The place of GLP-1-based therapy in diabetes management: Differences between DPP-4 inhibitors and GLP-1 receptor agonists

Current Diabetes Reports

Volumn 13, Issue 3, 2013, Pages 307-318

  Eckerle Mize, Dara L ^a   Salehi, Marzieh ^b  

^a VANDERBILT UNIVERSITY MEDICAL CENTER   (United States)

^b UNIVERSITY OF CINCINNATI COLLEGE OF MEDICINE   (United States)

Author keywords

Cardiovascular risk factors; DPP 4; DPP 4 inhibitors; GLP 1; GLP 1 receptor agonists; Hypoglycemia; Incretin; Type 2 diabetes; Weight loss

Indexed keywords

ALOGLIPTIN; ANTIDIABETIC AGENT; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EXENDIN 4; GLIBENCLAMIDE; GLIMEPIRIDE; GLITAZONE DERIVATIVE; GLUCAGON LIKE PEPTIDE 1; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; GLUCOSE; INSULIN; INSULIN ASPART; INSULIN GLARGINE; LINAGLIPTIN; LIRAGLUTIDE; METFORMIN; ORAL ANTIDIABETIC AGENT; PARACETAMOL; PIOGLITAZONE; PLACEBO; ROSIGLITAZONE; SAXAGLIPTIN; SITAGLIPTIN; SULFONYLUREA; VILDAGLIPTIN; GLUCAGON RECEPTOR; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR;

ADD ON THERAPY; ARTICLE; CARDIOVASCULAR DISEASE; DIABETES MELLITUS; DIARRHEA; DOSAGE SCHEDULE COMPARISON; DRUG APPROVAL; DRUG BLOOD LEVEL; DRUG DOSAGE FORM COMPARISON; DRUG DOSE COMPARISON; DRUG DOSE INCREASE; DRUG DOSE REDUCTION; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG EXCRETION; DRUG HALF LIFE; DRUG MEGADOSE; DRUG METABOLISM; DRUG SAFETY; DRUG TOLERABILITY; DRUG TREATMENT FAILURE; DRUG WITHDRAWAL; ENZYME ACTIVATION; GASTROINTESTINAL SYMPTOM; GLUCOSE BLOOD LEVEL; GLYCEMIC CONTROL; HUMAN; HYPERGLYCEMIA; HYPOGLYCEMIA; INSULIN RELEASE; LIFESTYLE MODIFICATION; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREATITIS; PROTEIN EXPRESSION; PROTEIN FUNCTION; RECOMMENDED DRUG DOSE; RESPIRATORY TRACT INFECTION; SIDE EFFECT; SYSTOLIC BLOOD PRESSURE; VOMITING; WEIGHT GAIN; WEIGHT REDUCTION; AGONISTS; ANIMAL; DIABETES MELLITUS, TYPE 2; METABOLISM;

ANIMALS; DIABETES MELLITUS, TYPE 2; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; GLUCAGON-LIKE PEPTIDE 1; HUMANS; HYPOGLYCEMIC AGENTS; RECEPTORS, GLUCAGON;

EID: 84877757399     PISSN: 15344827     EISSN: 15390829     Source Type: Journal    
DOI: 10.1007/s11892-013-0377-9     Document Type: Article

References (124)

