.

Background Gliptins are indicated for diabetes mellitus type-2 (DM-II). They inhibit dipeptidyl peptidase IV (DPP-IV), an enzyme which is responsible for deterioration of incretin hormones. They increase insulemic secretion in manner glucose dependent, therefore they have positive effects in glycaemic control. Several cases of bullous pemphigoid (BP) have been described since they came on the market. Epidermal keratinocytes have DPP-IV, consequently a possible mechanism implied in the pathogenesis of the BP derived from gliptins is the amendment of immune response and/or alteration of antigenic qualities of the epidermal basement membrane. Purpose To describe one case of BP associated with vildagliptin and revision of the literature of BP associated with gliptins. Material and methods We made a bibliographic search in the Pubmed database using the keywords ‘Bullous phemphigoid’ and ‘Dipeptidyl peptidase IV inhibitors’. We also tracked one patient with BP associated withvildagliptin. Results 51-years-old male with DM-II, being treated with vildagliptin 50 mg and metformin 850 mg twice a day. After two months of therapy he developed erythemateous plaques and pruritic blisters. Biopsy confirmed BP diagnosis. Vildagliptin therapy was cancelled but metformin therapy continued and insulin was introduced temporarily. Clobetasol propionate 0.05% foam was prescribed three times a day in a downward trend to cure lesions. Optimum results were obtained with a full recovery. Literature review 12 articles connected to BP and gliptins were found, all of them case series and, added to that, two authors described all BP cases related to gliptins that were registered in the French and European Database of Pharmacovigilance. This bibliographic review included 239 patients: 47.2% men, 31.7% females and 20.9% unknown. Average age: 77.8. DPP-IV inhibitor: vildagliptin 66.9%, sitagliptin 22.55%, linagliptin 7.9%, saxagliptin 1.6%, anagliptin 0.4%. The average time from start to development of BP was 8.5 months. Therapy: 73.9% with topic corticosteroid, 20.5% oral and 5.4% others. Outcome after withdrawal of gliptins: 70.2% sustained; refractory: 15.4% and 14.2% unknown. Conclusion Our case and literature review show the connexion between DPP-IV inhibitors and the development of BP. This connexion can be useful in stopping possible adverse reactions, together with considering other therapies and giving the right information to the patient. No conflict of interest

Dipeptidyl peptidase IV (DPP-IV) inhibitors are novel oral anti-hyperglycemic agents. Here, the anti-apoptotic effect of Anagliptin in human umbilical vein endothelial cells (HUVECs) was evaluated. Cultured HUVECs were pre-incubated with Anagliptin, and then treated hydrongen peroxide (H2O2) to induce apoptosis. The apoptosis of HUVECs were detected by viability, LIVE/DEAD staining assay and flow cytometry assays. HUVECs were transfected with plasmid harboring human NADPH oxidases (NOX) 4 or an empty vector. The formation of reactive oxygen species (ROS) was measured by immunofluorescence. Apoptotic and anti-apoptotic factor were detected by Western Blot. Pre-incubation with Anagliptin protected HUVECs from H2O2 induced apoptosis. The transfection assay also indicated that pre-incubation with Anagliptin inhibited the apoptosis of HUVECs induced by NADPH oxidase 4 (NOX-4) overexpression. Immunofluorescence demonstrated that pre-incubation with Anagliptin suppressed the formation of ROS in apoptotic HUVECs. Pre-incubation with Anagliptin inhibited NOX-4 mediated the Bax, caspase-3, cleave caspase-3 and Cyto C overexpression, but up-regulated the protein level of Bcl-2 in HUVECs. The data help us to better understand the effect of Anagliptin on apoptosis, and will be valuable in identifying new targets to prevent the endothelial cell apoptosis after injury.

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.

Dipeptidyl peptidase IV (DPP-IV) expression in visceral adipose tissue is reportedly increased in obese patients, suggesting an association of DPP-IV with inflammation. In this study, first, lipopolysaccharide (LPS)- or palmitate-induced elevations of inflammatory cytokine mRNA expressions in RAW264.7 macrophages were shown to be significantly suppressed by coincubation with a DPP-IV inhibitor, anagliptin (10 μM), despite low DPP-IV expression in the RAW264.7 cells. Regarding the molecular mechanism, LPS-induced degradation of IκBα and phosphorylations of p65, JNK, and p38, as well as NF-κB and AP-1 promoter activities, were revealed to be suppressed by incubation with anagliptin, indicating suppressive effects of anagliptin on both NF-κB and AP-1 signaling pathways. Anagliptin also acted on 3T3-L1 adipocytes, weakly suppressing the inflammatory cytokine expressions induced by LPS and TNFα. When 3T3-L1 and RAW cells were cocultured and stimulated with LPS, the effects of anagliptin on the suppression of cytokine expressions in 3T3-L1 adipocytes were more marked and became evident at the 10 μM concentration. Anti-inflammatory effects of anagliptin were also observed in vivo on the elevated hepatic and adipose expressions and serum concentrations of inflammatory cytokines in association with the suppression of hepatic NF-κB transcriptional activity in LPS-infused mice. Taking these observations together, the anti-inflammatory properties of anagliptin may be beneficial in terms of preventing exacerbation of diabetes and cardiovascular events.

