NRF2 activation by antioxidant antidiabetic agents accelerates tumor metastasis

Science Translational Medicine

Volumn 8, Issue 334, 2016, Pages

  Wang, Hui ^a   Liu, Xiufei ^a   Long, Min ^a   Huang, Yi ^b   Zhang, Linlin ^a   Zhang, Rui ^a   Zheng, Yi ^a   Liao, Xiaoyu ^a   Wang, Yuren ^a   Liao, Qian ^a   Li, Wenjie ^a   Tang, Zili ^c   Tong, Qiang ^a   Wang, Xiaocui ^a   Fang, Fang ^a   De La Vega, Montserrat Rojo ^d   Ouyang, Qin ^a   Zhang, Donna D ^d   Yu, Shicang ^a   Zheng, Hongting ^a  

^a THIRD MILITARY MEDICAL UNIVERSITY   (China)

^b CHILDREN S HOSPITAL OF CHONGQING MEDICAL UNIVERSITY   (China)

^c UNIVERSITY OF HEIDELBERG   (Germany)

^d UNIVERSITY OF ARIZONA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

DIPEPTIDYL PEPTIDASE IV; KELCH LIKE ECH ASSOCIATED PROTEIN 1; SAXAGLIPTIN; SITAGLIPTIN; THIOCTIC ACID; TRANSCRIPTION FACTOR NRF2; ADAMANTANE; ANTIDIABETIC AGENT; ANTIOXIDANT; DIPEPTIDE; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUTAMATE CYSTEINE LIGASE; GLUTAMATE-CYSTEINE LIGASE MODIFIER SUBUNIT, HUMAN; KEAP1 PROTEIN, HUMAN; TUMOR MARKER;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIOXIDANT ACTIVITY; CANCER RISK; CELL MIGRATION; CONTROLLED STUDY; HUMAN; HUMAN CELL; HUMAN TISSUE; LIVER CANCER; METASTASIS; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RISK FACTOR; UBIQUITINATION; UPREGULATION; ANALOGS AND DERIVATIVES; ANIMAL; DRUG EFFECTS; LIVER TUMOR; METABOLISM; PATHOLOGY; SIGNAL TRANSDUCTION; TUMOR CELL LINE;

ADAMANTANE; ANIMALS; ANTIOXIDANTS; BIOMARKERS, TUMOR; CELL LINE, TUMOR; DIPEPTIDES; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; GLUTAMATE-CYSTEINE LIGASE; HUMANS; HYPOGLYCEMIC AGENTS; KELCH-LIKE ECH-ASSOCIATED PROTEIN 1; LIVER NEOPLASMS; MICE; NEOPLASM METASTASIS; NF-E2-RELATED FACTOR 2; RISK FACTORS; SIGNAL TRANSDUCTION; SITAGLIPTIN PHOSPHATE; THIOCTIC ACID; UBIQUITINATION;

EID: 84963799947     PISSN: 19466234     EISSN: 19466242     Source Type: Journal    
DOI: 10.1126/scitranslmed.aad6095     Document Type: Review

References (113)

1. E. Giovannucci, D. M. Harlan, M. C. Archer, R. M. Bergenstal, S. M. Gapstur, L. A. Habel, M. Pollak, J. G. Regensteiner, D. Yee, Diabetes and cancer: A consensus report. CA Cancer J. Clin. 60, 207-221 (2010).
2. U. Smith, E. A. M. Gale, Does diabetes therapy influence the risk of cancer? Diabetologia 52, 1699-1708 (2009).
3. J. J. Walker, J. A. Johnson, S. H. Wild, Diabetes treatments and cancer risk: The importance of considering aspects of drug exposure. Lancet Diabetes Endocrinol. 1, 132-139 (2013).
4. J. D. Lewis, A. Ferrara, T. Peng, M. Hedderson, W. B. Bilker, C. P. Quesenberry Jr., D. J. Vaughn, L. Nessel, J. Selby, B. L. Strom, Risk of bladder cancer among diabetic patients treated with pioglitazone: Interim report of a longitudinal cohort study. Diabetes Care 34, 916-922 (2011).
5. C. Piccinni, D. Motola, G. Marchesini, E. Poluzzi, Assessing the association of pioglitazone use and bladder cancer through drug adverse event reporting. Diabetes Care 34, 1369-1371 (2011).
6. E. Mannucci, M. Monami, D. Balzi, B. Cresci, L. Pala, C. Melani, C. Lamanna, I. Bracali, M. Bigiarini, A. Barchielli, N. Marchionni, C. M. Rotella, Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care 33, 1997-2003 (2010).
