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Clinical Focus: Metabolic Disorders, Diabetes, and Cardiovascular Disease

Focus on Incretin-Based Therapies: Targeting the Core Defects of Type 2 Diabetes

, MD, MACE
Pages 53-65 | Published online: 13 Mar 2015

References

  • . Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004;27(5):1047–1053
  • . National Diabetes Information Clearinghouse. National diabetes statistics, 2007. http://diabetes.niddk.nih.gov/dm/pubs/statistics/. Updated June 2008. Accessed September 23, 2009
  • . Eeg-Olofsson K, Cederholm J, Nilsson PM, . Risk of cardiovascular disease and mortality in overweight and obese patients with type 2 diabetes: an observational study in 13,087 patients. Diabetologia. 2009;52(1):65–73
  • . Preis SR, Pencina MJ, Hwang SJ, . Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study. Circulation. 2009;120(3):212–220
  • . Burant CF. Medical Management of Type 2 Diabetes, 6th ed. Alexandria, VA: American Diabetes Association, Inc; 2008
  • . DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–795
  • . Wajchenberg BL. β-Cell failure in diabetes and preservation by clinical treatment. Endocr Rev. 2007;28(2):187–218
  • . Jellinger PS. Metabolic consequences of hyperglycemia and insulin resistance. Clin Cornerstone. 2007;8( suppl 7):S30–S42
  • . Holst JJ, Vilsbøll T, Deacon CF. The incretin system and its role in type 2 diabetes mellitus. Mol Cell Endocrinol. 2009;297(1–2): 127–136
  • . Vollmer K, Holst JJ, Baller B, . Predictors of incretin concentrations in subjects with normal, impaired, and diabetic glucose tolerance. Diabetes. 2008;57(3):678–687
  • . Vilsbøll T, Holst JJ. Incretins, insulin secretion and type 2 diabetes mellitus. Diabetologia. 2004;47(3):357–366
  • . Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076–1082
  • . Toft-Nielsen MB, Damholt MB, Madsbad S, . Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86(8):3717–3723
  • . Drucker DJ. Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care. 2003;26(10):2929–2940
  • . Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60(4):470–512
  • . Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):153–165
  • . Mayo K, Miller L, Bataille D, . International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev. 2003;55:167–194
  • . Ban K, Noyan-Ashraf MH, Hoefer J, Bolz SS, Drucker DJ, Husain M. Cardioprotective and vasodilatory actions of glucagon-like peptide 1 receptor are mediated through both glucagon-like peptide 1 receptor-dependent and -independent pathways. Circulation. 2008;117(18):2340–2350
  • . Dozier KC, Cureton EL, Kwan RO, . Glucagon-like peptide-1 protects mesenteric endothelium from injury during inflammation. Peptides. 2009;30:1735–1741
  • . Sulistio M, Carothers C, Mangat M, Lujan M, Oliveros R, Chilton R. GLP-1 agonist-based therapies: an emerging new class of antidiabetic drug with potential cardioprotective effects. Curr Atheroscler Rep. 2009;11(2):93–99
  • . Deacon CF, Nauck MA, Toft-Nielsen M, . Both subcutaneously and intravenously administered glucagons-like peptide I are rapidly degraded from NH2-terminus in type II diabetic patients and in healthy subjects. Diabetes. 1995;44(9):1126–1131
  • . 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(9548):1696–1705
  • . Morimoto C, Schlossman SF. The structure and function of CD26 in the T-cell immune response. Immunol Rev. 1998;161:55–70
  • . Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis. JAMA. 2007;298(2):194–206
  • . Young AA, Gedulin BR, Bhavsar S, Bodkin N, Jodka C, Hansen B, Denaro M. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes. 1999;48(5):1026–1034
  • . Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. J Biol Chem. 1992;267(11):7402–7405
  • . Byetta (exenatide) [package insert]. San Diego, CA: Amylin Pharmaceuticals, Inc; 2010
  • . Kolterman OG, Kim DD, Shen L, . Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm. 2005;62(2): 173–181
  • . Tourrel C, Bailbe D, Lacorne M, . Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes. 2002;51(5):1443–1452
  • . Bunck MC, Diamant M, Cornér A, . One-year treatment with exenatide improves beta-cell function, compared with insulin glargine, in metformin-treated type 2 diabetic patients: a randomized, controlled trial. Diabetes Care. 2009;32(5):762–768
  • . Turner RC, Cull CA, Frighi V, . Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA. 1999;281:2005–2012
  • . Hui H, Nourparvar A, Zhao X, Perfetti R. Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5′-adenosine monophosphate-dependent protein kinase A-and a phosphatidylinositol 3-kinase-dependent pathway. Endocrinology. 2003;144(4):1444–1455
  • . Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27(11):2628–2635
  • . DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28(5):1092–1100
  • . Kendall DM, Riddle MC, Rosenstock J, . 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(5):1083–1091
  • . Derosa G, Maffioli P, Salvadeo SA, . Exenatide versus glibenclamide is patients with diabetes. Diabetes Technol Ther. 2010;12(3):233–240