The mechanism responsible for the lipid-lowering effect of dipeptidyl peptidase-4 (DPP-4) inhibitors remains unknown in humans. We evaluated the effect of anagliptin on serum lipid profiles, including cholesterol synthesis and absorption markers, in Japanese patients with type 2 diabetes.Thirty patients with type 2 diabetes (20 - 70 years old, low-density lipoprotein cholesterol (LDL-C) level over 120 mg/dl, and no history of treatment with antidiabetic or antihyperlipidemic drugs) were enrolled. One hundred milligrams of anagliptin were administered twice a day for a month.After treatment of anagliptin, the LDL-C and total cholesterol (TC) levels did not decrease overall, but the TC level decreased significantly in 28 patients whose HbA1c levels decreased. Lathosterol decreased significantly, whereas no changes in campesterol, sitosterol or cholestanol were observed.These results of our study show no significant change in LDL-C, a tendency of decrease in TC and non-high-density lipoprotein cholesterol (non-HDL-C) after treatment of anagliptin for 1 month. Anagliptin therapy decreased the cholesterol synthesis marker lathosterol without changing cholesterol absorption markers.

We conducted a 24-week, multicentre, double-blind, randomized study with a 28-week extension to compare the efficacy and safety of anagliptin and sitagliptin as an add-on to metformin in patients with type 2 diabetes. Patients inadequately controlled on metformin were randomized to either anagliptin (100 mg twice daily, n = 92) or sitagliptin (100 mg once daily, n = 88). The primary endpoint was the change in glycated haemoglobin (HbA1c) from baseline to week 24. The mean changes in HbA1c were -0.85 ± 0.70% (p < 0.0001) for anagliptin and -0.83 ± 0.61% (p < 0.0001) for sitagliptin, with a mean difference of -0.02% (95% confidence interval of difference, -0.22 to 0.18%). In both groups, the fasting proinsulin : insulin ratio significantly decreased from baseline, with improved insulin secretion. Safety profiles were similar in each group. In conclusion, the non-inferiority of the efficacy of anagliptin to sitagliptin as an add-on therapy was established with regard to efficacy and safety.

Objective The objective of this study is to elucidate the effect of anagliptin on glucose/lipid metabolism and renoprotection in patients with type 2 diabetic nephropathy. Methods Twenty-five patients with type 2 diabetic nephropathy received anagliptin 200 mg/day for 24 weeks, and 20 patients who were switched to anagliptin from other dipeptidyl peptidase-4 (DPP-4) inhibitors were analyzed regarding primary and secondary endpoints. The primary endpoint was change in hemoglobin A1c (HbA1c) during treatment with anagliptin. Additionally, we evaluated changes in lipid data (low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglyceride), blood pressure (BP), urinary albumin to creatinine ratio (UACR), liver-type fatty acid-binding protein to creatinine ratio (ULFABP) and renal function (estimated glomerular filtration rate and serum cystatin C) as secondary endpoints. Results After switching to anagliptin from other DPP-4 inhibitors, the levels of HbA1c in the 20 participants showed no significant change, 7.5%±1.2% at 24 weeks compared with 7.3%±0.9% at baseline. The levels of the log10-transformed UACR were significantly reduced from 1.95±0.51 mg/g creatinine (Cr) at baseline to 1.76±0.53 mg/g Cr at 24 weeks after anagliptin treatment (p

Background Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms ( IA s). DPP‐4 (dipeptidyl peptidase‐4) inhibitors have anti‐inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP ‐4 inhibitor, anagliptin, could suppress the growth of IA s in a rodent aneurysm model. Methods and Results IA s were surgically induced in 7‐week‐old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide‐treated RAW 264.7 macrophages. In the anagliptin‐treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IA s, reduced the expression of MCP‐1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide‐stimulated RAW 264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP ‐1, and IL‐6 (interleukin 6) independent of GLP‐1 (glucagon‐like peptide 1), the key mediator in the antidiabetic effects of DPP ‐4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal–regulated kinase 5), which mediates the anti‐inflammatory effects of statins, in RAW 264.7 macrophages. Preadministration with an ERK 5 inhibitor blocked the inhibitory effect of anagliptin on MCP ‐1 and IL ‐6 expression. Accordingly, the ERK 5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. Conclusions A DPP ‐4 inhibitor, anagliptin, prevents the growth of IA s via its anti‐inflammatory effects on macrophages.

The inhibition of dipeptidyl peptidase-IV (DPPIV) is a popular route for the treatment of type-2 diabetes. Commercially available gliptin-based drugs such as sitagliptin, anagliptin, linagliptin, saxagliptin, and alogliptin were specifically developed as DPPIV inhibitors for diabetic patients. The use of Gynura bicolor in treating diabetes had been reported in various in vitro experiments. However, an understanding of the inhibitory actions of G. bicolor bioactive compounds on DPPIV is still lacking and this may provide crucial information for the development of more potent and natural sources of DPPIV inhibitors. Evaluation of G. bicolor bioactive compounds for potent DPPIV inhibitors was computationally conducted using Lead IT and iGEMDOCK software, and the best free-binding energy scores for G. bicolor bioactive compounds were evaluated in comparison with the commercial DPPIV inhibitors, sitagliptin, anagliptin, linagliptin, saxagliptin, and alogliptin. Drug-likeness and absorption, distribution, metabolism, and excretion (ADME) analysis were also performed. Based on molecular docking analysis, four of the identified bioactive compounds in G. bicolor, 3-caffeoylquinic acid, 5-O-caffeoylquinic acid, 3,4-dicaffeoylquinic acid, and trans-5-p-coumaroylquinic acid, resulted in lower free-binding energy scores when compared with two of the commercially available gliptin inhibitors. The results revealed that bioactive compounds in G. bicolor are potential natural inhibitors of DPPIV.