7. N. Sadeghi, J. L. Abbruzzese, S.-C. J. Yeung, M. Hassan, D. Li, Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clin. Cancer Res. 18, 2905-2912 (2012).
8. M. Zakikhani, R. Dowling, I. G. Fantus, N. Sonenberg, M. Pollak, Metformin is an AMP kinase-dependent growth inhibitor for breast cancer cells. Cancer Res. 66, 10269-10273 (2006).
9. Y. Handelsman, Z. T. Bloomgarden, G. Grunberger, G. Umpierrez, R. S. Zimmerman, T. S. Bailey, L. Blonde, G. A. Bray, A. J. Cohen, S. Dagogo-Jack, J. A.Davidson, D. Einhorn, O. P. Ganda, A. J. Garber, W. T. Garvey, R. R. Henry, I. B. Hirsch, E. S. Horton, D. L. Hurley, P. S. Jellinger, L. Jovanovič, H. E. Lebovitz, D. LeRoith, P. Levy, J. B. McGill, J. I. Mechanick, J. H. Mestman, E. S. Moghissi, E. A. Orzeck, R. Pessah-Pollack, P. D. Rosenblit, A. I. Vinik, K. Wyne, F. Zangeneh, American Association of Clinical Endocrinologists and American College Of Endocrinology-Clinical Practice Guidelines for Developing a Diabetes Mellitus Comprehensive Care Plan-2015. Endocr. Pract. 21 (Suppl. 1), 1-87 (2015).
10. M. Monami, I. Dicembrini, E. Mannucci, Dipeptidyl peptidase-4 inhibitors and pancreatitis risk: A meta-analysis of randomized clinical trials. Diabetes Obes. Metab. 16, 48-56 (2014).
11. K. Nakatani, T. Kurose, T. Hyo, K. Watanabe, D. Yabe, T. Kawamoto, Y. Seino, Drug-induced generalized skin eruption in a diabetes mellitus patient receiving a dipeptidyl peptidase- 4 inhibitor plus metformin. Diabetes Ther. 3, 14 (2012).
12. X. Yang, H. Zhao, Y. Sui, R. C. W. Ma, W. Y. So, G. T. C. Ko, A. P. S. Kong, R. Ozaki, C. Y. Yeung, G. Xu, P. C. Y. Tong, J. C. N. Chan, Additive interaction between the renin-angiotensin system and lipid metabolism for cancer in type 2 diabetes. Diabetes 58, 1518-1525 (2009).
13. C. Branco-Price, N. Zhang, M. Schnelle, C. Evans, D. M. Katschinski, D. Liao, L. Ellies, R. S. Johnson, Endothelial cell HIF-1a and HIF-2a differentially regulate metastatic success. Cancer Cell 21, 52-65 (2012).
14. G. Zhang, D. Panigrahy, S. H. Hwang, J. Yang, L. M. Mahakian, H. I. Wettersten, J.-Y. Liu, Y. Wang, E. S. Ingham, S. Tam, M. W. Kieran, R. H. Weiss, K. W. Ferrara, B. D. Hammock, Dual inhibition of cyclooxygenase-2 and soluble epoxide hydrolase synergistically suppresses primary tumor growth and metastasis. Proc. Natl. Acad. Sci. U.S.A. 111, 11127-11132 (2014).
15. J. Fritzmann, M. Morkel, D. Besser, J. Budczies, F. Kosel, F. H. Brembeck, U. Stein, I. Fichtner, P. M. Schlag, W. Birchmeier, A colorectal cancer expression profile that includes transforming growth factor b inhibitor BAMBI predicts metastatic potential. Gastroenterology 137, 165-175 (2009).
16. G. Wang, F. Wang, W. Ding, J. Wang, R. Jing, H. Li, X. Wang, Y. Wang, S. Ju, H. Wang, APRIL induces tumorigenesis and metastasis of colorectal cancer cells via activation of the PI3K/Akt pathway. PLOS One 8, e55298 (2013).
17. M. Chuma, M. Sakamoto, J. Yasuda, G. Fujii, K. Nakanishi, A. Tsuchiya, T. Ohta, M. Asaka, S. Hirohashi, Overexpression of cortactin is involved in motility and metastasis of hepatocellular carcinoma. J. Hepatol. 41, 629-636 (2004).
18. C. Khanna, K. Hunter, Modeling metastasis in vivo. Carcinogenesis 26, 513-523 (2005).
19. M. Sauve, K. Ban, M. A. Momen, Y.-Q. Zhou, R. M. Henkelman, M. Husain, D. J. Drucker, Genetic deletion or pharmacological inhibition of dipeptidyl peptidase-4 improves cardiovascular outcomes after myocardial infarction in mice. Diabetes 59, 1063-1073 (2010).
