Deprecated: Creation of dynamic property cls_session::$session_data_table is deprecated in /www/sites/www.188bio.com/index/systems/cls_session.php on line 49
Clinical pharmacology of dipeptidyl peptidase 4 inhibitors...188bio精品生物—专注于实验室精品爆款的电商平台 - 蚂蚁淘旗下精选188款生物医学科研用品
您好,欢迎您进入188进口试剂采购网网站! 服务热线:4000-520-616
蚂蚁淘商城 | 现货促销 | 科研狗 | 生物在线

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors...

Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus - Chen - 2015 - Clinical and Experimental Pharmacology and Physiology - Wiley Online LibraryClinical and Experimental Pharmacology and PhysiologyVolume 42, Issue 10 p. 999-1024 Invited Review Free Access Clinical pharmacology of dipeptidyl peptidase 4 inhibitors indicated for the treatment of type 2 diabetes mellitus Xiao-Wu Chen, Department of General Surgery, The First People\'s Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, ChinaSearch for more papers by this authorZhi-Xu He, Corresponding Author Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China Correspondence: Professor Shu-Feng Zhou, Global Medical Development, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA. Email: szhou@health.usf.edu and Professor Zhi-Xu He, Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, 9 Beijing Road, Guiyang 550004, Guizhou, China. Email: hzx@gmc.edu.cnSearch for more papers by this authorZhi-Wei Zhou, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USASearch for more papers by this authorTianxin Yang, Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Centre, Salt Lake City, UT, USASearch for more papers by this authorXueji Zhang, Research Centre for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, ChinaSearch for more papers by this authorYin-Xue Yang, Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, ChinaSearch for more papers by this authorWei Duan, School of Medicine, Deakin University, Waurn Ponds, Vic., AustraliaSearch for more papers by this authorShu-Feng Zhou, Corresponding Author Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA Correspondence: Professor Shu-Feng Zhou, Global Medical Development, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA. Email: szhou@health.usf.edu and Professor Zhi-Xu He, Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, 9 Beijing Road, Guiyang 550004, Guizhou, China. Email: hzx@gmc.edu.cnSearch for more papers by this author Xiao-Wu Chen, Department of General Surgery, The First People\'s Hospital of Shunde, Southern Medical University, Shunde, Foshan, Guangdong, ChinaSearch for more papers by this authorZhi-Xu He, Corresponding Author Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China Correspondence: Professor Shu-Feng Zhou, Global Medical Development, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA. Email: szhou@health.usf.edu and Professor Zhi-Xu He, Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, 9 Beijing Road, Guiyang 550004, Guizhou, China. Email: hzx@gmc.edu.cnSearch for more papers by this authorZhi-Wei Zhou, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USASearch for more papers by this authorTianxin Yang, Department of Internal Medicine, University of Utah and Salt Lake Veterans Affairs Medical Centre, Salt Lake City, UT, USASearch for more papers by this authorXueji Zhang, Research Centre for Bioengineering and Sensing Technology, University of Science and Technology Beijing, Beijing, ChinaSearch for more papers by this authorYin-Xue Yang, Department of Colorectal Surgery, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, ChinaSearch for more papers by this authorWei Duan, School of Medicine, Deakin University, Waurn Ponds, Vic., AustraliaSearch for more papers by this authorShu-Feng Zhou, Corresponding Author Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, Guiyang, Guizhou, China Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA Correspondence: Professor Shu-Feng Zhou, Global Medical Development, Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL 33612, USA. Email: szhou@health.usf.edu and Professor Zhi-Xu He, Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Centre & Sino-US Joint Laboratory for Medical Sciences, Guiyang Medical University, 9 Beijing Road, Guiyang 550004, Guizhou, China. Email: hzx@gmc.edu.cnSearch for more papers by this author Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URLShare a linkShare onEmailFacebookTwitterLinked InRedditWechat Summary 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. Introduction Diabetes mellitus is a major health problem around the world, with continued expansion of diabetes mellitus associated morbidity, mortality, reduced quality of life and increased healthcare costs.1-3 Despite extensive research into diabetes and ongoing education about diabetes prevention, its prevalence is still on the rise. According to the International Diabetes Federation (IDF) Diabetes Atlas Sixth Edition, 382million people have diabetes; 5.1million people died due to diabetes in 2013; the greatest number of people with diabetes are between 40 and 59years of age; 175million people with diabetes are undiagnosed; and at least 548billion US dollars were spent on healthcare for diabetes in 2013.4 The IDF forecasts that the total number of people with diabetes will rise to 592million worldwide by 2035. Based on the data from the 2014 National Diabetes Fact Sheet in the US, 29.1million people (i.e. 9.3% of the population) had diabetes with 8.1million people undiagnosed, and 1.7million new cases of diabetes are diagnosed in people aged 20years and older in 2012.5 Diabetes was the seventh leading cause of death in the US in 2010 based on the 69071 death certificates in which diabetes was listed as the underlying cause of death.5 Diabetes increases the risk of heart disease or stroke by up to four times. The estimated total medical cost for diabetes was 245billion dollars with 176billion dollars as the direct cost in the US in 2012.5 In China, one in four people with diabetes worldwide were in China in 2013, where 11.6% of adults had diabetes and 50.1% had prediabetes.6 In adults, type 2 diabetes mellitus (previously called non-insulin-dependent diabetes mellitus or adult-onset diabetes; T2DM) accounts for about 90–95% of all diagnosed cases of diabetes. T2DM is a chronic endocrine and metabolic disorder characterized by progressive hyperglycaemia secondary to declining β-cell function, and usually accompanied by a reduced sensitivity to insulin in peripheral tissues, such as liver and muscles.1, 3, 7 When β cells are no longer able to secrete sufficient insulin to overcome insulin resistance, impaired glucose tolerance progresses to T2DM. Abnormalities in other hormones such as reduced secretion of the incretin glucagon-like peptide 1 (GLP-1), hyperglucagonemia, and raised concentrations of other counter-regulatory hormones also contribute to insulin resistance, reduced insulin secretion, and hyperglycaemia in T2DM.3, 8 T2DM is associated with older age, obesity, family history of diabetes, history of gestational diabetes, impaired glucose metabolism, physical inactivity, and race/ethnicity.1, 2, 9 Although genetic predisposition establishes susceptibility, rapid changes in the environment (i.e., lifestyle factors) are the most probable explanation for the increase in incidence of both forms of diabetes.1 Key genes, including PPARG, CAPN10, KCNJ11, TCF7L2, HHEXIIDE, KCNQ1, FTO, and MC4R, act in conjunction with environmental factors, including pregnancy, physical inactivity, quality and quantity of nutrients, puberty and ageing, to promote adiposity, impair β-cell function, and impair insulin action.9 The decline in β-cell function seems to involve chronic hyperglycaemia (glucotoxicity), chronic exposure to non-esterified fatty acids (lipotoxicity), oxidative stress, inflammation, and amyloid formation. Insulin is a vital hormone produced by the pancreas that allows blood glucose passage into the body\'s cells, fuelling the body\'s systems. Patients with T2DM usually have pancreatic α-cell dysfunction that results in increased glucagon secretion in the presence of hyperglycaemia and probably reduced prandial GLP-1 secretion.3, 8, 9 Without insulin, excess glucose builds up in the bloodstream that leads to hyperglycaemia, a hallmark metabolic abnormality associated with T2DM. If untreated or not well managed, long term hyperglycaemia can lead to increased risk of macrovasulcar (cardiovascular, cerebrovascular and peripheral vascular diseases) and microvasulcar (nephropathy, neuropathy, and retinopathy) complications.10-12 Being the key factor underlying complications of T2DM, to reduce hyperglycaemia and reach target blood glucose level is a critical goal in T2DM treatment.7, 8, 11-14 Tight glycaemic control, to maintain an HbA1C concentration of ≤7%, is recommended by The American Diabetes Association for T2DM to minimize the risk of long-term vascular complications.15 Despite the need for intensive glucose control, only 57.1% of adults in the US with T2DM reached this target.16 Glycaemic control can be accomplished via different mechanisms either through the promotion of insulin level in the body or an increase in the insulin sensitivity of target cells, or via other glucose metabolism associated pathways. These therapeutic effects can be achieved through insulin sensitisers (e.g. biguanides), insulin secretagogues (e.g. sulfonylureas and meglitinides) and external insulin delivery (insulin analogues).8, 14, 15 These therapies can control the glucose homeostasis, however, they will bring about undesirable side effects such as hypoglycaemia, weight gain, gastrointestinal disturbances, water retention, peripheral oedema, and potential cardiovascular events. Most of the initial improvements in glycaemia by pharmacotherapy are not sustained because of continued β-cell dysfunction. A number of newer compounds with different mechanisms of action have been developed for the treatment of T2DM. These new treatments are expected to sustain glycaemic control, reverse or halt the decline in β-cell function, assist with weight loss, improve insulin action, minimize hypoglycaemia, and have a favourable effect on cardiovascular system. This article aimed to highlight our knowledge on currently clinically approved oral dipeptidyl peptidase 4 (DPP-4) inhibitors used for the treatment of T2DM. The DPP family includes DPP-4, fibroblast activation protein alpha (FAP; seprase), DPP-7 (DPP II; quiescent cell proline dipeptidase), DPP-8, DPP-9, and prolyl carboxypeptidase (PCP; angiotensinase C).17-19 Each of them shows different patterns of distribution, structure and substrate recognition. DPP-4, also known as adenosine deaminase complexing protein 2 (ADCP2), adenosine deaminase binding protein (ADABP), TP103 protein, and T cell activation antigen CD26, is a serine protease that is widely distributed throughout the body, expressed as an ectoenzyme on endothelial cells, on the surface of T lymphocytes, and in a circulating form.20, 21 As a membrane-spanning, cell-surface aminopeptidase, it is ubiquitously expressed in many tissues, such as gut, lymphocytes, liver, kidneys, and lungs. DPP-4 cleaves the two N-terminal amino acids from peptides with a proline or alanine in the penultimate (P1) position. DPP-4 has at least 63 substrates including growth factors, chemokines, neuropeptides, and vasoactive peptides. Chemokines regulated by DPP-4 include but are not limited to: CCL3/MIP-1α, CCL4/MIP-1β, CCL5/RANTES, CCL11/Eotaxin, CXCL9/MIG, CXCL10/IP-10, CXCL11/I-TAC and CXCL12/SDF-1α.22 The non-enzymatic function of DPP-4 plays a critical role in providing co-stimulatory signals to T cells via adenosine deaminase.22 DPP-4 may also regulate inflammatory responses in innate immune cells such as monocytes and dendritic cells. DPP-4 appears to be especially critical for the inactivation of GLP-1 and glucose-dependent insulinotropic polypeptide [also known as gastric inhibitory polypeptide (GIP)].20, 21 The human DPP-4 gene is conserved in chimpanzee, Rhesus monkey, dog, mouse, rat, chicken, zebrafish, fruit fly, mosquito, Caenorhabditis elegans, Saccharomyces cerevisiae, Kluyveromyces lactis, Eremothecium gossypii, Schizosaccharomyces pombe, Magnaporthe oryzae, Neurospora crassa, and frog. It has been mapped to chromosomal 2q24.3 with 26 exons, encoding a 766-amino acid protein.23-25 DPP-4 is a 110-kDa transmembrane glycoprotein constitutively expressed as a dimer on epithelial cells of the liver, hepatocytes, kidney and intestinal tissues, as well as in some endothelial cells, fibroblasts and lymphocytes. It also exists in soluble form lacking the cytoplasmic and transmembrane domain, and is present in different biological fluids such as serum, plasma, and seminal fluid and in low amounts in the cerebrospinal fluid. DPP-4 cleaves N-terminal dipeptides from polypeptides with either l-proline or l-alanine at the penultimate position.22 In many instances, this results in regulation of the substrate, inactivating the ligand activity or altering its function. Glucagon-like peptide 1 and GIP are intestinal incretin hormones released in response to food ingestion.26 GLP-1, secreted from intestinal L cells, is an incretin derived from the transcriptional product of the proglucagon gene. GIP is derived from a 153-amino acid proprotein encoded by the GIP gene and circulates as a biologically active 42-amino acid peptide. It is synthesized by K cells, which are located in the mucosa of the duodenum and the jejunum of the gastrointestinal tract. Both GLP-1 and GIP enhance meal-related insulin secretion and promote glucose tolerance, a phenomenon called ‘incretin effect’.21, 26 Besides insulin secretion enhancement via cAMP-dependent signalling pathways, GLP-1 also suppress glucagon secretion from α-cells in the islets of Langerhans in the pancreas in a glucose-dependent manner, and glucagon secretion is inhibited under hyperglycaemic conditions and even increased under hypoglycaemia. Animal studies indicate that GLP-1 independently promotes the accumulation of glycogen in the liver, increases glucose uptake, and lowers concentrations of triglycerides.27 Moreover, GLP-1 slows gastric emptying and gastrointestinal motility, slowing down the rise of blood glucose level.26 All of which result in a glucose-lowering effect. It also acts as a mediator of satiety in the hypothalamus. In healthy and T2DM patients, these actions are responsible for decreased caloric intake and consecutive weight loss followed by GLP-1 infusions.26 GLP-1 also promotes β-cell regeneration and reduces β-cell apoptosis, which provide hope for preservation of β-cell functions in T2DM patients.26 In patients with T2DM, concentrations of GLP-1 are reduced but the insulin response to GLP-1 is preserved. Continuous infusion of GLP-1 for 6weeks to patients with T2DM increased insulin secretion, reduced HbA1C by 1.3%, and normalized both fasting and post-prandial blood glucose levels without seeing serious adverse effects.28 However, active GLP-1 (GLP-1[7–36]amide) is rapidly degraded by DPP-4. Endogenously released GLP-1 has a short biological half-life of 1.5–5min and the serum half-life of GIP is 5–7min.26 Upon secretion, GLP-1 and GIP are rapidly degraded and inactivated by DPP-4. To extend the half-life, DPP-4-resistant GLP-1 analogues with GLP-1 receptor agonist properties have been developed, including exenatide, liraglutide, lixisenatide, albiglutide, and dulaglutide that have been approved by the Food and Drug Administration (FDA).29-33 On the other hand, DPP-4 inhibitors have been developed and used to prevent degradation of endogenously released GLP-1 and GIP, consequently enhancing plasma level of active incretins in circulation, prolonging the actions of the incretin, consequently leading to increased insulin level.34 In patients with T2DM, the ‘incretin effect’ is reduced, thus scientists have adopted the ‘incretin concept’ in attempts to develop incretin-based therapeutic agents. Dipeptidyl peptidase-4 inhibitors may be classified into peptidomimetic (i.e., sitagliptin, teneligliptin, vildagliptin, saxagliptin, and anagliptin) and non-peptidomimetic (i.e., alogliptin and linagliptin) subtypes (Fig.1, Table1). Due to the substrate site specificity, many DPP-4 inhibitors have substituted pyrrolidines or thiazolidines as a proline mimetic in the P1 part. DPP-4 inhibitors developed initially possess an electrophilic trap such as a nitrile group to form a covalent bond with Ser630 of the catalytic triad in the active site, but these DPP-4 inhibitors possessing the electrophilic trap are unstable and have a low selectivity against other related prolyl peptidases, DPP-8 and DPP-9. The chemical instability is due to intramolecular cyclization between the electrophilic nitrile and the amine of the P2 part, and the poor selectivity is probably due to covalent bond formation with Ser630 which is a conserved amino acid located in the S1 subsite of DPP-4, DPP-8, and DPP-9.35 Inhibition of DPP-8 and DPP-9 are associated with multiorgan toxicities in rats and dogs and inhibition of T cell activation and proliferation,36 a high DPP-4 selectivity is critical for DPP-4 inhibitor development and clinical application. Table 1. Clinical pharmacokinetic and pharmacodynamics properties of selective DPP-4 inhibitors Nasopharyngitis, headache, and upper respiratory tract infection; Rare: acute pancreatitis (0.2%), hypersensitivity (0.6%), hypoglycaemia (1.5%) Headache, nasopharyngitis, upper respiratory tract infections, and urinary tract infections Gastrointestinal adverse events such as diarrhoea and nausea Nasopharyngitis, increased levels of alanine aminotransferase and γ-glutamyltransferase Cmax, maximal concentration; CL, systematic clearance; i.v., intravenous; SC, subcutaneous injection; t½β, elimination half-life. Alogliptin (Nesina); 2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl]methyl)benzonitrile) developed by Takeda Pharmaceuticals (Osaka, Japan), obtained approval by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan in April 2010.37, 38 In January 2013, the FDA of the US approved the drug in three formulations: as a stand-alone, in combination with metformin (Kazano) or with pioglitazone (Oseni). Alogliptin selectively inhibits DPP-4 with an IC50 of 7nmol/L and has exhibited more than 14000-fold selectivity over the related serine proteases DPP-8 and DPP-9.39, 40 It is intended to be used as an adjunct to diet and exercise to improve glycaemic control in adults with T2DM. Alogliptin can be used as monotherapy or in combination with other antidiabetic agents, including metformin, pioglitazone, sulfonylureas, and insulin. Alogliptin