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17 August 1999 | Volume 131 Issue 4 | Pages 281-303
Type 2 diabetes mellitus is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. An elevated rate of basal hepatic glucose production in the presence of hyperinsulinemia is the primary cause of fasting hyperglycemia; after a meal, impaired suppression of hepatic glucose production by insulin and decreased insulin-mediated glucose uptake by muscle contribute almost equally to postprandial hyperglycemia. In the United States, five classes of oral agents, each of which works through a different mechanism of action, are currently available to improve glycemic control in patients with type 2 diabetes. The recently completed United Kingdom Prospective Diabetes Study (UKPDS) has shown that type 2 diabetes mellitus is a progressive disorder that can be treated initially with oral agent monotherapy but will eventually require the addition of other oral agents, and that in many patients, insulin therapy will be needed to achieve targeted glycemic levels. In the UKPDS, improved glycemic control, irrespective of the agent used (sulfonylureas, metformin, or insulin), decreased the incidence of microvascular complications (retinopathy, neuropathy, and nephropathy). This review examines the goals of antihyperglycemic therapy and reviews the mechanism of action, efficacy, nonglycemic benefits, cost, and safety profile of each of the five approved classes of oral agents. A rationale for the use of these oral agents as monotherapy, in combination with each other, and in combination with insulin is provided.
Author and Article Information
From the University of Texas Health Science Center, San Antonio, Texas.
Note: Over the past 3 years, the author has received funding from the following organizations and companies: American Diabetes Association, National Institutes of Health (National Institute of Diabetes and Digestive and Kidney Diseases), Veterans Administration System, Parke-Davis, Bristol-Myers Squibb, SmithKline Beecham, Takeda America, Hoechst Marion Roussel, Novo Nordisk Pharmaceuticals, Pfizer, ERGO Science, Bayer Corp., and Merck & Co. The information contained in this review represents an objective synthesis, which is based on published data in the literature and is not influenced by grant support from any of the preceding pharmaceutical companies.
Requests for Reprints: Ralph A. DeFronzo, MD, Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, TX 78284. REVIEW
Pharmacologic Therapy for Type 2 Diabetes Mellitus
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E. Faure, L. F. Pallardo, J. Mesa, M. Puig-Domingo, R. Garcia-Mayor, P. Benito, R. Ravella, M. Artes, and J. S. Lopez HbA1c and Glycemic Profile, Basal- and Post-Treatment With Miglitol, in an Area With a Mediterranean Diet Diabetes Care, October 1, 2002; 25(10): 1896 - 1897. [Full Text]
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S. A. Hinke, C. H. S. McIntosh, T. Hoffmann, K. Kuhn-Wache, L. Wagner, J. Bar, S. Manhart, M. Wermann, R. A. Pederson, and H.-U. Demuth On Combination Therapy of Diabetes With Metformin and Dipeptidyl Peptidase IV Inhibitors Diabetes Care, August 1, 2002; 25(8): 1490 - 1491. [Full Text]
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D. Kirpichnikov, S. I. McFarlane, and J. R. Sowers Metformin: An Update Ann Intern Med, July 2, 2002; 137(1): 25 - 33. [Abstract] [Full Text] [PDF]
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J. M. Miles, L. Leiter, P. Hollander, T. Wadden, J. W. Anderson, M. Doyle, J. Foreyt, L. Aronne, and S. Klein Effect of Orlistat in Overweight and Obese Patients With Type 2 Diabetes Treated With Metformin Diabetes Care, July 1, 2002; 25(7): 1123 - 1128. [Abstract] [Full Text] [PDF]
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D. E. Kelley, G. A. Bray, F. X. Pi-Sunyer, S. Klein, J. Hill, J. Miles, and P. Hollander Clinical Efficacy of Orlistat Therapy in Overweight and Obese Patients With Insulin-Treated Type 2 Diabetes: A 1-year randomized controlled trial Diabetes Care, June 1, 2002; 25(6): 1033 - 1041. [Abstract] [Full Text] [PDF]
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A. S. Attele, Y.-P. Zhou, J.-T. Xie, J. A. Wu, L. Zhang, L. Dey, W. Pugh, P. A. Rue, K. S. Polonsky, and C.-S. Yuan Antidiabetic Effects of Panax ginseng Berry Extract and the Identification of an Effective Component Diabetes, June 1, 2002; 51(6): 1851 - 1858. [Abstract] [Full Text] [PDF]
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A. T. Calabrese, K. C. Coley, S. V. DaPos, D. Swanson, and R. H. Rao Evaluation of Prescribing Practices: Risk of Lactic Acidosis With Metformin Therapy Arch Intern Med, February 25, 2002; 162(4): 434 - 437. [Abstract] [Full Text] [PDF]
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 Diabetes Prevention Program Research Group Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin N. Engl. J. Med., February 7, 2002; 346(6): 393 - 403. [Abstract] [Full Text] [PDF]
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E. S. Holmboe Oral Antihyperglycemic Therapy for Type 2 Diabetes: Clinical Applications JAMA, January 16, 2002; 287(3): 373 - 376. [Abstract] [Full Text] [PDF]