20. F. Hirschhaeuser, U. G. A. Sattler, W. Mueller-Klieser, Lactate: A metabolic key player in cancer. Cancer Res. 71, 6921-6925 (2011).
21. R. Kang, D. Tang, N. E. Schapiro, T. Loux, K. M. Livesey, T. R. Billiar, H. Wang, B. Van Houten, M. T. Lotze, H. J. Zeh, The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics. Oncogene 33, 567-577 (2014).
22. G.M.DeNicola, F.A. Karreth, T. J. Humpton, A. Gopinathan, C.Wei, K. Frese, D. Mangal, K. H. Yu, C. J. Yeo, E. S. Calhoun, F. Scrimieri, J. M. Winter, R. H. Hruban, C. Iacobuzio-Donahue, S. E. Kern, I. A. Blair, D. A. Tuveson, Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106-109 (2011).
23. D. D. Zhang, M. Hannink, Distinct cysteine residues in Keap1 are required for Keap1- dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress. Mol. Cell. Biol. 23, 8137-8151 (2003).
24. S. Tao, Y. Zheng, A. Lau, M. C. Jaramillo, B. T. Chau, R. C. Lantz, P. K. Wong, G. T. Wondrak, D. D. Zhang, Tanshinone I activates the Nrf2-dependent antioxidant response and protects against As(III)-induced lung inflammation in vitro and in vivo. Antioxid. Redox Signal. 19, 1647-1661 (2013).
25. H. Zheng, S. A. Whitman, W.Wu, G. T. Wondrak, P. K. Wong, D. Fang, D. D. Zhang, Therapeutic potential of Nrf2 activators in streptozotocin-induced diabetic nephropathy. Diabetes 60, 3055-3066 (2011).
26. N. Kashihara, Y. Haruna, V. K. Kondeti, Y. S. Kanwar, Oxidative stress in diabetic nephropathy. Curr. Med. Chem. 17, 4256-4269 (2010).
27. J. H. Suh, S. V. Shenvi, B. M. Dixon, H. Liu, A. K. Jaiswal, R.-M. Liu, T. M. Hagen, Decline in transcriptional activity of Nrf2 causes age-related loss of glutathione synthesis, which is reversible with lipoic acid. Proc. Natl. Acad. Sci. U.S.A. 101, 3381-3386 (2004).
28. X. Cui, P. Zuo, Q. Zhang, X. Li, Y. Hu, J. Long, L. Packer, J. Liu, Chronic systemic D-galactose exposure induces memory loss, neurodegeneration, and oxidative damage in mice: Protective effects of R-a-lipoic acid. J. Neurosci. Res. 84, 647-654 (2006).
29. V. Pech, K. Abusaada, C. Alemany, Dipeptidyl peptidase-4 inhibition may stimulate progression of carcinoid tumor. Case Rep. Endocrinol. 2015, 952019 (2015).
30. R. Barreira da Silva, M. E. Laird, N. Yatim, L. Fiette, M. A. Ingersoll, M. L. Albert, Dipeptidylpeptidase 4 inhibition enhances lymphocyte trafficking, improving both naturally occurring tumor immunity and immunotherapy. Nat. Immunol. 16, 850-858 (2015).
31. H. Michikoshi, T. Nakamura, K. Sakai, Y. Suzuki, E. Adachi, S. Matsugo, K. Matsumoto, a-Lipoic acid-induced inhibition of proliferation and met phosphorylation in human non-small cell lung cancer cells. Cancer Lett. 335, 472-478 (2013).
32. M. McMahon, D. J. Lamont, K. A. Beattie, J. D. Hayes, Keap1 perceives stress via three sensors for the endogenous signaling molecules nitric oxide, zinc, and alkenals. Proc. Natl. Acad. Sci. U.S.A. 107, 18838-18843 (2010).
33. S. Fujii, T. Sawa, H. Ihara, K. I. Tong, T. Ida, T. Okamoto, A. K. Ahtesham, Y. Ishima, H. Motohashi, M. Yamamoto, T. Akaike, The critical role of nitric oxide signaling, via protein S-guanylation and nitrated cyclic GMP, in the antioxidant adaptive response. J. Biol. Chem. 285, 23970-23984 (2010).
34. S. Chowdhry, Y. Zhang, M. McMahon, C. Sutherland, A. Cuadrado, J. D. Hayes, Nrf2 is controlled by two distinct b-TrCP recognition motifs in its Neh6 domain, one of which can be modulated by GSK-3 activity. Oncogene 32, 3765-3781 (2013).