is available as a 6.25, 12.5, and 25mg tablet. For detailed clinical pharmacology of alogliptin, please read recent reviews about this drug.38, 41-49 Alogliptin as monotherapy or added to metformin,50-52 pioglitazone,53-56 glipizide,57, 58 glyburide/glibenclamide,59 voglibose,60-62 miglitol,62 acarbose,63 or insulin64, 65 significantly improves glycaemic control compared with placebo or active comparators in adult or elderly patients with inadequately controlled T2DM. This is associated with good gastrointestinal tolerability and a low incidence of hypoglycaemia. Single-dose administration of alogliptin to healthy subjects resulted in a peak inhibition of DPP-4 within 2–3h after dosing. Single doses of alogliptin from 25 to 800mg produced peak DPP-4 inhibition ranging from 93.3% to 98.8%. The mean DPP-4 inhibition ranged from 74.3% to 97% at 24h and from 47.5% to 83% at 72h. Multiple-dose administration of alogliptin to patients with T2DM also resulted in a peak inhibition of DPP-4 within 1–2h and exceeded 93% across all doses (25, 100, and 400mg) after a single dose and after 14days of once-daily dosing. At these doses of alogliptin, inhibition of DPP-4 remained above 81% at 24h after 14days of dosing. Following 14days of once-daily dosing with doses from 25 to 400mg alogliptin, peak DPP-4 inhibition ranged from 94% to 99%, and mean inhibition at 24h after the last dose ranged from 82% to 97%.66 Plasma GLP-1 concentrations were increased two to sixfold in alogliptin-treated subjects.66 A total of 1768 patients with T2DM with inadequate glycaemic control through diet and exercise were randomized to receive alogliptin or placebo in three double-blind Phase II/III studies.53, 67 All three studies had a 4-week, single-blind, placebo run-in period followed by a 26-week treatment period. Patients who failed to meet prespecified hyperglycaemic goals during the 26-week treatment periods received glycaemic rescue therapy. In a 26-week, double-blind, placebo-controlled study, a total of 329 drug-naïve patients with a mean baseline HbA1C of 7.9% were randomized to receive alogliptin 12.5mg, alogliptin 25mg, or placebo once daily.67 Treatment with alogliptin 12.5 and 25mg resulted in significant improvements from baseline HbA1C and fasting plasma glucose (FPG) compared to placebo at week 26. Patients treated with 25mg alogliptin (n=128) had a reduction of −0.6% HbA1C, with 44% of the patients achieving HbA1C≤7.0% at week 26. Significant changes in FPG were seen as early as week 1, and significant changes in HbA1c were observed as early as week 4. A total of 8% of patients receiving alogliptin 25mg and 30% of those receiving placebo required glycaemic rescue therapy. There was no body weight gain observed. In a 26-week, double-blind, active-controlled, parallel-group study, a total of 655 drug-naïve patients with mean baseline HbA1C 8.8% were randomized to receive alogliptin 25mg alone (n=160), pioglitazone 30mg alone (n=153), alogliptin 12.5mg with pioglitazone 30mg (n=184), or alogliptin 25mg with pioglitazone 30mg once daily (n=158).53 Patients treated with 25mg alogliptin alone (n=160) had a reduction of −1.0% HbA1C, with 24% (40/164) of the patients achieving HbA1C≤7.0% at week 26. Combined use of alogliptin 25mg and pioglitazone 30mg once daily resulted in significant reduction in plasma HbA1C (−1.7%) and FPG (−24mg/dL) compared to either monotherapy, with 63% (103/164) achieving HbA1C≤7.0% at week 26.53 The combination therapy was as well tolerated as the monotherapies.53 In the double-blind, placebo-controlled phase of a two-part study, 480 drug-naïve Japanese patients with T2DM inadequately controlled by diet and exercise were randomized to receive alogliptin, placebo, or voglibose (an α-glucosidase inhibitor).68 Patients were first treated with alogliptin 6.25, 12.5, 25 or 50mg once daily, placebo, or voglibose 0.2mg three times daily for 12weeks. In a subsequent open-label, long-term extension phase, patients continued on the same treatment for an additional 40weeks (patients in the placebo group were reassigned equally to one of the four alogliptin dosages). HbA1C was dose-dependently reduced by alogliptin, and the changes versus baseline were statistically significant with all four dosages in comparison with both placebo and voglibose at week 12. In addition, changes in FPG and PPG AUC1–2h values were significantly greater with all four dosages of alogliptin in comparison with placebo.68 The incidence of adverse events with alogliptin over 52weeks was not dose-dependent and was lower than with voglibose. Hypoglycaemia occurred infrequently and was generally mild. Changes in body weight with alogliptin were minimal ( 0.5kg). In a multicentre, randomized, double-blind, placebo-controlled, and 26-week study, 784 patients with T2DM (mean baseline HbA1C=8.4%) were randomized to receive placebo (n=102), metformin 500mg twice daily (n=103), metformin 1000mg twice daily (n=108), alogliptin 12.5mg twice daily (n=104), alogliptin 25mg daily (n=154), alogliptin 12.5mg twice daily with metformin 500mg twice daily (n=102), or alogliptin 12.5mg twice daily with metformin 1000mg twice daily (n=111). Alogliptin 12.5mg twice daily was paired with twice daily metformin immediate release in two treatment arms. Both alogliptin 12.5mg and metformin 500 or 1000mg resulted in statistically significant improvements in HbA1C and FPG control when compared to the monotherapies. The coadministration treatment arms also demonstrated improvements in 2-h postprandial plasma glucose (PPG) and enabled more patients to reach goal HbA1C compared to the monotherapy arms (47 and 59% vs 20–34%). A total of 12.3% of patients receiving alogliptin 12.5mg plus metformin 500mg, 2.6% of patients receiving alogliptin 12.5mg plus metformin 1000mg, 17.3% of patients receiving alogliptin 12.5mg, 22.9% of patients receiving metformin 500mg, 10.8% of patients receiving metformin 1000mg and 38.7% of patients receiving placebo required glycaemic rescue. Two clinical studies have investigated the efficacy and safety of alogliptin as add-on therapy to metformin in 2081 patients with T2DM.50, 55 In both studies, patients were inadequately controlled on metformin at a dose of at least 1500mg per day or at the maximum tolerated dose. All patients entered a 4-week, single-blind, placebo run-in period prior to randomization. Patients who failed to meet pre-specified hyperglycaemic goals during the 26-week treatment periods received glycaemic rescue therapy. The first study evaluated the efficacy and safety of alogliptin for 26weeks at once-daily doses of 12.5 or 25mg in 527 patients with T2DM on metformin (median dose=1700mg) whose HbA1c levels were inadequately controlled on metformin alone.50 Patients were randomized to continue a stable daily metformin dose regimen (≥1500mg) plus placebo (n=104) or alogliptin at once-daily doses of 12.5 (n=213) or 25mg (n=210). Alogliptin at either dose resulted in a significant decrease in HbA1C (−0.6%) and FPG (−17.0mg/dL) than those observed with placebo. The between treatment differences (alogliptin – placebo) in FPG reached statistical significance (P 0.001) as early as week 1 and persisted for the duration of the study. Overall, adverse events observed with alogliptin were not substantially different from those observed with placebo. This included low event rates for gastrointestinal side effects and hypoglycaemic episodes.50 The second 26-week study assessed the efficacy and tolerability of alogliptin plus pioglitazone in 1554 metformin-treated patients on stable-dose metformin monotherapy (≥1500mg/day) with inadequate glycaemic control.55 The doses for alogliptin were 12.5 or 25mg once daily alone or combined with pioglitazone at 15, 30, or 45mg once daily. When added to metformin, the least squares mean change from baseline HbA1C was −0.9% in the pioglitazone-alone group and −1.4% in both the alogliptin 12.5 or 25mg plus pioglitazone groups (P 0.001).55 Alogliptin at 12.5 or 25mg plus pioglitazone produced greater reductions in FPG than pioglitazone alone. In addition, alogliptin at 12.5 or 25mg plus pioglitazone significantly improved β-cell function, but had no effect on insulin resistance. Hypoglycaemia was reported by 1.0, 1.5, and 2.1% of patients in the 12.5mg alogliptin plus pioglitazone, alogliptin 25mg plus pioglitazone, and pioglitazone alone groups, respectively. In a randomized, double-blind, placebo-controlled, 26-week study, T2DM patients (n=784) received placebo, alogliptin 12.5mg twice daily or 25mg once daily, metformin (500 or 1000mg twice daily), or alogliptin 12.5mg twice daily plus metformin 500 or 1000mg twice daily.52 The mean HbA1C reduction from baseline (8.45%) was −1.22% and −1.55% for alogliptin 12.5mg twice daily plus metformin 500mg or 1000 twice daily groups versus −0.56%, −0.65%, and −1.11% for alogliptin 12.5mg, metformin 500mg and 1000mg twice daily groups, respectively (P 0.001). FPG reduction was −1.76 and −2.55mmol/L for alogliptin 12.5mg twice daily plus metformin 500mg or 1000 twice daily groups versus −0.54, −0.64 and −1.78mmol/L for alogliptin 12.5mg, metformin 500mg and 1000mg twice daily groups, respectively (P 0.05).52 Alogliptin plus metformin caused only mild to moderate hypoglycaemia (1.9–5.3%) and weight loss (0.6–1.2kg). These data demonstrate that alogliptin plus metformin initial combination therapy was more efficacious in controlling glycaemia in drug-naïve T2DM patients than either as monotherapy and well tolerated. In a 26-week, placebo-controlled study, a total of 493 patients inadequately controlled on a thiazolidinedione alone or in combination with metformin or a sulfonylurea (10mg) (mean baseline HbA1C=8%) were randomized to receive alogliptin 12.5mg, alogliptin 25mg, or placebo.54 Patients were maintained on a stable dose of pioglitazone (median dose=30mg) during the treatment period; those who were also previously treated on metformin (median dose=2000mg) or sulfonylurea (median dose=10mg) prior to randomization were maintained on the combination therapy during the treatment period. All patients entered into a 4-week single-blind, placebo run-in period prior to randomization. Patients who failed to meet pre-specified hyperglycaemic goals during the 26-week treatment period received glycaemic rescue therapy. The addition of alogliptin 25mg once daily to pioglitazone therapy resulted in statistically significant improvements from baseline in HbA1C and FPG at week 26, compared to placebo.54 A total of 9% of patients who were receiving alogliptin 25mg and 12% of patients receiving placebo required glycaemic rescue. Improvements in HbA1C were not affected by gender, age, baseline body mass index (BMI), or baseline pioglitazone dose. Clinically meaningful reductions in HbA1C were observed with alogliptin compared to placebo regardless of whether subjects were receiving concomitant metformin or sulfonylurea (−0.2% placebo vs −0.9% alogliptin) therapy or pioglitazone alone (0% placebo vs −0.52% alogliptin).54 The mean increase in body weight was similar between alogliptin and placebo when given in combination with pioglitazone. In a randomized, double-blind, placebo-controlled study, 71 patients with well-controlled T2DM (mean HbA1C 6.7%) were treated with combined alogliptin 25mg and pioglitazone 30mg daily or alogliptin 25mg daily monotherapy or placebo for 16weeks.56 Main outcome measures included change in HbA1C and FPG from baseline to week 16. In addition, change in β-cell function parameters obtained from standardized meal tests at baseline and at week 16 was measured. Alogliptin plus pioglitazone and alogliptin decreased HbA1C from baseline by 0.9 and 0.4%, respectively (both P 0.001 vs placebo).56 FPG was decreased to a greater extent by alogliptin plus pioglitazone compared with alogliptin alone (P 0.01). The combination treatment also improved β-cell glucose sensitivity (P 0.001; vs placebo) and fasting secretory tone (P=0.001; vs placebo), while alogliptin monotherapy did not change β-cell function. All treatments were well tolerated. In a 52-week, active-comparator study, a total of 803 patients inadequately controlled (mean baseline HbA1C=8.2%) on a current regimen of pioglitazone 30mg and metformin at least 1500mg per day or at the maximum tolerated dose were randomized to receive either the addition of alogliptin 25mg or the titration of pioglitazone 30–45mg following a 4-week single-blind, placebo run-in period.51 Patients were maintained on a stable dose of metformin (median dose=1700mg). Patients who failed to meet prespecified hyperglycaemic goals during the 52-week treatment period received glycaemic rescue therapy. In combination with pioglitazone and metformin, alogliptin 25mg was shown to be statistically superior in lowering HbA1C and FPG compared with the titration of pioglitazone from 30mg to 45mg at week 26 and week 52.51 A total of 11% of patients in the alogliptin 25mg treatment group and 22% of patients in the pioglitazone up titration group required glycaemic rescue. There was no body weight gain in both treatment arms. In a randomized, placebo-controlled study, 500 T2DM patients inadequately controlled on a sulfonylurea (mean baseline HbA1C=8.1%) were randomized to receive alogliptin 12.5mg, alogliptin 25mg, or placebo for 26weeks.59 Patients were maintained on a stable dose of glyburide (median dose=10mg) during the treatment period. All patients entered into a 4-week single-blind, placebo run-in period prior to randomization. Patients who failed to meet pre-specified hyperglycaemic goals during the 26-week treatment period received glycaemic rescue therapy. The addition of alogliptin 25mg to glyburide therapy resulted in statistically significant improvements from baseline in HbA1C at week 26 when compared to placebo.59 Improvements in FPG observed with alogliptin 25mg were not statistically significant compared with placebo. A total of 16% of patients receiving alogliptin 25mg and 28% of those receiving placebo required glycaemic rescue. No body weight gain was observed in all treatment groups. Combination treatment with alogliptin and voglibose for 3weeks increased active GLP-1 circulation, prevented the development of diabetes and preserved pancreatic β-cells in prediabetic db/db mice.69 In a randomized, double-blind study, the efficacy and safety of alogliptin and placebo as add-on therapy were explored in Japanese patients with T2DM who experienced inadequate glycaemic control on voglibose plus diet/exercise therapy.60 During an 8week screening phase, patients aged ≥20years were stabilized on voglibose 0.2mg three times daily plus diet/exercise therapy. Those with HbA1C between ≥6.9% and 10.4% were randomly assigned to treatment with once daily alogliptin 12.5 or 25mg, or placebo for 12weeks. Patients then entered an open-label, 40week extension trial (patients in the placebo group were randomly allocated to alogliptin 12.5 or 25mg). The mean change in HbA1C at week 12 from baseline was significantly greater in the alogliptin 12.5mg (−0.96%) and 25mg (−0.93%) groups compared with placebo.60 This was associated with statistically reduced FPS and PPS. These benefits were maintained for the duration of the 1year study without detrimental effects on tolerability/safety. Addition of once daily alogliptin to voglibose monotherapy in Japanese patients with uncontrolled T2Dm produced clinically significant improvements in glycaemic control, and was well tolerated. In a 26-week, placebo-controlled study, a total of 390 patients inadequately controlled on insulin alone (42%) or in combination with metformin (58%) (mean baseline HbA1C=9.3%) were randomized to receive alogliptin 12.5mg, alogliptin 25mg, or placebo.64 Patients were maintained on their insulin regimen (median dose=55IU) upon randomization and those previously treated with insulin in combination with metformin (median dose=1700mg) prior to randomization continued on the combination regimen during the treatment period. Patients entered the trial on short-, intermediate- or long-acting (basal) insulin or premixed insulin. Patients who failed to meet pre-specified hyperglycaemic goals during the 26month treatment period received glycaemic rescue therapy. The addition of alogliptin 25mg once daily to insulin therapy resulted in statistically significant improvements from baseline in HbA1C and FPG at week 26, when compared to placebo.64 A total of 20% of patients receiving alogliptin 25mg and 40% of those receiving placebo required glycaemic rescue. Improvements in HbA1C were not affected by gender, age, baseline BMI, or baseline insulin dose. Clinically meaningful reductions in HbA1C were observed with alogliptin compared to placebo regardless of whether subjects were receiving concomitant metformin and insulin (−0.2% placebo vs −0.8% alogliptin) therapy or insulin alone (0.1% placebo vs −0.7% alogliptin).64 A pooled analysis of six randomized, double-blind, placebo-controlled Phase II/III studies reviewed patients aged 18–80.70 A total of 455 patients were ≥65years of age. The pooled analysis showed that changes in HbA1C were similar between younger and elderly patients taking alogliptin 25mg daily (−0.6% younger and −0.8% elderly). The changes in HbA1C and FPG, although slightly improved in the elderly when compared to the younger, were not statistically significant.70 The percentage of elderly patients achieving goal HbA1C of ≤7% was slightly improved over the younger patient but not statistically significant. Regardless of age, patients with a baseline HbA1C of 8% had larger absolute decreases in HbA1C than those patients with a baseline HbA1C 8.0%. The incidence of hypoglycaemia was 8.3% or less in both alogliptin groups for both age groups and did not seem to be dose related.70 The majority of patients experiencing hypoglycaemia were also taking a sulfonylurea or insulin. In this pooled analysis, alogliptin 12.5mg and 25mg were similarly efficacious in younger and elderly patients. Moreover, there was no increased risk of hypoglycaemia or other adverse events in elderly patients taking alogliptin. After administration of single, oral doses up to 800mg in healthy subjects or patients with T2DM, the peak plasma alogliptin concentration (Cmax) occurred 1–2h postdosing.39, 40, 71 The area under the plasma concentration-time curve (AUC) increases in a dose-dependent manner over a range of doses from 25 to 800mg.66 The absolute bioavailability of alogliptin is approximately 100%.72 Alogliptin is 20% bound to plasma proteins. At the maximum recommended clinical dose of 25mg, alogliptin was eliminated with an elimination half-life (t½β) of about 21h.39, 40 The systemic clearance is 233mL/min (i.e. 14.0L/h), with a renal clearance of 160mL/min (i.e. 9.6L/h), indicating some active renal tubular secretion. Following a single, 12.5mg intravenous infusion of alogliptin to healthy subjects, the volume of distribution (Vd) was 417L. After multiple-dose administration up to 400mg for 14days in patients with T2DM, accumulation of alogliptin was minimal with an increase in AUC and Cmax of alogliptin by 34% and 9%, respectively. The inter-individual coefficient of variation for alogliptin AUC was 17%. The pharmacokinetics of alogliptin was shown to be similar in healthy subjects and in patients with T2DM. Alogliptin exists predominantly as the (R)-enantiomer ( 99%) and undergoes little or no chiral conversion invivo to the (S)-enantiomer. The (S)-enantiomer is not detectable at the 25mg dose. About 10% of alogliptin is metabolized and 60–71% of the dose is excreted as unchanged drug in the urine within 24–72h.39 Two minor metabolites were detected following administration of an oral dose of [14C]-alogliptin, N-demethylated, M-I ( 1% of the dose), and N-acetylated alogliptin, M-II ( 6% of the dose).72 M-I is an active metabolite that inhibits DPP-4 similar to the parent molecule, but M-II is inactive. Alogliptin is mainly metabolized by CYP2D6 and 3A4.71, 73 Alogliptin is mainly cleared renally. However, dose adjustment for patients with mild renal impairment (creatinine clearance≥60mL/min) is not recommended.74 In patients with moderate renal impairment (creatinine clearance≥30 to 60mL/min), a 2.1-fold increase in plasma AUC of alogliptin was observed, and the recommended dose is 12.5mg once daily.74 In patients with severe renal impairment (creatinine clearance≥15 to 30mL/min) and end-stage renal disease (creatinine clearance 15mL/min or requiring dialysis), a 3.2- to 3.8-fold increase in plasma AUC of alogliptin were observed, and the recommended dose is 6.25mg once daily.74 The Cmax of alogliptin was increased 1.1- to 1.4-fold. Metabolite exposure remained low in all subjects. Approximately 7.2% (3.6mg) of a 50-mg oral dose was removed after 3h of hemodialysis.74 The AUC of alogliptin was about 10% lower and Cmax was approximately 8% lower in patients with moderate hepatic impairment (Child-Pugh Grade B) compared to healthy subjects.71, 75 Alogliptin pharmacokinetics were not significantly altered in subjects with mild to moderate hepatic impairment. Age did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Race (white, black, and Asian) did not have any clinically meaningful effect on the pharmacokinetics of alogliptin. Approximately 8500 patients with T2DM have been treated with alogliptin in 14 randomized, double-blind, controlled clinical studies with approximately 2900 subjects randomized to placebo and approximately 2200 to an active comparator.50, 54, 58, 59, 64, 76 The mean exposure to alogliptin was 40weeks with more than 2400 subjects treated for more than 1year. Among these patients, 63% had a history of hypertension, 51% had a history of dyslipidemia, 25% had a history of myocardial infarction, 8% had a history of unstable angina, and 7% had a history of congestive heart failure. The mean duration of T2DM was 7years, the mean BMI was 31kg/m² (51% of patients had a BMI≥30kg/m²), and the mean age was 57years (24% of patients≥65years of age). Two placebo-controlled monotherapy trials of 12 and 26weeks of duration were conducted in patients treated with alogliptin 12.5mg daily, alogliptin 25mg daily and placebo. Four placebo-controlled add-on combination therapy trials of 26weeks duration were also conducted: with metformin, with a sulfonylurea, with a thiazolidinedione, and with insulin. Five placebo-controlled trials of 16weeks up through 2years in duration were conducted in combination with metformin, in combination with pioglitazone and with pioglitazone added to a background of metformin therapy. Three active-controlled trials of 52weeks in duration were conducted in patients treated with pioglitazone and metformin, in combination with metformin and as monotherapy compared to glipizide.51, 58 In a pooled analysis of these 14 controlled clinical trials, the overall incidence of adverse events was 66% in patients treated with alogliptin 25mg compared to 62% with placebo and 70% with active comparator. Overall discontinuation of therapy due to adverse events was 4.7% with alogliptin 25mg compared to 4.5% with placebo or 6.2% with active comparator. More than 4% of 5902 patients taking 25mg alogliptin from 14 randomized, double-blind, controlled clinical trials experience mild adverse reactions including nasopharyngitis (4.4%), headache (4.2%), and upper respiratory tract infection (4.2%). Hypoglycaemia is seen in about 1.5% of the patients. In the 26-week monotherapy study, the incidence of hypoglycaemia was 1.5% in patients treated with 12.5 or 25mg alogliptin daily (n=264) compared to 1.6% with placebo (n=65).67 The 26-week use of alogliptin as add-on therapy to glyburide (9.6% vs 11.1%) or insulin (27% vs 24%) did not significantly increase the incidence of hypoglycaemia compared to placebo.59, 64 In a 52-week monotherapy study comparing alogliptin to a sulfonylurea in elderly patients, the incidence of hypoglycaemia was 5.4% (22/222) with alogliptin compared to 26% with glipizide (57/219).58 Rare but severe adverse reactions such as acute pancreatitis, serious hypersensitivity including anaphylaxis, angioedema, and severe cutaneous reactions such as Stevens–Johnson syndrome have been reported from postmarketing monitoring.41-46, 66 The overall incidence of hypersensitivity reactions was 0.6% in patients taking alogliptin 25mg compared to 0.8% with all comparators including glipizide, glyburide, insulin, metformin, pioglitazone, and placebo. In the clinical trial program, pancreatitis was reported in 11 of 5902 (0.2%) patients receiving alogliptin 25mg daily compared to five of 5183 ( 0.1%) patients receiving all comparators. In a pooled analysis, the overall incidence of hypersensitivity reactions was 0.6% with alogliptin 25mg compared to 0.8% with all comparators. A single event of serum sickness was reported in a patient treated with alogliptin 25mg. Treatment of T2DM patients with alogliptin at 50 or 400mg for 7days does not prolong QTc. White etal.77 have conducted a pooled analysis and concluded that the incidence rate of adverse cardiovascular (CV) events in patients treated with 12.5 or 25mg alogliptin daily is rare. The composite major adverse cardiovascular event (MACE) end points included CV death, nonfatal myocardial infarction, and nonfatal stroke. The pooled analysis included 4168 patients treated with alogliptin compared to 691 patients treated with placebo and 1169 patients treated with other antidiabetic agents such as metformin, sulfonylureas and thiazolidinediones with a duration of 16–52weeks. A total of 13 MACEs were seen in the 4168 patients randomized to alogliptin and 10 MACEs in 1860 patients randomized to comparator therapies.77 The incidence rates of the combined MACE were not significantly different between patients treated with alogliptin and comparator therapies. A total of 10 non-MACEs occurred in the 4168 patients randomized to alogliptin and three non-MACEs in 1855 patients randomized to comparator therapies. The CV events (MACE and non-MACE) were distributed similarly between event types. These analyses do not show a signal of increased CV risk with alogliptin. The long-term CV safety of alogliptin was evaluated in a recent randomized, placebo-controlled, noninferiority trial, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE), involving 5380 patients with T2DM and a recent acute coronary syndrome (ACS).78 The primary end point included a composite of CV death, nonfatal myocardial infarction, or nonfatal stroke. Patients were followed for up to 40months. The primary end point occurred in 305 (11.3%) patients taking alogliptin and in 316 (11.8%) patients taking placebo (hazard ratio, 0.96; upper boundary of the one-sided repeated confidence interval, 1.16; P 0.001 for noninferiority). EXAMINE concludes that among patients with type 2 diabetes who have had a recent ACS, the rates of major adverse CV events are not increased with alogliptin when compared to placebo. Alogliptin is not an inducer or inhibitor of human CYP1A2, CYP2B6, CYP2C9, CYP2C19, and CYP3A4. Clinically relevant interactions have not been observed with the CYP substrates or inhibitors tested or with renally excreted drugs including caffeine (CYP1A2 substrate), tolbutamide (CYP2C9 substrate), dextromethorphan (CYP2D6 substrate), midazolam or atorvastatin (CYP3A4 substrates), and digoxin and fexofenadine (P-gp/MDR1 substrates). Alogliptin pharmacokinetics were not altered by administration with a potent CYP2C9 inhibitor (fluconazole), CYP3A4 inhibitor (ketoconazole), or CYP2C8/9 inhibitor (gemfibrozil).73 Pharmacokinetic interactions have also not been observed between alogliptin and glyburide, metformin, or pioglitazone.76 Alogliptin did not have a significant effect on the pharmacokinetics or pharmacodynamics (prothrombin time or international normalized ratio) of warfarin with coadministration.73 When used in conjunction with alogliptin, a reduced dose of insulin or insulin secretagogues, such as sulfonylureas, may be required to minimize the risk of hypoglycaemia. Anagliptin (Suiny); N-[2-[[2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl]amino]-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide) was developed by Sanwa Kagaku Kenkyusho Co. (Mie, Japan) and approved by the PMDA of Japan in September 2012. It is indicated for the treatment of T2DM patients given orally at 100mg once daily. It is a highly selective and potent inhibitor for DPP-4, with an IC50 of 3.4nmol/L.79, 80 Anagliptin improved glycaemic control in T2DM patients with a minimal risk of hypoglycaemia and weight gain. The pharmacokinetics of anagliptin has been investigated after a single oral dose of 100mg [14C]anagliptin to healthy men (n=6).81 Almost all the dose (98.2%) was recovered within 168h, with 73.2% in urine and 25.0% in faeces. Anagliptin was rapidly absorbed, with peak plasma concentrations of unchanged drug achieved at a mean time of 1.8h postdose. Mean fraction of the dose absorbed was 73%. Unchanged drug and a carboxylate metabolite (M1) were the major components detected in plasma, accounting for 66.0 and 23.4% of total plasma radioactivity AUC, respectively.81 Anagliptin was partially metabolized, with approximately 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. The t1/2β of anagliptin and M1 was 4.37 and 9.88h, respectively. Renal clearance of unbound anagliptin and M1 far exceeded glomerular filtration rate, indicating transporter-mediated active renal elimination.81 Two phase III trials to evaluate the efficacy and safety of anagliptin in drug-naïve T2DM patients and compare the efficacy and safety of anagliptin as an add-on to metformin in T2DM patients have shown that the use of anagliptin in patients with T2DM is considered to be safe and effective for both monotherapy and combination therapy.82-84 Gemigliptin tartrate sesquihydrate (Zemiglo); previously known as LC15-0444; (3S)-3-amino-4-(5,5-difluoro-2-oxopiperidino)-1-[2,4-di(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]butan-1-one) was co-developed by LG Life Science (Seoul, Korea) and Double-Crane Pharmaceutical Co. (Beijing, China). It gained approval from Korea Food & Drug Administration in June 2012, indicated for T2DM as a monotherapy or in combination with metformin.85 Gemigliptin is a potent, competitive, reversible, long-acting DPP-4 inhibitor (IC50=16nmol/L) with over 3000-fold selectivity over other DPP-2, DPP-8, DPP-9, elastase, trypsin, urokinase, and cathepsin G.85 Gemigliptin resulted in a dose-dependent inhibition of plasma DPP-4 activity and ~80% inhibition of plasma DPP-4 activity were observed at the plasma gemigliptin levels of 9, 7, and 2ng/mL in rats, dogs and monkeys, respectively, with better invivo potency compared to sitagliptin. In healthy subjects, a single oral dose of ≥200mg of gemigliptin inhibited plasma DPP-4 activity by 80% over a 24-h dosing interval, and a 600-mg dose increased active GLP-1 levels after a standardized meal.86 Similar DPP-4 inhibition was observed when healthy volunteers were treated with multiple doses of gemigliptin at 200, 400, and 600mg once daily for 10days.87 Inhibition of DPP-4 activity by 80% was maintained for the whole duration of the dosing interval after the first dose, for at least 36h after the last dose, and for 48h in the 600-mg group.87 Multiple doses of gemigliptin produced 1.8–2.8-fold increases in weighted active GLP-1 levels after meals, compared with placebo, at 4, 10 and 24h after administration. Multiple doses of gemigliptin generally decreased the PPG levels, and there was a statistically significant decrease in glucose at 10h after dosing on day 10, but had no remarkable effect on insulin levels.87 In a multicentre, randomized, placebo-controlled, double-blind Phase II trial in 145 drug-naïve patients with T2DM treated by diet and exercise, the optimal dose, efficacy and safety of gemigliptin were evaluated.88 The median baseline FPG was 8.1mmol/L, and the median HbA1C was 7.9% and the median time since the diagnosis of T2DM was 3years. After 2weeks of an exercise/diet program followed by 2weeks of a placebo period, the subjects were randomized to one of the four following groups for a 12-week active treatment period: placebo and 50, 100 or 200mg of gemigliptin.88 All three doses of gemigliptin significantly reduced the HbA1C from baseline compared to the placebo group (−0.06 vs −0.98, −0.74 and −0.78% in the placebo and 50, 100 and 200mg groups, respectively), without a significant difference between the doses. Subjects with a higher baseline HbA1C (≥8.5%) had a greater reduction in HbA1C. Insulin secretory function improved significantly with gemigliptin treatment.88 Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12weeks of treatment. The 50 and 200mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12weeks compared to the placebo group. No body weight gain was observed. The incidences of adverse events were similar and not different from placebo in all study subjects. This study showed that gemigliptin 50mg for 12weeks improved the HbA1C, FPG level, oral glucose tolerance test results, β-cell function and insulin sensitivity in T2DM patients. Based on the results from this Phase II trial, the daily dose of 50mg gemigliptin was selected for the next Phase III studies. Next, a 24-week, randomized, double-blind, placebo-controlled Phase III trial was conducted in 182 patients (74 from Korea and 108 from India) with T2DM.89 After an initial 2weeks of a diet and exercise program followed by 2weeks of a single-blind placebo run-in period, eligible patients were randomized to gemigliptin 50mg or placebo, receiving the assigned treatment for 24weeks. HbA1C and FPG were measured periodically, and oral glucose tolerance test was performed at baseline and weeks 12 and 24. At week 24, gemigliptin treatment led to significant reductions in HbA1c compared to placebo (adjust mean after subtracting the placebo effect size: −0.71%).89 A significantly greater proportion of patients achieved an HbA1C 7% with gemigliptin than with placebo (43% vs 18%). The placebo-subtracted FPG change from baseline at week 24 was −19.80mg/dL. The overall incidence rates for adverse events were similar in the gemigliptin and placebo groups.89 This study showed the efficacy and safety of gemigliptin 50mg administered once daily as a monotherapy for T2DM patients. The efficacy of gemigliptin as an add-on therapy was evaluated in a 24-week, multinational, active-controlled, parallel group, double-blind Phase III study in patients with T2DM inadequately controlled with metformin alone.90 In this add-on therapy trial, the efficacy of gemigliptin was compared with sitagliptin as head to head trial. A total of 425 patients were randomized into one of three treatments: 50mg gemigliptin once daily, 25mg gemigliptin twice daily, or 100mg sitagliptin once daily as add-on to on-going metformin therapy. At week 24, both gemigliptin treatments of 50mg once daily and 25mg twice daily reduced HbA1C by 0.81 and 0.77%, respectively, which were non-inferior to 0.80% with 100mg sitagliptin once daily.90 The proportion of patients achieving HbA1C 7% with gemigliptin 25mg twice daily (50%) or 50mg once daily (54%) was comparable to the results with sitagliptin 100mg once daily (49%). There were significant decreases in FPG and PPG, improvements in glucose tolerance during OGTT, and increases in GLP-1 and β-cell sensitivity to glucose in patients receiving gemigliptin treatment with their metformin therapy.90 There was no increased risk of adverse effects with gemigliptin compared to sitagliptin 100mg once daily. In a Phase I single-dose study with 60 healthy male subjects, gemigliptin was readily absorbed after single oral dosing with median Tmax occurring at 2.0h (0.5–5.1h) post-dose and its mean t1/2β was 16.7–21.3h at all dose levels from 25 to 600mg daily.86 Gemigliptin exhibited linear kinetic properties over the range of 50–400mg. The mean fraction of unchanged drug excreted in urine ranged from 0.21 to 0.34 and mean renal clearance was 15.5–23.6L/h.86 Pharmacokinetic profiles of gemigliptin were not significantly influenced by high-fat diet. The pharmacokinetics of gemigliptin were examined after multiple oral doses at 200, 400 and 600mg once daily for 10days in 30 healthy non-smoking Korean male subjects in a randomized, double-blind, placebo-controlled, parallel group study.87 Gemigliptin was readily absorbed during multiple oral dosing, reaching maximum plasma levels (Tmax) at 1.0–5.0h after dosing and apparently achieving a steady state after the second dose. The mean t1/2β was 16.6–20.1h across the dose groups. The mean CL/F by dose groups ranged from 43.0 to 52.7L/h under steady state conditions. The AUC during the dosing interval generally increased in proportion to the dose over the dose range studied. The mean accumulation ratios were between 1.22 and 1.31 among the dose groups.87 The mean renal clearance and fraction of unchanged drug excreted in urine was independent of dose in the range of 0.40–0.48L/h and 18.6–21.9L/h at steady state, respectively.87 No dose- or time-dependent change in CL/F or renal CL of gemigliptin was observed. These data demonstrate that the pharmacokinetics of gemigliptin are linear from 200 to 600mg. Following oral administration of 