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B. Keidan, J. Hsia, and R. Katz Plasma lipids and antidiabetic agents: a brief overview The British Journal of Diabetes & Vascular Disease, January 1, 2002; 2(1): 40 - 43. [PDF]
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T. P. Ciaraldi, A. P.S. Kong, N. V. Chu, D. D. Kim, S. Baxi, M. Loviscach, R. Plodkowski, R. Reitz, M. Caulfield, S. Mudaliar, et al. Regulation of Glucose Transport and Insulin Signaling by Troglitazone or Metformin in Adipose Tissue of Type 2 Diabetic Subjects Diabetes, January 1, 2002; 51(1): 30 - 36. [Abstract] [Full Text] [PDF]
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 J. Xiao, S. Gregersen, M. Kruhoffer, S. B. Pedersen, T. F. Orntoft, and K. Hermansen The Effect of Chronic Exposure to Fatty Acids on Gene Expression in Clonal Insulin-Producing Cells: Studies Using High Density Oligonucleotide Microarray Endocrinology, November 1, 2001; 142(11): 4777 - 4784. [Abstract] [Full Text] [PDF]
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J. R. White Jr. and R. K. Campbell Recent Developments in the Pharmacological Reduction of Blood Glucose in Patients With Type 2 Diabetes Clin. Diabetes, October 1, 2001; 19(4): 153 - 159. [Abstract] [Full Text] [PDF]
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T. P. Erlinger and F. L. Brancati Postchallenge Hyperglycemia in a National Sample of U.S. Adults With Type 2 Diabetes Diabetes Care, October 1, 2001; 24(10): 1734 - 1738. [Abstract] [Full Text] [PDF]
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V. Vuksan, J. L. Sievenpiper, Z. Xu, E. Y. Y. Wong, A. L. Jenkins, U. Beljan-Zdravkovic, L. A. Leiter, R. G. Josse, and M. P. Stavro Konjac-Mannan and American Ginsing: Emerging Alternative Therapies for Type 2 Diabetes Mellitus J. Am. Coll. Nutr., October 1, 2001; 20(90005): 370S - 380. [Abstract] [Full Text]
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R. K. Campbell, J. R. White, and D. Nomura The Clinical Importance of Postprandial Hyperglycemia The Diabetes Educator, September 1, 2001; 27(5): 624 - 637. [PDF]
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M. Federici, M. Hribal, L. Perego, M. Ranalli, Z. Caradonna, C. Perego, L. Usellini, R. Nano, P. Bonini, F. Bertuzzi, et al. High Glucose Causes Apoptosis in Cultured Human Pancreatic Islets of Langerhans: A Potential Role for Regulation of Specific Bcl Family Genes Toward an Apoptotic Cell Death Program Diabetes, June 1, 2001; 50(6): 1290 - 1301. [Abstract] [Full Text]
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C. B. Chan, D. De Leo, J. W. Joseph, T. S. McQuaid, X. F. Ha, F. Xu, R. G. Tsushima, P. S. Pennefather, A. M. F. Salapatek, and M. B. Wheeler Increased Uncoupling Protein-2 Levels in {beta}-cells Are Associated With Impaired Glucose-Stimulated Insulin Secretion: Mechanism of Action Diabetes, June 1, 2001; 50(6): 1302 - 1310. [Abstract] [Full Text]
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P. Staehr, O. Hother-Nielsen, K. Levin, J. J. Holst, and H. Beck-Nielsen Assessment of Hepatic Insulin Action in Obese Type 2 Diabetic Patients Diabetes, June 1, 2001; 50(6): 1363 - 1370. [Abstract] [Full Text]
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F. de Vegt, J. M. Dekker, A. Jager, E. Hienkens, P. J. Kostense, C. D. A. Stehouwer, G. Nijpels, L. M. Bouter, and R. J. Heine Relation of Impaired Fasting and Postload Glucose With Incident Type 2 Diabetes in a Dutch Population: The Hoorn Study JAMA, April 25, 2001; 285(16): 2109 - 2113. [Abstract] [Full Text] [PDF]
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Y. Miyazaki, A. Mahankali, M. Matsuda, L. Glass, S. Mahankali, E. Ferrannini, K. Cusi, L. J. Mandarino, and R. A. DeFronzo Improved Glycemic Control and Enhanced Insulin Sensitivity in Type 2 Diabetic Subjects Treated With Pioglitazone Diabetes Care, April 1, 2001; 24(4): 710 - 719. [Abstract] [Full Text]
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M. Zander, M. Taskiran, M.-B. Toft-Nielsen, S. Madsbad, and J. J. Holst Additive Glucose-Lowering Effects of Glucagon-Like Peptide-1 and Metformin in Type 2 Diabetes Diabetes Care, April 1, 2001; 24(4): 720 - 725. [Abstract] [Full Text]
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V. P. Manchem, I. D. Goldfine, R. A. Kohanski, C. P. Cristobal, R. T. Lum, S. R. Schow, S. Shi, W. R. Spevak, E. Laborde, D. K. Toavs, et al. A Novel Small Molecule That Directly Sensitizes the Insulin Receptor In Vitro and In Vivo Diabetes, April 1, 2001; 50(4): 824 - 830. [Abstract] [Full Text]
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M. Freemark and D. Bursey The Effects of Metformin on Body Mass Index and Glucose Tolerance in Obese Adolescents With Fasting Hyperinsulinemia and a Family History of Type 2 Diabetes Pediatrics, April 1, 2001; 107(4): e55 - e55. [Abstract] [Full Text] [PDF]
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J. M. Olefsky Prospects for Research in Diabetes Mellitus JAMA, February 7, 2001; 285(5): 628 - 632. [Abstract] [Full Text] [PDF]
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I. Gabriely, R. Wozniak, M. Hawkins, and H. Shamoon Troglitazone Amplifies Counterregulatory Responses to Hypoglycemia in Nondiabetic Subjects J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 521 - 528. [Abstract] [Full Text]
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