A systematic review of the safety of incretin-based therapies in type 2 diabetes

References

• Byetta (Exenatide daily). Prescribing information highlights. 2015. Accessed 2015 Aug 5. Available from http://www.azpicentral.com/byetta/pi_byetta.pdf#page=1.
   Google Scholar
• Bydureon (Exenatide OW). Prescribing information highlights. 2012. Accessed 2015 Aug 4. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022200s000lbl.pdf.
   Google Scholar
• Novo Nordisk A/S. Victoza (Liraglutide) Summary of Product Characteristics. Accessed 2015 Aug 4. Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2012/022341s017lbl.pdf.
   Google Scholar
• Eperzan (Albiglutide). Albiglutide SPC. 2015. Accessed 2015 Aug 4. Available from: https://www.gsksource.com/gskprm/htdocs/documents/TANZEUM-PI-MG-IFU-COMBINED.PDF.
   Google Scholar
• Trulicity. Dulaglutide prescribing information. 2015. Accessed 2015 Aug 4. Available from: http://pi.lilly.com/us/trulicity-uspi.pdfAccessed.
   Google Scholar
• Lyxumia. Lixisenatide: Summary of product characteristics. Sanofi. 2013. Accessed 2015 Aug 4. Available from: https://www.diabetesmatters.co.uk/sites/default/files/Lixi%20PI%20Feb.pdf.
   Google Scholar
• Januvia (Sitagliptin). Prescribing information highlights. 2015. Accessed 2015 Aug 25. Available from: http://www.merck.com/product/usa/pi_circulars/j/januvia/januvia_pi.pdf.
   Google Scholar
• Onglyza (Saxagliptin). Prescribing information highlights. 2015. Available from: http://www.medicines.org.uk/emc/medicine/22315/SPC/. Accessed 2015 Aug 04
   Google Scholar
• Tradjenta (linagliptin). Prescribing information highlights. 2015. Accessed 2015 Aug 4. Available from: http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Tradjenta/Tradjenta.pdf.
   Google Scholar
• Nesina (Alogliptin). Prescribing information highlights. 2013. Accessed 2015 Aug 4. Available from: http://general.takedapharm.com/content/file.aspx?applicationcode=5D2277FD-CFC0-423C-B543-811D41F4771E&filetypecode=NESINAPI&cacheRandomizer=c938c44c-ae0a-4147-9f03-26fd40a8afda.
   Google Scholar
• Galvus (Vildagliptin). EMA: Summaries of Product Characteristics. 2015. Accessed 2015 Aug 4. Available from: http://www.medicines.org.uk/emc/medicine/20734.
   Google Scholar
• Davies MJ, Donnelly R, Barnett AH, et al. Exenatide compared with long-acting insulin to achieve glycaemic control with minimal weight gain in patients with type 2 diabetes: results of the Helping Evaluate Exenatide in patients with diabetes compared with Long-Acting insulin (HEELA) study. Diabetes Obes Metab. 2009;11:1153–1162.
   PubMed Web of Science ®Google Scholar
• Diamant M, Van GL, Stranks S, 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;35:683–689.
   PubMed Web of Science ®Google Scholar
• Diamant M, Van Gaal L, Stranks S, et al. 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;375:2234–2243.
   PubMed Web of Science ®Google Scholar
• Heine RJ, Van Gaal LF, Johns D, et al. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2005;143:559–569.
   PubMed Web of Science ®Google Scholar
• Htike ZZ, Khunti K, Davies M. A review of exenatide: optimizing glycemic control and associated cardiovascular risk factors in type 2 diabetes. Diabetes Ther. 2012;3:1–16.
   PubMedGoogle Scholar
• Buse JB, Rosenstock J, Sesti G, 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;374:39–47.
   PubMed Web of Science ®Google Scholar
• Garber A. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet. 2009;373:473–481.
   PubMed Web of Science ®Google Scholar
• Marre M, Shaw J, Brandle M, 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;26:268–278.
   PubMed Web of Science ®Google Scholar
• Nauck M, Frid A, Hermansen K, 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.
   PubMed Web of Science ®Google Scholar
• Pratley RE, Nauck MA, Bailey T, et al. Efficacy and safety of switching from the DPP-4 inhibitor sitagliptin to the human GLP-1 analog liraglutide after 52 weeks in metformin-treated patients with type 2 diabetes: A randomized, open-label trial. Diabetes Care. 2012;35:1986–1993.