50mg (5.4MBq) 14C-gemigliptin to healthy male subjects, its absorption, metabolism and excretion were investigated.91 A total of 90.5% of administered dose was recovered over 192h postdose, with 63.4% from urine and 27.1% from faeces. Based on urinary recovery of radioactivity, a minimum 63.4% absorption from gastrointestinal tract could be confirmed. Twenty-three metabolites were identified in plasma, urine and faeces. In plasma, gemigliptin was the most abundant component, accounting for 67.2% (approximately 100% of plasma radioactivity). LC15-0636, a hydroxylated metabolite of gemigliptin, was the only human metabolite with systemic exposure more than 10% of total drug-related exposure.91 Unchanged gemigliptin accounted for 44.8% (approximately 67.2% of urinary radioactivity) and 27.7% (approximately 51.8% of faecal radioactivity). The elimination of gemigliptin was balanced between metabolism and excretion through urine and faeces. CYP3A4 was identified as the dominant CYP converting gemigliptin to LC15-0636 in recombinant CYP enzymes.91 In an open-label, randomized, single dose, two-period, two-sequence crossover study in 24 healthy male volunteers, the effect of food on the pharmacokinetics of gemigliptin/metformin sustained-release 50/1000mg (25/500mg×two tablets) fixed dose combination tablet was investigated.92 The gemigliptin/metformin sustained-release tablets (25/500mg×two tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. Pharmacokinetic blood samplings were conducted from predose to 48h after dosing. Tolerability assessments were performed throughout the study. Nine adverse events of mild intensity were reported from eight subjects after study drug administration, and the adverse event frequency was similar between treatment groups.92 No serious adverse effects were reported. The pharmacokinetic parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (fed vs fasted state) of the Cmax and AUC were 0.886 and 1.021, respectively.92 For metformin, the geometric mean ratios of the Cmax and AUC were 0.811 and 1.144, respectively. A prolonged Tmax for metformin was observed. These results are similar to the effects of food on each component. The gemigliptin/metformin sustained-release fixed dose tablet may have a similar pharmacokinetic profile as that of individual drugs and is generally tolerable when administered with food. In early Phase I clinical trials, gemigliptin was well tolerated: in both a single ascending dose study from 25mg to 600mg86 and a multiple ascending dose study from 200 mg to 600mg87 in healthy Korean male subjects. In both the single and multiple ascending dose studies, none of the subjects developed any serious clinical or laboratory adverse events or discontinued the study due to an adverse event.86, 87 All adverse events were mild or moderate, and no dose-related trends were observed. In the single ascending dose study, 46 adverse events were reported in 18 subjects (30.0%).86 Adverse events considered to be related to the study drug were headache (six cases), dizziness (two), nausea (three), epistaxis (four), and increased heart rate (five). All adverse events resolved spontaneously.86 In the multiple ascending dose study, 13 of the 30 subjects (43.3%) reported a total of 26 adverse events.87 Of these adverse events, a total of 14 (11 in the gemigliptin group and three in the placebo group) were considered to be possibly related to the study drug. Adverse events considered to be related to the study drug were headache and dizziness (three cases each), somnolence, dyspepsia, aphthous stomatitis, rash morbilliform, hyperthermia, pyrexia, palpitations and increased heart rate (a single case each).87 All adverse events resolved spontaneously without any concomitant medication. In both clinical studies, there were no reports of hypoglycaemic symptoms or signs, or of any significant abnormalities on clinical laboratory tests, 12-lead electrocardiogram, or impedance cardiography. This drug was well tolerated in T2DM patients and the tolerability profiles of gemigliptin were similar to placebo in Phase II and III trials.88-90 In vitro studies suggested that gemigliptin had no significant inhibition or induction potential of major human CYPs and P-gp, whilst gemigliptin was a substrate of both CYP3A4 and P-gp.85 Co-administration of a single dose of gemigliptin 50mg and multiple once daily doses of ketoconazole 400mg, a potent inhibitor of CYP3A4 and P-gp, increased the total active moiety by 1.94-fold. Calculation of total active moiety was based on both the systemic exposure and relative activities of gemigliptin and active metabolite. Rifampin (600mg once daily at steady state), a strong inducer of CYP3A4 and P-gp, significantly decreased the total active moiety by 70%. These CYP3A-based studies suggested no need of gemigliptin dose adjustment with CYP3A4 inhibitors but efficacy of gemigliptin may be reduced with several CYP3A4 inducers including rifampin, rifabutin, rifapentin, dexamethasone, phenytoin, carbamazepine, and phenobarbital in humans.93 Co-administration of multiple once daily doses of gemigliptin 200mg and pioglitazone 30mg decreased the plasma Cmax and AUC of pioglitazone by 16% and 15%, respectively, while it caused no alteration in the pharmacokinetics of gemigliptin.94 Linagliptin (Tradjenta & Trajenta); previously called BI-1356; 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-3,7-dihydro-1H-purine-2,6-dione) was approved by the FDA in May 2011. It is used as a monotherapy or in combination with metformin (Jenadueto). The chemical structure of linagliptin has a xanthine base, differing from other DPP-4 inhibitors, and may reflect differences in pharmacokinetic and pharmacodynamic properties.95 For the clinical pharmacology of linagliptin, please read recent reviews.95-123 Linagliptin is highly potent, selective, long-acting, and orally bioavailable inhibitor for DPP-4, but not for DPP-8 (40000-fold) or DPP-9 ( 10000-fold) activity invitro, with a relatively low selectivity for FAP-α (89-fold).124 It is a competitive, selective and reversible inhibitor for DPP-4 with a Ki of 1nmol/L, indicating strong binding, and a low dissociation rate of the enzyme. The maximal efficacy for invitro DPP-4 inhibition is similar among all DPP-4 inhibitors, however, linagliptin has greater potency than other DPP-4 inhibitors (IC50=~1nmol/L for linagliptin vs 19, 62, 50 and 24nmol/L for sitagliptin, vildagliptin, saxagliptin and alogliptin, respectively).95 In healthy male volunteers, linagliptin at 2.5–600mg demonstrated dose-dependent inhibition of DPP-4 over 24h with a 5mg dose inhibiting 86.1% of the enzyme activity.125 Early clinical studies with linagliptin suggested a reduction in the HbA1C levels in patients with T2DM while maintaining a placebo-like safety and tolerability profile.126 The efficacy of linagliptin as monotherapy, compared to placebo, was assessed in two studies of 12 and 24weeks.127, 128 The linagliptin was significantly more effective than placebo in reducing HbA1C. Also independent of baseline HbA1C, the results were favourable for linagliptin; for baseline HbA1C≥9.0%, 8.0% to 9.0%, 7.5% to 8.0% and 7.5%, the respective placebo-adjusted mean changes were −1.1% (P 0.0001), −0.71% (P 0.0001), −0.55% (P 0.005) and −0.57.127 The results of linagliptin monotherapy were also better than placebo in the secondary endpoints. There was more reduction in FPG and 2-h PPG in the linagliptin group. The adjusted mean change in FPG was −1.3mmol/L (P 0.0001), and in 2-h PPG was −3.2mmol/L (P 0.0001). The percentage of patients with HbA1C 7% after 24weeks was 25.2% (77/306) in the linagliptin group compared to 11.6% (17/147) in the placebo group (OR=2.9, P=0.0006).128 Besides, there was significant improvement in β-cell function markers in those receiving linagliptin.127, 128 Kawamori etal.127 also compared linagliptin monotherapy with voglibose, an α-glucosidase inhibitor, in a 26-week study. More patients receiving linagliptin achieved HbA1C≤7% (30.3%) when compared to voglibose (22.2%). The percentage of patients achieving a reduction ≥0.5% in HbA1C with linagliptin (57.2%) was also greater than those with voglibose (37.7%) (P 0.0001). Graefe-Mody etal.129 evaluated in a randomized, open-label, crossover, single-centre study, the potential pharmacokinetic and pharmacodynamic interaction between metformin and linagliptin. The coadministration of metformin 850mg, three times daily and linagliptin (10mg once daily) did not modify the pharmacological profile of each drug alone. This study suggested that the combination of metformin and linagliptin can be done safely in patients with T2DM, without requiring dose adjustment. In a 24-week study with about 700 patients, the addition of linagliptin to the therapeutic regimen in diabetic patients inadequately controlled on metformin, HbA1C reduction from baseline was 0.64% with the linagliptin versus placebo.130 Haak115 reported the findings of early combination of linagliptin and metformin in treatment-naïve diabetic patients, in a 24-week double-blind study. Compared to metformin monotherapy (1000mg), the early combination of metformin (1000mg) and linagliptin (5mg) was more effective in reducing HbA1C (−1.7% vs −0.8%, P 0.0001). Substantial reduction in FPG from baseline to Week 24 was found with the combination therapy.115 The adjusted mean reduction in FPG was 1.2mmol/L in the group with added linagliptin, and in 2-h PPG was 3.7mmol/L (P 0.0001 for all comparisons).115 In a 12-week study, linagliptin 5mg (single daily dose) was added to the metformin treatment (n=333 patients), and was significantly more effective than placebo and the 1-mg or 10-mg doses.131 In a 12-week analysis, 333 T2DM patients inadequately controlled on metformin monotherapy were randomized to receive linagliptin or glimepiride, in a single daily dose.132 After 12weeks, HbA1C has decreased both in the linagliptin or glimepiride groups. This study showed that linagliptin has the same efficacy as sulfonylureas, without risk of weight gain and hypoglycaemia. Linagliptin was also evaluated in combination with pioglitazone, in a 24-week investigation (n=389 patients).133 The addition of linagliptin (5mg) to pioglitazone (30mg), both administered in a single daily dose, caused an adjusted mean placebo-corrected reduction of 0.5% in HbA1C levels from baseline at the end of 12weeks, remaining constant until the 24th week. The group receiving the linagliptin/pioglitazone combination showed more significant reductions in FPG than placebo/pioglitazone group (P 0.0001). More patients in the linagliptin/pioglitazone group (42.9%) achieved the target HbA1C 7%, compared to the placebo-pioglitazone group (30.5%, P 0.0051). The HbA1C reduction was greater in patients with baseline HbA1C≥9% and treated with linagliptin in combination with pioglitazone (−1.49%).133 Body weight remained stable up to 24weeks in the two groups. This combination can be interesting, even for early therapy in patients with an intolerance or contraindication to metformin. In patients inadequately controlled on sulfonylurea alone, the addition of linagliptin 5mg (single daily dose) proved more effective than the combination with placebo.132 In this double-blind study, 245 patients were randomized to receive linagliptin (n=161) or placebo (n=84) for 18weeks.134 The HbA1c reductions were significant in favour of linagliptin at weeks 6, 12 and 18 (P 0.0001). In a randomized, double-blind, placebo-controlled study, investigators have screened 1058 T2DM patients inadequately controlled on metformin ( 1500mg/day) and sulfonylurea (maximum tolerated dose) to receive the combination with linagliptin 5mg (single daily dose) or placebo.135 Assessing the total patients included, the adjusted mean change in HbA1C level was −0.72% in the linagliptin group compared with −0.10% in the placebo group, resulting in a difference of −0.62% (P 0.0001) with placebo. Fewer patients receiving linagliptin required rescue therapy compared with placebo (5.4% vs 13.0%). More patients on linagliptin also achieved the target HbA1C. The importance of this study in practice is the possibility to improve glycaemic control in patients already receiving two oral antidiabetic agents and who are outside the proposed targets. Linagliptin shows modest oral bioavailability, but is rapidly absorbed. The absolute bioavailability of linagliptin is around 30%. Following oral administration, the majority (about 90%) of linagliptin is excreted unchanged. After oral administration of a single 5-mg dose to healthy subjects, peak plasma concentrations of linagliptin occurred at approximately 1.5h postdose; the mean AUC was 139nmol/h per L and Cmax was 8.9nmol/L. The Cmax at steady state was reached on average 1.5h after administration of linagliptin 5mg once daily in T2DM patients.126 Linagliptin had an elimination half-life of 131h. High-fat food did not affect the absorption profile of linagliptin in healthy subjects receiving a single oral dose of 5mg linagliptin.136 The concurrent intake of food increased the Tmax by approximately 2h and reduced Cmax by about 15% only. After a single intravenous dose of 5mg and a single oral dose of 10mg of [14C]linagliptin, the parent compound was detectable in plasma of 12 healthy male subjects up to 264h.137 After intravenous administration, the Cmax of linagliptin and its pharmacologically inactive metabolite CD1790 was 82.7 and 5.3nmol/L at 1.25 and 2.14h postdose, respectively. CD1790 was identified as S-3-hydroxy piperidinyl derivative of linagliptin with R-configuration at the chiral aminopiperidine moiety. Linagliptin showed a low total clearance with 150mL/min and a long terminal half-life of 142h in plasma.137 The half-life of CD1790 was 15.9h. After oral administration, the absorption of linagliptin was variable, which demonstrated a biphasic absorption profile.137 CD1790 in plasma was observed almost simultaneously with linagliptin. The Cmax of linagliptin and CD1790 of 16.3 and 4.2nmol/L was observed at 2.75 and 2.26h postdose, respectively.137 The total clearance of linagliptin was 374mL/min, and the terminal half-life was 155h in plasma. The half-life of CD1790 was 10.8h. The ratio of total radioactivity of plasma to whole blood was 0.679 and 0.703 after intravenous and oral administration, respectively, indicating that most of the radioactivity was associated to plasma.137 After intravenous administration, the mean recovery of the administered dose was 89.0% (range, 87.2–91.6%), with 30.8% (range, 27.0–32.7%) excreted in urine and 58.2% (range, 55.5–62.6%) excreted in faeces.137 The renal excretion of linagliptin accounted for 21.2% of the dose. After oral administration, the mean recovery of the administered dose was 90.1% (range, 84.0–95.9%), with 5.4% (range, 1.3–11.6%) excreted in urine and 84.7% (range, 78.3–91.9%) excreted in faeces.137 After 120h, 2.4% of the dose was excreted as unchanged linagliptin in urine. Renal excretion of CD1790 was negligible with less than 0.1% of the dose after both oral and intravenous administration. Urine up to 48h and faeces up to 240h were analyzed for metabolites covering 80.7% (i.v.) and 87.0% (oral) of excreted radioactivity. Linagliptin was predominantly eliminated unchanged after both oral and intravenous administration.137 The sum of 78.0% of the oral dose and 61.1% of the intravenous dose was assigned to the parent compound in excreta corresponding to 89.7% (oral) and 75.7% (i.v.) of recovered radioactivity of the investigated sample material. M489(1) formed by hydroxylation of the methyl group of the butinyl side chain was observed as metabolite with highest abundance in excreta with 9.6% (i.v.) and 4.7% (oral) of the dose.137 Several minor metabolites accounted for ≤2.5% (i.v.) and ≤4.5% (oral) of the dose in excreta. They were formed by combinations of the following reactions: oxidation of the butinyl side chain and the piperidine moiety [M490(1), M478(1), M504(2)] followed by oxidative degradation of the piperidine moiety [M506(1), M476(1)], N-acetylation [M515(1), M531(1), M531(2)], and glucuronidation [M650(1), M665(3) M665(8)].137 The oxidation of the methyl group at position 4 of the quinazoline moiety resulted in the corresponding carboxylic acid derivative M503(1). A cysteine adduct [M636(2)] and its sulphate conjugate [M716(1)] were additionally observed with 0.1% of the dose after intravenous administration in urine.137 CD1790 was formed via the corresponding ketone by oxidative desamination followed by stereoselective reduction predominantly by cytosolic aldo-keto reductases.137 In plasma after oral administration only CD1790 accounted for more than 10% of total drug-related compounds (16.9%).137 The turnover of [14C]linagliptin (50μmol/L) with human liver microsomes and human hepatocytes in the presence of NADPH was low. CD1790, which was identified as a major metabolite invivo, accounted for 2–3% of total radioactivity.137 When linagliptin was incubated with recombinant human P450 enzymes, the only enzyme that was active in metabolizing linagliptin was CYP3A4. A two-step mechanism was proposed for the formation of CD1790: in the first step, the secondary amine of linagliptin was converted by oxidative desamination to the corresponding ketone CD10604. This step was rate-limiting and CYP3A4-dependent. Subsequently, CD1790 was formed by reduction of CD10604, with high stereoselectivity. Incubations of CD10604 with human liver microsomes and human liver cytosol demonstrated the preferential contribution of cytosolic enzymes in the formation of CD1790.137 The formation of CD1790 was higher by a factor of 2–5 in cytosol compared with human liver microsomes, indicating the involvement of aldo-keto reductase (AKR) enzymes or carbonyl reductases (CR). Maximal turnover rates were achieved at pH 5.5. Enzyme kinetic investigations resulted in Km and Vmax values of 12.6μmol/L and 1138 pmol/min per mg protein, respectively.137 CD1790 formation was inhibited by phenolphthalein, flufenamic acid, medroxyprogesterone acetate, and dexamethasone, indicating an involvement of AKR enzymes. In additional, the ketone-reducing activity of human whole blood and human plasma was investigated. Twenty-three percent of CD10604 was converted to CD1790 in blood within 1h, whereas no turnover was observed in human plasma.137 The potential chiral inversion of linagliptin to BI1355 and the stereoselectivity of the formation of CD1790 were investigated in human plasma samples after a single oral dose of 600mg of linagliptin.137 Here, only the parent compound with R-configuration and the metabolite CD1790 with