The pharmacokinetic considerations and adverse effects of DDP-4 inhibitors

Expert Opinion on Drug Metabolism and Toxicology

Volumn 10, Issue 6, 2014, Pages 787-812

  Filippatos, Theodosios D ^a,b   Athyros, Vasilios G ^a   Elisaf, Moses S ^b  

^a ARISTOTLE UNIVERSITY OF THESSALONIKI   (Greece)

^b UNIVERSITY OF IOANNINA   (Greece)

Author keywords

Adverse effects; Dipeptidyl peptidase inhibitors; Drug interactions; Elimination; Excretion; Gliptins; Metabolism; Pharmacokinetics; Safety; Tolerability

Indexed keywords

ALOGLIPTIN; ANAGLIPTIN; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; DIPEPTIDYL PEPTIDASE; DIPEPTIDYL PEPTIDASE 8; DIPEPTIDYL PEPTIDASE 9; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GEMFIBROZIL; GEMIGLIPTIN; INCRETIN; KETOCONAZOLE; LINAGLIPTIN; RIFAMPICIN; SAXAGLIPTIN; SIMVASTATIN; SITAGLIPTIN; TENELIGLIPTIN; UNCLASSIFIED DRUG; VILDAGLIPTIN; VOGLIBOSE; 3-(4-(4-(3-METHYL-1-PHENYL-1H-PYRAZOL-5-YL)PIPERAZIN-1-YL)PYRROLIDIN-2-YLCARBONYL)THIAZOLIDINE; ADAMANTANE; DIPEPTIDE; LC15-0444; NITRILE; PIPERIDINE DERIVATIVE; PIPERIDONE DERIVATIVE; PURINE DERIVATIVE; PYRAZINE DERIVATIVE; PYRAZOLE DERIVATIVE; PYRIMIDINE DERIVATIVE; PYRROLIDINE DERIVATIVE; QUINAZOLINE DERIVATIVE; THIAZOLIDINE DERIVATIVE; TRIAZOLE DERIVATIVE; URACIL;

ACUTE PANCREATITIS; ALANINE AMINOTRANSFERASE BLOOD LEVEL; ALLERGIC CONJUNCTIVITIS; AMYLASE BLOOD LEVEL; ANGIONEUROTIC EDEMA; ARTHRALGIA; ASTHENIA; BACKACHE; BRONCHITIS; CHRONIC PANCREATITIS; CONNECTIVE TISSUE DISEASE; COUGHING; CREATINE KINASE BLOOD LEVEL; DEPRESSION; DIABETIC PATIENT; DIARRHEA; DIZZINESS; DRUG EFFICACY; DRUG HYPERSENSITIVITY; DRUG MECHANISM; DRUG METABOLISM; DRUG SAFETY; DRUG SELECTIVITY; ECZEMA; FATIGUE; FATTY LIVER; GASTROINTESTINAL DISEASE; GASTROINTESTINAL SYMPTOM; HEADACHE; HEART FAILURE; HUMAN; HYPERHIDROSIS; HYPOGLYCEMIA; IMMUNOPATHOLOGY; INFECTION; INFESTATION; INFLUENZA; LIVER DYSFUNCTION; MYALGIA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OSTEOARTHRITIS; PAIN; PANCREAS CANCER; PANCREATITIS; PERIPHERAL EDEMA; PHARYNGITIS; POSTMARKETING SURVEILLANCE; PRURITUS; QT PROLONGATION; RASH; REVIEW; RHINOPHARYNGITIS; SIDE EFFECT; SKIN TOXICITY; SORE THROAT; TREMOR; UNSPECIFIED SIDE EFFECT; UPPER RESPIRATORY TRACT INFECTION; URINARY TRACT INFECTION; ANALOGS AND DERIVATIVES; DIABETES MELLITUS, TYPE 2; DRUG INTERACTION;

ADAMANTANE; DIABETES MELLITUS, TYPE 2; DIPEPTIDES; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DRUG INTERACTIONS; HUMANS; NITRILES; PIPERIDINES; PIPERIDONES; PURINES; PYRAZINES; PYRAZOLES; PYRIMIDINES; PYRROLIDINES; QUINAZOLINES; THIAZOLIDINES; TRIAZOLES; URACIL;

EID: 84900988588     PISSN: 17425255     EISSN: 17447607     Source Type: Journal    
DOI: 10.1517/17425255.2014.907274     Document Type: Review

References (247)

1. American Diabetes Association. Standards of medical care in diabetes - 2014. Diabetes Care 2014;37:S14-80
2. Filippatos TD, Rizos EC, Gazi IF, et al. Differences in metabolic parameters and cardiovascular risk between American Diabetes Association and World Health Organization definition of impaired fasting glucose in European Caucasian subjects: a cross-sectional study. Arch Med Sci 2013;9:788-95
3. Filippatos TD, Rizos EC, Tsimihodimos V, et al. Small highdensity lipoprotein (HDL) subclasses are increased with decreased activity of HDL-associated phospholipase A(2) in subjects with prediabetes. Lipids 2013;48:547-55
4. Agouridis AP, Rizos CV, Elisaf MS, et al. Does combination therapy with statins and fibrates prevent cardiovascular disease in diabetic patients with atherogenic mixed dyslipidemia? Rev Diabet Stud 2013;10:171-90
5. Filippatos TD, Elisaf MS. Combination drug treatment in obese diabetic patients. World J Diabetes 2010;1:8-11
6. Filippatos TD, Elisaf MS. Effects of glucagon-like peptide-1 receptor agonists on renal function. World J Diabetes 2013;4:190-201
7. Agouridis AP, Filippatos TD, Derdemezis CS, et al. Combination of fenofibrate with non-statin drug regimens. Curr Pharm Des 2010;16:3401-16
8. Filippatos T, Milionis HJ. Treatment of hyperlipidaemia with fenofibrate and related fibrates. Expert Opin Investig Drugs 2008;17:1599-614
9. Filippatos TD, Elisaf MS. Fenofibrate plus simvastatin (fixed-dose combination) for the treatment of dyslipidaemia. Expert Opin Pharmacother 2011;12:1945-58
10. Filippatos TD, Kiortsis DN, Liberopoulos EN, et al. Effect of orlistat, micronised fenofibrate and their combination on metabolic parameters in overweight and obese patients with the metabolic syndrome: the FenOrli study. Curr Med Res Opin 2005;21:1997-2006
11. Filippatos TD, Liberopoulos EN, Kostapanos M, et al. The effects of orlistat and fenofibrate, alone or in combination, on high-density lipoprotein subfractions and pre-beta1-HDL levels in obese patients with metabolic syndrome. Diabetes Obes Metab 2008;10:476-83
12. Agouridis AP, Tsimihodimos V, Filippatos TD, et al. The effects of rosuvastatin alone or in combination with fenofibrate or omega 3 fatty acids on inflammation and oxidative stress in patients with mixed dyslipidemia. Expert Opin Pharmacother 2011;12:2605-11
13. Filippatos TD. A review of time courses and predictors of lipid changes with fenofibric acid-statin combination. Cardiovasc Drugs Ther 2012;26:245-55
14. Eckerle Mize DL, Salehi M. The place of GLP-1-based therapy in diabetes management: differences between DPP-4 inhibitors and GLP-1 receptor agonists. Curr Diab Rep 2013;13:307-18
15. Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care 2011;34(Suppl 2):S276-8
16. Jose T, Inzucchi SE. Cardiovascular effects of the DPP-4 inhibitors. Diab Vasc Dis Res 2012;9:109-16
17. Kirby M, Yu DM, O?Connor S, et al. Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. Clin Sci (Lond) 2010;118:31-41
18. Yu DM, Yao TW, Chowdhury S, et al. The dipeptidyl peptidase IV family in cancer and cell biology. FEBS J 2010;277:1126-44
19. Vora KA, Porter G, Peng R, et al. Genetic ablation or pharmacological blockade of dipeptidyl peptidase IV does not impact T cell-dependent immune responses. BMC Immunol 2009;10:19
20. Underwood R, Chiravuri M, Lee H, et al. Sequence, purification, and cloning of an intracellular serine protease, quiescent cell proline dipeptidase. J Biol Chem 1999;274:34053-8
21. Abbott CA, Yu DM, Woollatt E, et al. Cloning, expression and chromosomal localization of a novel human dipeptidyl peptidase (DPP) IV homolog, DPP8. Eur J Biochem 2000;267:6140-50
22. Ajami K, Abbott CA, McCaughan GW, et al. Dipeptidyl peptidase 9 has two forms, a broad tissue distribution, cytoplasmic localization and DPIV-like peptidase activity. Biochim Biophys Acta 2004;1679:18-28
23. Maes MB, Dubois V, Brandt I, et al. Dipeptidyl peptidase 8/9-like activity in human leukocytes. J Leukoc Biol 2007;81:1252-7
24. Lankas GR, Leiting B, Roy RS, et al. 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
25. Gupta V, Kalra S. Choosing a gliptin. Indian J Endocrinol Metab 2011;15:298-308
26. Burkey BF, Hoffmann PK, Hassiepen U, et al. Adverse effects of dipeptidyl peptidases 8 and 9 inhibition in rodents revisited. Diabetes Obes Metab 2008;10:1057-61
27. Wu JJ, Tang HK, Yeh TK, et al. Biochemistry, pharmacokinetics, and toxicology of a potent and selective DPP8/9 inhibitor. Biochem Pharmacol 2009;78:203-10
28. Liu Y, Hu Y, Liu T. Recent advances in non-peptidomimetic dipeptidyl peptidase 4 inhibitors: medicinal chemistry and preclinical aspects. Curr Med Chem 2012;19:3982-99
29. Vincent SH, Reed JR, Bergman AJ, et al. Metabolism and excretion of the dipeptidyl peptidase 4 inhibitor [14C] sitagliptin in humans. Drug Metab Dispos 2007;35:533-8
30. Migoya EM, Stevens CH, Bergman AJ, et al. Effect of moderate hepatic insufficiency on the pharmacokinetics of sitagliptin. Can J Clin Pharmacol 2009;16:e165-70
31. Sitagliptin SPC. Available from: http:// www.merck.com/product/usa/ picirculars/j/januvia/januviapi.pdf [Accessed at 23 December 2013]
32. Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 2007;30:1862-4
33. He H, Tran P, Yin H, et al. Absorption, metabolism, and excretion of [14C] vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Drug Metab Dispos 2009;37:536-44
34. Galvus SPC. Available from: http://www. ema.europa.eu/docs/enGB/ documentlibrary/EPAR-ProductInformation/human/000771/ WC500020327.pdf [Accessed at 24 December 2013]
35. He YL, Sabo R, Campestrini J, et al. The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibitor vildagliptin. Eur J Clin Pharmacol 2007;63:677-86
36. He YL, Kulmatycki K, Zhang Y, et al. Pharmacokinetics of vildagliptin in patients with varying degrees of renal impairment. Int J Clin Pharmacol Ther 2013;51:693-703
37. Augeri DJ, Robl JA, Betebenner DA, et al. Discovery and preclinical profile of saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005;48:5025-37
38. Wang A, Dorso C, Kopcho L, et al. Potency, selectivity and prolonged binding of saxagliptin to DPP4: maintenance of DPP4 inhibition by saxagliptin in vitro and ex vivo when compared to a rapidly-dissociating DPP4 inhibitor. BMC Pharmacol 2012;12:2
39. Fura A, Khanna A, Vyas V, et al. Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections. Drug Metab Dispos 2009;37:1164-71
40. Onglyza package insert. Available from: http://packageinserts.bms.com/pi/ pionglyza.pdf [Accessed at 24 December 2013]
41. Boulton DW, Li L, Frevert EU, et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin Pharmacokinet 2011;50:253-65
42. Alogliptin SPC. Available from: http:// general.takedapharm.com/content/ file/pi. pdf?applicationcode=66B0B942-E82B- 46AD-886A-F4AA59F5F33C&File TypeCode=NESINAPI [Accessed at 24 December 2013]
43. Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, et al. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos 2010;38:667-78
44. Fuchs H, Runge F, Held HD. Excretion of the dipeptidyl peptidase-4 inhibitor linagliptin in rats is primarily by biliary excretion and P-gp-mediated efflux. Eur J Pharm Sci 2012;45:533-8
45. Linagliptin EMEA EPAR. Available from: http://www.ema.europa.eu/docs/ enGB/documentlibrary/EPAR-ProductInformation/human/002110/ WC500115745.pdf [Accessed at 24 December 2013]
46. Graefe-Mody U, Rose P, Retlich S, et al. Pharmacokinetics of linagliptin in subjects with hepatic impairment. Br J Clin Pharmacol 2012;74:75-85
47. Friedrich C, Emser A, Woerle HJ, et al. Renal impairment has no clinically relevant effect on the long-term exposure of linagliptin in patients with type 2 diabetes. Am J Ther 2013;20:618-21
48. Anagliptin information. Available from: http://www.rad-ar.or.jp/siori/ english/ kekka.cgi?n=32790 [Accessed at 24 December 2013]
49. Furuta S, Smart C, Hackett A, et al. Pharmacokinetics and metabolism of [14C]anagliptin, a novel dipeptidyl peptidase-4 inhibitor, in humans. Xenobiotica 2013;43:432-42
