Incretin based therapy for Type 2 Diabetes Mellitus
Keywords:
Incretin, Glucagon-like peptide (GLP-1), GLP-1 receptor agonist, and DPP-4 inhibitors
Abstract
Type 2 Diabetes Mellitus (T2DM) is associated with obesity, insulin resistance, beta-cell dysfunction and hyperglucagonaemia, leading to hyperglycaemia. With the currently available antidiabetic agents, long term glycaemic control remains poor and attaining a glycosylated Hb (HbA1c) of < 7% is often not achievable. Further the antidiabetic agents available induce weight gain (except metformin), hypoglycaemia and have a negligible effect on beta-cell dysfunction. New classes of drugs that affect incretin hormones show promise in the treatment of T2DM. Incretins
i.e. Glucagon-like peptide (GLP-1) and glucose-dependent insulinotropic peptides (GIP) are peptide hormones secreted from the gut in response to ingestion of food and enhance the glucose-stimulated insulin secretion from the pancreas. T2DM patients are resistant to the insulin secreting action of GIP but are responsive to GLP-1. Therefore, GLP-1 shows promise in the treatment of T2DM as it enhances glucose-stimulated insulin secretion and there are less chances of hypoglycaemia. In addition, it promotes insulin biosynthesis, suppresses glucagon secretion, improves
fasting and post-prandial blood sugar, HbA1c, inhibits gastric emptying, reduces appetite and food intake. Further, GLP-1 has been found to prevent or reverse the destruction of β cells in preclinical studies and is also associated with beneficial effect on cardio-vascular risk factor including blood pressure (BP), weight, endothelial dysfunction and lipid profiles. The clinical use of GLP-1 is limited by its short t½ of 2 minutes, due to its degradation by the enzyme, dipeptidyl peptidase-4 (DPP-4). To combat this problem, drugs have been developed to increase the level of GLP-1 in the body i.e. GLP-1 receptor agonist (incretin mimetics) and DPP-4 inhibitors (incretin enhancers).
References
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9. Bond A. Exenatide (Byetta) as a novel treatment option for type 2 diabetes mellitus. Proc (Bayl Univ Med Cent) 2006; 19:281–4.
10. Schnabel CA, Wintle M, Kolterman O. Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes. Vasc Health Risk Manag 2006; 2:69-77.
11. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-91.
12. Nelson P, Poon T, Guan X, Schnabelm C, Wintle M,Fineman M. The incretin mimetic exenatide as monotherapy in patients with type-2 diabetes. Diabetes Technol Ther. 2007;9:317- 26.
13. Pinelli NR, Cha R, Brown MB, Jaber LA. Addition of Thiazolidinedione or Exenatide to Oral Agents in Type-2 Diabetes: A Meta-Analysis., The Annals of Pharmacotherapy. 2008;42(11):1541-1551.
14. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005; 143:559-69.
15. Moretto TJ, Milton DR, Ridge TD, Macoconell LA, Okerson T, Wolka AM, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naïve patients with T2DM: A randomized, double-blind, placebocontrolled, parallel group study. Clin Ther 2008; 30:1448-60.
16. Denker SP, Dimarco PE. Exenatide (Exendin-4)-induced pancreatitis : a case report Diabetes Care. 2006; 29:471.
17. Soon D, Kothare PA, Linnebjerg H, Park S, Yuen E, Mace KF, et al. Effect of exenatide on the pharmacokinetics and pharmacodynamics of warfarin in healthy Asian men. J Clin Pharmacol. 2006; 46:1179-87.
18. Krause A and Kirwin J. Exenatide LAR: A sustained-release formulation of Exenatide for the treatment of type 2 Diabetes. Formulary 2010. Available at http://formularyjournal.
modernmedicine.com/formulary.../exenatidelar- sustained- release-formulation-exenatide. Accesed November 21, 2013.
19. Feinglos MN, Saad MF, Pi-Sunyer FX, An B, Santiago O. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes. Diabet Med. 2005; 22:1016-23.
20. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog Liraglutide (NN2211): A 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004; 27:1335-42.