S-configuration were identified. The antipodes BI1355 and CD1789 were not detectable. With mean concentrations of linagliptin and CD1790 of 1736 and 110ng/mL, the plasma concentrations of linagliptin and CD1790 were at least 7500- and 2300-fold higher than the concentration of the antipodes.137 Therefore, the enantiomeric excess for both linagliptin and CD1790 accounted for 99.9%. The results demonstrate that there was negligible chiral inversion of linagliptin invivo in humans, if present it all, and that the formation of the corresponding S-configured alcohol CD1790 was highly stereoselective.137 The pharmacokinetics of linagliptin were shown to be nonlinear due to target-mediated, concentration-dependent changes in binding to DPP-4.125, 126, 138 Unlike other DPP-4 inhibitors, linagliptin excretion was not via the kidneys, but rather through the enterohepatic system, unchanged. Most gliptins exhibit a low binding to plasma proteins.40, 75 Linagliptin, however, extensively binds to plasma proteins in a dose-dependent manner, and at the therapeutic dose of 5mg, most of the drug is bound to proteins due to a saturable high affinity binding to the DPP-4 target in plasma.138 In plasma, only the pharmacologically inactive metabolite CD18790 represents over 10% of the total drug concentration.137 An open-label pharmacokinetic study evaluated the pharmacokinetics of linagliptin 5mg in male and female patients with varying degrees of chronic renal impairment.139 The study included six healthy subjects with normal renal function (CrCl≥80mL/min), six patients with mild renal impairment (CrCl 50 to 80mL/min), six patients with moderate renal impairment (CrCl 30 to 50mL/min), 10 patients with type 2 diabetes mellitus and severe renal impairment (CrCl 30mL/min), and 11 patients with T2DM and normal renal function. CrCl was measured by 24-h urinary creatinine clearance measurements or estimated from serum creatinine based on the Cockcroft-Gault formula. Under steady state conditions, linagliptin exposure in patients with mild renal impairment was comparable to healthy subjects. In patients with moderate renal impairment under steady state conditions, mean AUC and Cmax of linagliptin increased by 71% and 46%, respectively, compared with healthy subjects.139 This increase was not associated with a prolonged accumulation half-life, terminal half-life, or an increased accumulation factor. Renal excretion of linagliptin was below 5% of the administered dose and was not affected by decreased renal function. Patients with T2DM and severe renal impairment showed steady state exposure approximately 40% higher than that of patients with T2DM and normal renal function (increase in AUC by 42% and Cmax by 35%).139 For both T2DM groups, renal excretion was below 7% of the administered dose. In an analysis of three Phase III, randomized, placebo-controlled studies, the effect of renal function on the efficacy and safety of linagliptin was evaluated. Patients (n=2141) were grouped according to renal function, and it was found that reductions in HbA1C with linagliptin did not differ among groups (mild, moderate, or severe renal impairment), as well as adverse event occurrences that were similar to placebo.140 In patients with mild hepatic impairment (Child-Pugh class A), steady state AUC of linagliptin was approximately 25% lower and Cmax was approximately 36% lower than in healthy subjects.141 In patients with moderate hepatic impairment (Child-Pugh class B), AUC of linagliptin was about 14% lower and Cmax was approximately 8% lower than in healthy subjects.141 Patients with severe hepatic impairment (Child-Pugh class C) had comparable exposure of linagliptin in terms of AUC and approximately 23% lower Cmax compared with healthy subjects.141 Reductions in the pharmacokinetic parameters seen in patients with hepatic impairment did not result in reductions in DPP-4 inhibition. No dose adjustment is necessary based on BMI. BMI had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. No dose adjustment is necessary based on gender. Gender had no clinically meaningful effect on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. Age did not have a clinically meaningful impact on the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis. No dose adjustment is necessary based on race. Race had no clinically meaningful effect on the pharmacokinetics of linagliptin based on available pharmacokinetic data, including subjects of white, Hispanic, black, and Asian racial groups. The incidence of hypoglycaemia was 8.2% in patients receiving linagliptin and 5.1% in those receiving placebo. The somewhat higher incidence of hypoglycaemia associated with linagliptin was almost exclusively attributable to the combination with sulphonylurea. In studies where patients were receiving sulphonylurea, the incidence of hypoglycaemia was 20.7% and 13.3% in the linagliptin- and placebo-treated groups, respectively; 38% of patients on sulphonylurea background therapy accounted for 96% of all hypoglycaemic events in the linagliptin-treated group.142 As observed with other gliptins, the combination with linagliptin to patients inadequately controlled on metformin plus sulfonylurea showed a higher occurrence of hypoglycaemia than the placebo group (22.7% vs 14.8%).135 The T2DM treatment with glitazone, sulfonylurea, or insulin may be associated with weight gain. Most T2DM patients are overweight or obese, so it is not desirable to gain additional weight due to the treatment. DPP-4 inhibitors have a neutral effect on body weight. Linagliptin showed no weight increase in monotherapy or in combination with metformin. In combination with pioglitazone, the linagliptin was associated with greater weight gain than placebo (2.3kg vs 1.2kg, P 0.01), in a 24-week study, but these changes were minimal from baseline.133 There was also no change in waist circumference with linagliptin treatment. In 2008, the FDA (Food and Drug Administration) recommended the inclusion of a warning on the package insert of some drugs acting on the incretin system, after case reports of pancreatitis with the use of GLP-1 analogs. Postmarketing analyses have also identified isolated cases of pancreatitis with DPP-4 inhibitors, but a cause-effect relationship was not identified. It is important to consider that patients with T2DM and hypertriglyceridemia exhibit increased risk of pancreatitis. In clinical studies, 8 pancreatitis cases were reported in 4687 patients on linagliptin and no cases among 1183 patients receiving placebo; however, no relationship between linagliptin and pancreatitis has been established.143 The gliptins may exert beneficial cardiovascular effects through different mechanisms. Recent studies also demonstrated that intensive control may be associated with increased CV risk; therefore, another potential benefit of gliptins would be a low risk of hypoglycaemia.144 In studies using animal models, activation of GLP-1 receptor is associated with limiting the size of the area of myocardial infarction (MI).145 Furthermore, linagliptin has anti-oxidant properties, probably due to its xanthine-based molecular structure. Even when administered in supratherapeutic doses, linagliptin does not prolong the QT interval.146 A recent meta-analysis has assessed the cardiovascular safety profile of linagliptin in patients who participated in eight Phase III studies.144 Of the 5239 patients, 3319 received linagliptin, and 1920 received a comparator (placebo, glimepiride, or voglibose). A composite of CV death, stroke, MI, or hospitalization for unstable angina was considered as the primary endpoint. In the linagliptin group, the primary endpoint occurred in 11 (0.3%) patients, whereas in the comparator group there were 23 cases (1.2%), demonstrating lower risk in those who received linagliptin.144 Animportant conclusion is that, as other DPP-4 inhibitors have also demonstrated, linagliptin shows no increase in CV risk. The adverse events most frequently reported with DPP-4 inhibitors are mild infections (such as nasopharyngitis, urinary tract infection, and upper respiratory tract infections) and diarrhoea, back pain, headache and hypertension. Data presented with linagliptin indicate an overall incidence similar to placebo for these most frequently observed adverse events.142 Linagliptin weakly inhibited CYP3A4 activity in human liver microsomes in a competitive manner, with a Ki of 115μmol/L.137 In addition, linagliptin was a poor to moderate mechanism-based inhibitor of CYP3A4. KI and the maximal rate of enzyme inactivation (kinact) were 1.75μmol/L and 0.041min−1, respectively, for CYP3A4-mediated testosterone 6β-hydroxylation.137 Linagliptin did not inhibit other main CYPs and was not an inducer of CYPs, including CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, and 4A11. Since linagliptin is only a weak competitive inhibitor of CYP3A4, there would be a less than twofold decrease in the clearance of other drugs metabolized by this pathway, so linagliptin is considered as having low potential for clinically relevant interactions. Linagliptin is a P-gp substrate. Linagliptin inhibits P-gp mediated transport of digoxin at high concentrations. Based on these results and invivo drug interaction studies, linagliptin is considered unlikely to cause interactions with other P-gp substrates at therapeutic concentrations. In different pharmacokinetic drug-drug interaction studies, linagliptin exhibited low potential for drug interaction. Linagliptin did not change the pharmacokinetic steady state of ethinyl estradiol and levonorgestrel,147 digoxin,148 warfarin,149 glyburide,150 pioglitazone,151 simvastatin,152 and metformin.117 Rifampicin, in turn, can reduce the exposure to linagliptin, suggesting that linagliptin efficacy may be reduced by concomitant use with rifampicin.107 Thus, inducers of CYP3A4 or P-gp (e.g., rifampin) should not be used in combination with linagliptin to avoid therapeutic failure. For patients who require use of such drugs, an alternative to linagliptin is strongly recommended. Saxagliptin (Onglyza); (1S,3S,5S)-2-[(2S)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile) co-developed by Bristol-Myers Squibb (New York City, USA) and AstraZeneca (London, United Kingdom) was approved by the FDA in July 2009. It is also used in combination with metformin (Kombiglyze XR). In patients with T2DM, administration of saxagliptin inhibited DPP-4 activity for a 24-h period. After an oral glucose load or a meal, this DPP-4 inhibition resulted in a two to threefold increase in circulating levels of active GLP-1 and GIP, decreased glucagon concentrations, and increased glucose-dependent insulin secretion from pancreatic β-cells. The pharmacokinetics of saxagliptin and its active metabolite, 5-hydroxy saxagliptin (BMS510849, 50% potency of saxagliptin), were similar in healthy subjects and in patients with T2DM. The Cmax and AUC values of saxagliptin and its active metabolite increased proportionally in the 2.5–400mg dose range. No appreciable accumulation of either saxagliptin or its active metabolite was observed with repeated once-daily dosing at any dose level. No dose- and time-dependence were observed in the clearance of saxagliptin and its active metabolite over 14days of once-daily dosing with saxagliptin at doses ranging from 2.5 to 400mg. Following a single oral dose of 5mg saxagliptin to healthy subjects, the mean plasma t½β for saxagliptin and its active metabolite was 2.5 and 3.1h, respectively. Saxagliptin is mainly metabolized by CYP3A4/5, resulting in an active metabolite. Saxagliptin is eliminated by both renal and hepatic pathways. The recommended dose for adult with T2DM is 2.5 or 5mg orally once a day, regardless of meal. Dose adjustment for patients with mild renal impairment (creatinine clearance 50mL/min) is not recommended; however, the dosage needs to be reduced to 2.5mg orally once a day for patients with moderate or severe renal dysfunction (CrCl≤50mL/min).153 There is a raising concern on the safety of saxagliptin in clinical practice, such as hypoglycaemia, pancreatitis, hypersensitivity reactions, and cardiovascular risk. Although there is no evident association between the application of saxagliptin and the incidence of gastrointestinal adverse events, infections, hypersensitivity, pancreatitis, skin lesions, lymphopenia, thrombocytopenia, hypoglycaemia, bone fracture, severe cutaneous adverse reactions, opportunistic infection, angioedema, malignancy, and worsening renal function, the patients still need to be cautious to initiate the saxagliptin treatment.154 For example, hypersensitivity-related urticaria and facial oedema in the 5-study pooled analysis up to week 24 were reported in 1.5%, 1.5%, and 0.4% of patients who received saxagliptin 2.5mg, saxagliptin 5mg, and placebo, respectively, though none of these events in patients who received saxagliptin required hospitalization or were reported as a life-threatening event.155, 156 Notably, the concern about the possible association between saxagliptin and cardiovascular risk has been raised. It has been reported that an increased rate of hospitalization for heart failure occurred, when the heart does not pump blood well enough, with use of saxagliptin compared to placebo treatment in a randomized trial with 16492 patients enrolled in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus-thrombolysis in myocardial infarction (SAVOR-TIMI 53) trial.157 Although this study did not find increased rates of death or other major cardiovascular risks, including heart attack or stroke, in patients who received saxagliptin, other approaches are necessary to reduce cardiovascular risk in patients with diabetes.157 Sitagliptin (Januvia; previously known as MK-0431; (R)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine) is the first DPP-4 inhibitor developed by Merck & Co. (Whitehouse Station, NJ, USA), approved by the FDA in October 2006. Sitagliptin demonstrates selectivity towards DPP-4 and does not inhibit DPP-8 or DPP-9 activity invitro at concentrations approximating those achieved at therapeutic doses. In healthy subjects, sitagliptin markedly and dose-dependently inhibited ~80% of plasma DPP-4 activity over 24h and produced a two to threefold increase in postprandial active plasma GLP-1 and GIP levels compared to placebo.158 In patients with T2DM, treatment with sitagliptin resulted in significant improvements in HbA1C, FPG and 2-h PPG compared to placebo. Sitagliptin was well tolerated and was not associated with hypoglycaemia.158 Further, a fixed-dose combination tablet containing 50mg sitagliptin and 500 or 1000mg metformin was approved by FDA in April 2007. This is marketed in the US as Janumet. Coadministration of sitagliptin and metformin resulted in an additive effect on active GLP-1 concentrations. Sitagliptin, but not metformin, increased active GIP concentrations. A 24-week, randomized, double-blind, placebo-controlled factorial study indicates that the combination provided significant improvements in HbA1C, FPG, and 2-h PPG compared to placebo, to metformin alone, and to sitagliptin alone. After oral administration of a 100mg dose to healthy subjects, sitagliptin was rapidly absorbed, with peak plasma concentrations occurring 1–4h postdose. Plasma AUC of sitagliptin increased in a dose-proportional manner. Following a single oral 100mg dose to healthy volunteers, mean plasma AUC of sitagliptin was 8.52μmol/L per h, Cmax was 950nmol/L, and apparent t½β was 12.4h. Plasma AUC of sitagliptin increased ~14% following 100mg doses at steady state compared to the first dose. Sitagliptin is not extensively bound to plasma proteins. In vitro studies indicated that sitagliptin was primarily metabolized by CYP3A4, with contribution from CYP2C8. Approximately 79% of sitagliptin is excreted unchanged in the urine with metabolism being a minor pathway of elimination accounting for around 16%. Elimination of sitagliptin occurs primarily via renal excretion and involves active tubular secretion. Sitagliptin is a substrate for human organic anion transporter-3, which may be involved in the renal elimination of sitagliptin. Sitagliptin is also a substrate of P-gp/MDR1, which may also be involved in mediating the renal elimination of sitagliptin. In clinical studies, sitagliptin did not meaningfully alter the pharmacokinetics of metformin, glyburide, simvastatin, digoxin, rosiglitazone, warfarin, or oral contraceptives. Coadministration of multiple twice-daily doses of metformin with sitagliptin did not meaningfully alter the pharmacokinetics of sitagliptin in patients with T2DM. The recommended dosage for adult with T2DM is 100mg orally once a day. Dose adjustment for patients with mild renal impairment (creatinine clearance 50mL/min) is not recommended; however, the dosage needs to be reduced to 50mg orally once a day for patients with moderate renal dysfunction (creatinine clearance ranging from 30 to 49mL/min), and the dosage needs to be further reduced to 25mg orally once a day for patients with severe renal insufficiency (creatinine clearance≤29mL/min) or end stage renal disease requiring hemodialysis or peritoneal dialysis.159, 160 Sitagliptin is a well-tolerated, moderately efficacious, weight-neutral DPP-4 inhibitor for T2DM treatment, with a low incidence of hypoglycaemia, and it may have a particular role in the management of diabetic patients with kidney or liver dysfunction.161, 162 However, there is a safety concern of sitagliptin on the risk of pancreatitis, inflammation of the pancreas, and pancreatic duct metaplasia in T2DM patients. It has been reported that current use of GLP-1-based therapy (sitagliptin) within 30days [adjusted odds ratio, 2.24 (95% CI, 1.36, 3.68)] and recent use past 30days and less than 2years [2.01 (1.37–3.18)] were associated with significantly increased odds of acute pancreatitis relative to the odds in nonusers, indicating that treatment with sitagliptin was associated with increased odds of hospitalization for acute pancreatitis.163 A Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) has reported the baseline characteristics and CV risk management by region, age, sex and CV event type for 14724 participants,164 which is a randomized, double-blind, placebo-controlled trial to explore whether sitagliptin added to usual T2DM care affects time to first event in the composite endpoint of CV death, non-fatal myocardial infarction (MI), non-fatal stroke or unstable angina hospitalization. TECOS concludes that the CV risk factors of enrolled patients are reasonably controlled, however, there are differences in CV risk