Role of conventional oral antidiabetic drugs in management of type 2 diabetes mellitus

Vaishali Thakare, Shrikrishna S. Shende, Prashant A. Shirure, Onkar C. Swami


Type 2 diabetes mellitus (T2DM) is caused by insulin resistance and characterized by progressive pancreatic β-cell dysfunction. Recent innovative treatment approaches target the multiple pathophysiological defects present in type 2 diabetes. The targets for glycemic control as set by the American Diabetes Association (HbA1C<7%) and the American Association of Clinical Endocrinologists (HbA1C<6.5%) sometimes appear daunting and unattainable. It is therefore of the utmost importance to have an excellent understanding of the mechanism of action of these drugs in order to optimize patient therapy. Here, we present a corresponding discussion of all the available oral antidiabetic drugs according to the different classes, their mechanisms of action and pharmacological profiles.


India, Oral antidiabetic drugs, T2DM

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American Diabetes Association. Statistics about diabetes. Data from the national diabetes statistics report, 2014.

American Diabetes Association. Economic costs of diabetes in the US in 2012. Dia Care. 2013;36:1033-46

Wilper AP, Woolhandler S, Lasser KE, McCormick D, Bor DH, Himmelstein DU. Hypertension, diabetes, and elevated cholesterol among insured and uninsured US adults. Health Aff (Millwood). 2009;28:1151-9.

American Diabetes Association; European association for the study of diabetes; International federation of clinical chemistry and laboratory; international diabetes federation medicine. consensus statement on the worldwide standardization of the HbA1C measurement. Diabetologia. 2007;50(10):2042-3.

American association of clinical endocrinologists medical guidelines for clinical practice for the management of diabetes mellitus. Endo Pract. 2007;13(1):1-68.

Ganz ML, Wintfeld NS, Li Q, Lee YC, Gatt E, Huang JC. Severe hypoglycemia rates and associated costs among type 2 diabetics starting basal insulin therapy in the United States. Curr Med Res Opin. 2014;30(10):1991-2000.

Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA, 2002;287:360-72.

TaplinCE, BarkerJM. Autoantibodies in type 1 diabetes. Autoimmunity. 2008;41:118.

Bottazzo GF, Florin-Christensen A, Doniach D. Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet. 1974;2:1279-83.

Schatz D, Krischer J, Horne G. Islet cell antibodies predict insulin-dependent diabetes in United States school age children as powerfully as in unaffected relatives. J Clin Invest. 1994;93:2403-7.

Bolli G, de Feo P, Compagnucci P. Abnormal glucose counter-regulation in insulin-dependent diabetes mellitus. Interaction of anti-insulin antibodies and impaired glucagon and epinephrine secretion. Diabetes. 1983;32:134-41.

Moloney PJ, Coval M. Antigenicity of insulin: diabetes induced by specific antibodies. Biochem J. 1955;59:179-85.

Meier JJ, Ueberberg S, Korbas S, Schneider S. Diminished glucagon suppression after beta-cell reduction is due to impaired alpha-cell function rather than an expansion of alpha-cell mass. Am J Physiol Endocrinol Metab. 2011;300:E717-23.

Ferrannini E. The stunned beta cell: a brief history. Cell Metab. 2010;11:349-52.

Krentz A, Bailey C. Oral antidiabetic drugs- current role in type 2 diabetes mellitus. Drugs. 2005;65(3):385-411.

Miller RA, Chu Q, Xie J, Foretz M, Viollet B, BirnbaumMJ. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013;494:256-60.

Klip A, Leiter LA. Cellular mechanism of action of Metformin. Dia Care. 1990;13(6):696-704.

Bailey CJ. Metformin. N Engl J Med 1996;334(9):574-9.

UK Prospective Diabetes Study Group: Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;52:837-53.

Nasri H. On the occasion of the world diabetes day 2013; Diabetes education and prevention; a nephrology point of view. J Ren Inj Prev. 2013;2:31-2.

Tertti K, Ekblad U, Vahlberg T, Rönnemaa T. Comparison of metformin and insulin in the treatment of gestational diabetes: A retrospective, case-control study. Rev Diabet Stud. 2008;5:95-101.

Kar P, Holt RI. The effect of sulphonylureas on the microvascular and macrovascular complications of diabetes. Cardiovasc Drugs Ther. 2008;22(3):207-13.