21. Courrèges JP, Vilsbøll T, Zdravkovic M, et al. Beneficial effects of once-daily liraglutide, a human glucagon-like peptide- 1 analogue, on cardiovascular risk biomarkers in patients with Type 2 diabetes. Diabet Med. 2008; 25: 1129-31.
22. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009; 3: 84-90.
23. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, doubleblind, placebo-controlled studies with single oral doses. Clin Pharm Ther. 2005; 78:675– 88.
24. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor Sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes, Diabetes Care. 2006; 29:2632- 37.
25. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P, 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.
26. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. 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.
27. Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallelgroup, open-label trial. Lancet 2010; 375:1447-56.
28. Krishna R, Bergman A, Larson P, Cote J, Lasseter K, Dilzer S, 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.
29. Mari A, Sallas WM, He YL. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes. J Clin Metab. 2005; 90:4888-94.
30. DeaconCF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes, Obesity and Metabolism. 2011;13:7–18.
31. Rosenstock J, Baron MA, Dejager S, Schweizer A, Mills D. Comparison of Vildagliptin and Rosiglitazone monotherapy in patients with type 2 diabetes: A 24-week, doubleblind, randomized trial. Diabetes Care. 2007; 30:217-23.
32. Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007;50:1148- 55.
33. 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.
34. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009; 25:2401-11.
35. DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S et al. The efficacy and safety of saxagliptin when added to metformin therapy in patientswith inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009; 32:1649-55.
36. Hollander P, Li J, Allen E, Chen R. 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.
37. Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R. 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.
38. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q. 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.
39. Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Algoliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009; 11:1145-52.
40. Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized,
double-blind, placebo-controlled study. Diabetes Obes Metab. 2011; 13:65-74.
2. Harris MI, Eastman RC, Cowie CC, Flegal KM, Eberhardt MS. Racial and ethnic differences in glycaemic control of adults with type 2 diabetes. Diabetes Care. 1999; 22(3):403–8.
3. Unger RH, Eisentraut AM. Entero-insular axis. Arch Intern Med 1969;123: 261-6.
4. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W et al. Preserved incretin activity of glucagonlike peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus. J Clin Invest 1993; 91:301-7.
5. Ratner RE. Therapeutic role on incretin mimetics. Medscape Diabetes and Endocrinology. 2005;7. Available at http://www.medcape.com/viewrticle/506476. Accessed on September 17,2013.
6. Deacon CF, Nauck MA, Toft-Nielsen M, Pridel L, Wilms B, Holst JJ et al. Both subcutaneously and intravenously administered glucagon-like peptide I are rapidly degraded from the NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995; 44:1126-31.
7. Eng J, Andrews PC, Kleinman WA, Singh L and Raufman JP. Purification and structure of exendin-3, a new pancreatic secretagogue isolated from Heloderma horridum venom. J Biol Chem. 1990; 265(33):20259-62.
8. Parkes DG, Pittner R, Jodka C, Smith P, Young A. Insulinotropic actions of exendin-4 and glucagon-like peptide- 1 in vivo and in vitro. Metabolism. 2001;50:583-9.
9. Bond A. Exenatide (Byetta) as a novel treatment option for type 2 diabetes mellitus. Proc (Bayl Univ Med Cent) 2006; 19:281–4.
10. Schnabel CA, Wintle M, Kolterman O. Metabolic effects of the incretin mimetic exenatide in the treatment of type 2 diabetes. Vasc Health Risk Manag 2006; 2:69-77.
11. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea. Diabetes Care. 2005;28:1083-91.
12. Nelson P, Poon T, Guan X, Schnabelm C, Wintle M,Fineman M. The incretin mimetic exenatide as monotherapy in patients with type-2 diabetes. Diabetes Technol Ther. 2007;9:317- 26.
13. Pinelli NR, Cha R, Brown MB, Jaber LA. Addition of Thiazolidinedione or Exenatide to Oral Agents in Type-2 Diabetes: A Meta-Analysis., The Annals of Pharmacotherapy. 2008;42(11):1541-1551.
14. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005; 143:559-69.
15. Moretto TJ, Milton DR, Ridge TD, Macoconell LA, Okerson T, Wolka AM, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naïve patients with T2DM: A randomized, double-blind, placebocontrolled, parallel group study. Clin Ther 2008; 30:1448-60.