The aim of this case study was to examine the efficacy of a dipeptidyl peptidase-4 inhibitor (anagliptin) and an α-glucosidase inhibitor (miglitol) when added to ongoing insulin treatment in patients with type 2 diabetes mellitus. Continuous glucose monitoring was performed in four Japanese insulin-treated inpatients with type 2 diabetes. Baseline data were collected on day 1. Miglitol was administered on days 2 and 3. On day 4, miglitol and anagliptin were coadministered before breakfast. On days 1, 3, and 5, blood was drawn for plasma glucose, serum C-peptide, plasma glucagon, total and active glucagon-like peptide-1 (GLP-1), and total and active glucose-dependent insulinotropic peptide (GIP) measurements. Coadministration of anagliptin with miglitol resulted in additional improvements in glycemic control over the entire day in three of the four patients. The C-peptide, glucagon, and total and active GLP-1 and GIP responded differently to the medications for each patient, suggesting interindividual differences in hormonal responses, which may be complicated by multifactorial effects. Electronic supplementary material The online version of this article (doi:10.1007/s40261-014-0260-8) contains supplementary material, which is available to authorized users.

REVIEW QUESTION/OBJECTIVE What is the effectiveness of GLP-1 analogues compared to DPP-4 inhibitors for beta cell function and diabetes related complications among adults with type 2 diabetes? INCLUSION CRITERIA Types of participants This review will include adults (over 18 years of age) with type 2 diabetes mellitus. The diagnosis of type 2 diabetes mellitus should have been made using standard criteria that were valid at the beginning of the study. Ideally, diagnostic criteria should have been described, and should be consistent with changes in classification and diagnosis over the years. The author’s definition of diabetes will be used, if necessary. Types of intervention(s) The interventions of interest for this review will be treatment with a GLP-1 analogue (primary intervention) and DPP-4 inhibitor (active comparator). GLP-1 analogue injectable preparations include exenatide, liraglutide and lixisenatide. The GLP-1 analogues still in the developmental stage, albiglutide, semaglutide and dulaglutide will also be of interest. The DPP-4 inhibitor tablet preparations of interest include alogliptin, linagliptin, saxagliptin, sitagliptin gemigliptin, anagliptin, teneligliptin or vildagliptin. Treatment with either class of drug should be for a minimum of eight weeks, either alone or in combination with metformin (any dose). Types of outcomes Primary Outcomes: Primary outcomes of interest for this review will focus on beta cell function, and this will be assessed by a range of measurements. Firstly, the total amount of glucose metabolized during a glucose infusion will be used to quantify the response of beta cells. This is measured by the hyperglycemic clamp TRUNCATED AT 250 WORDS

The effects of antidiabetic agents on lipoprotein subclasses are assumed to be pivotal, but this assumption has not been studied. We evaluated lipoprotein subclasses in patients, randomly selected from REASON (Randomized Evaluation of Anagliptin versus Sitagliptin On low-density lipoproteiN cholesterol in diabetes) Trial participants, with type-2 diabetes treated with either anagliptin or sitagliptin. We measured total cholesterol (TC) and triglycerides (TG) in 4 (chylomicron (CM), very low-density lipoprotein (VLDL), low density lipoprotein (LDL), and high-density lipoprotein (HDL)) lipoprotein classes and 20 (2 CM, 5 VLDL, 6 LDL, and 7 HDL) lipoprotein subclasses. Between 0 and 52 weeks, TC and TG in lipoprotein and the lipoprotein subclass were distributed differently in patients treated with anagliptin and sitagliptin. The preferable changes in TC and TG levels were observed dominantly in the anagliptin-treated group under standard statin therapy, but the benefits were observed in both the anagliptin- and sitagliptin-treated groups, at least partially under strong statin therapy. In future studies, the atherogenic properties of lipoprotein subclasses might be considered when employing antidiabetic dipeptidyl peptidase-4 (DPP-4) inhibitors, especially in patients with type-2 diabetes who are at risk of atherosclerotic cardiovascular disease (ASCVD) or are undergoing statin treatment.

The dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) are novel oral hypoglycemic drugs which have been in clinical use for the past 7 years. The drugs are safe, weight neutral and widely prescribed. There are currently eight gliptins registered worldwide with several more in advanced stages of development.The place of the gliptins in the treatment algorithm of type 2 diabetes is discussed as well as unique features of the individual drugs. The gliptins may possess cardiovascular protective effects and their administration may promote β-cell survival; claims currently being evaluated in clinical and preclinical studies. The global market revenues and future prospects of the gliptins are discussed and the gliptins in Phases II and III of development are reviewed.The gliptins are an optional second-line therapy after metformin; they are generally well tolerated with low risk of hypoglycemia. The various compounds differ with respect to their pharmacokinetic and pharmacodynamic properties; however, their clinical efficacy appears to be similar. The clinical differences between the various compounds stem from effects other than hypoglycemic effects, their safety and side effects profile. The currently registered compounds appear to have maximized the clinical potential of DPP-4 inhibition, and the new compounds in the companies' pipelines seem to be as effective as the ones presently in use. There are two gliptins in advanced stages of development which will be registered for once-weekly dosing, possibly increasing patient adherence to therapy. Several individual gliptins are being evaluated for treatment in diabetes subpopulations such as type 1 patients or adolescents.