management according to region, sex and history of disease. It indicates that this diversity will enhance the generalizability of the trial results.164 Teneligliptin (Tenelia; 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine) was developed by Mitsubishi Tanabe Pharma (Osaka, Japan) and gained approval from the PMDA of Japan in September 2012. Teneligliptin is currently used in T2DM patients showing insufficient improvement in glycaemic control even after diet control and exercise or a combination of diet control, exercise, and sulfonylurea or thiazolidine therapy. Unlike other DPP-4 inhibitors, it exhibits a unique structure characterized by five consecutive rings (Fig.1) belonging to a peptidomimetic. Teneligliptin significantly inhibited human plasma DPP-4 and recombinant human DPP-4 activity, with IC50 of 1.75nmol/L and 0.889nmol/L (Ki=0.406nmol/L), respectively.165 In addition, the IC50 values of teneligliptin for DPP-8, DPP-9, and fibroblast activation protein are 0.189, 0.150, and 10μmol/L, respectively, all of which are 168 to 11248 times the value for recombinant human DPP-4.165 Oral administration of teneligliptin at 0.03–1.0mg/kg to Zucker fatty rats significantly inhibited DPP-4 activity and normalized the plasma glucose levels after an oral glucose load of 1.0g/kg.165 An X-ray co-crystal structure of teneligliptin complexed with human DPP-4 (33-766; protein database ID: 3VJM) has demonstrated that there are tight interactions between five rings of teneligliptin and the active site of DPP-4.165 The thiazolidine moiety fully occupies the S1 hydrophobic subsite; the secondary amino group of the proline moiety forms salt bridges with Glu205 and Glu206; the carbonyl oxygen forms a hydrogen bond with Asn710; and the pyrazolyl ring is stacked with the side chain of Phe357 and the piperazinyl ring forms CH–π interaction with Phe357.165 In addition, the phenyl substituent on the pyrazolyl ring is oriented favourably for hydrophobic interactions with the side chains of Ser209 and Arg358. In the S2 extensive subsite, C4 of the phenyl ring is highly possible to form hydrogen bond with the carbonyl oxygen of the main chain of Val207.165 These findings support the high therapeutic potency and selectivity towards DPP-4 of teneligliptin. In a Phase II clinical study conducted in Japan, 324 T2DM patients who did not achieve optimal glycaemic control with diet and exercise treatment alone for more than 12weeks were randomly assigned into four groups: placebo, 10mg, 20mg, or 40mg teneligliptin.166 The drug was administered once daily for 12weeks. After 12weeks, treatment with 10, 20, and 40mg teneligliptin reduced the HbA1C levels 0.77%, 0.80%, and 0.91%, respectively. The FPG and 2-h PPG levels were also reduced in patients with T2DM with a minimal risk of hypoglycaemia and weight gain. In a flowing Phase III trial with 20mg teneligliptin for 12weeks in 203 T2DM patients, the therapy reduced the HbA1C level 0.79%. In a Phase III trial, T2DM patients (n=151) were treated with 20mg teneligliptin orally for 52weeks (the dose was increased to 40mg if plasma HbA1C levels were 7.3% at any time after week 24), the HbA1C level was reduced by 0.63%.167, 168 When 20mg of teneligliptin was administered to 96 T2DM patients treated with glimepiride at 1–4mg/day in addition to diet and exercise treatment, the HbA1C level and FPG and 2-h PPG levels were reduced by 0.71%, −17.3mg/dL, and −43.1mg/dL, respectively, compared to the values at week 12. In rat, monkey and human, teneligliptin is metabolized to five metabolites, M1, M2, M3, M4, and M5, which all show some DPP-4 inhibitory activity.169 In vitro studies indicate that teneligliptin was metabolized by CYP3A4 and flavin-containing monooxygenases FMO1 and FMO3.167 In T2DM patients (n=33 per group), the plasma Cmax of teneligliptin following the oral administration of 10 or 20mg once daily for 4weeks was 125.0 and 274.5ng/mL, respectively, with a Tmax of 1.0h in both groups and a mean t1/2β of 20.8 and 18.9h, respectively. The AUC0–24h was 830.9 and 1625.1ng/h per mL, respectively. In the meantime, the maximum percentage of the inhibition in plasma DPP-4 activity (81.3–89.7%) was achieved within 2h after 4-week multiple-dose administration.167 In the mass balance study in healthy male subjects receiving a single oral dose of 20mg 14C-labeled teneligliptin, the cumulative urinary excretion rate of unchanged drug, M1, M2, and M3 over 120h was 14.8%, 17.7%, 1.4% and 1.9%, respectively.167 The cumulative faecal excretion rate of teneligliptin, M1, M2, M3, M4, and M5 was 26.1%, 4.0%, 1.6%, 0.3%, and 1.3%, respectively. These findings indicate that teneligliptin is metabolized and eliminated via renal and hepatic excretion. Because the metabolites of the drug are eliminated via renal and hepatic excretion, no dose adjustment is needed in T2DM patients with renal impairment. The safety profile of teneligliptin is similar to those of other available DPP-4 inhibitors.167 The incidence of adverse drug reactions was ~10% in all clinical studies of patients (n=1183) with T2DM. These mainly included abnormalities in clinical examination values such as levels of liver and kidney function, blood cell count, creatinine phosphokinase, and electrolytes. The main adverse effects included hypoglycaemia (35 patients: 3.0%) and constipation (11 patients: 0.9%). No adverse effects related to QT prolongation were detected with 40mg/day of teneligliptin, which is the maximal dosage used in clinical practice. The pharmaceutical company warned of serious adverse effects such as hypoglycaemia, which could occur when other antidiabetic drugs were coadministered. In addition, they cautioned that intestinal obstruction could occur with an unknown frequency. GLP-1 is involved in gastrointestinal motility,21, 26 and the patients with intestinal obstruction had a past medical history of intestinal obstruction or abdominal surgery. Therefore, we should be cautious when T2DM patients with a history of these conditions are treated with DPP-4 inhibitors. Continued evaluation of adverse effects and post-market monitoring is warranted to define the benefit/risk ratio. Vildagliptin (Zomelis & Galvus; previously known as LAF237; (S)-1-[N-(3-hydroxy-1-adamantyl)glycyl]pyrrolidine-2-carbonitrile) gained approval from the European Medicines Agency (EMEA) in February 2008, which is the second DPP-4 inhibitor reaching the market behind sitagliptin. Its approval in the US is still pending. In the meantime, the EMEA has also approved a combination use of vildagliptin with metformin (brand name: Eucreas). Vildagliptin is a potent, competitive, and reversible inhibitor for DPP-4, with an IC50 of 3.5nmol/L.170, 171 The vildagliptin-DPP-4 complex exhibited a slow dissociation half-life of 55min. Maximum inhibition of DPP-4 activity was seen 30min after a vildagliptin dose, and ≥50% inhibition of DPP-4 continued for 10h or longer. DPP-4 levels was dropped to 60% of baseline 24h after a 100-mg dose of vildagliptin in patients with dietary controlled diabetes.172 In the Novartis-sponsored INTERVAL study, elderly patients with T2DM who were treated with vildagliptin achieved greater reductions in HbA1C and were three times more likely to reach individualized treatment goals without major tolerability issues than those treated with placebo on top of background oral antidiabetic treatment.173 This study was a 24-week, multi-centre, randomized, double-blind, placebo-controlled study that enrolled 278 patients from 45 outpatient centres across several European countries including Belgium, Bulgaria, Germany, Finland, Slovakia, Spain and the UK. The absolute oral bioavailability of vildagliptin exceeded 90% and its average clearance rate from plasma was 1.5L/h per kg with a volume of distribution of 0.7L/kg following a 1-μmol/kg oral dose administered to cynomolgus monkeys.171 The pharmacokinetics of vildagliptin has been investigated in healthy volunteers and patients with T2DM.174-177 Following oral administration in the fasting state, vildagliptin was rapidly absorbed, with peak plasma concentrations observed at 1–2 (mean 1.7) hours. Its oral bioavailability was 85% in healthy volunteers and its pharmacokinetics was not affected by food. The plasma protein binding of vildagliptin was low (9.3%) and vildagliptin distributed equally between plasma and red blood cells. The mean volume of distribution of vildagliptin at steady state after intravenous administration (Vss) was 70.5L, suggesting extravascular distribution. Following oral administration of [14C]vildagliptin, ~85% of the dose was excreted into the urine and 15% of the dose is recovered in the faeces. Renal excretion of the unchanged vildagliptin accounted for 23% of the dose after oral administration. After intravenous administration to healthy subjects, the total plasma and renal clearances of vildagliptin are 41 and 13L/h, respectively. The t1/2β of vildagliptin after oral administration is 2.8h. Metabolism was the major elimination pathway for vildagliptin in humans, accounting for 69% of the dose.171 The major metabolite (LAY151) is pharmacologically inactive and is the hydrolysis product of the cyano moiety, accounting for 57% of the dose, followed by the glucuronide (BQS867) and the amide hydrolysis products (4% of dose). In vitro data in human kidney microsomes suggest that the kidney may be one of the major organs contributing to the hydrolysis of vildagliptin to its major inactive metabolite, LAY151.171 DPP-4 contributes partially to the hydrolysis of vildagliptin based on an invivo study using DPP-4 deficient rats. Vildagliptin is not metabolized by CYPs to any quantifiable extent. Vildagliptin was largely excreted in the urine with 18–22% of the amount excreted as unmetabolized drug.171 Vildagliptin did inhibit or induce any human CYPs. Vildagliptin AUC increased on average 1.4, 1.7 and 2-fold in patients with mild, moderate and severe renal impairment, respectively, compared to normal healthy subjects. No dose adjustment is required in patients with mild renal impairment (creatinine clearance≥50mL/min), but the recommended dose of vildagliptin is 50mg once daily in patients with moderate or severe renal impairment or with end-stage renal disease. No dose adjustments are necessary in elderly patients.178, 179 A meta-analysis of independently and prospectively adjudicated cardiovascular events from 25 phase III clinical studies of up to more than 2years duration was performed and showed that vildagliptin treatment was not associated with an increase in cardiovascular risk versus comparators. The eight available DPP-4 inhibitors, including alogliptin, anagliptin, gemigliptin, saxagliptin, sitagliptin, teneligliptin, and vildagliptin, are small molecules used orally with similar overall clinical efficacy and safety profiles in patients with T2DM. Sitagliptin was the first gliptin licensed by the FDA in 2006 and is now available worldwide. Vildagliptin and saxagliptin were approved in 2007 and 2009, respectively. More recent compounds are alogliptin (available only in Japan in 2010) and linagliptin (authorized by the FDA and EU in 2011). DPP-4 inhibitors may be used as monotherapy or in double or triple combination with other oral glucose-lowering agents, as metformin, thiazolidinediones, or sulfonylureas. Dipeptidyl peptidase-4 inhibitors reduce plasma DPP-4 activity by 70–90% in a sustained manner for 24h with an increase of GLP-1 levels (1.5- to 4-fold). They do not pass the blood–brain barrier, have no direct central effect on satiety, and in contrast with GLP-1 agonists (incretin mimetics), did not alter gastric emptying. 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 on the market include: potency, target selectivity, oral bioavailability, elimination half-life, extent of 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. Regarding potency, linagliptin, compared with sitagliptin, alogliptin, saxagliptin, and vildagliptin demonstrated the highest potency of DPP-4 inhibition. The duration of action of DPP-4 inhibitors with comparatively shorter half-lives may be strongly influenced by binding strength and reversibility with the receptor. All gliptins exhibit a greater selectivity for DPP-4 enzyme, ranging from 30- to 40000-fold superior to the other enzymes, i.e., DPP-8 and DPP-9. However, because DPP-8 and DPP-9 are proteases responsible for T-cell activation which play an important role in immune function, the off-target inhibition of selective DPP-4 inhibitors is responsible for multiorgan toxicities such as immune dysfunction, impaired healing, and skin reactions. After oral administration in humans, all DPP-4 inhibitors are well absorbed with oral bioavailability ranges from about 30% for linagliptin to 75–87% for all others and are not significantly influenced by food intake. Linagliptin has the longest half-life (120–184h), followed by alogliptin (12.4–21.4h), and sitagliptin (8–14h), whereas saxagliptin and vildagliptin have shorter half-lives (2.2–3.8 and 2–3h, respectively). Due to a sustained DPP-4 enzyme inhibition and a long half-life, sitagliptin, alogliptin, and linagliptin are generally prescribed once a day. Saxagliptin is also administrated once daily due to the presence of an active metabolite (5-hydroxy saxagliptin) which is half as potent as the parent compound. Due to the shorter half-life, vildagliptin needs twice-daily dosing. The apparent volume of distribution (Vd) among the gliptins range from 70 to 918L. Moreover, the distribution of DPP-4 inhibitors is strongly influenced by protein binding. All gliptins are not extensively bound to plasma proteins, except for linagliptin, which has the highest binding level to proteins. The metabolism of DPP-4 inhibitors varies. While sitagliptin does not appear to undergo extensive metabolism, both vildagliptin and saxagliptin are extensively metabolized in the liver. However, vildagliptin produces a large amount of inactive metabolites through several pathways (hydrolysis, glucuronidation, and oxidation) not mediated by the CYP system, while saxagliptin is mainly metabolized by CYP3A4/5 to a major active metabolite, 5-hydroxy saxagliptin. Both saxagliptin and its major metabolite are not inhibitors or inducers of various CYPs. Although the potential for drug interactions with saxagliptin and its metabolite is low, their pharmacokinetic profile may be influenced in co-administration with strong CYP3A4/5 inducers (such as rifampicin) or inhibitors (such as ketoconazole); in these cases, it is recommended to modify the dosage of saxagliptin. The pharmacokinetic profiles of the other DPP-4 inhibitors suggest a low risk of drug–drug interactions, which is especially favourable in patients older than 65years. All DPP-4 inhibitors predominantly (75–87%) undergo renal excretion, with 76–87% of each dose eliminated as unchanged parent compound in the urine. In contrast, linagliptin is excreted mostly (~90%) unchanged in faeces via biliary excretion, and therefore appears to be safe in diabetic patients suffering from renal complications. An appropriate dose reduction of the gliptins with predominantly renal excretion (sitagliptin, saxagliptin, and alogliptin, but not vildagliptin) is needed in case of renal impairment. In patients with mild to severe liver impairment, no dose adjustment seems necessary for linagliptin despite its liver excretion. The difference in the glucose-lowering efficacy of DPP-4 inhibitors between Asian and non-Asian patients with T2DM was concluded in a meta-analysis.180 The meta-analysis included 55 randomized controlled trials that compared a DPP-4 inhibitor with a placebo as either monotherapy or oral combination therapy for at least 12weeks with information on ethnicity and HbA1c values.180 It revealed that DPP-4 inhibitors exhibited a stronger HbA1c lowering effect in studies with ≥50% Asian participants [weighted mean difference (WMD) −0.92%; 95% CI −1.03, −0.82] than that in studies with 50% Asian participants (WMD −0.65%; 95% CI −0.69, −0.60), with a between-group difference of −0.26% (95% CI −0.36, −0.17, P   0.001).180 The meta-analysis showed that the baseline BMI significantly correlated with the HbA1c-lowering efficacy of DPP-4 inhibitors. The RR of achieving the goal of HbA1c 7.0% (53.0mmol/mol) was 3.4 [95% CI 2.6, 4.7] vs 1.9 [95% CI 1.8, 2.0] in studies with ≥50% Asian participants and in studies with 50% Asian participants, respectively. Moreover, there was a stronger fasting plasma glucose-lowering efficacy in the Asian-dominant studies with monotherapy, but the postprandial glucose-lowering efficacy and changes in body weight were comparable between the two groups. The meta-analysis concludes that DPP-4 inhibitors show higher glucose-lowering efficacy in Asians than that in other ethnic groups, however, this requires further investigation to understand the underlying mechanism, particularly in relation to BMI.180 Clinically approved DPP-4 inhibitors are generally well tolerated in T2DM patients. 