Monami M, Lamanna C, Marchionni N. Comparison of different drugs as add-on treatments to metformin in type 2 diabetes: a meta-analysis. Diabetes Res Clin Pract. 2008;79(2):196-203.

Intestinal lipoprotein secretion: incretin-based physiology and pharmacology beyond glucose. Diabetes. 2015;64(7):2338-40.

Holst JJ. The physiology of glucagon-like peptide 1. Physiol. Rev. 2007;87(4):1409-39.

Lund A. Emerging GLP-1 receptor agonists. Expert Opin Emerg Drugs. 2011;16(4):607-18.

Butler PC. GLP-1-based therapy for diabetes: what you do not know can hurt you. Dia Care 2010;33:453-5.

Bjerre Knudsen L. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151:1473-86.

Gier B. Glucagon like peptide-1 receptor expression in the human thyroid gland. J Clin Endocrinol Metab. 2012;97:121-31.

Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374(9683):39-47.

Ahrén B. Dipeptidyl peptidase-4 inhibitors: clinical data and clinical implications. Dia Care. 2007;30(6):1344-50.

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.

Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-65.

Drucker DJ, Nauck MA. The incretin system: Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-705.

Meier JJ, Nauck MA. Incretins and the development of type 2 diabetes. Curr Dia Rep. 2006;6:194-201.

Nathan DM, Buse JB, Davidson MB, Heine RJ, Holman RR, Sherwin R, Zinman B. 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. Dia Care. 2006;29:1963-72.

Babu A. Canagliflozin for the treatment of type 2 diabetes. Drugs Today. 2013;49:363-76.

Gurnell M, Savage DB, Chatterjee VK, O’Rahilly S. The metabolic syndrome: peroxisome proliferator-activated receptor gamma and its therapeutic modulation. J Clin Endocrinol Metab. 2003;88:2412-21.

Oakes ND, Kennedy CJ, Jenkins AB, Laybutt DR, Chisholm DJ, Kraegen EW. A new antidiabetic agent, BRL 49653, reduces lipid availability and improves insulin action and glucoregulation in the rat. Diabetes. 1994;43:1203-10.

Sotiropoulos KB, Clermont A, Yasuda Y. Adipose specific effect of rosiglitazone on vascular permeability and protein kinase C activation: novel mechanism for PPAR𝛾 agonist’s effects on edema and weight gain. FASEB J 2006;20(8):1203-5.

Lago RM, Singh |PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of randomised clinical trials. Lancet. 2007;370(9593):1129-36.

Ge R, Huang Y, Liang G, Li X. 11B-hydroxysteroid dehydrogenase type 1 inhibitors as promising therapeutic drugs for diabetes: status and development. Curr Med Chem. 2010;17:412-22.

Andrews RC, Rooyackers O, Walker BR. Effects of the 11beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone in insulin sensitivity in men with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:285-91.

Henke BR, Sparks SM. Glycogen phosphorylase inhibitors. Mini Rev Med Chem. 2006;6:845-57.

Matschinsky FM, Porte D Jr. Glucokinase activators (GKAs) promise a new pharmacotherapy for diabetics. F1000. Med Rep. 2010;2:43.

Shah P, Vella A, Basu A. Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2000;85:4053-9.

Knop FK, Vilsbøll T, Hojberg PV. Reduced incretin effect in type 2 diabetes: cause or consequence of the diabetic state? Diabetes. 2007;56:1951-9.

Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a metaanalysis of randomized trials. JAMA. 2007;12(298):1180-8.

Flynn DM, Smith AH, Treadway JL, Levy CB, Soeller WC, Boettner WA, et al. The sulfonylurea glipizide does not inhibit ischemic preconditioning in anesthetized rabbits. Cardiovasc Drugs Ther. 2005;19:337-46.

Mocanu MM, Maddock HL, Baxter GF, Lawrence CL, Standen NB, Yellon DM. Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide. Circulation. 2001;103:3111-6.

Letter: Clark MH, FDA, to Silberstein D, Squibb BM, dated November 1, 2006. Available at:,021202s015ltr.pdf. Accessed August 13,2007.

Glucophage [prescribing information]. New York, NY; Bristol-Myers Squibb; 2006.

Smooke S, Horwich TB, Fonarow GC. Insulin-treated diabetes is associated with a marked increase in mortality in patients with advanced heart failure. Am Heart J. 2005;149:168-74.