50. Teneligliptin information. Available from: http://www.rad-ar.or.jp/siori/ english/kekka.cgi?n=32722 [Accessed at 24 December 2013]
51. Nakamaru Y, Hayashi Y, Ikegawa R, et al. Metabolism and disposition of the dipeptidyl peptidase IV inhibitor teneligliptin in humans. Xenobiotica 2014;44:242-53
52. Kim N, Patrick L, Mair S, et al. Absorption, metabolism and excretion of [14C]gemigliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Xenobiotica 2013. [Epub ahead of print]
53. Kim 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 Pharm Res 2013;36:1185-8
54. Nonaka K, Kakikawa T, Sato A, et al. Efficacy and safety of sitagliptin monotherapy in Japanese patients with type 2 diabetes. Diabetes Res Clin Pract 2008;79:291-8
55. Goldstein BJ, Feinglos MN, Lunceford JK, et al. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007;30:1979-87
56. Williams-Herman D, Johnson J, Teng R, et al. Efficacy and safety of initial combination therapy with sitagliptin and metformin in patients with type 2 diabetes: a 54-week study. Curr Med Res Opin 2009;25:569-83
57. Gross BN, Cross LB, Foard J, et al. Elevated hepatic enzymes potentially associated with sitagliptin. Ann Pharmacother 2010;44:394-5
58. Toyoda-Akui M, Yokomori H, Kaneko F, et al. A case of drug-induced hepatic injury associated with sitagliptin. Intern Med 2011;50:1015-20
59. Kutoh E. Probable linagliptin-induced liver toxicity: a case report. Diabetes Metab 2014;40:82-4
60. Ligueros-Saylan M, Foley JE, Schweizer A, et al. An assessment of adverse effects of vildagliptin versus comparators on the liver, the pancreas, the immune system, the skin and in patients with impaired renal function from a large pooled database of Phase II and III clinical trials. Diabetes Obes Metab 2010;12:495-509
61. Aston-Mourney K, Subramanian SL, Zraika S, et al. One year of sitagliptin treatment protects against islet amyloidassociated beta-cell loss and does not induce pancreatitis or pancreatic neoplasia in mice. Am J Physiol Endocrinol Metab 2013;305:E475-84
62. Shah P, Ardestani A, Dharmadhikari G, et al. The DPP-4 inhibitor linagliptin restores beta-cell function and survival in human isolated islets through GLP-1 stabilization. J Clin Endocrinol Metab 2013;98:E1163-72
63. Takeda Y, Fujita Y, Honjo J, et al. Reduction of both beta cell death and alpha cell proliferation by dipeptidyl peptidase-4 inhibition in a streptozotocin-induced model of diabetes in mice. Diabetologia 2012;55:404-12
64. Lando HM, Alattar M, Dua AP. Elevated amylase and lipase levels in patients using glucagonlike peptide-1 receptor agonists or dipeptidyl-peptidase- 4 inhibitors in the outpatient setting. Endocr Pract 2012;18:472-7
65. Shetty AS, Nanditha A, Snehalatha C, et al. Treatment with DPP-4 inhibitors does not increase the chance of pancreatitis in patients with type 2 diabetes. J Assoc Phys India 2013;61:543-4
66. US FDA. Available from: http://www. fda.gov/drugs/drugsafety/ucm343187. htm [Accessed at 24 December 2013]
67. Kunjathaya P, Ramaswami PK, Krishnamurthy AN, et al. Acute necrotizing pancreatitis associated with vildagliptin. JOP 2013;14:81-4
68. Nakata H, Sugitani S, Yamaji S, et al. Pancreatitis with pancreatic tail swelling associated with incretin-based therapies detected radiologically in two cases of diabetic patients with end-stage renal disease. Intern Med 2012;51:3045-9
69. Sue M, Yoshihara A, Kuboki K, et al. A case of severe acute necrotizing pancreatitis after administration of sitagliptin. Clin Med Insights Case Rep 2013;6:23-7
70. Saraogi R, Mallik R, Ghosh S. Mild acute pancreatitis with vildagliptin use. Indian J Endocrinol Metab 2012;16:S480-2
71. Singh S, Chang HY, Richards TM, et al. Glucagon-like 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
72. Faillie JL, Babai S, Crepin S, et al. Pancreatitis associated with the use of GLP-1 analogs and DPP-4 inhibitors: a case/non-case study from the French Pharmacovigilance Database. Acta Diabetol 2013. [Epub ahead of print]
73. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes Care 2010;33:2349-54
74. Dore DD, Seeger JD, Arnold Chan K. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin 2009;25:1019-27
75. Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-26
76. White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-35
77. Monami M, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2014;16:48-56
78. Scheen A. Gliptins (dipeptidyl peptidase- 4 inhibitors) and risk of acute pancreatitis. Expert Opin Drug Saf 2013;12:545-57
79. Hollander PL, Li J, Frederich R, et al. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab Vasc Dis Res 2011;8:125-35
80. Hollander P, Li J, Allen E, et al. Saxagliptin added to a thiazolidinedione improves glycemic control in patients with type 2 diabetes and inadequate control on thiazolidinedione alone. J Clin Endocrinol Metab 2009;94:4810-19
81. Filippatos TD, Elisaf MS. Hyponatremia in patients with heart failure. World J Cardiol 2013;5:317-28
82. Seifalian AM, Filippatos TD, Joshi J, et al. Obesity and arterial compliance alterations. Curr Vasc Pharmacol 2010;8:155-68
83. Ayaori M, Iwakami N, Uto-Kondo H, et al. Dipeptidyl peptidase-4 inhibitors attenuate endothelial function as evaluated by flow-mediated vasodilatation in type 2 diabetic patients. J Am Heart Assoc 2013;2:e003277