アナグリプチン（スイニー®錠）は（株）三和化学研究所で創製され，興和（株）と共同で開発されたジペプチジルペプチダーゼ-4（DPP-4）阻害薬である．アナグリプチンは濃度依存的にDPP-4を可逆的かつ競合的に阻害し，ヒト組換えDPP-4活性を50%阻害する濃度（IC50）は3.3 nMである．また，極めて高い酵素選択性を有し，DPP-8，DPP-9等のDPP-4類縁酵素に対する阻害作用は極めて弱く，他のプロテアーゼに対する作用もほとんど認められない．ラットまたはイヌを用いた検討において，アナグリプチンの経口投与は，用量に依存した強力な血漿DPP-4活性阻害作用を示した．また，アナグリプチンは糖尿病モデルラットにおいても，血中のDPP-4を強力に阻害し，インスリン濃度を増加させ，糖負荷後の血糖上昇を抑制した．グルカゴン様ペプチド-1（GLP-1）分泌促進作用が知られているα-グルコシダーゼ阻害薬またはビグアナイド薬とアナグリプチンを併用投与した結果では，糖尿病モデルラットにおいて，血中活性型GLP-1濃度がさらに増加し，これらの薬剤との併用によるGLP-1作用の増強が期待された．臨床試験では，健康成人を対象とした第I相試験において，アナグリプチンの投与量依存的な血中濃度の上昇と血漿DPP-4活性阻害率の上昇が確認され，1回100 mgを1日2回投与することにより24時間にわたって血漿DPP-4活性の阻害を高率に維持できることが示された．2型糖尿病患者を対象として，アナグリプチンを1回50～200 mg，1日2回（BID），12週間投与した第II相試験では，用量依存的なHbA1cの低下が確認され，推奨されるアナグリプチンの用法・用量は100 mg BIDであることが示された．続く第II／III相試験では，アナグリプチンの1回100または200 mg，1日2回，12週間投与の有効性および安全性が再確認され，ボグリボースを有意に上回るHbA1c低下作用が示された．さらに，第III相の単独長期投与試験および経口血糖降下薬（α-グルコシダーゼ阻害薬，ビグアナイド薬，スルホニルウレア薬またはチアゾリジン薬）との併用長期投与試験では，いずれの単独または併用療法においても，アナグリプチン100 mg，1日2回投与の有効性および安全性が確認され，血糖コントロール改善効果が治療期52週まで持続することが示された．また，効果不十分な患者では，200 mg，1日2回に増量することにより，37.6%～59.7%の患者でさらなるHbA1cの低下が認められた．これまでの臨床試験において低血糖症の発現率は低く，報告された低血糖症はいずれも軽度の事象であった．また，アナグリプチン投与による重篤な副作用は認められていない．以上の結果が示すように，アナグリプチンは優れた有効性と安全性を有しており，新しい糖尿病治療薬として期待される．

Background & objective: The gliptins, dipeptidyl peptidase inhibitors (DPP-4 inhibitors) are a relatively new class of antidiabetic drugs that, via their inhibition of DPP-4, a cell membrane–associated serine-type protease enzyme, promote the effects of the endogenous incretins such as glucagon-like peptide 1 (GLP-1) and enhance glucose disposal. The advantage of the gliptins over GLP-1 analogues is that they are orally effective whereas the clinically used incretins, exenatide and liraglutide, have to be administered via sub-cutaneous injection. The first gliptin, sitagliptin, was approved by the FDA in 2006 and six other gliptins have subsequently been approved – vildagliptin (2007 in Europe); saxagliptin (2009, FDA); linagliptin (2011, FDA); anagliptin (2012, Japan); teneligliptin (2012, Japan); alogliptin (2013, FDA). There is a close association between diabetes and cardiovascular disease (CVD) and vascular complications associated with diabetes are responsible for 75% of the deaths of diabetics. Therefore it is important that for any new class of antidiabetic drugs introduced for clinical use that we determine whether such drugs not only show therapeutic efficacy as antidiabetic drugs, but also that they are vasculoprotective and reduce both cardiovascular morbidity and mortality. Endothelial dysfunction that can be functionally defined as a reduced vasorelaxation response to an endothelium-dependent vasodilator, such as acetylcholine, or, at the molecular level, a reduction in the bioavailability of nitric oxide (NO) and/or reduced activity of the enzyme responsible for the generation of NO, namely, endothelial nitric oxide synthase (eNOS). Endothelial dysfunction is a very early indicator of the onset of vascular disease and thus determining whether the gliptins also reduce endothelial dysfunction is very important. The literature concerning the vasculoprotective effects of the gliptins is contradictory with some of the clinical data suggesting a negative effect of the gliptins on vascular function. Thus, the objective of this study was to determine whether the gliptins possess positive or negative effects on endothelial function. Materials & methods: In the present study we used a cell culture protocol with mouse vascular endothelial endothelial cells (MS1-VEGF; CRL-2460, from ATCC, USA) of micro-vascular endothelial origin. The endothelial cells, MMECs, were either cultured under normoglycaemic (NG) conditions for a mouse, 11 mM, or high glucose 40 mM (HG) – a level that equates to the plasma glucose levels that are seen in mouse models of type 2 diabetes, such as the db/db leptin receptor mutant model of type 2 diabetes. The gliptin, alogliptin was chosen for this study and the protocols were designed to determine whether this gliptin reduced, or prevented, the high glucose induced reduction in eNOS phosphorylation at serine 1177 (p-eNOSser1177) as determined by western immunoblot densitometry quantification. A reduction in p-eNOSser1177 will result in a reduced activity of eNOS and hence a reduction in the generation of NO. Thus, the quantification of p-eNOSser1177 serves as a measure of endothelial function. The band densities of the western blot images for eNOS and p-eNOSser1177 were quantified using the basic Quantity One software (Biorad, Inc. CA, USA). Statistical analysis was performed using one-way analysis of variance (ANOVA) and post-hoc comparisons between groups were performed by Tukey's multiple comparison tests. ‘p’ values less than 0.05 were considered to be statistically significant. Results: Our data indicates that a 24-hour exposure to HG reduced p-eNOSser1177 phosphorylation, but the presence of alogliptin reverses the effects of HG and significantly increased the phosphorylation of eNOS, suggesting that this gliptin does protect the microvascular endothelium against hyperglycaemia-induced endothelial dysfunction. Furthermore, the effects of alogliptin were concentration-dependent and were significant with 50 or 100 μM, but not 10 μM alogliptin. Conclusion: Our findings indicate that, in a concentration-dependent manner, alogliptin protects endothelial cells against the negative effects that hyperglycaemia (high glucose) has on endothelial function as measured by alogliptin-induced changes in the phosphorylation of eNOS at serine 1177. Further studies are underway, using a functional myograph assay, to determine whether alogliptin can also prevent hyperglycaemia-induced endothelial dysfunction in mouse aortic vessels.AcknowledgementThis work was supported by a Summer Student Research Fellowship (SSRF) from Weill Cornell Medicine-Qatar and an Undergraduate Research Experience Program grant, UREP 18-055-3-012 from the Qatar National Research Fund (QNRF). The statements made herein are solely the responsibility of the authors.