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. DPP-4 inhibitors can cause mild to moderate adverse effects, including nasopharyngitis, headache, urinary tract infection, nausea, and vomiting, have been observed. Other adverse effects of DPP-4 inhibitors, including hypersensitivity reactions (e.g. angioedema and Stevens–Johnson syndrome) and acute pancreatitis, have been reported post-marketing. A recent population-based, case–control study, conducted on a large administrative database in the US from 2005 to 2008, showed roughly a doubling of the risk of acute pancreatitis among users receiving incretin-based therapy (sitagliptin and exenatide). A study has examined the FDA adverse event reporting system (AERS) database, and has noted a sixfold risk for pancreatitis with the use of sitagliptin or exenatide as compared with other therapies. Moreover, this analysis showed the reported event rate for pancreatic cancer was 2.9-fold greater in patients treated with sitagliptin and exenatide compared with other therapies. However, it is unclear if DPP-4 inhibitors increase the risk of cancer in T2DM patients. These effects may be associated with the inhibitory activity of DPP-4 on the inflammatory actions of the chemokine CCL11/eotaxin. Careful long-term surveillance on the safety profile of DPP-4 inhibitors is mandatory. Diabetic patients are at increased risk of cardiovascular diseases. Rosiglitazone was been withdrawn from the market in the European Union (EU) in 2010, because of a possible increased risk of ischemic heart disease associated with its use. Several preclinical and clinical studies have suggested a possible beneficial effect on cardiovascular risk associated with DPP-4 inhibitors, which also seem to possess a direct effect on the heart, independent of the incretin system. They may exert some favourable effects on risk factors, resulting in a reduction of blood pressure, an improvement of postprandial lipid levels, and a reduction of high-sensitivity C-reactive protein. The endothelial dysfunction is also improved by gliptins. Several large randomized Phase III trials are ongoing and will increase our knowledge about the effect on cardiovascular outcomes and safety. The insulin-release effects of the incretins are glucose-dependent and have no insulinotropic activity at lower glucose concentration ( 4mmol/L), therefore reducing the chance of hypoglycaemia, which is one of the major concerns of other antidiabetic drug classes. So far, no characteristic pattern of adverse events has been associated with the DPP-4 inhibitors despite the large number of potential substrates for DPP-4. DPP-4 inhibitors are less associated with several specific AEs of traditional antidiabetic treatments. The neutral effect on body weight of DPP-4 inhibitors can be useful in overweight or obese patients with T2DM, while the low risk of hypoglycaemia may be an advantage in the elderly. Hypoglycaemic events are mainly observed when DPP-4 inhibitors are associated with sulfonylureas (in 20% of the patients treated in combination) than without sulfonylureas. Numerous clinical trials have demonstrated that DPP-4 inhibitors provide effective and consistent glycaemic control with a good tolerability profile, including no severe hypoglycaemia and weight gain. Although different DPP-4 inhibitors are distinctive in their metabolic properties, excretion, recommended dosage, and daily dosage, and head-to-head clinical trials comparing the various DPP-4 inhibitors are scarce, the available data regarding indirect comparisons suggest that all available DPP-4 inhibitors have nearly the same efficacy and safety profile. Thus, we may expect a similar efficacy and safety with the novel DPP-4 inhibitor, teneligliptin, although this drug requires careful long-term postmarketing surveillance and additional clinical trials to evaluate its efficacy and safety as well as to gain additional indications for its clinical use. DPP-4 inhibitors are the first substances having a glucose-dependent dual action on α- and β-cell functions stimulating insulin secretion and suppressing glucagon secretion under hyperglycaemic conditions (Fig.2). This dual action leads to an improved time course of islet hormone secretion after a meal and hyperglycaemia. Taken together, the discovery and advance of incretin therapy may help overcome the limitations of the classical treatment options of T2DM. The National Institute for Health and Clinical Excellence (NICE) clinical guideline for T2DM suggests adding a DPP-4 inhibitor instead of a sulfonylurea as second line treatment to first line metformin if there is a considerable risk for hypoglycaemia or if a sulfonylurea is contraindicated or not tolerated. Figure 2Open in figure viewerPowerPoint Mechanism of actions of dipeptidyl peptidase-4 (DPP-4) inhibitors. DPP-4 inhibitors suppress the enzymatic activity of DPP-4, resulting in an increase in incretin levels (GLP-1 and GIP), which subsequently inhibit glucagon release and glucose production in the liver and increase insulin secretion and glucose uptake in skeletal muscle. Consequently, it leads to a decrease in blood glucose level. GLP-1, glucagon-like peptide 1; GIP, gastric inhibitory polypeptide. The DPP-4 inhibitors represent a highly promising, novel class of oral agents for the treatment of type 2 diabetes. Their novelty lies in their dual action on α- and β-cell function, leading to an improved profile of glucagon and insulin secretion patterns after meal. These drugs are weight-neutral, do not provoke hypoglycaemia, and are not associated with gastrointestinal adverse events. Long-term clinical trial data are not yet available to assess the sustainability of glycaemic control and protection of β-cell mass. The interference of the DPP-4 inhibitors with immune function is poorly understood and warrants further research. Another potential disadvantage is a higher cost per day of clinical use as compared to insulin, metformin, or pioglitazone, which is an economic drawback for the DPP-4 inhibitors. 1Tuomi T, Santoro N, Caprio S, Cai M, Weng J, Groop L. The many faces of diabetes: A disease with increasing heterogeneity. Lancet 2014; 383: 1084– 94. 2Chan JC, Malik V, Jia W, etal. Diabetes in Asia: Epidemiology, risk factors, and pathophysiology. JAMA 2009; 301: 2129– 40. 3Inzucchi SE. Clinical practice. Diagnosis of diabetes. N. Engl. J. Med. 2012; 367: 542– 50. 4 International Diabetes Federation. IDF Diabetes Atlas, 6th edn. International Diabetes Federation, Brussels. 2013. 5 Centres for Disease Control and Prevention. National Diabetes Statistics Report: Estimates of Diabetes and Its Burden in the United States, 2014. Centres for Disease Control and Prevention, Atlanta, GA. 2014. 6Chan JC, Zhang Y, Ning G. Diabetes in China: A societal solution for a personal challenge. Lancet Diabetes Endocrinol. 2014; 2: 969– 79. 7Holman RR. Type 2 diabetes mellitus in 2012: Optimal management of T2DM remains elusive. Nat. Rev. Endocrinol. 2013; 9: 67– 8. 8Tahrani AA, Bailey CJ, Del Prato S, Barnett AH. Management of type 2 diabetes: New and future developments in treatment. Lancet 2011; 378: 182– 97. 9McCarthy MI. Genomics, type 2 diabetes, and obesity. N. Engl. J. Med. 2010; 363: 2339– 50. 10Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N. Engl. J. Med. 2012; 366: 1227– 39. 11Nolan CJ, Damm P, Prentki M. Type 2 diabetes across generations: From pathophysiology to prevention and management. Lancet 2011; 378: 169– 81. 12Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: Clinical manifestations and current treatments. Lancet Neurol. 2012; 11: 521– 34. 13Mehanna A. Antidiabetic agents: Past, present and future. Future Med. Chem. 2013; 5: 411– 30. 14Ley SH, Hamdy O, Mohan V, Hu FB. Prevention and management of type 2 diabetes: Dietary components and nutritional strategies. Lancet 2014; 383: 1999– 2007. 15Giugliano D, Ceriello A, Esposito K. HbA1c targets for type 2 diabetes: How many,…how far!. Diabetes Res. Clin. Pract. 2012; 96: 414– 15. 16Ong KL, Cheung BM, Wong LY, Wat NM, Tan KC, Lam KS. Prevalence, treatment, and control of diagnosed diabetes in the U.S. National Health and Nutrition Examination Survey 1999–2004. Ann. Epidemiol. 2008; 18: 222– 9. 17Rea D, Fulop V. Structure-function properties of prolyl oligopeptidase family enzymes. Cell Biochem. Biophys. 2006; 44: 349– 65. 19Szeltner Z, Polgar L. Structure, function and biological relevance of prolyl oligopeptidase. Curr. Protein Pept. Sci. 2008; 9: 96– 107. 20Edwards KL, Stapleton M, Weis J, Irons BK. An update in incretin-based therapy: A focus on glucagon-like peptide-1 receptor agonists. Diabetes Technol. Ther. 2012; 14: 951– 67. 21Stonehouse AH, Darsow T, Maggs DG. Incretin-based therapies. J Diabetes 2012; 4: 55– 67. Wiley Online Library 22Zhong J, Rao X, Rajagopalan S. An emerging role of dipeptidyl peptidase 4 (DPP4) beyond glucose control: Potential implications in cardiovascular disease. Atherosclerosis 2013; 226: 305– 14. 23Darmoul D, Lacasa M, Chantret I, Swallow DM, Trugnan G. Isolation of a cDNA probe for the human intestinal dipeptidylpeptidase IV and assignment of the gene locus DPP4 to chromosome 2. Ann. Human Genet. 1990; 54: 191– 7. Wiley Online Library 24Darmoul D, Lacasa M, Baricault L etal. Dipeptidyl peptidase IV (CD 26) gene expression in enterocyte-like colon cancer cell lines HT-29 and Caco-2. Cloning of the complete human coding sequence and changes of dipeptidyl peptidase IV mRNA levels during cell differentiation. J. Biol. Chem. 1992; 267: 4824– 33. 25Tanaka T, Camerini D, Seed B, etal. Cloning and functional expression of the T cell activation antigen CD26. J. Immunol. 1992; 149: 481– 6. 26Dailey MJ, Moran TH. Glucagon-like peptide 1 and appetite. Trends Endocrinol. Metab. 2013; 24: 85– 91. 27Abu-Hamdah R, Rabiee A, Meneilly GS, Shannon RP, Andersen DK, Elahi D. Clinical review: The extrapancreatic effects of glucagon-like peptide-1 and related peptides. J. Clin. Endocrinol. Metab. 2009; 94: 1843– 52. 28Zander M, Madsbad S, Madsen JL, Holst JJ. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and β-cell function in type 2 diabetes: A parallel-group study. Lancet 2002; 359: 824– 30. 29Amblee A. Dulaglutide for the treatment of type 2 diabetes. Drugs Today 2014; 50: 277– 89. 30Sisson EM. Liraglutide: Clinical pharmacology and considerations for therapy. Pharmacotherapy 2011; 31: 896– 911. Wiley Online Library 31Neumiller JJ. Incretin pharmacology: A review of the incretin effect and current incretin–based therapies. Cardiovasc. Hematol. Agents Med. Chem. 2012; 10: 276– 88. 32Angeli FS, Shannon RP. Incretin-based therapies: Can we achieve glycemic control and cardioprotection? J. Endocrinol. 2014; 221: T17– 30. 33Forst T, Pfutzner A. Pharmacological profile, efficacy and safety of lixisenatide in type 2 diabetes mellitus. Expert Opin. Pharmacother. 2013; 14: 2281– 96. 34Russell S. Incretin-based therapies for type 2 diabetes mellitus: A review of direct comparisons of efficacy, safety and patient satisfaction. Int. J. Clin. Pharm. 2013; 35: 159– 72. 35Rummey C, Metz G. Homology models of dipeptidyl peptidases 8 and 9 with a focus on loop predictions near the active site. Proteins 2007; 66: 160– 71. Wiley Online Library 36Lankas GR, Leiting B, Roy RS, etal. Dipeptidyl peptidase IV inhibition for the treatment of type 2 diabetes: Potential importance of selectivity over dipeptidyl peptidases 8 and 9. Diabetes 2005; 54: 2988– 94. 37Agrawal R, Bahare RS, Jain P, Dikshit SN, Ganguly S. Novel serine protease dipeptidyl peptidase IV inhibitor: Alogliptin. Mini Rev. Med. Chem. 2012; 12: 1345– 58. 38Capuano A, Sportiello L, Maiorino MI, Rossi F, Giugliano D, Esposito K. Dipeptidyl peptidase–4 inhibitors in type 2 diabetes therapy-focus on alogliptin. Drug Des. Devel. Ther. 2013; 7: 989– 1001. 39Christopher R, Covington P, Davenport M etal. Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase–4 inhibitor alogliptin in healthy male subjects. Clin. Ther. 2008; 30: 513– 27. 40Golightly LK, Drayna CC, McDermott MT. Comparative clinical pharmacokinetics of dipeptidyl peptidase-4 inhibitors. Clin. Pharmacokinet. 2012; 51: 501– 14. 41Jarvis CI, Cabrera A, Charron D. Alogliptin: A new dipeptidyl peptidase–4 inhibitor for type 2 diabetes mellitus. Ann. Pharmacother. 2013; 47: 1532– 9. 42Ndefo UA, Okoli O, Erowele G. Alogliptin: A new dipeptidyl peptidase-4 inhibitor for the management of type 2 diabetes mellitus. Am. J. Health Syst. Pharm. 2014; 71: 103– 9. 44Marino AB, Cole SW. Alogliptin: Safety, efficacy, and clinical implications. J. Pharm. Pract. 2015; 28: 99– 106. 45Seino Y, Yabe D. Alogliptin benzoate for the treatment of type 2 diabetes. Expert Opin. Pharmacother. 2014; 15: 851– 63. 46Dineen L, Law C, Scher R, Pyon E. Alogliptin (nesina) for adults with type-2 diabetes. P. T. 2014; 39: 186– 202. 47Said S, Nwosu AC, Mukherjee D, Hernandez GT. Alogliptin; A review of a new dipeptidyl peptidase–4 (DPP–4) inhibitor for the treatment of type 2 diabetes mellitus. Cardiovasc. Hematol. Disord. Drug Targets 2014; 14: 64– 70. 48Kutoh E, Kaneoka N, Hirate M. Alogliptin: A new dipeptidyl peptidase–4 inhibitor with potential anti-atherogenic properties. Endocr. Res. 2014; 40: 1– 9. 49Ceriello A, Sportiello L, Rafaniello C, Rossi F. DPP-4 inhibitors: Pharmacological differences and their clinical implications. Expert Opin. Drug Saf. 2014; 13 (Suppl. 1): 57– 68. 50Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q, Alogliptin Study G. Efficacy and safety of adding the dipeptidyl peptidase–4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: A multicentre, randomised, double–blind, placebo–controlled study. Int. J. Clin. Pract. 2009; 63: 46– 55. Wiley Online Library 51Bosi E, Ellis GC, Wilson CA, Fleck PR. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: A 52-week, randomized, double-blind, active-controlled, parallel-group study. Diabetes Obes. Metab. 2011; 13: 1088– 96. Wiley Online Library 52Pratley RE, Fleck P, Wilson C. Efficacy and safety of initial combination therapy with alogliptin plus metformin versus either as monotherapy in drug–naïve patients with type 2 diabetes: A randomized, double-blind, 6-month study. Diabetes Obes. Metab. 2014; 16: 613– 21. Wiley Online Library 53Rosenstock J, Inzucchi SE, Seufert J, Fleck PR, Wilson CA, Mekki Q. Initial combination therapy with alogliptin and pioglitazone in drug–naïve patients with type 2 diabetes. Diabetes Care 2010; 33: 2406– 8. 54Pratley RE, Reusch JE, Fleck PR, Wilson CA, Mekki Q, Alogliptin Study G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study. Curr. Med. Res. Opin. 2009; 25: 2361– 71. 55DeFronzo RA, Burant CF, Fleck P, Wilson C, Mekki Q, Pratley RE. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 2012; 97: 1615– 22. 56Van Raalte DH, van Genugten RE, Eliasson B, etal. The effect of alogliptin and pioglitazone combination therapy on various aspects of β-cell function in patients with recent-onset type 2 diabetes. Eur. J. Endocrinol. 2014; 170: 565– 74. 57Del Prato S, Camisasca R, Wilson C, Fleck P. Durability of the efficacy and safety of alogliptin compared with glipizide in type 2 diabetes mellitus: A two-year study. Diabetes Obes. Metab. 2014; 16: 1239– 46. Wiley Online Library 58Rosenstock J, Wilson C, Fleck P. Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: A prospective, double-blind, randomized, 1-year study. Diabetes Obes. Metab. 2013; 15: 906– 14. Wiley Online Library 59Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q, Alogliptin Study G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes. Metab. 2009; 11: 167– 76. Wiley Online Library 60Seino Y, Fujita T, Hiroi S, Hirayama M, Kaku K. Alogliptin plus voglibose in Japanese patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial with an open-label, long-term extension. Curr. Med. Res. Opin. 2011; 27 (Suppl. 3): 21– 9. 61Takahara M, Shiraiwa T, Katakami N, Kaneto H, Matsuoka TA, Shimomura I. Efficacy of adding once- and thrice-daily voglibose in Japanese type 2 diabetic patients treated with alogliptin. Endocr. J. 2014; 61: 447– 56. 62Kurozumi A, Okada Y, Mori H, Arao T, Tanaka Y. Efficacy of α-glucosidase inhibitors combined with dipeptidyl-peptidase-4 inhibitor (alogliptin) for glucose fluctuation in patients with type 2 diabetes mellitus by continuous glucose monitoring. J. Diabetes Investig. 2013; 4: 393– 8. Wiley Online Library 63Kusunoki Y, Katsuno T, Myojin M, etal. Effect of additional administration of acarbose on blood glucose fluctuations and postprandial hyperglycemia in patients with type 2 diabetes mellitus under treatment with alogliptin. Endocr. J. 2013; 60: 431– 9. 64Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1C without causing weight gain or increased hypoglycaemia. Diabetes Obes. Metab. 2009; 11: 1145– 52. Wiley Online Library 65Kaku K, Mori M, Kanoo T, Katou M, Seino Y. Efficacy and safety of alogliptin added to insulin in Japanese patients with type 2 diabetes: A randomized, double-blind, 12-week, placebo-controlled trial followed by an open-label, long-term extension phase. Expert Opin. Pharmacother. 2014; 15: 2121– 30. 66Covington P, Christopher R, Davenport M etal. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase–4 inhibitor alogliptin: A randomized, double–blind, placebo–controlled, multiple–dose study in adult patients with type 2 diabetes. Clin. Ther. 2008; 30: 499– 512. 67DeFronzo RA, Fleck PR, Wilson CA, Mekki Q, Alogliptin Study G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: A randomized, double-blind, placebo-controlled study. Diabetes Care 2008; 31: 2315– 17. 68Seino Y, Fujita T, Hiroi S, Hirayama M, Kaku K. Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: A randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study. Curr. Med. Res. Opin. 2011; 27: 1781– 92. 69Moritoh Y, Takeuchi K, Hazama M. Combination treatment with alogliptin and voglibose increases active GLP-1 circulation, prevents the development of diabetes and preserves pancreatic β-cells in prediabetic db/db mice. Diabetes Obes. Metab. 2010; 12: 224– 33. Wiley Online Library 70Pratley RE, McCall T, Fleck PR, Wilson CA, Mekki Q. Alogliptin use in elderly people: A pooled analysis from phase 2 and 3 studies. J. Am. Geriatr. Soc. 2009; 57: 2011– 19. Wiley Online Library 71Scheen AJ. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes. Metab. 2010; 12: 648– 58. Wiley Online Library 72Feng J, Zhang Z, Wallace MB, etal. Discovery of alogliptin: A potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J. Med. Chem. 2007; 50: 2297– 300. 73Scheen AJ. Dipeptidylpeptidase–4 inhibitors (gliptins): Focus on drug–drug interactions. Clin. Pharmacokinet. 2010; 49: 573– 88. 74Davis TM. Dipeptidyl peptidase-4 inhibitors: Pharmacokinetics, efficacy, tolerability and safety in renal impairment. Diabetes Obes. Metab. 2014; 16: 891– 9. Wiley Online Library 75Baetta R, Corsini A. Pharmacology of dipeptidyl peptidase-4 inhibitors: Similarities and differences. Drugs 2011; 71: 1441– 67. 76Karim A, Laurent A, Munsaka M, Wann E, Fleck P, Mekki Q. Coadministration of pioglitazone or glyburide and alogliptin: Pharmacokinetic drug interaction assessment in healthy participants. J. Clin. Pharmacol. 2009; 49: 1210– 19. Wiley Online Library 77White WB, Pratley R, Fleck P, etal. Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes. Metab. 2013; 15: 668– 73. Wiley Online Library 78White WB, Cannon CP, Heller SR, etal. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 2013; 369: 1327– 35. 79Kato N, Oka M, Murase T, etal. Discovery and pharmacological characterization of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-yl]-2-oxoethyl}amino)-2-methylpropyl]-2-methyl pyrazolo[1,5-a]pyrimidine-6-carboxamide hydrochloride (anagliptin hydrochloride salt) as a potent and selective DPP–IV inhibitor. Bioorg. Med. Chem. 2011; 19: 7221– 7. 80Tsubamoto Y, Goto M. Preclinical and clinical aspects of the dipeptidyl peptidase-4 inhibitor anagliptin. Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica 2013; 141: 339– 49. 81Furuta S, Smart C, Hackett A, Benning R, Warrington S. Pharmacokinetics and metabolism of [14C]anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans. Xenobiotica 2013; 43: 432– 42. 