84. Bloomfield DM, Krishna R, Hreniuk D, et al. A thorough QTc study to assess the effect of sitagliptin, a DPP4 inhibitor, on ventricular repolarization in healthy subjects. J Clin Pharmacol 2009;49:937-46
85. Kishimoto M. Teneligliptin: a DPP-4 inhibitor for the treatment of type 2 diabetes. Diabetes Metab Syndr Obes 2013;6:187-95
86. Desai S, Brinker A, Swann J, et al. Sitagliptin-associated drug allergy: review of spontaneous adverse event reports. Arch Intern Med 2010;170:1169-71
87. Hamasaki H, Yanai H. The development of angioedema in a patient with type 2 diabetes due to a novel dipeptidyl peptidase-IV inhibitor, anagliptin. Int J Cardiol 2013;168:e106
88. Gosmanov AR, Fontenot EC. Sitagliptin-associated angioedema. Diabetes Care 2012;35:e60
89. Grouzmann E, Monod M, Landis B, et al. Loss of dipeptidylpeptidase IV activity in chronic rhinosinusitis contributes to the neurogenic inflammation induced by substance P in the nasal mucosa. FASEB J 2002;16:1132-4
90. Russell JS, Chi H, Lantry LE, et al. Substance P and neurokinin A metabolism by cultured human skeletal muscle myocytes and fibroblasts. Peptides 1996;17:1397-403
91. Byrd JB, Touzin K, Sile S, et al. Dipeptidyl peptidase IV in angiotensinconverting enzyme inhibitor associated angioedema. Hypertension 2008;51:141-7
92. Skalli S, Wion-Barbot N, Baudrant M, et al. Angio-oedema induced by dual dipeptidyl peptidase inhibitor and angiotensin II receptor blocker: a first case report. Diabet Med 2010;27:486-7
93. Brown NJ, Byiers S, Carr D, et al. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema. Hypertension 2009;54:516-23
94. Williams-Herman D, Engel SS, Round E, et al. Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord 2010;10:7
95. Saisho Y, Itoh H. Dipeptidyl peptidase-4 inhibitors and angioedema: a class effect? Diabet Med 2013;30:e149-50
96. Mas-Vidal A, Santos-Juanes J, Esteve-Martinez A, et al. Psoriasiform eruption triggered by a dipeptidyl peptidase IV inhibitor. Australas J Dermatol 2012;53:70-2
97. Tanaka K, Ogawa Y, Shimada S. Drug eruption caused by sitagliptin, a dipeptidyl peptidase-IV inhibitor. J Dermatol 2012;39:726-8
98. Stricklin SM, Stoecker WV, Rader RK, et al. Persistent edematous-plaque photosensitivity observed with sitagliptin phosphate (Januvia(R)). Dermatol Online J 2012;18:9
99. Kania DS, Gonzalvo JD, Weber ZA. Saxagliptin: a clinical review in the treatment of type 2 diabetes mellitus. Clin Ther 2011;33:1005-22
100. Skandalis K, Spirova M, Gaitanis G, et al. Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin. J Eur Acad Dermatol Venereol 2012;26:249-53
101. Aouidad I, Fite C, Marinho E, et al. A case report of bullous pemphigoid induced by dipeptidyl peptidase-4 inhibitors. JAMA Dermatol 2013;149:243-5
102. Karyekar CS, Frederich R, Ravichandran S. Clinically relevant reductions in HbA1c without hypoglycaemia: results across four studies of saxagliptin. Int J Clin Pract 2013;67:759-67
103. Scott R, Loeys T, Davies MJ, et al. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2008;10:959-69
104. Furukawa S, Kumagi T, Miyake T, et al. Suicide attempt by an overdose of sitagliptin, an oral hypoglycemic agent: a case report and a review of the literature. Endocr J 2012;59:329-33
105. Chacra AR, Tan GH, Apanovitch A, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomised controlled trial. Int J Clin Pract 2009;63:1395-406
106. Hermansen K, Kipnes M, Luo E, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007;9:733-45
107. Rosenstock J, Rendell MS, Gross JL, et al. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab 2009;11:1145-52
108. Tarapues M, Cereza G, Figueras A. Association of musculoskeletal complaints and gliptin use: review of spontaneous reports. Pharmacoepidemiol Drug Saf 2013;22:1115-18
109. Kao DP, Kohrt HE, Kugler J. Renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use. Diabet Med 2008;25:1229-30
110. Bhome R, Penn H. Rhabdomyolysis precipitated by a sitagliptin- atorvastatin drug interaction. Diabet Med 2012;29:693-4
111. DiGregorio RV, Pasikhova Y. Rhabdomyolysis caused by a potential sitagliptin-lovastatin interaction. Pharmacotherapy 2009;29:352-6
112. Kiortsis DN, Filippatos TD, Mikhailidis DP, et al. Statin-associated adverse effects beyond muscle and liver toxicity. Atherosclerosis 2007;195:7-16
113. Gallagher EJ, Sun H, Kornhauser C, et al. The effect of dipeptidyl peptidase- IV inhibition on bone in a mouse model of type 2 diabetes. Diabetes Metab Res Rev 2014;30:191-200
114. El Yacoubi M, Vaugeois JM, Marguet D, et al. Behavioral characterization of CD26 deficient mice in animal tests of anxiety and antidepressant-like activity. Behav Brain Res 2006;171:279-85
115. Yan S, Marguet D, Dobers J, et al. Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen. Eur J Immunol 2003;33:1519-27
116. Kim SJ, Nian C, Doudet DJ, et al. Dipeptidyl peptidase IV inhibition with MK0431 improves islet graft survival in diabetic NOD mice partially via T-cell modulation. Diabetes 2009;58:641-51
117. Rosenstock J, Sankoh S, List JF. Glucose-lowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008;10:376-86
118. Goodwin SR, Reeds DN, Royal M, et al. Dipeptidyl peptidase IV inhibition does not adversely affect immune or virological status in HIV infected men and women: a pilot safety study. J Clin Endocrinol Metab 2013;98:743-51