   PubMed Web of Science ®Google Scholar
• Russell-Jones D, Vaag A, Schmitz O, 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 randomised controlled trial. Diabetologia. 2009;52:2046–2055.
   PubMed Web of Science ®Google Scholar
• Zinman B, Gerich J, Buse JB, 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;32:1224–1230.
   PubMed Web of Science ®Google Scholar
• Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013;381:117–124.
   PubMed Web of Science ®Google Scholar
• Ahren B, Leguizamo DA, Miossec P, et al. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care. 2013;36:2543–2550.
   PubMed Web of Science ®Google Scholar
• Bolli GB, Munteanu M, Dotsenko S, et al. Efficacy and safety of lixisenatide once daily vs. placebo in people with Type 2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabet Med. 2014;31:176–184.
   PubMed Web of Science ®Google Scholar
• Pinget M, Goldenberg R, Niemoeller E, et al. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes Metab. 2013;15:1000–1007.
   PubMed Web of Science ®Google Scholar
• Riddle MC, Aronson R, Home P, et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled by established basal insulin: A 24-week, randomized, placebo-controlled comparison (GetGoal-l). Diabetes Care. 2013;36:2489–2496.
   Web of Science ®Google Scholar
• Seino Y, Min KW, Niemoeller E, et al. Randomized, double-blind, placebo-controlled trial of the once-daily GLP-1 receptor agonist lixisenatide in Asian patients with type 2 diabetes insufficiently controlled on basal insulin with or without a sulfonylurea (GetGoal-L-Asia). Diabetes Obes Metab. 2012;14:910–917.
   PubMed Web of Science ®Google Scholar
• Ahren B, Johnson SL, Stewart M, et al. HARMONY 3: 104-week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 2 diabetes taking metformin. Diabetes Care. 2014;37:2141–2148.
   PubMed Web of Science ®Google Scholar
• Home PD, Shamanna P, Stewart M, et al. Efficacy and tolerability of albiglutide versus placebo or pioglitazone over 1 year in people with type 2 diabetes currently taking metformin and glimepiride: HARMONY 5. Diabetes Obes Metab. 2015;17:179–187.
   PubMed Web of Science ®Google Scholar
• Pratley RE, Nauck MA, Barnett AH, et al. Once-weekly albiglutide versus once-daily liraglutide in patients with type 2 diabetes inadequately controlled on oral drugs (HARMONY 7): a randomised, open-label, multicentre, non-inferiority phase 3 study. Lancet Diabetes Endocrinol. 2014;2:289–297.
   PubMed Web of Science ®Google Scholar
• Reusch J, Stewart MW, Perkins CM, et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonist albiglutide (HARMONY 1 trial): 52-week primary endpoint results from a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes mellitus not controlled on pioglitazone, with or without metformin. Diabetes Obes Metab. 2014;16:1257–1264.
   PubMed Web of Science ®Google Scholar
• Seino Y, Nakajima H, Miyahara H, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics of albiglutide, a long-acting GLP-1-receptor agonist, in Japanese subjects with type 2 diabetes mellitus. Curr Med Res Opin. 2009;25:3049–3057.
   PubMed Web of Science ®Google Scholar
• Weissman PN, Carr MC, Ye J, et al. HARMONY 4: randomised clinical trial comparing once-weekly albiglutide and insulin glargine in patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea. Diabetologia. 2014;57:2475–2484.
   PubMed Web of Science ®Google Scholar
• Dungan KM, Povedano ST, Forst T, et al. Once-weekly dulaglutide versus once-daily liraglutide in metformin-treated patients with type 2 diabetes (AWARD-6): a randomised, open-label, phase 3, non-inferiority trial. Lancet. 2014;384:1349–1357.
   PubMed Web of Science ®Google Scholar
• Nauck M, Weinstock RS, Umpierrez GE, et al. Efficacy and safety of dulaglutide versus sitagliptin after 52 weeks in type 2 diabetes in a randomized controlled trial (AWARD-5). Diabetes Care. 2014;37:2149–2158.
   PubMed Web of Science ®Google Scholar
• Umpierrez G, Tofe PS, Perez MF, et al. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care. 2014;37:2168–2176.