  • . DeFronzo RA, Okerson T, Viswanathan P, Guan X, Holcome JH, MacConell. Effects of exenatide versus sitagliptin on postprandial glucose, insulin and glucagons secretion, gastric emptying, and caloric intake: a randomized, cross-over study. Curr Med Res Opin. 2008;24(10):2943–2952
  • . DeFronzo RA, Triplitt C, Qu Y, Lewis MS, Maggs D, Glass LC. Effects of exenatide plus rosiglitazone on beta cell function and insulin sensitivity in subjects with type 2 diabetes on metformin. Diabetes Care. 2010;33(5):951–957
  • . Klonoff DC, Buse JB, Nielsen LL, . Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years. Curr Med Res Opin. 2008;24(1):275–286
  • . Okerson T, Yan P, Stonehouse A, Brodows R. Effects of exenatide on systolic blood pressure in subjects with type 2 diabetes. Am J Hypertension. 2010;23(3):334–339
  • . Kothare PA, Linnebjerg H, Isaka Y, . Pharmacokinetics, pharmacodynamics, tolerability, and safety of exenatide in Japanese patients with type 2 diabetes mellitus. J Clin Pharmacol. 2008;48(12): 1389–1399
  • . Noel RA, Braun DK, Patterson RE, Bloomgren G. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2009;32(5): 834–838
  • . Kingsnorth A, O'Reilly D. Acute pancreatitis. BMJ. 2006;332 (7549):1072–1076
  • . World Health Organization. Obesity and overweight. 2009. www.who.int/dietphysicalactivity/publications/facts/obesity/en. Accessed December 7, 2009
  • . Idris I. FDA reviews incidences of acute pancreatitis in patients taking Byetta. Diabetes Obes Metab. 2008;10:96–98
  • . Dore DD, Seeger JD, Arnold Chan K. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin. 2009;25(4):1019–1027
  • . Bloomgren G, Dore D, Patterson R, . Incidence of acute pancreatitis in exenatide initiators compared to other antidiabetic drug initiators: a retrospective, cohort study (abstract no. 158-OR). Diabetes. 2009;58( suppl 1):A41
  • . Kim D, MacConell L, Zhuang D, . Effects of once-weekly dosing of a long-acting release formulation of exenatide on glucose control and body weight in subjects with type 2 diabetes. Diabetes Care. 2007;30(6):1487–1493
  • . Drucker DJ, Buse JB, Taylor K, ; DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372(9645):1240–1250
  • . Buse JB, Drucker DJ, Taylor KL, ; DURATION-1 Study Group. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010;33(6):1255–1261
  • . Bergenstal RM, Kim T, Trautmann ME, . Exenatide once weekly elicited improvements in blood pressure and lipid profile over 52 weeks in patients with type 2 diabetes (abstract no. 1239). Circulation. 2008;118( suppl 1):S1086
  • . Bergenstal RM, Wysham C, Macconell L, ; 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. 2010;376(9739):431–439
  • . Diamant M, Van Gaal L, Stranks S, . Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomised trial. Lancet. 2010;375(9733):2234–2243
  • . Nauck M, Frid A, Hermansen K, ; LEAD-2 Study Group. 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;32(1):84–90
  • . Victoza (liraglutide) [package insert]. Princeton, NJ: Novo Nordisk, Inc; 2010
  • . Madsbad S. Liraglutide effect and action in diabetes (LEAD) trial. Expert Rev Endocrinol Metab. 2009;4(2):119–129
  • . Garber A, Henry R, Ratner R, ; LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373(9662):473–481
  • . Marre M, Shaw J, Brändle M, ; LEAD-1 SU study group. Liraglutide, a once-daily human GLP-1 analogue, added to a sulphonylurea over 26 weeks produces greater improvements in glycaemic and weight control compared with adding rosiglitazone or placebo in subjects with type 2 diabetes (LEAD-1 SU). Diabet Med. 2009;26(3):268–278
  • . Zinman B, Gerich J, Buse JB, . Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and TZD in patients with type 2 diabetes mellitus (LEAD-4 Met+TZD). Diabetes Care. 2009;32(7):1224–1230
  • . Buse JB, Rosenstock J, Sesti G, , for the LEAD-6 Study Group. 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
  • . Pratley RE, Nauck M, Bailey T, , for the 1860-LIRA-DPP-4 Study Group. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycemic control with metformin: a 26-week, randomized, parallel-group, open-label trial. Lancet. 2010;375(9724):1447–1456
  • . Crespel A, DeBoisvilliers F, Gros L, Kervran A. Effects of glucagon and glucagon-like-peptide-1 (7–36) amide on C cells from rat thyroid and medullary thyroid carcinoma CA-77 cell line. Endocrinology. 1996;137(9):3674–3680
  • . Kumar V, Abbas AK, Fausto N, Aster JC. Robbins and Coltran Pathologic Basis of Disease, Professional Edition, 8th ed. Philadelphia, PA: WB Saunders; 2010
  • . US Food and Drug Administration. Briefing materials. Dated April 2, 2009. http://www.fda.gov/ohrms/dockets/ac/09/briefing/2009–4422b2–01-FDA.pdf. Accessed November 3, 2009
  • . Knudsen LB, Madsen LW, Andersen S, . Glucagon-like peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151(4):1473–1486
  • . Kieffer TJ, McIntosh CH, Pederson RA. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology. 1995;136(8):3585–3596
  • . Ahrén B. DPP-4 inhibitors. Best Pract Res Clin Endocrinol Metab. 2007;21(4):517–533