119. Martin JH, Deacon CF, Gorrell MD, et al. Incretin-based therapies - review of the physiology, pharmacology and emerging clinical experience. Intern Med J 2011;41:299-307
120. Gorrell MD. Dipeptidyl peptidase IV and related enzymes in cell biology and liver disorders. Clin Sci (Lond) 2005;108:277-92
121. Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA 2007;298:194-206
122. Schernthaner G, Barnett AH, Emser A, et al. 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
123. Cai L, Cai Y, Lu ZJ, et al. The efficacy and safety of vildagliptin in patients with type 2 diabetes: a meta-analysis of randomized clinical trials. J Clin Pharm Ther 2012;37:386-98
124. Yazbeck R, Howarth GS, Abbott CA. Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? Trends Pharmacol Sci 2009;30:600-7
125. DeFronzo RA, Burant CF, Fleck P, et al. 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
126. Nauck MA, Ellis GC, Fleck PR, et al. 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
127. Hibi H, Ohori T, Yamada Y. DPP-IV inhibitor may affect spermatogenesis. Diabetes Res Clin Pract 2011;93:e74-5
128. Aschner P, Kipnes MS, Lunceford JK, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006;29:2632-7
129. Pitocco D, Zaccardi F, Martini F, et al. Severe leucopenia associated with sitagliptin use. Diabetes Res Clin Pract 2011;91:e30-2
130. Pendergrass M, Fenton C, Haffner SM, et al. Exenatide and sitagliptin are not associated with increased risk of acute renal failure: a retrospective claims analysis. Diabetes Obes Metab 2012;14:596-600
131. Matveyenko AV, Dry S, Cox HI, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes 2009;58:1604-15
132. Tourrel C, Bailbe D, Meile MJ, et al. Glucagon-like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes 2001;50:1562-70
133. Xu G, Stoffers DA, Habener JF, et al. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999;48:2270-6
134. Gier B, Matveyenko AV, Kirakossian D, et al. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras (G12D) mouse model. Diabetes 2012;61:1250-62
135. Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes 2013;62:2595-604
136. Institute for Safe Medication Practices. Perspectives on GLP-1 agents for diabetes. 2013. Available from: www.ismp.org/QuarterWatch/pdfs/ 2012Q3.pdf [Accessed at 24 December 2013]
137. Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology 2011;141:150-6
138. Feng X, Cai A, Dong K, et al. Assessing pancreatic cancer risk associated with dipeptidyl peptidase 4 inhibitors: data mining of FDA Adverse Event Reporting System (FAERS). J Pharmacovigilance 2013;1:110
139. Cohen D. Has pancreatic damage from glucagon suppressing diabetes drugs been underplayed? BMJ 2013;346:f3680
140. European Medicines Agency investigates findings on pancreatic risks with GLP-1-based therapies for type-2 diabetes. Available from: http://www. ema.europa.eu/ema/index.jsp?curl=pages/ newsandevents/news/2013/03/ newsdetail001753. jsp&mid=WC0b01ac058004d5c1 [Accessed at 24 December 2013]
141. Butler PC, Elashoff M, Elashoff R, et al. A critical analysis of the clinical use of incretin-based therapies: are the GLP-1 therapies safe? Diabetes Care 2013;36:2118-25
142. Nauck MA. A critical analysis of the clinical use of incretin-based therapies: the benefits by far outweigh the potential risks. Diabetes Care 2013;36:2126-32
143. Monami M, Dicembrini I, Martelli D, et al. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin 2011;27(Suppl 3):57-64
144. ADA/EASD/IDF Statement Concerning the Use of Incretin Therapy and Pancreatic Disease. Available from: http://www.diabetes.org/for-media/2013/ recommendations-for.html [Accessed at 24 December 13]
145. Frohlich E, Wahl R. Do antidiabetic medications play a specific role in differentiated thyroid cancer compared to other cancer types? Diabetes Obes Metab 2012;14:204-13
146. Kissow H, Hartmann B, Holst JJ, et al. Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice. Regul Pept 2012;179:91-100
147. Chu XY, Bleasby K, Yabut J, et al. Transport of the dipeptidyl peptidase-4 inhibitor sitagliptin by human organic anion transporter 3, organic anion transporting polypeptide 4C1, and multidrug resistance P-glycoprotein. J Pharmacol Exp Ther 2007;321:673-83
148. Bergman AJ, Cote J, Maes A, et al. Effect of sitagliptin on the pharmacokinetics of simvastatin. J Clin Pharmacol 2009;49:483-8
149. Mistry GC, Bergman AJ, Zheng W, et al. Sitagliptin, an dipeptidyl peptidase- 4 inhibitor, does not alter the pharmacokinetics of the sulphonylurea, glyburide, in healthy subjects. Br J Clin Pharmacol 2008;66:36-42
150. Mistry GC, Bergman AJ, Luo WL, et al. Multiple-dose administration of sitagliptin, a dipeptidyl peptidase-4 inhibitor, does not alter the single-dose pharmacokinetics of rosiglitazone in healthy subjects. J Clin Pharmacol 2007;47:159-64
151. Krishna R, Bergman A, Larson P, et al. Effect of a single cyclosporine dose on the single-dose pharmacokinetics of sitagliptin (MK-0431), a dipeptidyl peptidase-4 inhibitor, in healthy male subjects. J Clin Pharmacol 2007;47:165-74
152. Wright D, Maes A, Yi B, et al. Multiple dose administration of MK-0431 (sitagliptin), an inhibitor of dipeptidyl peptidase-IV, does not meaningfully alter the plasma pharmacokinetics or pharmacodynamics of single doses of warfarin. Clin Phar 2005;79:PIII-64