   PubMed Web of Science ®Google Scholar
• Wysham C, Blevins T, Arakaki R, et al. Efficacy and safety of dulaglutide added onto pioglitazone and metformin versus exenatide in type 2 diabetes in a randomized controlled trial (AWARD-1). Diabetes Care. 2014;37:2159–2167.
   PubMed Web of Science ®Google Scholar
• Aschner P, Katzeff HL, Guo H, et al. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:252–261.
   PubMed Web of Science ®Google Scholar
• Nauck MA, Meininger G, Sheng D, et al. 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.
   PubMed Web of Science ®Google Scholar
• Pratley RE, Nauck M, Bailey T, et al. Liraglutide versus sitagliptin for patients with type 2 diabetes who did not have adequate glycaemic control with metformin: a 26-week, randomised, parallel-group, open-label trial. Lancet. 2010;375:1447–1456.
   PubMed Web of Science ®Google Scholar
• Chacra AR, Tan GH, Ravichandran S, et al. Safety and efficacy of saxagliptin in combination with submaximal sulphonylurea versus up-titrated sulphonylurea over 76 weeks. Diab Vasc Dis Res. 2011;8:150–159.
   PubMed Web of Science ®Google Scholar
• DeFronzo RA, Hissa MN, Garber AJ, 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;32:1649–1655.
   PubMed Web of Science ®Google Scholar
• Hollander PL, Li J, Frederich R, et al. Safety and efficacy of saxagliptin added to thiazolidinedione over 76 weeks in patients with type 2 diabetes mellitus. Diab Vasc Dis Res. 2011;8:125–135.
   PubMed Web of Science ®Google Scholar
• Del Prato S, Barnett AH, Huisman H, et al. 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;13:258–267.
   PubMed Web of Science ®Google Scholar
• Taskinen MR, Rosenstock J, Tamminen I, 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.
   PubMed Web of Science ®Google Scholar
• Owens DR, Swallow R, Dugi KA, et al. 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;28:1352–1361.
   PubMed Web of Science ®Google Scholar
• Bosi E, Ellis GC, Wilson CA, et al. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study. Diabetes Obes Metab. 2011;13:1088–1096.
   PubMed Web of Science ®Google Scholar
• Nauck MA, Ellis GC, Fleck PR, et al. 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 multicentre, randomised, double-blind, placebo-controlled study. Int J Clin Pract. 2009;63:46–55.
   PubMed Web of Science ®Google Scholar
• Pratley RE, Kipnes MS, Fleck PR, et al. 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;11:167–176.
   PubMed Web of Science ®Google Scholar
• Bolli G, Dotta F, Rochotte E, et al. Efficacy and tolerability of vildagliptin vs. pioglitazone when added to metformin: a 24-week, randomized, double-blind study. Diabetes Obes Metab. 2008;10:82–90.
   PubMed Web of Science ®Google Scholar
• Schweizer A, Couturier A, Foley JE, et al. Comparison between vildagliptin and metformin to sustain reductions in HbA(1c) over 1 year in drug-naive patients with Type 2 diabetes. Diabet Med. 2007;24:955–961.
   PubMed Web of Science ®Google Scholar
• Foley JE, Sreenan S. Efficacy and safety comparison between the DPP-4 inhibitor vildagliptin and the sulfonylurea gliclazide after two years of monotherapy in drug-naive patients with type 2 diabetes. Horm Metab Res. 2009;41:905–909.
   PubMed Web of Science ®Google Scholar
• Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med. 2011;124:S3–18.
   PubMed Web of Science ®Google Scholar
• Nauck MA, Niedereichholz U, Ettler R, et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am J Physiol. 1997;273:E981–E988.
   PubMed Web of Science ®Google Scholar
• Elashoff M, Matveyenko AV, Gier B, et al. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like Peptide-1-based therapies. Gastroenterology. 2011;141:150–156.
   PubMed Web of Science ®Google Scholar
• Butler AE, Campbell-Thompson M, Gurlo T, et al. Marked expansion of exocrine and endocrine pancreas with incretin therapy in humans with increased exocrine pancreas dysplasia and the potential for glucagon-producing neuroendocrine tumors. Diabetes. 2013;62:2595–2604.
