“Sweet is Sweet but until it is not too Sweet”. As the sweet spoon of diabetes challenges the global population, diabetic organizations across the globe call for unanimous resonance of Diabetes Voice to tackle diabetes with healthy living. With the discovery of new pathophysiology associated with diabetes, patients are gaining access to the newer therapeutic classes. Teneligliptin, a third generation DPP-4 inhibitor exhibits unique “J-shaped” structure with “anchor-lock domain” mechanism which provides potent & long duration of action. It acts like an insulin/glucagon modulator controlling blood glucose over 24 hours. It is effective in tackling short-term glycemic fluctuations and improvement in β -cell parameters is observed soon after treatment. Half-life of 26.9 hours ensures once a day administration. Because the metabolites of this drug are eliminated via renal and hepatic excretion, no dose adjustment is necessary in patients with renal impairment. Improvement in lipid profile, LV function, adiponectin levels & natriuretic effect is among the added pleiotropic benefits. With the effective glycemic control & capability for improvement in β -cell function, Teneligliptin promises to be a preferable antidiabetic agent with long-term efficacy & safety in patients with type 2 diabetes. The objective of this paper is to provide a comprehensive datum analysis of Teneligliptin in the management of type 2 diabetes. It summarizes the unique pharmacodynamic & pharmacokinetic advantages of Teneligliptin and additionally its pleiotropic benefits of cardioprotection. It provides a comprehensive comparison of Teneligliptin vis-à-vis other gliptins in the class & provides a concise summary of all clinical trials till the date with Teneligliptin monotherapy & combination with other antidiabetic drugs.
Cho, N.H., Whiting, D., Forouhi, N., Guariguata, L., Hambleton, I., Li, R., Majeed, A., Mbanya, J.C., Montoya, P.A., Motala, A., Narayan, V., Ramachandran, A., Rathmann, W., Roglic, G., Shaw, J., Silink, M. and Zhang, P. (2015) IDF Diabetes Atlas. 7th Edition, International Diabetes Federation, Karakas Print, Brussels, 1-144.
Kalra, S., Das, A.K. and Sahay, R. (2013) Managing Diabetes: The Drivers of Change. Journal of Social Health & Diabetes, 1, 3-5. http://dx.doi.org/10.4103/2321-0656.109827
Kalra, S. (2013) Recent Advances in Pathophysiology of Diabetes: Beyond the Dirty Dozen. Journal of Pakistan Medical Association, 2, 277-280.
Baetta, R. and Corsini, A. (2011) Pharmacology of Dipeptidyl Peptidase-4 Inhibitors. Drugs, 71, 1441-1467. http://dx.doi.org/10.2165/11591400-000000000-00000
Drucker, D.J. and Nauck, M.A. (2006) The Incretin System: Glucagon Like Peptide-1 Receptor Agonists & Dipeptidyl Peptidase-4 Inhibitors in Type 2 Diabetes. The Lancet, 368, 1696-1705. http://dx.doi.org/10.1016/S0140-6736(06)69705-5
Verspohl, E.J. (2009) Novel Therapeutics for Type 2 Diabetes: Incretin Hormone Mimetics (Glucagon-Like Peptide-1 Receptor Agonists) and Dipeptidyl Peptidase-4 Inhibitors. Pharmacology & Therapeutics, 124, 113-138. http://dx.doi.org/10.1016/j.pharmthera.2009.06.002
Nabeno, M., Akahoshi, F., Kishida, H., Miyaguchi, I., Tanaka, Y., Ishii, S. and Kadowaki, T. (2013) A Comparative Study of the Binding Modes of Recently Launched Dipeptidyl Peptidase IV Inhibitors in the Active Site. Biochemical and Biophysical Research Communications, 434,191-196. http://dx.doi.org/10.1016/j.bbrc.2013.03.010
Kushwaha, R.N., Haq, W. and Katti, S.B. (2014) Discovery of 17 Gliptins in 17-Years of Research for the Treatment of Type 2 Diabetes: A Synthetic Overview. Chemistry & Biology Interface, 4, 137-162.