35. K. Le Gal, M. X. Ibrahim, C. Wiel, V. I. Sayin, M. K. Akula, C. Karlsson, M. G. Dalin, L. M. Akyürek, P. Lindahl, J. Nilsson, M. O. Bergo, Antioxidants can increase melanoma metastasis in mice. Sci. Transl. Med. 7, 308re308 (2015).
36. E. Piskounova, M. Agathocleous, M. M. Murphy, Z. Hu, S. E. Huddlestun, Z. Zhao, A. M. Leitch, T. M. Johnson, R. J. DeBerardinis, S. J. Morrison, Oxidative stress inhibits distant metastasis by human melanoma cells. Nature 527, 186-191 (2015).
37. F. L. Meyskens Jr., S. E. McNulty, J. A. Buckmeier, N. B. Tohidian, T. J. Spillane, R. S. Kahlon, R. I. Gonzalez, Aberrant redox regulation in human metastatic melanoma cells compared to normal melanocytes. Free Radic. Biol. Med. 31, 799-808 (2001).
38. T. Jiang, N. Chen, F. Zhao, X.-J. Wang, B. Kong, W. Zheng, D. D. Zhang, High levels of Nrf2 determine chemoresistance in type II endometrial cancer. Cancer Res. 70, 5486-5496 (2010).
39. M. C. Jaramillo, D. D. Zhang, The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 27, 2179-2191 (2013).
40. D.-Y. Lu, W.-L. Yeh, S.-M. Huang, C.-H. Tang, H.-Y. Lin, S.-J. Chou, Osteopontin increases heme oxygenase-1 expression and subsequently induces cell migration and invasion in glioma cells. Neuro Oncol. 14, 1367-1378 (2012).
41. X. Ji, H. Wang, J. Zhu, L. Zhu, H. Pan, W. Li, Y. Zhou, Z. Cong, F. Yan, S. Chen, Knockdown of Nrf2 suppresses glioblastoma angiogenesis by inhibiting hypoxia-induced activation of HIF-1a. Int. J. Cancer 135, 574-584 (2014).
42. T.-H. Kim, E.-g. Hur, S.-J. Kang, J.-A. Kim, D. Thapa, Y. M. Lee, S. K. Ku, Y. Jung, M.-K. Kwak, NRF2 blockade suppresses colon tumor angiogenesis by inhibiting hypoxia-induced activation of HIF-1a. Cancer Res. 71, 2260-2275 (2011).
43. O. Gjyshi, V. Bottero, M. V. Veettil, S. Dutta, V. V. Singh, L. Chikoti, B. Chandran, Kaposi's sarcoma-associated herpesvirus induces Nrf2 during de novo infection of endothelial cells to create a microenvironment conducive to infection. PLOS Pathog. 10, e1004460 (2014).
44. T. Ishikawa, Genetic polymorphism in the NRF2 gene as a prognosis marker for cancer chemotherapy. Front. Genet. 5, 383 (2014).
45. Y. Fang, Y. Chen, L. Yu, C. Zheng, Y. Qi, Z. Li, Z. Yang, Y. Zhang, T. Shi, J. Luo, M. Liu, Inhibition of breast cancer metastases by a novel inhibitor of TGFb receptor 1. J. Natl. Cancer Inst. 105, 47-58 (2013).
46. C. Christoforides, E. Rainero, K. K. Brown, J. C. Norman, A. Toker, PKD controls avb3 integrin recycling and tumor cell invasive migration through its substrate Rabaptin-5. Dev. Cell 23, 560-572 (2012).
47. M. Long, S. Tao, M. Rojo de la Vega, T. Jiang, Q. Wen, S. L. Park, D. D. Zhang, G. T. Wondrak, Nrf2-dependent suppression of azoxymethane/dextran sulfate sodium-induced colon carcinogenesis by the cinnamon-derived dietary factor cinnamaldehyde. Cancer Prev. Res. (Phila.) 8, 444-454 (2015).
48. T. Shen, T. Jiang, M. Long, J. Chen, D.-M. Ren, P. K. Wong, E. Chapman, B. Zhou, D. D. Zhang, A curcumin derivative that inhibits vinyl carbamate-induced lung carcinogenesis via activation of the Nrf2 protective response. Antioxid. Redox Signal. 23, 651-664 (2015).