82Jin SM, Park SW, Yoon KH, etal. Anagliptin and sitagliptin as add-ons to metformin for patients with type 2 diabetes: A 24-week, multicentre, randomized, double-blind, active-controlled, phase III clinical trial with a 28-week extension. Diabetes Obes. Metab. 2015; 17: 511– 15. Wiley Online Library 83Yang HK, Min KW, Park SW, etal. A randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of anagliptin in drug-naïve patients with type 2 diabetes. Endocr. J. 2015; 62: 449– 62. 84Nishio S, Abe M, Ito H. Anagliptin in the treatment of type 2 diabetes: Safety, efficacy, and patient acceptability. Diabetes Metab. Syndr. Obes. 2015; 8: 163– 71. 85Kim SH, Lee SH, Yim HJ. Gemigliptin, a novel dipeptidyl peptidase 4 inhibitor: First new anti–diabetic drug in the history of Korean pharmaceutical industry. Arch. Pharmacal Res. 2013; 36: 1185– 8. 86Lim KS, Kim JR, Choi YJ, etal. Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15–0444 in healthy Korean men: A dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study. Clin. Ther. 2008; 30: 1817– 30. 87Lim KS, Cho JY, Kim BH, etal. Pharmacokinetics and pharmacodynamics of LC15–0444, a novel dipeptidyl peptidase IV inhibitor, after multiple dosing in healthy volunteers. Br. J. Clin. Pharmacol. 2009; 68: 883– 90. Wiley Online Library 88Rhee EJ, Lee WY, Yoon KH. A multicentre, randomized, placebo-controlled, double-blind phase II trial evaluating the optimal dose, efficacy and safety of LC 15–0444 in patients with type 2 diabetes. Diabetes Obes. Metab. 2010; 12: 1113– 19. Wiley Online Library 89Yang SJ, Min KW, Gupta SK, etal. A multicentre, multinational, randomized, placebo-controlled, double-blind, phase 3 trial to evaluate the efficacy and safety of gemigliptin (LC15–0444) in patients with type 2 diabetes. Diabetes Obes. Metab. 2013; 15: 410– 16. Wiley Online Library 90Rhee EJ, Lee WY, Min KW, etal. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor gemigliptin compared with sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Obes. Metab. 2013; 15: 523– 30. Wiley Online Library 91Kim N, Patrick L, Mair S, etal. Absorption, metabolism and excretion of [14C]gemigliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Xenobiotica 2014; 44: 522– 30. 92Choi HY, Noh YH, Kim YH, etal. Effects of food on the pharmacokinetics of gemigliptin/metformin sustained-release 50/1,000mg (25/500mg×2 tablets) fixed dose combination tablet in healthy male volunteers. Int. J. Clin. Pharmacol. Ther. 2014; 52: 381– 91. 93Noh YH, Lim HS, Jin SJ, etal. Effects of ketoconazole and rifampicin on the pharmacokinetics of gemigliptin, a dipeptidyl peptidase-IV inhibitor: A crossover drug-drug interaction study in healthy male Korean volunteers. Clin. Ther. 2012; 34: 1182– 94. 94Kim SE, Yi S, Shin KH, etal. Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase IV inhibitor LC15–0444 and pioglitazone in healthy volunteers. Int. J. Clin. Pharmacol. Ther. 2012; 50: 17– 23. 95Deacon CF, Holst JJ. Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type 2 diabetes. Expert Opin. Investig. Drugs 2010; 19: 133– 40. 96Tiwari A. Linagliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Curr. Opin. Investig. Drugs 2009; 10: 1091– 104. 98Barnett AH. Linagliptin: A novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv. Ther. 2011; 28: 447– 59. 99Rendell M, Chrysant SG. Review of the safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study. Postgrad. Med. 2011; 123: 183– 6. 100Kalra S, Unnikrishnan AG, Agrawal N, Singh AK. Linagliptin and newer DPP–4 inhibitors: Newer uses and newer indications. Recent Pat. Endocr. Metab. Immune Drug Discov. 2011; 5: 197– 202. 101Ghatak SB, Patel DS, Shanker N, Srivastava A, Deshpande SS, Panchal SJ. Linagliptin: A novel xanthine–based dipeptidyl peptidase–4 inhibitor for treatment of type II diabetes mellitus. Curr. Diabetes Rev. 2011; 7: 325– 35. 102Scheen AJ. Linagliptin for the treatment of type 2 diabetes (pharmacokinetic evaluation). Expert Opin. Drug Metab. Toxicol. 2011; 7: 1561– 76. 103Aletti R, Cheng-Lai A. Linagliptin: The newest dipeptidyl peptidase–4 inhibitor for type 2 diabetes mellitus. Cardiol. Rev. 2012; 20: 45– 51. 104Forst T, Pfutzner A. Linagliptin, a dipeptidyl peptidase-4 inhibitor with a unique pharmacological profile, and efficacy in a broad range of patients with type 2 diabetes. Expert Opin. Pharmacother. 2012; 13: 101– 10. 105Singh-Franco D, McLaughlin-Middlekauff J, Elrod S, Harrington C. The effect of linagliptin on glycaemic control and tolerability in patients with type 2 diabetes mellitus: A systematic review and meta–analysis. Diabetes Obes. Metab. 2012; 14: 694– 708. Wiley Online Library 106Agrawal R, Jain P, Dikshit SN. Linagliptin: A novel methylxanthin based approved dipeptidyl peptidase-4 inhibitor. Curr. Drug Targets 2012; 13: 970– 83. 107Neumiller JJ, Setter SM. Review of linagliptin for the treatment of type 2 diabetes mellitus. Clin. Ther. 2012; 34: 993– 1005. 108Graefe-Mody U, Retlich S, Friedrich C. Clinical pharmacokinetics and pharmacodynamics of linagliptin. Clin. Pharmacokinet. 2012; 51: 411– 27. 109Deeks ED. Linagliptin: A review of its use in the management of type 2 diabetes mellitus. Drugs 2012; 72: 1793– 824. 110Hoimark L, Laursen T, Rungby J. Potential role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes. Diabetes Metab. Syndr. Obes. 2012; 5: 295– 302. 111Brown DX, Choudhury M, Evans M. Linagliptin as add-on therapy for type 2 diabetes – an overview. Drugs Today 2012; 48: 645– 54. 112Lajara R. Use of the dipeptidyl peptidase-4 inhibitor linagliptin in combination therapy for type 2 diabetes. Expert Opin. Pharmacother. 2012; 13: 2663– 71. 113Koliaki C, Doupis J. Linagliptin/Metformin fixed-dose combination treatment: A dual attack to type 2 diabetes pathophysiology. Adv. Ther. 2012; 29: 993– 1004. 114McGill JB. Linagliptin for type 2 diabetes mellitus: A review of the pivotal clinical trials. Ther. Adv. Endocrinol. Metab. 2012; 3: 113– 24. 115Haak T. Initial combination with linagliptin and metformin in newly diagnosed type 2 diabetes and severe hyperglycemia. Adv. Ther. 2012; 29: 1005– 15. 116Gallwitz B. Emerging DPP-4 inhibitors: Focus on linagliptin for type 2 diabetes. Diabetes Metab. Syndr. Obes. 2013; 6: 1– 9. 117Scheen AJ. Linagliptin plus metformin: A pharmacokinetic and pharmacodynamic evaluation. Expert Opin. Drug Metab. Toxicol. 2013; 9: 363– 77. 118Scheen AJ. Efficacy and safety of Jentadueto(R) (linagliptin plus metformin). Expert Opin. Drug Saf. 2013; 12: 275– 89. 119Maxwell LG, McFarland MS. Clinical utility and tolerability of linagliptin in diabetic patients. Drug Healthc. Patient Saf. 2013; 5: 67– 78. 120Guedes EP, Hohl A, de Melo TG, Lauand F. Linagliptin: Farmacology, efficacy and safety in type 2 diabetes treatment. Diabetol. Metab. Syndr. 2013; 5: 25. 121Gallwitz B. Safety and efficacy of linagliptin in type 2 diabetes patients with common renal and cardiovascular risk factors. Ther. Adv. Endocrinol. Metab. 2013; 4: 95– 105. 122Grunberger G. Clinical utility of the dipeptidyl peptidase-4 inhibitor linagliptin. Postgrad. Med. 2013; 125: 79– 90. 123von Websky K, Reichetzeder C, Hocher B. Linagliptin as add-on therapy to insulin for patients with type 2 diabetes. Vasc. Health Risk Manag. 2013; 9: 681– 94. 124Eckhardt M, Langkopf E, Mark M, etal. 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylme thyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 2007; 50: 6450– 3. 125Huttner S, Graefe-Mody EU, Withopf B, Ring A, Dugi KA. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers. J. Clin. Pharmacol. 2008; 48: 1171– 8. Wiley Online Library 126Heise T, Graefe-Mody EU, Huttner S, Ring A, Trommeshauser D, Dugi KA. Pharmacokinetics, pharmacodynamics and tolerability of multiple oral doses of linagliptin, a dipeptidyl peptidase-4 inhibitor in male type 2 diabetes patients. Diabetes Obes. Metab. 2009; 11: 786– 94. Wiley Online Library 127Kawamori R, Inagaki N, Araki E, etal. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: A randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes. Metab. 2012; 14: 348– 57. Wiley Online Library 128Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial. Diabetes Obes. Metab. 2011; 13: 258– 67. Wiley Online Library 129Graefe-Mody EU, Padula S, Ring A, Withopf B, Dugi KA. Evaluation of the potential for steady state pharmacokinetic and pharmacodynamic interactions between the DPP-4 inhibitor linagliptin and metformin in healthy subjects. Curr. Med. Res. Opin. 2009; 25: 1963– 72. 130Taskinen MR, Rosenstock J, Tamminen I etal. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes. Metab. 2011; 13: 65– 74. Wiley Online Library 131Forst T, Uhlig-Laske B, Ring A etal. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled Type 2 diabetes. Diabet. Med. 2010; 27: 1409– 19. Wiley Online Library 132Gallwitz B, Rosenstock J, Rauch T, etal. 2-Year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: A randomised, double-blind, non-inferiority trial. Lancet 2012; 380: 475– 83. 133Gomis R, Espadero RM, Jones R, Woerle HJ, Dugi KA. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes. Metab. 2011; 13: 653– 61. Wiley Online Library 134Gomis R, Owens DR, Taskinen MR, etal. Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucose-lowering agents in 2121 subjects with type 2 diabetes: Up to 2years exposure in 24-week phase III trials followed by a 78-week open-label extension. Int. J. Clin. Pract. 2012; 66: 731– 40. Wiley Online Library 135Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: A 24-week randomized study. Diabetic Med. 2011; 28: 1352– 61. Wiley Online Library 136Graefe-Mody U, Giessmann T, Ring A, Iovino M, Woerle HJ. A randomized, open-label, crossover study evaluating the effect of food on the relative bioavailability of linagliptin in healthy subjects. Clin. Ther. 2011; 33: 1096– 103. 137Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, Withopf B, Wagner K. The metabolism and disposition of the oral dipeptidyl peptidase–4 inhibitor, linagliptin, in humans. Drug Metab. Dispos. 2010; 38: 667– 78. 138Fuchs H, Tillement JP, Urien S, Greischel A, Roth W. Concentration-dependent plasma protein binding of the novel dipeptidyl peptidase 4 inhibitor BI 1356 due to saturable binding to its target in plasma of mice, rats and humans. J. Pharm. Pharmacol. 2009; 61: 55– 62. Wiley Online Library 139Graefe-Mody U, Friedrich C, Port A, etal. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes. Metab. 2011; 13: 939– 46. Wiley Online Library 140McGill JB, Sloan L, Newman J, etal. Long-term efficacy and safety of linagliptin in patients with type 2 diabetes and severe renal impairment: A 1-year, randomized, double-blind, placebo-controlled study. Diabetes Care 2013; 36: 237– 44. 141Graefe-Mody U, Rose P, Retlich S, etal. Pharmacokinetics of linagliptin in subjects with hepatic impairment. Br. J. Clin. Pharmacol. 2012; 74: 75– 85. Wiley Online Library 142Schernthaner G, Barnett AH, Emser A, etal. Safety and tolerability of linagliptin: A pooled analysis of data from randomized controlled trials in 3572 patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 2012; 14: 470– 8. Wiley Online Library 143Scheen AJ. A review of gliptins in 2011. Expert Opin. Pharmacother. 2012; 13: 81– 99. 144Johansen OE, Neubacher D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: A pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc. Diabetol. 2012; 11: 3. 145Hocher B, Sharkovska Y, Mark M, Klein T, Pfab T. The novel DPP-4 inhibitors linagliptin and BI 14361 reduce infarct size after myocardial ischemia/reperfusion in rats. Int. J. Cardiol. 2013; 167: 87– 93. 146Ring A, Port A, Graefe-Mody EU, Revollo I, Iovino M, Dugi KA. The DPP-4 inhibitor linagliptin does not prolong the QT interval at therapeutic and supratherapeutic doses. Br. J. Clin. Pharmacol. 2011; 72: 39– 50. Wiley Online Library 147Friedrich C, Port A, Ring A, etal. Effect of multiple oral doses of linagliptin on the steady state pharmacokinetics of a combination oral contraceptive in healthy female adults: An open-label, two-period, fixed-sequence, multiple-dose study. Clin. Drug Investig. 2011; 31: 643– 53. 148Friedrich C, Ring A, Brand T, Sennewald R, Graefe-Mody EU, Woerle HJ. Evaluation of the pharmacokinetic interaction after multiple oral doses of linagliptin and digoxin in healthy volunteers. Eur. J. Drug Metab. Pharmacokinet. 2011; 36: 17– 24. 149Graefe-Mody EU, Brand T, Ring A, etal. Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. Int. J. Clin. Pharmacol. Ther. 2011; 49: 300– 10. 150Graefe-Mody U, Rose P, Ring A, Zander K, Iovino M, Woerle HJ. Assessment of the pharmacokinetic interaction between the novel DPP-4 inhibitor linagliptin and a sulfonylurea, glyburide, in healthy subjects. Drug Metab. Pharmacokinet. 2011; 26: 123– 9. 151Graefe-Mody EU, Jungnik A, Ring A, Woerle HJ, Dugi KA. Evaluation of the pharmacokinetic interaction between the dipeptidyl peptidase-4 inhibitor linagliptin and pioglitazone in healthy volunteers. Int. J. Clin. Pharmacol. Ther. 2010; 48: 652– 61. 152Graefe-Mody U, Huettner S, Stahle H, Ring A, Dugi KA. Effect of linagliptin (BI 1356) on the steady state pharmacokinetics of simvastatin. Int. J. Clin. Pharmacol. Ther. 2010; 48: 367– 74. 153Nowicki M, Rychlik I, Haller H etal. Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: A randomised controlled 52-week efficacy and safety study. Int. J. Clin. Pract. 2011; 65: 1230– 9. Wiley Online Library 154Hirshberg B, Parker A, Edelberg H, Donovan M, Iqbal N. Safety of saxagliptin: Events of special interest in 9156 patients with type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 2014; 30: 556– 69. Wiley Online Library 155Dave DJ. Saxagliptin: A dipeptidyl peptidase-4 inhibitor in the treatment of type 2 diabetes mellitus. J. Pharmacol. Pharmacother. 2011; 2: 230– 5. 156Neumiller JJ, Campbell RK. Saxagliptin: A dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes mellitus. Am. J. Health Syst. Pharm. 2010; 67: 1515– 25. 157Scirica BM, Bhatt DL, Braunwald E, etal. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 2013; 369: 1317– 26. 158Subbarayan S, Kipnes M. Sitagliptin: A review. Expert Opin. Pharmacother. 2011; 12: 1613– 22. 159McFarland MS, Markley BM, Zhang P, Hudson JQ. Evaluation of Modification of Diet in Renal Disease Study and Cockcroft-Gault equations for sitagliptin dosing. J. Nephrol. 2012; 25: 515– 22. 160Eligar VS, Bain SC. A review of sitagliptin with special emphasis on its use in moderate to severe renal impairment. Drug Des. Devel. Ther. 2013; 7: 893– 903. 161Round EM, Engel SS, Golm GT, Davies MJ, Kaufman KD, Goldstein BJ. Safety of sitagliptin in elderly patients with type 2 diabetes: A pooled analysis of 25 clinical studies. Drugs Aging 2014; 31: 203– 14. 162Lee M, Rhee MK. Sitagliptin for Type 2 diabetes: A 2015 update. Expert Rev. Cardiovasc. Ther. 2015; 13: 597– 610. 163Singh S, Chang HY, Richards TM, Weiner JP, Clark JM, Segal JB. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: A population-based matched case-control study. JAMA Intern. Med. 2013; 173: 534– 9. 164Bethel MA, Green JB, Milton J, etal. Regional, age and sex differences in baseline characteristics of patients enrolled in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Diabetes Obes. Metab. 2015; 17: 395– 402. Wiley Online Library 165Yoshida T, Akahoshi F, Sakashita H, etal. Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-y lcarbonyl]thiazolidine): A highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Bioorg. Med. Chem. 2012; 20: 5705– 19. 166Kadowaki T, Kondo K. Efficacy, safety and dose-response relationship of teneligliptin, a dipeptidyl peptidase-4 inhibitor, in Japanese patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 2013; 15: 810– 18. Wiley Online Library 167Kishimoto M. Teneligliptin: A DPP-4 inhibitor for the treatment of type 2 diabetes. Diabetes Metab. Syndr. Obes. 2013; 6: 187– 95. 168Goda M, Kadowaki T. Teneligliptin for the treatment of type 2 diabetes. Drugs Today 2013; 49: 615– 29. 169Nakamaru Y, Hayashi Y, Ikegawa R, etal. Metabolism and disposition of the dipeptidyl peptidase IV inhibitor teneligliptin in humans. Xenobiotica 2014; 44: 242– 53. 170Brandt I, Joossens J, Chen X, etal. Inhibition of dipeptidyl-peptidase IV catalyzed peptide truncation by vildagliptin ((2S)-{[(3-hydroxyadamantan-1-yl)amino]acetyl}-pyrrolidine-2-carbonitrile). Biochem. Pharmacol. 2005; 70: 134– 43. 171Villhauer EB, Brinkman JA, Naderi GB, etal. 1-[[(3-Hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: A potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J. Med. Chem. 2003; 46: 2774– 89. 172Ahren B, Landin-Olsson M, Jansson PA, Svensson M, Holmes D, Schweizer A. Inhibition of dipeptidyl peptidase-4 reduces glycemia, sustains insulin levels, and reduces glucagon levels intype 2 diabetes. J. Clin. Endocrinol. Metab. 2004; 89: 2078– 84. 173Zhang C, Feng Y, Qu S, etal. Resveratrol attenuates doxorubicin-induced cardiomyocyte apoptosis in mice through SIRT1-mediated deacetylation of p53. Cardiovasc. Res. 2011; 90: 538– 45. 174He YL. Clinical pharmacokinetics and pharmacodynamics of vildagliptin. Clin. Pharmacokinet. 2012; 51: 147– 62. 175He YL, Serra D, Wang Y, etal. Pharmacokinetics and pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus. Clin. Pharmacokinet. 2007; 46: 577– 88. 176He YL, Yamaguchi M, Ito H, Terao S, Sekiguchi K. Pharmacokinetics and pharmacodynamics of vildagliptin in Japanese patients with type 2 diabetes. Int. J. Clin. Pharmacol. Ther. 2010; 48: 582– 95. 178Lukashevich V, Schweizer A, Shao Q, Groop PH, Kothny W. Safety and efficacy of vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: A prospective 24-week randomized placebo-controlled trial. Diabetes Obes. Metab. 2011; 13: 947– 54. Wiley Online Library 179Kothny W, Shao Q, Groop PH, Lukashevich V. One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment. Diabetes Obes. Metab. 2012; 14: 1032– 9. Wiley Online Library 180Kim YG, Hahn S, Oh TJ, Kwak SH, Park KS, Cho YM. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: A systematic review and meta-analysis. Diabetologia 2013; 56: 696– 708. The full text of this article hosted at iucr.org is unavailable due to technical difficulties. Please check your email for instructions on resetting your password. If you do not receive an email within 10 minutes, your email address may not be registered, and you may need to create a new Wiley Online Library account. Can\'t sign in? Forgot your username? Enter your email address below and we will send you your username If the address matches an existing account you will receive an email with instructions to retrieve your username

新闻动态
行业前沿
技术文章
最新产品

188进口试剂采购网 www.188bio.cn -中国试剂网,试剂网,化学试剂网,国药试剂,抗体公司,试剂公司,试剂盒公司,苏州试剂公司,北京化学试剂公司,天津化学试剂,试剂商城,试剂代理,流式抗体 细胞库查询 sitemap