Rohrborn, D., Wronkowitz, N. and Eckel, J. (2015) DPP4 in Diabetes. Frontiers in Immunology, 6, 1-20. http://dx.doi.org/10.3389/fimmu.2015.00386
Kishimoto, M. (2013) Teneligliptin: A DPP-4 Inhibitor for the Treatment of Type 2 Diabetes. Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 6, 187-195. http://dx.doi.org/10.2147/DMSO.S35682
Kadowaki, T. and Kondo, K. (2013) Efficacy, Safety and Dose-Response Relationship of Teneligliptin, a Dipeptidyl Peptidase-4 Inhibitor, in Japanese Patients with Type 2 Diabetes Mellitus. Diabetes, Obesity and Metabolism, 15, 810-818. http://dx.doi.org/10.1111/dom.12092
Eto, T., Inoue, S. and Kadowaki, T. (2012) Effects of Once-Daily Teneligliptin on 24-h Blood Glucose Control and Safety in Japanese Patients with Type 2 Diabetes Mellitus: A 4-Week, Randomized, Double-Blind, Placebo-Controlled Trial. Diabetes, Obesity and Metabolism, 14, 1040-1046. http://dx.doi.org/10.1111/j.1463-1326.2012.01662.x
Ito, R., Fukui, T., Hayashi, T., Osamura, A., Ohara, M., Hara, N., Higuchi, A., Yamamoto, T. and Hirano, T. (2015) Teneligliptin, a Dipeptidyl Peptidase-4 Inhibitor, Improves Early-Phase Insulin Secretion in Drug-Naive Patients with Type 2 Diabetes. Drugs in R & D, 15, 245-251.
Kutoha, E., Hiratea, M. and Ikenoa, Y. (2014) Teneligliptin as an Initial Therapy for Newly Diagnosed, Drug Naive Subjects With Type 2 Diabetes. Journal of Clinical Medicine Research, 6, 287-294.
Suh, S. and Kim, J.H. (2015) Glycemic Variability: How Do We Measure It and Why Is It Important? Diabetes & Metabolism Journal, 39, 273-282. http://dx.doi.org/10.4093/dmj.2015.39.4.273
Marling, C.R., Shubrook, H.J., Vernier, S.J., Wiley, M.T. and Schwartz, F.L. (2011) Characterizing Blood Glucose Variability Using New Metrics with Continuous Glucose Monitoring Data. Journal of Diabetes Science and Technology, 5, 871-878. http://dx.doi.org/10.1177/193229681100500408
Furusyo, N. and Hayashi, J. (2013) Glycated Albumin and Diabetes Mellitus. Biochimica et Biophysica Acta, 1830, 5509-5514. http://dx.doi.org/10.1016/j.bbagen.2013.05.010
Roche, M., Rondeau, P., Singh, N.R., Tarnus, E. and Bourdon, E. (2008) The Antioxidant Properties of Serum Albumin. Federation of European Biochemical Societies (FEBS) Letters, 582, 1783-1787. http://dx.doi.org/10.1016/j.febslet.2008.04.057
Dabrowska, A.M., Tarach, J.S. and Kurowska, M. (2012) 1,5-Anhydroglucitol (1,5-AG) and Its Usefulness in Clinical Practice. Medical and Biological Sciences, 26, 11-17. http://dx.doi.org/10.2478/v10251-012-0049-z
Watanabe, M., Kokubo, Y., Higashiyama, A., et al. (2011) Serum 1,5-Anhydrodglucitol Levels Predict First-Ever Cardiovascular Disease: An 11-Year Population-Based Cohort Study in Japan, the Suita Study. Atherosclerosis, 216, 477-483. http://dx.doi.org/10.1016/j.atherosclerosis.2011.02.033
Ceriello, A., Quagliaro, L., Piconi, L., Assaloni, R., Da Ros, R., Maier, A., Esposito, K. and Giugliano, D. (2004) Effect of Postprandial Hypertriglyceridemia and Hyperglycemia on Circulating Adhesion Molecules and Oxidative Stress Generation and the Possible Role of Simvastatin Treatment. Diabetes, 53, 701-710. http://dx.doi.org/10.2337/diabetes.53.3.701
Kawano, H., Motoyama, T., Hirashima, O., Hirai, N., Miyao, Y., Sakamoto, T., Kugiyama, K., Ogawa, H. and Yasue, H. (1999) Hyperglycemia Rapidly Suppresses Flow-Mediated Endothelium-Dependent Vasodilation of Brachial Artery. Journal of the American College of Cardiology, 34, 146-154. http://dx.doi.org/10.1016/S0735-1097(99)00168-0
Monnier, L., Mas, E., Ginet, C., Michel, F., Villon, L., Cristol, J.P. and Colette, C. (2006) Activation of Oxidative Stress by Acute Glucose Fluctuations Compared with Sustained Chronic Hyperglycemia in Patients with Type 2 Diabetes. The Journal of American Medical Association, 295, 1681-1687. http://dx.doi.org/10.1001/jama.295.14.1681
Goda, M. and Kadowaki, T. (2013) Teneligliptin for the Treatment of Type 2 Diabetes. Drugs of Today, 49, 615-629.