49. R. Frederich, R. McNeill, N. Berglind, D. Fleming, R. Chen, The efficacy and safety of the dipeptidyl peptidase-4 inhibitor saxagliptin in treatment-naive patients with type 2 diabetes mellitus: A randomized controlled trial. Diabetol. Metab. Syndr. 4, 36 (2012).
50. M. Jadzinsky, A. Pfützner, E. Paz-Pacheco, Z. Xu, E. Allen, R. Chen; CV181-039 Investigators, Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: A randomized controlled trial. Diabetes Obes. Metab. 11, 611-622 (2009).
51. J. Rosenstock, C. Aguilar-Salinas, E. Klein, S. Nepal, J. List, R. Chen; CV181-011 Study Investigators, Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr. Med. Res. Opin. 25, 2401-2411 (2009).
52. J. C. Arjona Ferreira, M. Marre, N. Barzilai, H. Guo, G. T. Golm, C. M. Sisk, K. D. Kaufman, B. J. Goldstein, Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency. Diabetes Care 36, 1067-1073 (2013).
53. J. C. Arjona Ferreira, D. Corry, C. E. Mogensen, L. Sloan, L. Xu, G. T. Golm, E. J.Gonzalez, M. J.Davies, K. D. Kaufman, B. J. Goldstein, Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: A 54-week randomized trial. Am. J. Kidney Dis. 61, 579-587 (2013).
54. P. Aschner, H. L. Katzeff, H. Guo, S. Sunga, D. Williams-Herman, K. D. Kaufman, B. J. Goldstein; Sitagliptin Study 049 Group, Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes. Metab. 12, 252-261 (2010).
55. N. Barzilai, H. Guo, E.M. Mahoney, S. Caporossi, G. T. Golm, R. B. Langdon, D. Williams-Herman, K. D. Kaufman, J. M. Amatruda, B. J. Goldstein, H. Steinberg, Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: A randomized, double-blind, placebo-controlled trial. Curr. Med. Res. Opin. 27, 1049-1058 (2011).
56. J. C. N. Chan, R. Scott, J. C. Arjona Ferreira, D. Sheng, E. Gonzalez, M. J. Davies, P. P. Stein, K. D. Kaufman, J. M. Amatruda, D. Williams-Herman, Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes. Metab. 10, 545-555 (2008).
57. P. Hartley, Y. Shentu, P. Betz-Schiff, G. T. Golm, C. M. Sisk, S. S. Engel, R. R. Shankar, Efficacy and tolerability of sitagliptin compared with glimepiride in elderly patients with type 2 diabetes mellitus and inadequate glycemic control: A randomized, double-blind, non-inferiority trial. Drugs Aging 32, 469-476 (2015).
58. M. Roden, J. Weng, J. Eilbracht, B. Delafont, G. Kim, H. J. Woerle, U. C. Broedl; EMPA-REG MONO trial investigators, Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: A randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 1, 208-219 (2013).
59. D. Russell-Jones, R. M. Cuddihy, M. Hanefeld, A. Kumar, J. G. González, M. Chan, A. M. Wolka, M. K. Boardman; DURATION-4 Study Group, Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): A 26-week double-blind study. Diabetes Care 35, 252-258 (2012).
60. K. Stenlöf, W. T. Cefalu, K.-A. Kim, E. Jodar, M. Alba, R. Edwards, C. Tong, W. Canovatchel, G. Meininger, Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: Findings from the 52-week CANTATA-M study. Curr. Med. Res. Opin. 30, 163-175 (2013).
61. M. C. Bunck, M. Poelma, E. M. Eekhoff, A. Schweizer, R. J. Heine, G. Nijpels, J. E. Foley, M. Diamant, Effects of vildagliptin on postprandial markers of bone resorption and calcium homeostasis in recently diagnosed, well-controlled type 2 diabetes patients. J. Diabetes 4, 181-185 (2012).
62. B. Göke, K. Hershon, D. Kerr, A. Calle Pascual, A. Schweizer, J. Foley, Q. Shao, S. Dejager, Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naïve patients with type 2 diabetes: Comparison with metformin. Horm. Metab. Res. 40, 892-895 (2008).
63. J. Rosenstock, M. Niggli, M. Maldonado-Lutomirsky, Long-term 2-year safety and efficacy of vildagliptin compared with rosiglitazone in drug-naïve patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 11, 571-578 (2009).
64. A. H. Barnett, S. Patel, R. Harper, R. Toorawa, S. Thiemann, M. von Eynatten, H.-J. Woerle, Linagliptin monotherapy in type 2 diabetes patients for whom metformin is inappropriate: An 18-week randomized, double-blind, placebo-controlled phase III trial with a 34-week active-controlled extension. Diabetes Obes. Metab. 14, 1145-1154 (2012).