16. Denker SP, Dimarco PE. Exenatide (Exendin-4)-induced pancreatitis : a case report Diabetes Care. 2006; 29:471.
17. Soon D, Kothare PA, Linnebjerg H, Park S, Yuen E, Mace KF, et al. Effect of exenatide on the pharmacokinetics and pharmacodynamics of warfarin in healthy Asian men. J Clin Pharmacol. 2006; 46:1179-87.
18. Krause A and Kirwin J. Exenatide LAR: A sustained-release formulation of Exenatide for the treatment of type 2 Diabetes. Formulary 2010. Available at http://formularyjournal.
modernmedicine.com/formulary.../exenatidelar- sustained- release-formulation-exenatide. Accesed November 21, 2013.
19. Feinglos MN, Saad MF, Pi-Sunyer FX, An B, Santiago O. Effects of liraglutide (NN2211), a long-acting GLP-1 analogue, on glycaemic control and bodyweight in subjects with Type 2 diabetes. Diabet Med. 2005; 22:1016-23.
20. Madsbad S, Schmitz O, Ranstam J, Jakobsen G, Matthews DR. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog Liraglutide (NN2211): A 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004; 27:1335-42.
21. Courrèges JP, Vilsbøll T, Zdravkovic M, et al. Beneficial effects of once-daily liraglutide, a human glucagon-like peptide- 1 analogue, on cardiovascular risk biomarkers in patients with Type 2 diabetes. Diabet Med. 2008; 25: 1129-31.
22. Nauck M, Frid A, Hermansen K, Shah NS, Tankova T, Mitha IH, et al. Efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin, in type 2 diabetes: the LEAD (liraglutide effect and action in diabetes)-2 study. Diabetes Care. 2009; 3: 84-90.
23. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, doubleblind, placebo-controlled studies with single oral doses. Clin Pharm Ther. 2005; 78:675– 88.
24. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE. Effect of the dipeptidyl peptidase-4 inhibitor Sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes, Diabetes Care. 2006; 29:2632- 37.
25. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P, 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.
26. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. 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.
27. Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallelgroup, open-label trial. Lancet 2010; 375:1447-56.
28. Krishna R, Bergman A, Larson P, Cote J, Lasseter K, Dilzer S, 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.
29. Mari A, Sallas WM, He YL. Vildagliptin, a dipeptidyl peptidase-IV inhibitor, improves model-assessed beta-cell function in patients with type 2 diabetes. J Clin Metab. 2005; 90:4888-94.
30. DeaconCF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes, Obesity and Metabolism. 2011;13:7–18.
31. Rosenstock J, Baron MA, Dejager S, Schweizer A, Mills D. Comparison of Vildagliptin and Rosiglitazone monotherapy in patients with type 2 diabetes: A 24-week, doubleblind, randomized trial. Diabetes Care. 2007; 30:217-23.
32. Fonseca V, Schweizer A, Albrecht D, Baron MA, Chang I, Dejager S. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007;50:1148- 55.
33. 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.
34. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009; 25:2401-11.
35. DeFronzo RA, Hissa MN, Garber AJ, Luiz Gross J, Yuyan Duan R, Ravichandran S et al. The efficacy and safety of saxagliptin when added to metformin therapy in patientswith inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009; 32:1649-55.
36. Hollander P, Li J, Allen E, Chen R. 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.
37. Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R. 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.
38. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q. 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.
39. Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Algoliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009; 11:1145-52.
40. Taskinen MR, Rosenstock J, Tamminen I, Kubiak R, Patel S, Dugi KA et al. Safety and efficacy of linagliptin as add-on therapy to metformin in patients with type 2 diabetes: a randomized,
double-blind, placebo-controlled study. Diabetes Obes Metab. 2011; 13:65-74.
Published
2019-09-09
How to Cite
Kaur J, Kwatra G, Badyal DK. (2019). Incretin based therapy for Type 2 Diabetes Mellitus. The Indian Practitioner, 67(9), 557-563. Retrieved from https://articles.theindianpractitioner.com/index.php/tip/article/view/750
Section
Review article