Tanaka, S., Suzuki, K., Aoki, C., Niitani, M., Kato, K., Tomotsune, T. and Aso, Y. (2014) Add-On Treatment with Teneligliptin Ameliorates Glucose Fluctuations and Improves Glycemic Control Index in Japanese Patients with Type 2 Diabetes on Insulin Therapy. Diabetes Technology & Therapeutics, 16, 840-845. http://dx.doi.org/10.1089/dia.2014.0095
Nakamaru, Y., Hayashi, Y., Ikegawa, R., Kinoshita, S., Madera, B.P., Gunput, D., et al. (2014) Metabolism and Disposition of the Dipeptidyl Peptidase IV Inhibitor Teneligliptin in Humans. Xenobiotica, 44, 242-253. http://dx.doi.org/10.3109/00498254.2013.816891
Investi Farma S.A. (2015) Teneglucon (Teneligliptin) via Oral: Argentina Prescribing Information. http://investi.e-tradeconsult.com/teneglucon/art_234/es/
Nakamaru, Y., Hayashi, Y., Sekine, M., Kinoshita, S., Thompson, J., Kawaguchi, A., et al. (2014) Effect of Ketoconazole on the Pharmacokinetics of the Dipeptidyl Peptidase-4 Inhibitor Teneligliptin: An Open-Label Study in Healthy White Subjects in Germany. Clinical Therapeutics, 36, 760-769. http://dx.doi.org/10.1016/j.clinthera.2014.03.002
Nakamaru, Y., Hayashi, Y., Davies, M., Heuer, H.J., Hisanaga, N. and Akimoto, K. (2015) Investigation of Potential Pharmacokinetic Interactions between Teneligliptin and Metformin in Steady-State Conditions in Healthy Adults. Clinical Therapeutics, 37, 2007-2018. http://dx.doi.org/10.1016/j.clinthera.2015.06.012
Kinoshita, S. and Kondo, K. (2015) Evaluation of Pharmacokinetic and Pharmacodynamic Interactions of Canagliflozin and Teneligliptin in Japanese Healthy Male Volunteers. Expert Opinion on Drug Metabolism & Toxicology, 11, 7-14.
Ceriello, A. (2000) The Post-Prandial State and Cardiovascular Disease: Relevance to Diabetes Mellitus. Diabetes/Metabolism Research and Reviews, 16, 125-132. http://dx.doi.org/10.1002/(SICI)1520-7560(200003/04)16:2 3.0.CO;2-4
Morishita, R. and Nakagami, H. (2015) Teneligliptin: Expectations for Its Pleiotropic Action. Expert Opinion on Pharmacotherapy, 16, 417-426.
Hashikata, T., Yamaoka-Tojo, M., Kakizaki, R., Nemoto, T., Fujiyoshi, K., Namba, S., Kitasato, L., Hashimoto, T., Kameda, R., Maekawa, E., Shimohama, T., Tojo, T. and Ako, J. (2015) Teneligliptin Improves Left Ventricular Diastolic Function and Endothelial Function in Patients with Diabetes. Heart Vessels, 1-8. http://dx.doi.org/10.1007/s00380-015-0724-7
Kusunoki, M., Sato, D., Nakamura, T., Oshida, Y., Tsutsui, H., Natsume, Y., Tsutsumi, K. and Miyata, T. (2015) DPP-4 Inhibitor Teneligliptin Improves Insulin Resistance and Serum Lipid Profile in Japanese Patients with Type 2 Diabetes. Drug Research, 65, 532-534.