  • . Herman GA, Stevens C, Van Dyck K, . Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005;78(6):675–688
  • . Triplitt CL, McGill JB, Porte D Jr, Conner CS. The changing landscape of type 2 diabetes: the role of incretin-based therapies in managed care outcomes. J Manag Care Pharm. 2007;13(9 suppl C):S2–S16
  • . Januvia [package insert]. Whitehouse Station, NJ: Merck and Co; 2007
  • . Raz I, Hanefeld M, Xu L, . Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49(11):2564–2571
  • . Aschner P, Kipnes MS, Lunceford JK, . Effect of dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29(12):2632–2637
  • . Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P, for the 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. 2006;28(10):1556–1568
  • . Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. 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(12):2638–2643
  • . Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R; CV181–011 Study Investigators. Effect of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25(10):2401–2411
  • . Traynor K. FDA approves saxagliptin for type 2 diabetes. Am J Health Syst Pharm. 2009;66(17):1513
  • . Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R; CV181–040 Investigators. 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(9):1395–1406
  • . DeFronzo RA, Hissa MN, Garber AJ, ; 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. 2009;32(9):1649–1655
  • . Study finds that onglyza (saxagliptin) when added to metformin was non-inferior to januvia (sitagliptin) when added to metformin in reducing hemoglobin (HbA1c) in adults with type 2 diabetes mellitus. Princeton, NJ: Business Wire; July 21, 2010. http://www.drugs.com/clinical_trials/study-finds-onglyza-saxagliptin-addedmetformin-non-inferior-januvia-sitagliptin-added-metformin-8189.html#ixzz0uXMlyruz. Accessed July 23, 2010
  • . Neumiller JJ, Wood L, Campbell RK. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus. Pharmacotherapy. 2010;30(5):463–484
  • . Monami M, Iacomelli I, Marchionni N, Mannucci E. Dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a meta-analysis of randomized clinical trials. Nutr Metab Cardiovasc Dis. 2010;20(4):224–235
  • . Mu J, Woods J, Zhou Y-P, . Chronic inhibition of dipeptidyl peptidase-4 with a sitagliptin analog preserves pancreatic beta-cell mass and function in a rodent model of type 2 diabetes. Diabetes. 2006;55(6):1695–1704
  • . Scott R, Loeys T, Davies MJ, Engel SS; Sitagliptin Study 801 Group. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2008;10(10):959–969
  • . Raz I, Chen Y, Wu M, . Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008;24(2):537–550
  • . Mistry GC, Maes AL, Lasseter KC, Davies MJ, Gottesdiener KM, Wagner JA, Herman GA. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008;48(5):592–598
  • . Matteucci E, Giampietro O. Dipeptidyl peptidase-4 (CD26). Knowing the function before inhibiting the enzyme. Curr Med Chem. 2009;16:2943–2951
  • . Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M, Kothny W. Assessing the cardio-cerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large phase III type 2 diabetes population. Diabetes Obes Metab. 2010;12(6):485–494
  • . Frederich R, Alexander JH, Fiedorek FT, . A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010;122(3):16–27
  • . Williams-Herman D, Engel SS, Round E, . Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes. BMC Endocr Disord. 2010;10:7
  • . Tabak AG, Jokela M, Akbaraly T, Brunner EJ, Kivimäki M, Witte DR. Trajectories of glycemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study. Lancet. 2009;373(9682):2215–2221
  • . Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC. UKPDS 26: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years. Diabetic Med. 1998;15(4):297–303
  • . Del Prato S, Wishner WJ, Gromada J, Schluchter BJ. Beta-cell mass plasticity in type 2 diabetes. Diabetes Obes Metab. 2004;6(5):319–331
  • . Nauck MA. Unraveling the science of incretin biology. Am J Med. 2009;122( 6 suppl):S3–S10
  • . Sulistio M, Carothers C, Mangat M, Lujan M, Oliveros R, Chilton R. GLP-1 agonist-based therapies: an emerging new class of antidiabetic drug with potential cardioprotective effects. Curr Atheroscler Rep. 2009;11(2):93–99
  • . Nyström T, Gonon AT, Sjöholm A, Pernow J. Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism. Regul Pept. 2005;125(1–3):173–177
  • . Nikolaidis LA, Mankad S, Sokos GG, . Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109(8):962–965
  • . Sokos GG, Nikolaidis LA, Mankad S, Elahi D, Shannon RP. Glucagon-like peptide-1 infusion improves left ventricular ejection fraction and functional status in patients with chronic heart failure. J Card Fail. 2006;12(9):694–699
  • . Sokos GG, Bolukoglu H, German J, . Effect of glucagon-like peptide-1 (GLP-1) on glycemic control and left ventricular function in patients undergoing coronary artery bypass grafting. Am J Cardiol. 2007;100(5):824–829

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