   Web of Science ®Google Scholar
• Singh S, Chang HY, Richards TM, et al. Glucagonlike peptide 1-based therapies and risk of hospitalization for acute pancreatitis in type 2 diabetes mellitus: a population-based matched case-control study. JAMA Intern Med. 2013;173:534–539.
   Web of Science ®Google Scholar
• Bulotta A, Hui H, Anastasi E, et al. Cultured pancreatic ductal cells undergo cell cycle re-distribution and beta-cell-like differentiation in response to glucagon-like peptide-1. J Mol Endocrinol. 2002;29:347–360.
   PubMed Web of Science ®Google Scholar
• Tatarkiewicz K, Belanger P, Gu G, et al. No evidence of drug-induced pancreatitis in rats treated with exenatide for 13 weeks. Diabetes Obes Metab. 2013;15:417–426.
   Web of Science ®Google Scholar
• Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–1326.
   PubMed Web of Science ®Google Scholar
• White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–1335.
   PubMed Web of Science ®Google Scholar
• Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugs–FDA and EMA assessment. N Engl J Med. 2014;370:794–797.
   PubMed Web of Science ®Google Scholar
• Bjerre Knudsen L, Madsen LW, Andersen SÃ, et al. Glucagon-like Peptide-1 receptor agonists activate rodent thyroid C-cells causing calcitonin release and C-cell proliferation. Endocrinology. 2010;151:1473–1486.
   PubMed Web of Science ®Google Scholar
• Madsen LW, Knauf JA, Gotfredsen C, et al. GLP-1 receptor agonists and the thyroid: C-cell effects in mice are mediated via the GLP-1 receptor and not associated with RET activation. Endocrinology. 2012;153:1538–1547.
   PubMed Web of Science ®Google Scholar
• Bergenstal RM, Wysham C, Macconell L, et al. 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;376:431–439.
   PubMed Web of Science ®Google Scholar
• Arjona Ferreira JC, Corry D, Mogensen CE, et al Efficacy and safety of sitagliptin in patients with type 2 diabetes and ESRD receiving dialysis: a 54-week randomized trial. Am J Kidney Dis. 2013;61:579–587.
   PubMed Web of Science ®Google Scholar
• Russell-Jones D, Cuddihy RM, Hanefeld M, et al. Efficacy and safety of exenatide once weekly versus metformin, pioglitazone, and sitagliptin used as monotherapy in drug-naive patients with type 2 diabetes (DURATION-4): a 26-week double-blind study. Diabetes Care. 2012;35:252–258.
   PubMed Web of Science ®Google Scholar
• Violante R, Oliveira JH, Yoon KH, et al. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin. Diabet Med. 2012;29:e417–e424.
   PubMed Web of Science ®Google Scholar
• Aschner P, Kipnes MS, Lunceford JK, et al. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 2006;29:2632–2637.
   PubMed Web of Science ®Google Scholar
• Aschner P, Chan J, Owens DR, et al. Insulin glargine versus sitagliptin in insulin-naive patients with type 2 diabetes mellitus uncontrolled on metformin (EASIE): a multicentre, randomised open-label trial. Lancet. 2012;379:2262–2269.
   PubMed Web of Science ®Google Scholar
• Barzilai N, Guo H, Mahoney EM, et al. Efficacy and tolerability of sitagliptin monotherapy in elderly patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial. Curr Med Res Opin. 2011;27:1049–1058.
   PubMed Web of Science ®Google Scholar
• Hermansen K, Kipnes M, Luo E, et al. 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;9:733–745.
   PubMed Web of Science ®Google Scholar
• Mohan V, Yang W, Son HY, et al Efficacy and safety of sitagliptin in the treatment of patients with type 2 diabetes in China, India, and Korea. Diabetes Res Clin Pract. 2009;83:106–116.
   PubMed Web of Science ®Google Scholar
• Olansky L, Reasner C, Seck TL, et al A treatment strategy implementing combination therapy with sitagliptin and metformin results in superior glycaemic control versus metformin monotherapy due to a low rate of addition of antihyperglycaemic agents. Diabetes Obes Metab. 2011;13:841–849.
   PubMed Web of Science ®Google Scholar
• Raz I, Chen Y, Wu M, et al Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes. Curr Med Res Opin. 2008;24:537–550.