Von Websky, K., Reichetzeder, C. and Hocher, B. (2014) Physiology and Pathophysiology of Incretins in the Kidney. Current Opinion in Nephrology and Hypertension, 23, 54-60. http://dx.doi.org/10.1097/01.mnh.0000437542.77175.a0
Girardi, A.C., Degray, B.C., Nagy, T., Biemesderfer, D. and Aronson, P. (2001) Association of Na+-H+ Exchanger Isoform NHE3 and Dipeptidyl Peptidase IV in the Renal Proximal Tubule. The Journal of Biological Chemistry, 276, 46671-46677. http://dx.doi.org/10.1074/jbc.M106897200
Girardi, A.C., Knauf, F., Demuth, H.U. and Aronson, P.S. (2004) Role of Dipeptidyl Peptidase IV in Regulating Activity of Na+/H+ Exchanger Isoform NHE3 in Proximal Tubule Cells. The American Journal of Physiology—Cell Physiology, 287, C1238-C1245. http://dx.doi.org/10.1152/ajpcell.00186.2004
Mason, R.P., Jacob, R.F., Kubant, R., Walter, M.F., Bellamine, A., Jacoby, A., Mizuno, Y. and Malinski, T. (2011) Effect of Enhanced Glycemic Control with Saxagliptin on Endothelial Nitric Oxide Release and CD40 Levels in Obese Rats. Journal of Atherosclerosis and Thrombosis, 18, 774-783. http://dx.doi.org/10.5551/jat.7666
Ishii, M., Shibata, R., Kondo, K., Kambara, T., Shimizu, Y., Tanigawa, T., Bando, Y.K., Nishimura, M., Ouchi, N. and Murohara, T. (2014) Vildagliptin Stimulates Endothelial Cell Network Formation and Ischemia-Induced Revascularization via an Endothelial Nitric Oxide Synthase-Dependent Mechanism. The Journal of Biological Chemistry, 289, 27235-27245. http://dx.doi.org/10.1074/jbc.M114.557835
Shih, C.M., Chen, Y.H., Lin, Y.W., Tsao, N.W., Wu, S.C., Kao, Y.T., Chiang, K.H., Li, C.Y., Chang, N.C., Lin, C.Y., Huang, C.Y. and Lin, F.Y. (2014) MK-0626, a Dipeptidyl Peptidase-4 Inhibitor, Improves Neovascularization by Increasing both the Number of Circulating Endothelial Progenitor Cells and Endothelial Nitric Oxide Synthetase Expression. Current Medicinal Chemistry, 21, 2012-2022. http://dx.doi.org/10.2174/09298673113206660273
Brandt, I., Lambeir, A.M., Ketelslegers, J.M., Vanderheyden, M., Scharpé, S. and De Meester, I. (2006) Dipeptidyl-Peptidase IV Converts Intact B-Type Natriuretic Peptide into Its Des-SerPro Form. Clinical Chemistry, 52, 82-87. http://dx.doi.org/10.1373/clinchem.2005.057638
Moroi, M. and Kubota, T. (2015) Diuretic and Natriuretic Effects of Dipeptidyl Peptidase-4 Inhibitor Teneligliptin: The Contribution of Glucagon-Like Peptide-1. Journal of Cardiovascular Pharmacology, 66, 159-164. http://dx.doi.org/10.1097/FJC.0000000000000258
Goldstein, B.J., Feinglos, M.N., Lunceford, J.K., Johnson, J. and Williams-Herman, D.E., Sitagliptin 036 Study Group (2007) 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, 30, 1979-1987. http://dx.doi.org/10.2337/dc07-0627
Scheen, A.J. (2012) A Review of Gliptins in 2011. Expert Opinion on Pharmacotherapy, 13, 81-99. http://dx.doi.org/10.1517/14656566.2012.642866
Barnett, A., Allsworth, J., Jameson, K. and Mann, R. (2007) A Review of the Effects of Antihyperglycaemic Agents on Body Weight: The Potential of Incretin Targeted Therapies. Current Medical Research and Opinion, 23, 1493-1507. http://dx.doi.org/10.1185/030079907X199691