65. S. Del Prato, A. H. Barnett, H. Huisman, D. Neubacher, H.-J. Woerle, K. A. Dugi, Effect of linagliptin monotherapy on glycaemic control and markers of b-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial. Diabetes Obes. Metab. 13, 258-267 (2011).
66. T. Haak, T. Meinicke, R. Jones, S. Weber, M. von Eynatten, H.-J. Woerle, Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: A randomized, double-blind, placebo-controlled study. Diabetes Obes. Metab. 14, 565-574 (2012).
67. M. Laakso, J. Rosenstock, P.-H. Groop, A. H. Barnett, B. Gallwitz, U. Hehnke, I. Tamminen, S. Patel, M. von Eynatten, H.-J. Woerle, Treatment with the dipeptidyl peptidase-4 inhibitor linagliptin or placebo followed by glimepiride in patients with type 2 diabetes with moderate to severe renal impairment: A 52-week, randomized, double-blind clinical trial. Diabetes Care 38, e15-e17 (2015).
68. R. A. DeFronzo, P. R. Fleck, C. A. Wilson, Q. Mekki; Alogliptin Study 010 Group, 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 31, 2315-2317 (2008).
69. J. Rosenstock, S. E. Inzucchi, J. Seufert, P. R. Fleck, C. A. Wilson, Q. Mekki, Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes. Diabetes Care 33, 2406-2408 (2010).
70. J. Rosenstock, C. Wilson, P. Fleck, 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. 15, 906-914 (2013).
71. Y. Seino, T. Fujita, S. Hiroi, M. Hirayama, K. Kaku, 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. 27, 1781-1792 (2011).
72. A. H. Barnett, B. Charbonnel, J. Li, M. Donovan, D. Fleming, N. Iqbal, Saxagliptin add-on therapy to insulin with or without metformin for type 2 diabetes mellitus: 52-week safety and efficacy. Clin. Drug Investig. 33, 707-717 (2013).
73. A. R. Chacra, G. H. Tan, S. Ravichandran, J. List, R. Chen; CV181040 Investigators, Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks. Diab. Vasc. Dis. Res. 8, 150-159 (2011).
74. R. A. DeFronzo, M. N. Hissa, A. J. Garber, J. Luiz Gross, R. Yuyan Duan, S. Ravichandran, R. S. Chen; Saxagliptin 014 Study Group, The efficacy and safety of saxagliptin when added to metformin therapy in patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care 32, 1649-1655 (2009).
75. B. Göke, B. Gallwitz, J. G. Eriksson, Å. Hellqvist, I. Gause-Nilsson, Saxagliptin vs. glipizide as add-on therapy in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: Long-term (52-week) extension of a 52-week randomised controlled trial. Int. J. Clin. Pract. 67, 307-316 (2013).
76. M. P. Hermans, T. Delibasi, I. Farmer, L. Lohm, P. Maheux, P. Piatti, E. Malvolti, S. Jörgens, B. Charbonnel, Effects of saxagliptin added to sub-maximal doses of metformin compared with uptitration of metformin in type 2 diabetes: The PROMPT study. Curr. Med. Res. Opin. 28, 1635-1645 (2012).
77. P. L. Hollander, J. Li, R. Frederich, E. Allen, R. Chen; CV181013 Investigators, Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab. Vasc. Dis. Res. 8, 125-135 (2011).
78. M. Nowicki, I. Rychlik, H. Haller, M. Warren, L. Suchower, I. Gause-Nilsson, K.-M. Schutzer, 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. 65, 1230-1239 (2011).
79. G. Schernthaner, S. Durán-Garcia, M. Hanefeld, G. Langslet, L. Niskanen, C. J. Östgren, E. Malvolti, E. Hardy, Efficacy and tolerability of saxagliptin compared with glimepiride in elderly patients with type 2 diabetes: A randomized, controlled study (GENERATION). Diabetes Obes. Metab. 17, 630-638 (2015).
80. B. M. Scirica, E. Braunwald, I. Raz, M. A. Cavender, D. A. Morrow, P. Jarolim, J. A. Udell, O. Mosenzon, K. Im, A. A. Umez-Eronini, P. S. Pollack, B. Hirshberg, R. Frederich, B. S. Lewis, D. K. McGuire, J. Davidson, P. G. Steg, D. L. Bhatt; SAVOR-TIMI 53 Steering Committee and Investigators, Heart failure, saxagliptin, and diabetes mellitus: Observations from the SAVORTIMI 53 randomized trial. Circulation 130, 1579-1588 (2014).