153. Scheen AJ. Pharmacokinetic evaluation of atorvastatin and sitagliptin in combination for the treatment of type 2 diabetes. Expert Opin Drug Metab Toxicol 2012;8:745-58
154. Aquilante CL, Wempe MF, Sidhom MS, et al. Effect of ABCB1 polymorphisms and atorvastatin on sitagliptin pharmacokinetics in healthy volunteers. Eur J Clin Pharmacol 2013;69:1401-9
155. Arun KP, Meda VS, Kucherlapati VS, et al. Pharmacokinetic drug interaction between gemfibrozil and sitagliptin in healthy Indian male volunteers. Eur J Clin Pharmacol 2012;68:709-14
156. Miller JL, Migoya E, Talaty JE, et al. American Society for Clinical Pharmacology and Therapeutics. The effect of MK-0431 on the pharmacokinetics of digoxin after concomitant administration for 10 days in healthy subjects. Clin Pharmacol Ther 2005;79:Poster PI-65
157. Scheen AJ. Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. Clin Pharmacokinet 2010;49:573-88
158. Australian Public Assessment Report for Vildagliptin. Available from: http://www. tga.gov.au/pdf/auspar/auspar-galvus.pdf [Accessed at 12-3-14]
159. He YL, Ligueros-Saylan M, Sunkara G, et al. Vildagliptin, a novel dipeptidyl peptidase IV inhibitor, has no pharmacokinetic interactions with the antihypertensive agents amlodipine, valsartan, and ramipril in healthy subjects. J Clin Pharmacol 2008;48:85-95
160. Ayalasomayajula SP, Dole K, He YL, et al. Evaluation of the potential for steady-state pharmacokinetic interaction between vildagliptin and simvastatin in healthy subjects. Curr Med Res Opin 2007;23:2913-20
161. He YL, Sabo R, Riviere GJ, et al. Effect of the novel oral dipeptidyl peptidase IV inhibitor vildagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects. Curr Med Res Opin 2007;23:1131-8
162. He YL, Sabo R, Picard F, et al. Study of the pharmacokinetic interaction of vildagliptin and metformin in patients with type 2 diabetes. Curr Med Res Opin 2009;25:1265-72
163. Serra D, He YL, Bullock J, et al. Evaluation of pharmacokinetic and pharmacodynamic interaction between the dipeptidyl peptidase IV inhibitor vildagliptin, glyburide and pioglitazone in patients with Type 2 diabetes. Int J Clin Pharmacol Ther 2008;46:349-64
164. He YL, Sabo R, Sunkara G, et al. Evaluation of pharmacokinetic interactions between vildagliptin and digoxin in healthy volunteers. J Clin Pharmacol 2007;47:998-1004
165. Su H, Boulton DW, Barros A Jr, et al. Characterization of the in vitro and in vivo metabolism and disposition and cytochrome P450 inhibition/induction profile of saxagliptin in human. Drug Metab Dispos 2012;40:1345-56
166. European Medicines Agency. Assessment report for Onglyza. Available from: http://www.ema.europa.eu/docs/enGB/ documentlibrary/EPAR- Publicassessmentreport/human/ 001039/WC500044319.pdf [Accessed at 12-3-14]
167. Girgis S, Patel CG, Li L, et al. Effect of diltiazem on the pharmacokinetics of saxagliptin in healthy subjects. J Clin Pharmacol 2007;47:abstract 1199
168. Patel CG, Li L, Girgis S, et al. Two-way pharmacokinetic interaction studies between saxagliptin and cytochrome P450 substrates or inhibitors: simvastatin, diltiazem extended-release, and ketoconazole. Clin Pharmacol 2011;3:13-25
169. Boulton DW, Brenner E, Royzman K, et al. Effect of ketoconazole on the pharmacokinetics of saxagliptin in healthy subjects. J Clin Pharmacol 2007;47:abstract 2003
170. Upreti VV, Boulton DW, Li L, et al. Effect of rifampicin on the pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in healthy subjects. Br J Clin Pharmacol 2011;72:92-102
171. Boulton DW, Adams D, Li L, et al. Magnesium and aluminum hydroxides plus simethicone, famotidine or omeprazole do not meaningfully affect the pharmacokinetics of saxagliptin in healthy subjects [abstract PIII-68]. Clin Pharmacol Ther 2008;83(Suppl 1):S92-S3
172. Patel CG, Kornhauser D, Vachharajani N, et al. Saxagliptin, a potent, selective inhibitor of DPP-4, does not alter the pharmacokinetics of three oral
173. Boulton DW, Li L, Patel CG, et al. No pharmacokinetic interaction between saxagliptin and digoxin in healthy subjects [abstract PIII-69]. Clin Pharmacol Ther 2008;83(Suppl 1):S93
174. Aloglipin SPC UK. Available from: http://www.medicines.org.uk/emc/ medicine/28513/SPC/Vipidia+6.25mg, +12.5mg,+25mg+film-coated+tablets/# PHARMACOKINETICPROPS [Accessed at 8 March 2014]
175. Karim A, Covington P, Christopher R, et al. Pharmacokinetics of alogliptin when administered with food, metformin, or cimetidine: a two-phase, crossover study in healthy subjects. Int J Clin Pharmacol Ther 2010;48:46-58
176. Karim A, Laurent A, Munsaka M, et al. Coadministration of pioglitazone or glyburide and alogliptin: pharmacokinetic drug interaction assessment in healthy participants. J Clin Pharmacol 2009;49:1210-19
177. Karim A, Copa A, Fleck P, et al. Effects of alogliptin on the pharmacokinetics and pharmaco-dynamics of norethindrone and ethinyl estradiol (Ortho-Novum 1/35) in healthy adult female subjects [abstract PI-6]. Clin Pharmacol Ther 2008;83(Suppl 1):S14
178. Karim A, Fleck P, Harris S, et al. Assessment of drug interaction between alogliptin, a highly selective dipeptidyl peptidase-4 inhibitor, and atorvastatin in healthy subjects [abstract PI-7]. Clin Pharmacol Ther 2008;83(Suppl 1):S14
179. Karim A, Fleck P, Harris S, et al. Lack of pharmacokinetic interaction between multiple doses of the dipeptidyl peptidase-4 inhibitor alogliptin and digoxin in health subjects [abstract PI-3]. Clin Pharmacol Ther 2008;83(Suppl 1):S12-S3