1. The disposition of anagliptin, an orally active, highly selective dipeptidyl peptidase-4 inhibitor, was investigated after a single oral dose of 100 mg/1.92 MBq [(14)C]anagliptin to six healthy men. Almost all the dose (98.2%) was recovered within 168 h: 73.2% in urine and 25.0% in faeces. 2. Anagliptin was rapidly absorbed, with peak plasma concentrations of unchanged drug attained at a mean time of 1.8-h postdose. Mean fraction of the dose absorbed was73%. Unchanged drug and a carboxylate metabolite (M1) were the major components in plasma, accounting for 66.0 and 23.4% of total plasma radioactivity area under the curve, respectively. 3. Anagliptin was incompletely metabolized, with about 50% dose eliminated as unchanged drug (46.6% in urine and 4.1% in faeces). Metabolism to M1 accounted for 29.2% of the dose. No other metabolite accounted for1% dose in excreta or yielded measurable systemic exposure. Terminal half-life of anagliptin and M1 was 4.37 and 9.88 h, respectively. Renal clearance of unbound anagliptin and unbound M1 far exceeded glomerular filtration rate, indicating active renal elimination: that might reflect the fact that anagliptin may be a substrate of OAT1, OAT3, MDR1 and MRP2, and M1 a substrate of OAT3, BCRP, MRP2 and MRP4.

Background: Inhibition of dipeptidyl peptidase-4 (DPP-4) has been proposed as a therapeutic target for type 2 diabetes (T2DM). Arterial stiffness, a predictor of future cardiovascular events and all-cause mortality, is augmented in these patients. However, effects of DPP-4 inhibitors on arterial stiffness remain unknown. In this study, we compared effects of anagliptin, an inhibitor of DPP-4 on arterial stiffness evaluated by cardio-ankle vascular index (CAVI) with those of an equipotent glucose-lowering agent, glimepiride in patients with T2DM. Methods: The study involved 50 consecutive outpatients (33 males and 17 females; mean age of 72.5±9.5 years) who visited our hospitals for a risk-screening test or treatment for T2DM. They underwent complete history and physical examination, and determination of blood chemistry and anthropometric variables, and then were randomized to receive either anagliptin (n=26) or glimepiride (n=24) for 6 months. Results: After 6-months treatment, fasting plasma glucose and HbA1c values were comparably reduced in both groups. Anagliptin, but not glimepiride treatment significantly decreased low-density lipoprotein cholesterol, malondialdehyde-modified LDL, remnant-like particle (RLP) cholesterol, CAVI, alanine transaminase (ALT), γ-glutamyl transferase and visceral fat volume. In multiple regression analysis, absolute changes from baseline of RLP cholesterol and ALT after anagliptin treatment for 6 months ( RLP cholesterol and ALT) were independently correlated with ΔCAVI (R2=0.445). Conclusion: The present study suggests that anagliptin may exert a beneficial effect on arterial stiffness in patients with T2DM, which is independent of its blood glucose-lowering property. Anagliptin may ameliorate arterial stiffness partly via reduction of RLP cholesterol and improvement of liver function.

It has been reported that postprandial hyperglycemia from the pre-diabetic stage, especially from the impaired glucose tolerance (IGT) stage, is positively associated with subsequent incidences of cardiovascular diseases (CVD) and type 2 diabetes. In this study, we aimed to investigate whether treatment with a dipeptidyl peptidase-4 inhibitor (DPP-4I) or an α-glucosidase inhibitor (α-GI), either of which suppresses postprandial hyperglycemia, reduces the expression of CVD risk factors in an IGT animal model. A DPP-4I, anagliptin (1,200 ppm), or an α-GI, miglitol (600 ppm), in the diet was administered for 47 wk to Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model for spontaneously-developed type 2 diabetes, at the IGT stage. We examined whether each treatment reduced the expression of CVD risk factors such as inflammatory cytokines/cytokine-like factors in peripheral leukocytes and adhesion molecules in the aortic tissues and circulation. Treatment with either drug reduced IGT development and repressed expression of the interleukin-1β, tumor necrosis factor-α, S100a9, and S100a11 genes in peripheral leukocytes in the fasting state at weeks 25 and 39. The mRNA levels of E-selectin in aortic tissues and protein levels of the soluble forms of E-selectin and ICAM-1 in arterial blood were significantly lower in the anagliptin and miglitol groups than in the control group. Our results suggest that long-term treatment with anagliptin or miglitol in OLETF rats at the IGT stage suppresses the expression of inflammatory cytokines in peripheral leukocytes and adhesion molecules in aortic tissues.