1. McIntyre N, Holdsworth CD, Turner DS. New interpretation of oral glucose tolerance. Lancet. 1964;2:20-1.
2. Vilsboll T, Krarup T, Madsbad S, Holst JJ. Both GLP-1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects. Regul Pept. 2003;114:115-21. (Pubitemid 36773875)
3. Nauck M, Stockmann F, Ebert R, Creutzfeldt W. Reduced incretin effect in type 2 (non-insulin-dependent) diabetes. Diabetologia. 1986;29:46-52. (Pubitemid 16162741)
4. Muscelli E, Mari A, Casolaro A, Camastra S, Seghieri G, Gastaldelli A, et al. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes. 2008;57:1340-8.
5. Salehi M, Prigeon RL, D'Alessio DA. Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans. Diabetes. 2011;60:2308-14.
6. Nauck MA, Heimesaat MM, Orskov C, Holst JJ, Ebert R, Creutzfeldt W. Preserved incretin activity of glucagon-like 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. (Pubitemid 23037285)
7. Hansen L, Deacon CF, Orskov C, Holst JJ. Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology. 1999;140:5356-63.
8. Nikolaidis LA, Mankad S, Sokos GG, Miske G, Shah A, Elahi D, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004;109:962-5. (Pubitemid 38282847)
9. Meier JJ, Weyhe D, Michaely M, Senkal M, Zumtobel V, Nauck MA, et al. Intravenous glucagon-like peptide 1 normalizes blood glucose after major surgery in patients with type 2 diabetes. Crit Care Med. 2004;32:848-51. (Pubitemid 38340086)
10. Eissele R, Goke R, Willemer S, Harthus HP, Vermeer H, Arnold R, et al. Glucagon-like peptide-1 cells in the gastrointestinal tract and pancreas of rat, pig, and man. Eur J Clin Invest. 1992;22:283-91.
11. Kieffer TJ, Habener JF. The glucagon-like peptides. Endocr Rev. 1999;20:876-913. (Pubitemid 30647076)
12. Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem. 1993;214:829-35. (Pubitemid 23188160)
13. 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;136:3585-96.
14. Vahl TP, Paty BW, Fuller BD, Prigeon RL, D'Alessio DA. Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1- (9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans. J Clin Endocrinol Metab. 2003;88:1772-9. (Pubitemid 36623403)
15. Bullock BP, Heller RS, Habener JF. Tissue distribution of messenger ribonucleic acid encoding the rat glucagon-like peptide-1 receptor. Endocrinology. 1996;137:2968-78. (Pubitemid 26192194)
16. Nakagawa A, Satake H, Nakabayashi H, Nishizawa M, Furuya K, Nakano S, et al. Receptor gene expression of glucagon-like peptide-1, but not glucose-dependent insulinotropic polypeptide, in rat nodose ganglion cells. Auton Neurosci. 2004;110:36-43. (Pubitemid 38180536)
17. Burcelin R, Da Costa A, Drucker D, Thorens B. Glucose competence of the hepatoportal vein sensor requires the presence of an activated glucagon-like peptide-1 receptor. Diabetes. 2001;50:1720-8. (Pubitemid 33641588)
18. Holst JJ, Deacon CF. Glucagon-like peptide-1 mediates the therapeutic actions of DPP-IV inhibitors. Diabetologia. 2005;48:612-5. (Pubitemid 40591213)
19. Vahl TP, Tauchi M, Durler TS, Elfers EE, Fernandes TM, Bitner RD, et al. Glucagon-like peptide-1 (GLP-1) receptors expressed on nerve terminals in the portal vein mediate the effects of endogenous GLP-1 on glucose tolerance in rats. Endocrinology. 2007;148:4965-73. (Pubitemid 47481523)
20. Kreymann B, Williams G, Ghatei MA, Bloom SR. Glucagon-like peptide-1 7-36: a physiological incretin in man. Lancet. 1987;2:1300-4. (Pubitemid 17156636)
21. Wang Y, Perfetti R, Greig NH, Holloway HW, DeOre KA, Montrose-Rafizadeh C, et al. Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats. J Clin Invest. 1997;99:2883-9. (Pubitemid 27278664)
22. Scrocchi LA, Brown TJ, MaClusky N, Brubaker PL, Auerbach AB, Joyner AL, et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat Med. 1996;2:1254-8. (Pubitemid 26375413)
23. Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem. 2003;278:471-8. (Pubitemid 36043598)
24. De Leon DD, Deng S, Madani R, Ahima RS, Drucker DJ, Stoffers DA. Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. Diabetes. 2003;52:365-71. (Pubitemid 36173191)
25. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 1999;48:2270-6. (Pubitemid 30395416)
26. Abraham EJ, Leech CA, Lin JC, Zulewski H, Habener JF. Insulinotropic hormone glucagon-like peptide-1 differentiation of human pancreatic islet-derived progenitor cells into insulin-producing cells. Endocrinology. 2002;143:3152-61. (Pubitemid 34809888)
27. Farilla L, Bulotta A, Hirshberg B, Li Calzi S, Khoury N, Noushmehr H, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology. 2003;144:5149-58. (Pubitemid 37476040)