81. B. Ahrén, S. L. Johnson, M. Stewart, D. T. Cirkel, F. Yang, C. Perry, M. N. Feinglos; HARMONY 3 Study Group, HARMONY 3: 104-week randomized, double-blind, placebo- And activecontrolled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin. Diabetes Care 37, 2141-2148 (2014).
82. R. Arechavaleta, T. Seck, Y. Chen, K. J. Krobot, E. A. O'Neill, L. Duran, K. D. Kaufman, D. Williams-Herman, B. J. Goldstein, Efficacy and safety of treatment with sitagliptin or glimepiride in patients with type 2 diabetes inadequately controlled on metformin monotherapy: A randomized, double-blind, non-inferiority trial. Diabetes Obes. Metab. 13, 160-168 (2011).
83. P. Aschner, J. Chan, D. R. Owens, S. Picard, E. Wang, M.-P. Dain, V. Pilorget, A. Echtay, V. Fonseca; EASIE investigators, Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): A multicentre, randomised open-label trial. Lancet 379, 2262-2269 (2012).
84. R. M. Bergenstal, C. Wysham, L. Macconell, J. Malloy, B. Walsh, P. Yan, K. Wilhelm, J. Malone, L. E. Porter; DURATION-2 Study Group, Efficacy and safety of exenatide once weekly versus sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): A randomised trial. Lancet 376, 431-439 (2010).
85. R. M. Bergenstal, A. Forti, J.-L. Chiasson, M. Woloschak, M. Boldrin, R. Balena, Efficacy and safety of taspoglutide versus sitagliptin for type 2 diabetes mellitus (T-emerge 4 trial). Diabetes Ther. 3, 13 (2012).
86. A. S. Dobs, B. J. Goldstein, P. Aschner, E. S. Horton, G. E. Umpierrez, L. Duran, J. S. Hill, Y. Chen, G. T. Golm, R. B. Langdon, D. E. Williams-Herman, K. D. Kaufman, J. M. Amatruda, J. C. A. Ferreira, Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized placebo-controlled 54-week trial in patients with type 2 diabetes. J. Diabetes 5, 68-79 (2013).
87. E. Ferrannini, A. Berk, S. Hantel, S. Pinnetti, T. Hach, H. J. Woerle, U. C. Broedl, Long-term safety and efficacy of empagliflozin, sitagliptin, and metformin: An active-controlled, parallel-group, randomized, 78-week open-label extension study in patients with type 2 diabetes. Diabetes Care 36, 4015-4021 (2013).
88. V. Fonseca, B. Staels, J. D. Morgan II, Y. Shentu, G. T. Golm, A. O. Johnson-Levonas, K. D. Kaufman, B. J. Goldstein, H. Steinberg, Efficacy and safety of sitagliptin added to ongoing metformin and pioglitazone combination therapy in a randomized, placebocontrolled, 26-week trial in patients with type 2 diabetes. J. Diabetes Complications 27, 177-183 (2013).
89. T. Forst, R. Guthrie, R. Goldenberg, J. Yee, U. Vijapurkar, G. Meininger, P. Stein, Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes. Metab. 16, 467-477 (2014).
90. F. J. Lavalle-González, A. Januszewicz, J. Davidson, C. Tong, R. Qiu, W. Canovatchel, G. Meininger, Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: A randomised trial. Diabetologia 56, 2582-2592 (2013).
91. L. A. Leiter, M. C. Carr, M. Stewart, A. Jones-Leone, R. Scott, F. Yang, Y. Handelsman, Efficacy and safety of the once-weekly GLP-1 receptor agonist albiglutide versus sitagliptin in patients with type 2 diabetes and renal impairment: A randomized phase III study. Diabetes Care 37, 2723-2730 (2014).
92. M. Nauck, R. S. Weinstock, G. E. Umpierrez, B. Guerci, Z. Skrivanek, Z. Milicevic, Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care 37, 2149-2158 (2014).
93. L. Olansky, C. Reasner, T. L. Seck, D. E. Williams-Herman, M. Chen, L. Terranella, A. Mehta, K. D. Kaufman, B. J. Goldstein, A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents. Diabetes Obes. Metab. 13, 841-849 (2011).
94. R. Pratley, M. Nauck, T. Bailey, E. Montanya, R. Cuddihy, S. Filetti, A. Garber, A. B. Thomsen, H. Hartvig, M. Davies; 1860-LIRA-DPP-4 Study Group, One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: A randomised, parallel-group, open-label trial. Int. J. Clin. Pract. 65, 397-407 (2011).