The traditional oral pharmacological therapy for type 2 diabetes mellitus (T2DM) has been based on the prescription of metformin, a biguanide, as first line antihyperglycemic agent world over. It has been demonstrated that after 3 years of treatment, approximately 50% of diabetic patients could achieve acceptable glucose levels with monotherapy; but by 9 years this had declined to only 25%. Therefore, the implementation of a combined pharmacological therapy acting via different pathways becomes necessary, and its combination with a compound of the sulfonylurea group was along decades the most frequently employed prescription in routine clinical practice. Meglitinides, glitazones and alpha-glucosidase inhibitors were subsequently developed, but the five mentioned groups of oral antihyperglycemic agents are associated with variable degrees of undesirable or even severe cardiovascular events. The gliptins-also called dipeptidyl peptidase 4 (DPP4) inhibitors--are an additional group of antidiabetic compounds with increasing clinical use. We review the status of the gliptins with emphasis on their capabilities to positively or negatively affect the cardiovascular system, and their potential involvement in major adverse cardiovascular events (MACE). Alogliptin, anagliptin, linagliptin, saxagliptin, sitagliptin, teneligliptin and vildagliptin are the compounds currently in clinical use. Regardless differences in chemical structure and metabolic pathways, gliptins as a group exert favorable changes in experimental models. These changes, as an almost general rule, include improved endothelial function, reduction of inflammatory markers, oxidative stress ischemia/reperfusion injury and atherogenesis. In addition, increased adiponectin levels and modest decreases in lipidemia and blood pressure were reported. In clinical settings, several trials--notably the longer one, employing sitagliptin, with a mean follow-up period of 3 years--did not show an increased risk for ischemic events. Anyway, it should be emphasized that the encouraging results from basic science were not yet translated into clinical evidence, probably due the multiple and pleiotropic enzymatic effects of DPP4 inhibition. Moreover, when employing saxagliptin, while the drug was not associated with an augmented risk for ischemic events, it should be pinpointed that the rate of hospitalization for heart failure was significantly increased. Gliptins as a group constitute a widely accepted therapy for the management of T2DM, usually as a second-line medication. Nonetheless, for the time being, a definite relationship between gliptins treatment and improved cardiovascular outcomes remains uncertain and needs yet to be proven.

The single-crystal structure of anagliptin, N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide, was determined. Two independent molecules were held together by intermolecular hydrogen bonds, and the absolute configuration of the 2-cyanopyrrolidine ring delivered from l-prolinamide was confirmed to be S. The interactions of anagliptin with DPP-4 were clarified by the co-crystal structure solved at 2.85 A resolution. Based on the structure determined by X-ray crystallography, the potency and selectivity of anagliptin were discussed, and an SAR study using anagliptin derivatives was performed.

Background DPP-4 inhibitors reportedly exert effects on both alpha and beta cells, and promote the proliferation and survival of beta cells. We investigated the effects of anagliptin on structurally-impaired islets of Langerhans in streptozotocin (STZ)-treated mice, fed either a normal or a high-fat diet. Pdx-1 expression in the pancreas and serum insulin/glucagon concentrations were also examined. Findings Anagliptin treatment significantly up-regulated pancreatic Pdx-1 expression, with elevated serum glucagon-like peptide-1 concentrations, regardless of whether the diet was normal or high-fat. However, interestingly, the beta cell regeneration, structural normalization of islets of Langerhans including alpha cell: beta cell area ratios, and serum insulin elevation, all observed with anagliptin administration in the animals fed a normal diet, were markedly suppressed in the high-fat fed group. Conclusions High-fat diet feeding clearly weakened the regenerative effects of anagliptin on the islets of Langerhans in STZ-treated mice. Our findings suggest the importance of normalizing lipid metabolism for full manifestation of DPP-4 inhibitor effects on the islets of Langerhans. Electronic supplementary material The online version of this article (doi:10.1186/s13098-015-0047-y) contains supplementary material, which is available to authorized users.

The aim of this study was to evaluate the efficacy and safety of anagliptin in drug-naive patients with type 2 diabetes in a double-blind randomized placebo-controlled study. A total of 109 patients were randomized to 100 mg (n=37) or 200 mg (n=33) anagliptin twice daily or placebo (n=39). The primary objective was to alter HbA1c levels from baseline at a 24-week endpoint. The overall baseline mean age and body mass index were 56.20 ± 9.77 years and 25.01 ± 2.97 kg/m(2), respectively, and the HbA1c level was of 7.14 ± 0.69 %. Anagliptin at 100 mg and 200 mg produced significant reductions in HbA1c (-0.50 ± 0.45 % and -0.51 ± 0.55%, respectively), and the placebo treatment resulted in an increase in HbA1c by 0.23 ± 0.62 %. Both doses of anagliptin produced significant decreases in fasting plasma glucose (-0.53 ± 1.25 mmol/L and -0.72 ± 1.25 mmol/L, respectively) and the proinsulin/insulin ratio (-0.04 ± 0.15 and -0.07 ± 0.18, respectively) compared with placebo. No meaningful body weight changes from baseline were observed in three groups. Plasma dipeptidyl peptidase (DPP)-4 activity was significantly inhibited after 24 weeks of anagliptin treatment, and >75% and >90% inhibitions were observed during the meal tolerance tests with 100 mg and 200 mg anagliptin, respectively. The incidences of adverse or serious adverse events were similar among the three study groups. Twice-daily anagliptin therapy effectively inhibited DPP-4 activity and improved glycemic control and was well-tolerated in patients with type 2 diabetes.