28. Schirra J, Nicolaus M, Roggel R, Katschinski M, Storr M, Woerle HJ, et al. Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans. Gut. 2006;55:243-51. (Pubitemid 43117285)
29. Nauck MA, Niedereichholz U, Ettler R, Holst JJ, Orskov C, Ritzel R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997;273(5 Pt 1):E981-8.
30. Wettergren A, Schjoldager B, Mortensen PE, Myhre J, Christiansen J, Holst JJ. Truncated GLP-1 (proglucagon 78-107-amide) inhibits gastric and pancreatic functions in man. Dig Dis Sci. 1993;38:665-73. (Pubitemid 23121274)
31. Meier JJ, Gallwitz B, Salmen S, Goetze O, Holst JJ, Schmidt WE, et al. Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:2719-25. (Pubitemid 36733545)
32. Flint A, Raben A, Astrup A, Holst JJ. Glucagon-like peptide 1 promotes satiety and suppresses energy intake in humans. J Clin Invest. 1998;101:515-20. (Pubitemid 28084232)
33. Prigeon RL, Quddusi S, Paty B, D'Alessio DA. Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect. Am J Physiol Endocrinol Metab. 2003;285:E701-7.
34. Kielgast U, Holst JJ, Madsbad S. Antidiabetic actions of endogenous and exogenous GLP-1 in type 1 diabetic patients with and without residual beta-cell function. Diabetes. 2011;60:1599-607.
35. Creutzfeldt WO, Kleine N, Willms B, Orskov C, Holst JJ, Nauck MA. Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide I(7-36) amide in type I diabetic patients. Diabetes Care. 1996;19:580-6.
36. Nauck MA, Kleine N, Orskov C, Holst JJ, Willms B, Creutzfeldt W. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741-4. (Pubitemid 23218642)
37. Nauck MA, Heimesaat MM, Behle K, Holst JJ, Nauck MS, Ritzel R, et al. Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab. 2002;87:1239-46. (Pubitemid 36121094)
38. Salehi M, Vahl TP, D'Alessio DA. Regulation of islet hormone release and gastric emptying by endogenous glucagon-like peptide 1 after glucose ingestion. J Clin Endocrinol Metab. 2008;93:4909-16.
39. Salehi M, Aulinger B, Prigeon RL, D'Alessio DA. Effect of endogenous GLP-1 on insulin secretion in type 2 diabetes. Diabetes. 2010;59:1330-7.
40. Nicolaus M, Brodl J, Linke R, Woerle HJ, Goke B, Schirra J. Endogenous GLP-1 regulates postprandial glycemia in humans: relative contributions of insulin, glucagon, and gastric emptying. J Clin Endocrinol Metab. 2011;96:229-36.
41. Vella A, Bock G, Giesler PD, Burton DB, Serra DB, Saylan ML, et al. Effects of dipeptidyl peptidase-4 inhibition on gastrointestinal function, meal appearance, and glucose metabolism in type 2 diabetes. Diabetes. 2007;56:1475-80. (Pubitemid 46715627)
42. Stevens JE, Horowitz M, Deacon CF, Nauck M, Rayner CK, Jones KL. The effects of sitagliptin on gastric emptying in healthy humans - a randomized, controlled study. Aliment Pharmacol Ther. 2012;36:379-90.
43. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem. 1992;267:7402-5.
44. Nielsen LL, Young AA, Parkes DG. Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept. 2004;117:77-88. (Pubitemid 38045329)
45. Kolterman OG, Kim DD, Shen L, Ruggles JA, Nielsen LL, Fineman MS, et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. American Journal of Health-System Pharmacy. 2005;62:173-81. (Pubitemid 40674548)
46. Edwards CM, Stanley SA, Davis R, Brynes AE, Frost GS, Seal LJ, et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab. 2001;281:E155-61.
47. Degn KB, Brock B, Juhl CB, Djurhuus CB, Grubert J, Kim D, et al. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes. 2004;53:2397-403. (Pubitemid 39145595)
48. Kolterman OG, Buse JB, Fineman MS, Gaines E, Heintz S, Bicsak TA, et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2003;88:3082-9. (Pubitemid 36877476)
49. Fehse F, Trautmann M, Holst JJ, Halseth AE, Nanayakkara N, Nielsen LL, et al. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab. 2005;90:5991-7. (Pubitemid 41606516)
50. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628-35. (Pubitemid 39441462)
51. 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;28:1092-100. (Pubitemid 40616618)
52. 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. (Pubitemid 40616617)
53. Zinman B, Hoogwerf BJ, Duran Garcia S, Milton DR, Giaconia JM, Kim DD, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2007;146:477-85. (Pubitemid 351650556)
54. Buse JB, Klonoff DC, Nielsen LL, Guan X, Bowlus CL, Holcombe JH, et al. Metabolic effects of 2 years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebo-controlled trials. Clin Ther. 2007;29:139-53. (Pubitemid 46414034)