95. I. Raz, Y. Chen, M. Wu, S. Hussain, K. D. Kaufman, J. M. Amatruda, R. B. Langdon, P. P. Stein, M. Alba, Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr. Med. Res. Opin. 24, 537-550 (2008).
96. J. Rosenstock, R. Brazg, P. J. Andryuk, K. Lu, P. Stein; Sitagliptin Study 019 Group, 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. 28, 1556-1568 (2006).
97. T. L. Seck, S. S. Engel, D. E. Williams-Herman, C. M. Sisk, G. T. Golm, H. Wang, K. D. Kaufman, B. J. Goldstein, Sitagliptin more effectively achieves a composite endpoint for A1C reduction, lack of hypoglycemia and no body weight gain compared with glipizide. Diabetes Res. Clin. Pract. 93, e15-e17 (2011).
98. Z. Skrivanek, B. L. Gaydos, J. Y. Chien, M. J. Geiger, M. A. Heathman, S. Berry, J. H. Anderson, T. Forst, Z. Milicevic, D. Berry, Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes. Metab. 16, 748-756 (2014).
99. T. Vilsbøll, J. Rosenstock, H. Yki-Järvinen, W. T. Cefalu, Y. Chen, E. Luo, B. Musser, P. J. Andryuk, Y. Ling, K. D. Kaufman, J. M. Amatruda, S. S. Engel, L. Katz, Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes. Metab. 12, 167-177 (2010).
100. J. Wainstein, L. Katz, S. S. Engel, L. Xu, G. T. Golm, S. Hussain, E. A. O'Neill, K. D. Kaufman, B. J. Goldstein, Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes. Diabetes Obes. Metab. 14, 409-418 (2012).
101. W. Yang, Y. Guan, Y. Shentu, Z. Li, A. O. Johnson-Levonas, S. S. Engel, K. D. Kaufman, B. J. Goldstein, M. Alba, The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes. J. Diabetes 4, 227-237 (2012).
102. E. Bosi, R. P. Camisasca, C. Collober, E. Rochotte, A. J. Garber, Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care 30, 890-895 (2007).
103. V. Fonseca, A. Schweizer, D. Albrecht, M. A. Baron, I. Chang, S. Dejager, Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia 50, 1148-1155 (2007).
104. A. J. Garber, J. E. Foley, M. A. Banerji, P. Ebeling, S. Gudbjörnsdottir, R.-P. Camisasca, A. Couturier, M. A. Baron, Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes. Metab. 10, 1047-1056 (2008).
105. M. Bajaj, R. Gilman, S. Patel, J. Kempthorne-Rawson, D. Lewis-D'Agostino, H.-J. Woerle, Linagliptin improved glycaemic control without weight gain or hypoglycaemia in patients with type 2 diabetes inadequately controlled by a combination of metformin and pioglitazone: A 24-week randomized, double-blind study. Diabet. Med. 31, 1505-1514 (2014).
106. A. H. Barnett, H. Huisman, R. Jones, M. von Eynatten, S. Patel, H.-J. Woerle, 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 382, 1413-1423 (2013).
107. B. Gallwitz, J. Rosenstock, T. Rauch, S. Bhattacharya, S. Patel, M. von Eynatten, K. A. Dugi, H.-J. Woerle, 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 380, 475-483 (2012).
108. E. Bosi, G. C. Ellis, C. A. Wilson, P. R. Fleck, 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. 13, 1088-1096 (2011).
109. M. A. Nauck, G. C. Ellis, P. R. Fleck, C. A. Wilson, Q. Mekki; Alogliptin Study 008 Group, 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. 63, 46-55 (2009).
110. R. E. Pratley, J. E.-B. Reusch, P. R. Fleck, C. A. Wilson, Q. Mekki; Alogliptin Study 009 Group, 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. 25, 2361-2371 (2009).
111. R. E. Pratley, M. S. Kipnes, P. R. Fleck, C. Wilson, Q. Mekki; Alogliptin Study 007 Group, Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes inadequately controlled by glyburide monotherapy. Diabetes Obes. Metab. 11, 167-176 (2009).
112. J. Rosenstock, M. S. Rendell, J. L. Gross, P. R. Fleck, C. A. Wilson, Q. Mekki, Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without causing weight gain or increased hypoglycaemia. Diabetes Obes. Metab. 11, 1145-1152 (2009).
113. F. Zannad, C. P. Cannon, W. C. Cushman, G. L. Bakris, V. Menon, A. T. Perez, P. R. Fleck, C. R. Mehta, S. Kupfer, C. Wilson, H. Lam, W. B. White; EXAMINE Investigators, Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: A multicentre, randomised, double-blind trial. Lancet 385, 2067-2076 (2015).