Hong, S., Park, C.Y., Han, K.A., Chung, C.H., Ku, B.J., Jang, H.C., Ahn, C.W., Lee, M.K., Moon, M.K., Son, H.S., Lee, C.B., Cho, Y.W. and Park, S.W. (2016) Efficacy and Safety of Teneligliptin, a Novel Dipeptidyl Peptidase-4 Inhibitor, in Korean Patients with Type 2 Diabetes Mellitus: A 24-Week Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase III Trial. Diabetes, Obesity and Metabolism. (Epub ahead of print) http://dx.doi.org/10.1111/dom.12631
Kadowaki, T. and Kondo, K. (2014) 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, Obesity and Metabolism, 16, 418-425. http://dx.doi.org/10.1111/dom.12235
Kadowaki, T. and Kondo, K. (2013) Efficacy and Safety of Teneligliptin in Combination with Pioglitazone in Japanese Patients with Type 2 Diabetes Mellitus. Journal of Diabetes Investigation, 4, 576-584. http://dx.doi.org/10.1111/jdi.12092
Kim, M.K., Rhee, E.J., Han, K.A., Woo, A.C., Lee, M.K., Ku, B.J., Chung, C.H., Kim, K.A., Lee, H.W., Park, I.B., Park, J.Y., Chul Jang, H.C., Park, K.S., Jang, W.I. and Cha, B.Y. (2015) Efficacy and Safety of Teneligliptin, a Dipeptidyl Peptidase-4 Inhibitor, Combined with Metformin in Korean Patients with Type 2 Diabetes Mellitus: A 16-Week, Randomized, Double-Blind, Placebo-Controlled Phase III Trial. Diabetes, Obesity and Metabolism, 17, 309-312. http://dx.doi.org/10.1111/dom.12424
Tsuchimochi, W., Uen, H., Yamashita, E., Tsubouchi, C., Sakoda, H., Nakamura, S. and Nakazato, M. (2015) Teneligliptin Improves Glycemic Control with the Reduction of Postprandial Insulin Requirement in Japanese Diabetic Patients. Endocrine Journal, 62, 13-20. http://dx.doi.org/10.1507/endocrj.EJ14-0393
Otsuki, H., Kosaka, T., Nakamura, K., Shimomura, F., Kuwahara, Y. and Tsukamoto, T. (2014) Safety and Efficacy of Teneligliptin: A Novel DPP-4 Inhibitor for Hemodialysis Patients with Type 2 Diabetes. International Urology and Nephrology, 46, 427-432. http://dx.doi.org/10.1007/s11255-013-0552-6
Kadowaki, T., Marubayashi, F., Yokota, S., Katoh, M. and Iijima, H. (2015) Safety and Efficacy of Teneligliptin in Japanese Patients with Type 2 Diabetes Mellitus: A Pooled Analysis of Two Phase III Clinical Studies. Expert Opinion on Pharmacotherapy, 16, 971-981. http://dx.doi.org/10.1517/14656566.2015.1032249
Kamiko, K., Aoki, K., Kamiyama, H., Taguri, M., Shibata, E., Ashiya, Y., Minagawa, F., Shinoda, K., Nakajima, S. and Terauchi, Y. (2015) Comparison of the Administration of Teneligliptin Every Day versus Every Other Day in Japanese Patients with Type 2 Diabetes: A Randomized Non-Inferior Test. The Journal of Clinical Pharmacology, 55, 144-151. http://dx.doi.org/10.1002/jcph.385
Wada, N., Mori, K., Nakagawa, C., Sawa, J., Kumeda, Y., Shoji, T., Emoto, M. and Inaba, M. (2015) Improved Glycemic Control with Teneligliptin in Patients with Type 2 Diabetes Mellitus on Hemodialysis: Evaluation by Continuous Glucose Monitoring. Journal of Diabetes and Its Complications, 29, 1310-1313. http://dx.doi.org/10.1016/j.jdiacomp.2015.07.002
Ministry of Health, Labour and Welfare & Pharmaceutical and Food Safety Bureau, Japan, Pharmaceuticals and Medical Devices Agency (PDMA) (2014) Pharmaceuticals and Medical Devices Safety Information. Teneligliptin Hydrobromide Hydrate, 318, 32-37.