55. Buse JB, Bergenstal RM, Glass LC, Heilmann CR, Lewis MS, Kwan AY, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154:103-12.
56. Knudsen LB, Nielsen PF, Huusfeldt PO, Johansen NL, Madsen K, Pedersen FZ, et al. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. J Med Chem. 2000;43:1664-9. (Pubitemid 30304999)
57. Vilsboll T, Zdravkovic M, Le-Thi T, Krarup T, Schmitz O, Courreges JP, et al. Liraglutide, a long-acting human glucagon-like peptide-1 analog, given as monotherapy significantly improves glycemic control and lowers body weight without risk of hypoglycemia in patients with type 2 diabetes. Diabetes Care. 2007;30:1608-10. (Pubitemid 46871185)
58. Zinman B, Gerich J, Buse JB, Lewin A, Schwartz S, Raskin P, et al. Efficacy and safety of the human glucagon-like peptide-1 analog liraglutide in combination with metformin and thiazolidinedione in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care. 2009;32:1224-30.
59. Marre M, Shaw J, Brandle M, Bebakar WM, Kamaruddin NA, Strand J, et al. 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;26:268-78.
60. Kim D, MacConell L, Zhuang D, Kothare PA, Trautmann M, Fineman M, et al. 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;30:1487-93. (Pubitemid 46871159)
61. Buse JB, Rosenstock J, Sesti G, Schmidt WE, Montanya E, Brett JH, et al. Liraglutide once a day vs exenatide twice a day for type 2 diabetes: a 26-week randomized, parallel-group, multinational, open-label trial (LEAD-6). Lancet. 2009;374:39-47.
62. Drucker DJ, Buse JB, Taylor K, Kendall DM, Trautmann M, Zhuang D, et al. Exenatide once weekly vs twice daily for the treatment of type 2 diabetes: a randomized, open-label, non-inferiority study. Lancet. 2008;372:1240-50.
63. Blevins T, Pullman J, Malloy J, Yan P, Taylor K, Schulteis C, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:1301-10.
64. Aroda VR, Henry RR, Han J, Huang W, DeYoung MB, Darsow T, et al. Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin Ther. 2012;34:1247-58. e22.
65. Buse JB, Nauck M, Forst T, Sheu WH, Shenouda SK, Heilmann CR, et al. Exenatide once weekly vs liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomized, open-label study. Lancet. 2013;381(9861):117-24.
66. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH, Brodows RG, et al. Exenatide vs insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143:559-69.
67. Nauck MA, Duran S, Kim D, Johns D, Northrup J, Festa A, et al. A comparison of twice-daily exenatide and biphasic insulin aspart in patients with type 2 diabetes who were suboptimally controlled with sulfonylurea and metformin: a non-inferiority study. Diabetologia. 2007;50:259-67.
68. Diamant M, Van Gaal L, Stranks S, Northrup J, Cao D, Taylor K, et al. Once weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes (DURATION-3): an open-label randomized trial. Lancet. 2010;375:2234-43
69. Diamant M, Van Gaal L, Stranks S, Guerci B, MacConell L, Haber H, et al. Safety and efficacy of once-weekly exenatide compared with insulin glargine titrated to target in patients with type 2 diabetes over 84 weeks. Diabetes Care. 2012;35:683-9.
70. Garber A, Henry R, Ratner R, Garcia-Hernandez PA, Rodriguez-Pattzi H, Olvera-Alvarez I, et al. Liraglutide vs glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomized, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473-81.
71. 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;32:84-90.
72. Nauck M, Frid A, Hermansen K, Thomsen AB, During M, Shah N, et al. Long-term efficacy and safety comparison of liraglutide, glimepiride, and placebo, all in combination with metformin in type 2 diabetes: 2-year results from the LEAD-2 study. Diabetes Obes Metab. 2013;15(3):204-12.
73. Russell-Jones D, Vaag A, Schmitz O, Sethi BK, Lalic N, Antic S, et al. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD-5 met+SU): a randomized controlled trial. Diabetologia. 2009;52:2046-55.
74. Bergman AJ, Stevens C, Zhou Y, Yi B, Laethem M, De Smet M, et al. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebo-controlled study in healthy male volunteers. Clin Ther. 2006;28:55-72. (Pubitemid 43254990)
75. Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H, et al. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49:2564-71.
76. Dobs AS, Goldstein BJ, Aschner P, Horton ES, Umpierrez GE, Duran L, et al. Efficacy and safety of sitagliptin added to ongoing metformin and rosiglitazone combination therapy in a randomized, placebo-controlled, 54-week trial in patients with type 2 diabetes. J Diabetes. 2013;5(1):68-79.
77. Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab. 2007;9:733-45. (Pubitemid 47261855)
78. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, Sitagliptin SG. 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. (Pubitemid 44912191)
79. Muscelli E, Casolaro A, Gastaldelli A, Mari A, Seghieri G, Astiarraga B, et al. Mechanisms for the antihyperglycemic effect of sitagliptin in patients with type 2 diabetes. J Clin Endocrinol Metab. 2012;97:2818-26.
80. Rosenstock J, Aguilar-Salinas C, Klein E, Nepal S, List J, Chen R, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401-11.
81. 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 patients with inadequately controlled type 2 diabetes with metformin alone. Diabetes Care. 2009;32:1649-55.
82. Hollander P, Li J, Allen E, Chen R, Investigators CV. 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;94:4810-9.
83. Baetta R, Corsini A. Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. Drugs. 2011;71:1441-67.
84. Taskinen M, Saarinen-Pihkala UM, Hovi L, Lipsanen-Nyman M. Impaired glucose tolerance and dyslipidaemia as late effects after bone-marrow transplantation in childhood. Lancet. 2000;356:993-7.
85. Owens DR, Swallow R, Dugi KA, Woerle HJ. Efficacy and safety of linagliptin in persons with type 2 diabetes inadequately controlled by a combination of metformin and sulphonylurea: a 24-week randomized study. Diabet Med. 2011;28:1352-61.
86. Covington P, Christopher R, Davenport M, Fleck P, Mekki QA, Wann ER, et al. Pharmacokinetic, pharmacodynamic, and tolerability profiles of the dipeptidyl peptidase-4 inhibitor alogliptin: a randomized, double-blind, placebo-controlled, multiple-dose study in adult patients with type 2 diabetes. Clin Ther. 2008;30:499-512. (Pubitemid 351483925)
87. DeFronzo RA, Fleck PR, Wilson CA, Mekki Q. Alogliptin Study G: efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin in patients with type 2 diabetes and inadequate glycemic control: a randomized, double-blind, placebo-controlled study. Diabetes Care. 2008;31:2315-7.
88. Nauck MA, Ellis GC, Fleck PR, Wilson CA, Mekki Q. Alogliptin Study G: efficacy and safety of adding the dipeptidyl peptidase-4 inhibitor alogliptin to metformin therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy: a multicenter, randomized, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63:46-55.
89. Kaku K, Itayasu T, Hiroi S, Hirayama M, Seino Y. Efficacy and safety of alogliptin added to pioglitazone in Japanese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial with an open-label long-term extension study. Diabetes Obes Metab. 2011;13:1028-35.
90. Pratley RE, Kipnes MS, Fleck PR, Wilson C, Mekki Q. Alogliptin Study G: 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.
91. Rosenstock J, Rendell MS, Gross JL, Fleck PR, Wilson CA, Mekki Q. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA(1C) without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009;11:1145-52.
92. Scheen AJ, Charpentier G, Ostgren CJ, Hellqvist A, Gause-Nilsson I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab Res Rev. 2010;26:540-9.
93. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of beta-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258-67.
94. Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE. Sitagliptin 036 Study G: 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. 2007;30:1979-87. (Pubitemid 47219404)
95. Williams-Herman D, Johnson J, Teng R, Golm G, Kaufman KD, Goldstein BJ, et al. Efficacy and safety of sitagliptin and metformin as initial combination therapy and as monotherapy over 2 years in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:442-51.
96. Aschner P, Katzeff HL, Guo H, Sunga S, Williams-Herman D, Kaufman KD, et al. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:252-61.
97. Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP. Sitagliptin Study G: efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194-205. (Pubitemid 46206563)
98. Gallwitz B, Rosenstock J, Rauch T, Bhattacharya S, Patel S, von Eynatten M, et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomized, double-blind, non-inferiority trial. Lancet. 2012;380:475-83.
99. Rosenstock J, Baron MA, Dejager S, Mills D, Schweizer A. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care. 2007;30:217-23. (Pubitemid 46198322)
100. Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R, et al. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: a randomized controlled trial. Int J Clin Pract. 2009;63:1395-406.
101. Aschner P, Chan J, Owens DR, Picard S, Wang E, Dain MP, et al. Insulin glargine vs sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicenter, randomized open-label trial. Lancet. 2012;379:2262-9.
102. Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. Effect of saxagliptin as add-on therapy in patients with poorly controlled type 2 diabetes on insulin alone or insulin combined with metformin. Curr Med Res Opin. 2012;28:513-23.
103. Vilsboll T, Rosenstock J, Yki-Jarvinen H, Cefalu WT, Chen Y, Luo E, et al. Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:167-77.
104. Pratley RE, Nauck M, Bailey T, Montanya E, Cuddihy R, Filetti S, et al. Liraglutide vs 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;375:1447-56.
105. Bergenstal RM, Wysham C, Macconell L, Malloy J, Walsh B, Yan P, et al. Efficacy and safety of exenatide once weekly vs sitagliptin or pioglitazone as an adjunct to metformin for treatment of type 2 diabetes (DURATION-2): a randomized trial. Lancet. 2010;376:431-9.
106. Gallwitz B, Vaag A, Falahati A, Madsbad S. Adding liraglutide to oral antidiabetic drug therapy: onset of treatment effects over time. Int J Clin Pract. 2010;64:267-76.
107. Aschner P, Kipnes MS, Lunceford JK, Sanchez M, Mickel C, Williams-Herman DE, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29:2632-7. (Pubitemid 44912190)
108. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies. Gastroenterology. 2011;141:150-6.
109. Noel RA, Braun DK, Patterson RE, Bloomgren GL. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2009;32:834-8.
110. Garg R, Chen W, Pendergrass M. Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis. Diabetes Care. 2010;33:2349-54.
111. Crespel A, De Boisvilliers 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;137:3674-80. (Pubitemid 26284632)
112. Bjerre Knudsen L, Madsen LW, Andersen S, Almholt K, de Boer AS, Drucker DJ, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151:1473-86.
113. Willemen MJ, Mantel-Teeuwisse AK, Straus SM, Meyboom RH, Egberts TC, Leufkens HG. Use of dipeptidyl peptidase-4 inhibitors and the reporting of infections: a disproportionality analysis in the World Health Organization VigiBase. Diabetes Care. 2011;34:369-74.
114. Williams-Herman D, Engel SS, Round E, Johnson J, Golm GT, Guo H, et al. 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.
115. Ligueros-Saylan M, Foley JE, Schweizer A, Couturier A, Kothny W. An assessment of adverse effects of vildagliptin vs comparators on the liver, the pancreas, the immune system, the skin, and in patients with impaired renal function from a large pooled database of Phase II and III clinical trials. Diabetes Obes Metab. 2010;12:495-509.
116. Russell S. Incretin-based therapies for type 2 diabetes mellitus: a review of direct comparisons of efficacy, safety, and patient satisfaction. Int J Clin Pharm. 2012. doi: 10.1007/s11096-012-9729-9
117. Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007;30:1862-4. (Pubitemid 47036366)
118. Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2012;35:1364-79.
119. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427-43. (Pubitemid 44903747)
120. Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology. 2002;143:4397-408. (Pubitemid 35239574)
121. Gallwitz B, Guzman J, Dotta F, Guerci B, Simo R, Basson BR, et al. Exenatide twice daily vs glimepiride for prevention of glycemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomized controlled trial. Lancet. 2012;379:2270-8. This study proves the beneficial long-term effect of GLP-1r agonists on islet cell function.
122. Astrup A, Rossner S, Van Gaal L, Rissanen A, Niskanen L, Al Hakim M, et al. Effects of liraglutide in the treatment of obesity: a randomized, double-blind, placebo-controlled study. Lancet. 2009;374:1606-16.
123. Best JH, Rubin RR, Peyrot M, Li Y, Yan P, Malloy J, et al. Weight-related quality of life, health utility, psychological well-being, and satisfaction with exenatide once weekly compared with sitagliptin or pioglitazone after 26 weeks of treatment. Diabetes Care. 2011;34:314-9.
124. Schwarz B, Gouveia M, Chen J, Nocea G, Jameson K, Cook J, et al. Cost-effectiveness of sitagliptin-based treatment regimens in European patients with type 2 diabetes and haemoglobin A1c above target on metformin monotherapy. Diabetes Obes Metab. 2008;10 Suppl 1:43-55.