180. Karim A, Chiselko P, Fleck P, et al. Lack of effect of cyclosporine on the single dose pharmacokinetics of alogliptin, a novel dipeptidyl peptidase-4 inhibitor, in health male subjects [abstract PI-5]. Clin Pharmacol Ther 2008;83(Suppl 1):S13
181. Ishiguro N, Shimizu H, Kishimoto W, et al. Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods. Drug Metab Dispos 2013;41:149-58
182. Fuchs H, Tillement JP, Urien S, et al. 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
183. Graefe-Mody U, Retlich S, Friedrich C. Clinical pharmacokinetics and pharmacodynamics of linagliptin. Clin Pharmacokinet 2012;51:411-27
184. Deeks ED. Linagliptin: a review of its use in the management of type 2 diabetes mellitus. Drugs 2012;72:1793-824
185. Gallwitz B. Linagliptin-a novel dipeptidyl peptidase inhibitor for type 2 diabetes therapy. Clin Med Insights Endocrinol Diabetes 2012;5:1-11
186. Graefe-Mody EU, Padula S, Ring A, et al. 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
187. Graefe-Mody EU, Jungnik A, Ring A, et al. 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
188. Friedrich C, Ring A, Brand T, et al. 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
189. Boucher BJ. Renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use. But what about the amiodarone? Diabet Med 2009;26:192-3
190. Forst 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
191. Tenelia. Report on the Deliberation Results. Available from: https://www. google.gr/url?sa=t&rct=j&q=&esrc=s& source=web&cd= 3&ved=0CD8QFjAC& url=http%3A%2F%2Fwww.pmda.go.jp% 2Fenglish%2Fservice%2Fpdf%2Fdrugs% 2Fteneliajun2012e.pdf&ei= unS4Us6QIbLc4QSpl4GwCg& usg=AFQjCNHy4aXqBaDBPnlqWui QIMvLnUgTCg&cad=rja [Accessed at 24 December 2013]
192. Noh YH, Lim HS, Jin SJ, et al. 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
193. Kim SE, Yi S, Shin KH, et al. 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
194. Scheen AJ, Charpentier G, Ostgren CJ, et al. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev 2010;26:540-9
195. Rhee EJ, Lee WY, Min KW, et al. 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
196. Kim D, Wang L, Beconi M, et al. (2R)- 4-oxo-4-[3-(trifluoromethyl)-5,6- dihydro [1,2,4]triazolo[4,3-a]pyrazin-7(8H)- yl]- 1-(2,4,5-trifluorophenyl) butan-2-amine: a potent, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. J Med Chem 2005;48:141-51
197. Herman GA, Bergman A, Liu F, et al. Pharmacokinetics and pharmacodynamic effects of the oral DPP-4 inhibitor sitagliptin in middle-aged obese subjects. J Clin Pharmacol 2006;46:876-86
198. Bergman AJ, Stevens C, Zhou Y, et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther 2006;28:55-72
199. Villhauer EB, Brinkman JA, Naderi GB, et al. 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
200. He YL. Clinical pharmacokinetics and pharmacodynamics of vildagliptin. Clin Pharmacokinet 2012;51:147-62
201. Li H, Yang L, Tou CK, et al. Pharmacokinetic study of saxagliptin in healthy Chinese subjects. Clin Drug Investig 2012;32:465-73
202. Kato N, Oka M, Murase T, et al. 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
203. Feng J, Zhang Z, Wallace MB, et al. Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV. J Med Chem 2007;50:2297-300
204. Lee B, Shi L, Kassel DB, et al. Pharmacokinetic, pharmacodynamic, and efficacy profiles of alogliptin, a novel inhibitor of dipeptidyl peptidase-4, in rats, dogs, and monkeys. Eur J Pharmacol 2008;589:306-14
205. Covington P, Christopher R, Davenport M, et al. 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
206. Christopher R, Covington P, Davenport M, et al. 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
207. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab 2011;13:7-18
208. Thomas L, Eckhardt M, Langkopf E, et al. (R)-8-(3-amino-piperidin-1-yl)- 7- but-2-ynyl-3-methyl-1-(4-methylquinazolin- 2-ylm ethyl)-3,7-dihydropurine- 2,6-dione (BI 1356), a novel xanthine-based dipeptidyl peptidase 4 inhibitor, has a superior potency and longer duration of action compared with other dipeptidyl peptidase-4 inhibitors. J Pharmacol Exp Ther 2008;325:175-82
209. Horie Y, Kanada S, Watada H, et al. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor linagliptin: a 4-week multicenter, randomized, double-blind, placebo-controlled phase IIa study in Japanese type 2 diabetes patients. Clin Ther 2011;33:973-89
210. Sarashina A, Sesoko S, Nakashima M, et al. Linagliptin, a dipeptidyl peptidase- 4 inhibitor in development for the treatment of type 2 diabetes mellitus: a Phase I, randomized, double-blind, placebo-controlled trial of single and multiple escalating doses in healthy adult male Japanese subjects. Clin Ther 2010;32:1188-204
211. Heise T, Graefe-Mody EU, Huttner S, et al. 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
212. Huttner S, Graefe-Mody EU, Withopf B, et al. 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
213. Graefe-Mody U, Friedrich C, Port A, et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin. Diabetes Obes Metab 2011;13:939-46
214. Nabeno M, Akahoshi F, Kishida H, et al. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem Biophys Res Commun 2013;434:191-6
215. Fukuda-Tsuru S, Anabuki J, Abe Y, et al. A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations. Eur J Pharmacol 2012;696:194-202