Egan, A.G., Blind, E., Dunder, K., de Graeff, P.A., Hummer, B.T., Bourcier, T. and Rosebraugh, C. (2014) Pancreatic Safety of Incretin-Based Drugs—FDA and EMA Assessment. The New England Journal of Medicine, 370, 794-797. http://dx.doi.org/10.1056/NEJMp1314078
Defronzo, R.A. (2009) From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus. Diabetes, 58, 773-795. http://dx.doi.org/10.2337/db09-9028
DeFronzo, R.A. and Goodman, A.M. (1995) Efficacy of Metformin in Patients with Non-Insulin-Dependent Diabetes Mellitus. The Multicenter Metformin Study Group. The New England Journal of Medicine, 333, 541-549. http://dx.doi.org/10.1056/NEJM199508313330902
United Kingdom Prospective Diabetes Study Group (1998) UKPDS 28: A Randomized Trial of Efficacy of Early Addition of Metformin in Sulfonylurea-Treated Type 2 Diabetes. Diabetes Care, 21, 87-92. http://dx.doi.org/10.2337/diacare.21.1.87
Nathan, D.M., Buse, J.B., Davidson, M.B., Heine, R.J., Holman, R.R., Sherwin, R. and Zinman, B. (2006) Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy: A Consensus Statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care, 29, 1963-1972. http://dx.doi.org/10.2337/dc06-9912
Bell, D.S. (2004) A Comparison of Agents Used to Manage Type 2 Diabetes Mellitus: Need for Reappraisal of Traditional Approaches. Treatments in Endocrinology, 3, 67-76. http://dx.doi.org/10.2165/00024677-200403020-00001
UK Prospective Diabetes Study Group (1995) U.K. Prospective Diabetes Study 16. Overview of 6 Years’ Therapy of Type II Diabetes: A Progressive Disease. Diabetes, 44, 1249-1258. http://dx.doi.org/10.2337/diab.44.11.1249
Sawada, F., Inoguchi, T., Tsubouchi, H., Sasaki, S., Fujii, M., Maeda, Y., Morinaga, H., Nomura, M., Kobayashi, K. and Takayanagi, R. (2008) Differential Effect of Sulfonylureas on Production of Reactive Oxygen Species and Apoptosis in Cultured Pancreatic Beta-Cell Line, MIN6. Metabolism, 57, 1038-1045. http://dx.doi.org/10.1016/j.metabol.2008.01.038
Maedler, K., Carr, R.D., Bosco, D., Zuellig, R.A., Berney, T. and Donath, M.Y. (2005) Sulfonylurea Induced Beta-Cell Apoptosis in Cultured Human Islets. The Journal of Clinical Endocrinology & Metabolism, 90, 501-506. http://dx.doi.org/10.1210/jc.2004-0699
Dormandy, J.A., Charbonnel, B., Eckland, D.J., Erdmann, E., Massi-Benedetti, M., Moules, I.K., Skene, A.M., Tan, M.H., Lefèbvre, P.J., Murray, G.D., Standl, E., Wilcox, R.G., Wilhelmsen, L., Betteridge, J., Birkeland, K., Golay, A., Heine, R.J., Korányi, L., Laakso, M., Mokán, M., Norkus, A., Pirags, V., Podar, T., Scheen, A., Scherbaum, W., Schernthaner, G., Schmitz, O., Skrha, J., Smith, U. and Taton, J., PROactive Investigators (2005) Secondary Prevention of Macrovascular Events in Patients with Type 2 Diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial in macroVascular Events): A Randomised Controlled Trial. The Lancet, 366, 1279-1289. http://dx.doi.org/10.1016/S0140-6736(05)67528-9
Weir, G.C. and Bonner-Weir, S. (2004) Five Stages of Evolving [Beta]-Cell Dysfunction during Progression to Diabetes. Diabetes, 53, S16-S21. http://dx.doi.org/10.2337/diabetes.53.suppl_3.s16
Turner, R.C., Cull, C.A., Frighi, V. and Holman, R.R. (1999) Glycemic Control with Diet, Sulfonylurea, Metformin, or Insulin in Patients with Type 2 Diabetes Mellitus: Progressive Requirement for Multiple Therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. Journal of American Medical Association, 281, 2005-2012. http://dx.doi.org/10.1001/jama.281.21.2005