Although several previous studies have been published on the effects of dipeptidase-4 (DPP-4) inhibitors in diabetic hemodialysis (HD) patients, the findings have yet to be reviewed comprehensively. Eyesight failure caused by diabetic retinopathy and aging-related dementia make multiple daily insulin injections difficult for HD patients. Therefore, we reviewed the effects of DPP-4 inhibitors with a focus on oral antidiabetic drugs as a new treatment strategy in HD patients with diabetes. The following 7 DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and saxagliptin. All of these are administered once daily with dose adjustments in HD patients. Four types of oral antidiabetic drugs can be administered for combination oral therapy with DPP-4 inhibitors, including sulfonylureas, meglitinide, thiazolidinediones, and alpha-glucosidase inhibitor. Nine studies examined the antidiabetic effects in HD patients. Treatments decreased hemoglobin A1c and glycated albumin levels by 0.3% to 1.3% and 1.7% to 4.9%, respectively. The efficacy of DPP-4 inhibitor treatment is high among HD patients, and no patients exhibited significant severe adverse effects such as hypoglycemia and liver dysfunction. DPP-4 inhibitors are key drugs in new treatment strategies for HD patients with diabetes and with limited choices for diabetes treatment.

Keywords Anagliptin Test meal Adiponectin Remnant Renal function 8-OHdGIt has been generally recognized that postprandial hyper-glycemia and hyperlipidemia are highly related to thedevelopment of atherosclerosis [1, 2]. Hyperglycemia isknown to damage vascular endothelial cells, increase oxi-dative stress, promote the expression of adhesion moleculeand inhibit nitric oxide (NO) production [3]. Remnantlipoprotein, an important component of postprandialhyperlipidemia, promotes foam cell formation of macro-phages and proliferation of smooth muscle cells [4].Dipeptidyl peptidase 4 (DPP-4) inhibitors have attractedattention as a new class of anti-diabetic agents for thetreatment of type 2 diabetes [5]. Anagliptin, a member ofthe medication class of DPP-4 inhibitors, has been recentlyavailable in the market in Japan. Animal studies suggestthat anagliptin treatment is associated with improvement ofglucose tolerance either by amelioration of insulin resis-tance or enhancing insulin secretion [6] and the decrease inthe development of atherosclerosis [7]. However, to ourknowledge, there has been no clinical study. In this back-ground, we investigated the effect of anagliptin treatmenton glucose and lipoprotein metabolism in fasting andpostprandial state using a test meal (JANEF E460F18 ,Q.P. Co., Tokyo, Japan).Ten Japanese men with type 2 diabetes (age66.3 ±9.5 years; body mass index (BMI) 26.6 2.2 kg/m

Treatment with the dipeptidyl peptidase-4 inhibitor, anagliptin, or with the α-glucosidase inhibitor, miglitol, reduced the oral sucrose load-inducible expression of interleukin (IL)-1β, IL-18, tumor necrosis factor-α, S100a8, S100a9, S100a11, IL-1R2, IL-1Rn and tumor necrosis factor receptor 2 genes in peripheral leukocytes of Otsuka Long-Evans Tokushima fatty (OLETF) rats at the stage of impaired glucose tolerance. Inhibiting postprandial hyperglycemia reduced the expression of genes related to inflammation in peripheral leukocytes of OLETF rats.

OBJECTIVE. Inflammatory bowel disease (IBD) is a chronic debilitating disease associated with severe damage to the intestinal mucosa. Glucagon-like peptide-2 (GLP-2) is a potent and specific gastrointestinal growth factor. GLP-2 released from enteroendocrine cells is inactivated by dipeptidyl peptidase-4 (DPP-4). The aim of this study was to examine whether the DPP-4 inhibitor anagliptin improves experimental murine colitis. MATERIAL AND METHODS. Male C57BL/6 mice aged 8 weeks were exposed to 1.5% dextran sulfate sodium (DSS) in drinking water for 7 days to induce experimental colitis. Anagliptin (0.1% in diet) was administrated from 2 days before the beginning of DSS to 7 days after the end of DSS. Changes in body weight and disease activity index were evaluated daily. Histological colitis severity, cellular proliferation and gene expression were determined in colonic tissues. RESULTS. Treatment with anagliptin clearly improved body weight loss and disease activity index in the recovery phase. Histological score in the DSS + anagliptin group at day 14 was significantly lower than that in the DSS alone group. Treatment with anagliptin increased the Ki67-positive rate at days 10 and 14, and tended to increase insulin-like growth factor-1 mRNA expression in the DSS + anagliptin group. CONCLUSION. In this model of experimental colitis, the DPP-4 inhibitor anagliptin facilitated the restoration of mucosal damage, thereby resulting in the acceleration of healing. These findings suggest a new and novel therapeutic approach for the treatment of IBD.