216. Yoshida T, Akahoshi F, Sakashita H, et al. 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
217. Halabi A, Maatouk H, Siegler KE, et al. Pharmacokinetics of teneligliptin in subjects with renal impairment. Clin Pharmacol Drug Dev 2013;2:246-54
218. Lim KS, Cho JY, Kim BH, et al. 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
219. Lim KS, Kim JR, Choi YJ, et al. Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: a dose-blockrandomized, double-blind, placebocontrolled, ascending single-dose, Phase I study. Clin Ther 2008;30:1817-30
220. Charbonnel B, Karasik A, Liu J, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29:2638-43
221. Rosenstock J, Brazg R, Andryuk PJ, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006;28:1556-68
222. Fonseca V, Staels B, Morgan JD II, et al. Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebo-controlled, 26-week trial in patients with type 2 diabetes. J Diabetes Complications 2013;27:177-83
223. Vilsboll T, Rosenstock J, Yki-Jarvinen H, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab 2010;12:167-77
224. Scherbaum WA, Schweizer A, Mari A, et al. Efficacy and tolerability of vildagliptin in drug-naive patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes Metab 2008;10:675-82
225. Kikuchi M, Haneda M, Koya D, et al. Efficacy and tolerability of vildagliptin as an add-on to glimepiride in Japanese patients with Type 2 diabetes mellitus. Diabetes Res Clin Pract 2010;89:216-23
226. Garber AJ, Foley JE, Banerji MA, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab 2008;10:1047-56
227. Pan CY, Yang W, Tou C, et al. Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Metab Res Rev 2012;28:268-75
228. DeFronzo RA, Hissa MN, Garber AJ, et al. The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 2009;32:1649-55
229. Seino Y, Miyata Y, Hiroi S, et al. Efficacy and safety of alogliptin added to metformin in Japanese patients with type 2 diabetes: a randomized, doubleblind, placebo-controlled trial with an open-label, long-term extension study. Diabetes Obes Metab 2012;14:927-36
230. Pratley RE, Kipnes MS, Fleck PR, et al. 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
231. Barnett AH, Patel S, Harper R, et al. Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: an 18-week randomized, double-blind, placebocontrolled phase III trial with a 34-week active-controlled extension. Diabetes Obes Metab 2012;14:1145-54
232. Barnett AH, Huisman H, Jones R, et al. Linagliptin for patients aged 70 years or older with type 2 diabetes inadequately controlled with common antidiabetes treatments: a randomised, double-blind, placebo-controlled trial. Lancet 2013;382:1413-23
233. Kadowaki 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
234. Kadowaki T, Kondo K. Efficacy and safety of teneligliptin added to glimepiride in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled study with an open-label, long-term extension. Diabetes Obes Metab 2013. [Epub ahead of print]
235. Yang SJ, Min KW, Gupta SK, et al. A multicentre, multinational, randomized, placebo-controlled, doubleblind, 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
236. Wright DH, Herman GA, Maes A, et al. Multiple doses of sitagliptin, a selective DPP-4 inhibitor, do not meaningfully alter pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 2009;49:1157-67
237. Cerra M, Luo WL, Li SX, et al. The effects of simvastatin on the pharmacokinectics of sitagliptin. J Popul Ther Clin Pharmacol 2012;19:e356-60
238. Kasichayanula S, Liu X, Shyu WC, et al. Lack of pharmacokinetic interaction between dapagliflozin, a novel sodiumglucose transporter 2 inhibitor, and metformin, pioglitazone, glimepiride or sitagliptin in healthy subjects. Diabetes Obes Metab 2011;13:47-54
239. Smulders RA, Zhang W, Veltkamp SA, et al. No pharmacokinetic interaction between ipragliflozin and sitagliptin, pioglitazone, or glimepiride in healthy subjects. Diabetes Obes Metab 2012;14:937-43
240. Brand T, Macha S, Mattheus M, et al. Pharmacokinetics of empagliflozin, a sodium glucose cotransporter-2 (SGLT-2) inhibitor, coadministered with sitagliptin in healthy volunteers. Adv Ther 2012;29:889-99
241. Migoya E, Larson P, Bergman A, et al. Sitagliptin, a dipeptidyl peptidase-4 inhibitor, does not affect the pharmacokinetics of ethinyl estradiol or norethindrone in healthy female subjects. J Clin Pharmacol 2011;51:1319-25
242. Yamaguchi M, Saji T, Mita S, et al. Pharmacokinetic and pharmacodynamic interaction of vildagliptin and voglibose in Japanese patients with Type 2 diabetes. Int J Clin Pharmacol Ther 2013;51:641-51
243. Graefe-Mody U, Rose P, Ring A, et al. 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
244. Graefe-Mody EU, Brand T, Ring A, et al. Effect of linagliptin on the pharmacokinetics and pharmacodynamics of warfarin in healthy volunteers. Int J Clin Pharmacol Ther 2011;49:300-10
245. Friedrich C, Metzmann K, Rose P, et al. A randomized, open-label, crossover study to evaluate the pharmacokinetics of empagliflozin and linagliptin after coadministration in healthy male volunteers. Clin Ther 2013;35:A33-42
246. Friedrich C, Port A, Ring A, et al. 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
247. Graefe-Mody U, Huettner S, Stahle H, et al. Effect of linagliptin (BI 1356) on the steady-state pharmacokinetics of simvastatin. Int J Clin Pharmacol Ther 2010;48:367-74