Dipeptyl peptidase-4 (DPP-4) inhibitors modulate the progression of atherosclerosis. To gain insights into their mechanism of action, 9-wk-old male apolipoprotein E (apoE)-deficient mice were fed a DPP-4 inhibitor, anagliptin-containing diet. The effects of anagliptin were investigated in, a monocyte cell line, human THP-1 cells, and rat smooth muscle cells (SMCs). Treatment with anagliptin for 16 wk significantly reduced accumulation of monocytes and macrophages in the vascular wall, SMC content in plaque areas, and oil red O-stained area around the aortic valve without affecting glucose tolerance or body weight. Serum DPP-4 concentrations were significantly higher in apoE-deficient mice than control mice, and the levels increased with aging, suggesting the involvement of DPP-4 in the progression of atherosclerosis. Indeed, soluble DPP-4 augmented cultured SMC proliferation, and anagliptin suppressed the proliferation by inhibiting ERK phosphorylation. In THP-1 cells, anagliptin reduced lipopolysaccharide-induced TNF-α production with inhibiting ERK phosphorylation and nuclear translocation of nuclear factor-κB. Quantitative analysis also showed that anagliptin reduced the area of atherosclerotic lesion in apoE-deficient mice. These results indicated that the anti-atherosclerotic effect of anagliptin is mediated, at least in part, through its direct inhibition of SMC proliferation and inflammatory reaction of monocytes.

Lipid profile is an important determinant of cardiovascular risk in type 2 diabetic patients. Available glucose-lowering agents can affect lipid levels. Dipeptidyl peptidase-4 (DPP-4) inhibitors have been reported to reduce total cholesterol, but results are inconsistent across trials. The present metaanalysis was designed to assess the effect of DPP-4 inhibitors on blood lipids, verifying possible differences across compounds of this class.An extensive search of Medline and the Cochrane Library (any date up to December 31, 2010, restricted to randomized clinical trials, published in English) was performed for all trials containing, in any field, the words "sitagliptin," "vildagliptin," "saxagliptin," "alogliptin," "linagliptin," and/or "dutogliptin." Completed but unpublished trials were identified through a search of the ClinicalTrials.gov website, using the same keywords as above. Differences in the endpoint levels and absolute or percent variations of lipids were assessed. A metaregression was performed on the trials specified above to assess the effect of putative moderators on the effect of DPP-4 inhibitors on plasma lipids, considering all drugs together and each one separately.Although the number of trials of appropriate size and duration was high (n=53), only a small fraction of those (n=17) reported data on endpoint total, high-density lipoprotein, and low-density lipoprotein cholesterol, and triglyceride. The difference-in-means for endpoint versus baseline total cholesterol in patients on DPP-4 inhibitors treatment was significantly higher in comparison with controls, meaning that treatment with DPP-4 inhibitors is associated with a significant reduction in total cholesterol (-0.18 [-0.29; -0.06] mmol/L (-7.0 [-11.2; -2.50] mg/dL); P=0.002).This meta-analysis suggests a possible beneficial effect of DPP-4 inhibitors on cholesterol, which, although small, could contribute to the reduction of cardiovascular risk.

Anagliptin is a novel dipeptidyl peptidase-4 inhibitor that has been available in Japan since 2012. Because anagliptin is not generally used in countries other than Japan, there are only a small number of reports investigating the effects of anagliptin. In the present article, we review the safety and efficacy of anagliptin according to data obtained from preclinical trials and postmarketing studies. The usual dose of anagliptin is 200 mg daily, and increases in the dose up to 400 mg daily have been approved in cases in which the blood glucose–lowering effect is insufficient. In a Phase II trial, the reduction in the HbA1c values from baseline after 12 weeks monotherapy with 200 mg and 400 mg of daily anagliptin was 0.75%±0.50% and 0.82%±0.46%, respectively, and more than 40% of the subjects receiving anagliptin at a dose of 200 mg or 400 mg daily achieved an HbA1c level below 6.9%. Furthermore, the levels of HbA1c, fasting blood glucose, and postprandial blood glucose were significantly decreased at 52 weeks compared with the baseline values in a Phase III trial investigating the effects of anagliptin included in combination therapy with other oral antidiabetic agents. In a pooled analysis of Phase II and Phase II/III trials, the goal achievement rates for an HbA1c level below 7.0% at 12 weeks were 40.3%, 39.4%, 30.0%, and 34.8% in the patients treated with anagliptin combined with α-glucosidase inhibitors, thiazolidinediones, sulfonylureas, and biguanides, respectively. Meanwhile, the serum lipid concentrations significantly improved after the administration of anagliptin in a pooled analysis of Phase III trials, and no serious adverse effects have been reported in preclinical trials. Therefore, the use of anagliptin in patients with type 2 diabetes is considered to be safe and effective for both monotherapy and combination therapy.

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

other drugs except for anagliptin. We considered that his edema was angioedema due to anagliptin, and stopped using anagliptin. His severe edema promptly and completely disappeared at two weeks after the discontinuation of anagliptin. The number of type 2 diabetic patients treated with both the renin– angiotensin system (RAS) inhibitors and DPP-IV inhibitors is increasing, because the RAS inhibitors have a favorable effect for type 2 diabetes [2,3]. Brown NJ et al. found that the DPP-IV inhibitor use was associated with an increased risk of angioedemaamong patients takingangiotensin converting enzyme (ACE) inhibitors in the meta-analysis [4]. However, they did not observe an association between the use of DPP-IV inhibitor alone and an increased risk of angioedema [4], suggesting that anigioedema is a possible drug–drug interaction, which is challenged by our observation. The DPP-IV is an enzyme that inactivates incretins and also influences the degradation of bradykinin [5]. Therefore, the DPP-IV inhibitors may increase the half-life of bradykinin which is a crucial mediator of ACE inhibitor-induced angioedema. The increased vascular permeability resulting from an increase in bradykinin due to the DPP-IV inhibition may be the most plausible explanation for the DPP-IV inhibitor-induced angioedema. In conclusion, we had a patient with type 2 diabetes who showed angioedema due to anagliptin. To our knowledge, this is the first to report the development of angioedema due to the DPP-IV inhibitor alone.