   PubMed Web of Science ®Google Scholar
• Rosenstock J, Brazg R, Andryuk PJ, et al. 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;28:1556–1568.
   PubMed Web of Science ®Google Scholar
• Scheen AJ, Charpentier G, Ostgren CJ, et al. 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;26:540–549.
   PubMed Web of Science ®Google Scholar
• Scott R, Loeys T, Davies MJ, et al. Efficacy and safety of sitagliptin when added to ongoing metformin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2008;10:959–969.
   PubMed Web of Science ®Google Scholar
• Seck T, Nauck M, Sheng D, et al Safety and efficacy of treatment with sitagliptin or glipizide in patients with type 2 diabetes inadequately controlled on metformin: a 2-year study. Int J Clin Pract. 2010;64:562–576.
   PubMed Web of Science ®Google Scholar
• Vilsbøll T, Rosenstock J, Yki-Jarvinen H, et al Efficacy and safety of sitagliptin when added to insulin therapy in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:167–177.
   PubMed Web of Science ®Google Scholar
• Wainstein J, Katz L, Engel SS, et al. Initial therapy with the fixed-dose combination of sitagliptin and metformin results in greater improvement in glycaemic control compared with pioglitazone monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2012;14:409–418.
   PubMed Web of Science ®Google Scholar
• Williams-Herman D, Johnson J, Teng R, 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;12:442–451.
   PubMed Web of Science ®Google Scholar
• Yang W, Guan Y, Shentu Y, et al. The addition of sitagliptin to ongoing metformin therapy significantly improves glycemic control in Chinese patients with type 2 diabetes. J Diabetes. 2012;4:227–237.
   PubMed Web of Science ®Google Scholar
• Yoon KH, Steinberg H, Teng R, et al. Efficacy and safety of initial combination therapy with sitagliptin and pioglitazone in patients with type 2 diabetes: a 54-week study. Diabetes Obes Metab. 2012;14:745–752.
   PubMed Web of Science ®Google Scholar
• Charbonnel B, Karasik A, Liu J, et al. 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;29:2638–2643.
   PubMed Web of Science ®Google Scholar
• Nowicki M, Rychlik I, Haller H, et al. Long-term treatment with the dipeptidyl peptidase-4 inhibitor saxagliptin in patients with type 2 diabetes mellitus and renal impairment: a randomised controlled 52-week efficacy and safety study. Int J Clin Pract. 2011;65:1230–1239.
   PubMed Web of Science ®Google Scholar
• Rosenstock J, Aguilar-Salinas C, Klein E, et al. Effect of saxagliptin monotherapy in treatment-naive patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401–2411.
   PubMed Web of Science ®Google Scholar
• Jadzinsky M, Pfutzner A, Paz-Pacheco E, et al. Saxagliptin given in combination with metformin as initial therapy improves glycaemic control in patients with type 2 diabetes compared with either monotherapy: a randomized controlled trial. Diabetes Obes Metab. 2009;11:611–622.
   PubMed Web of Science ®Google Scholar
• Pan CY, Yang W, Tou C, et al. Efficacy and safety of saxagliptin in drug-naive Asian patients with type 2 diabetes mellitus: a randomized controlled trial. Diabetes Metab Res Rev. 2012;28:268–275.
   PubMed Web of Science ®Google Scholar
• Goke B, Gallwitz B, Eriksson J, et al. Saxagliptin is non-inferior to glipizide in patients with type 2 diabetes mellitus inadequately controlled on metformin alone: a 52-week randomised controlled trial. Int J Clin Pract. 2010;64:1619–1631.
   PubMed Web of Science ®Google Scholar
• Barnett AH, Charbonnel B, Donovan M, et al. 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;28:513–523.
   PubMed Web of Science ®Google Scholar
• Karyekar C, Donovan M, Allen E, et al. Efficacy and safety of saxagliptin combination therapy in US patients with type 2 diabetes. Postgrad Med. 2011;123:63–70.
   PubMed Web of Science ®Google Scholar
• Moses RG, Kalra S, Brook D, et al A randomized controlled trial of the efficacy and safety of saxagliptin as add-on therapy in patients with type 2 diabetes and inadequate glycaemic control on metformin plus a sulphonylurea. Diabetes Obes Metab. 2014;16:443–450.
   PubMed Web of Science ®Google Scholar
• Pfutzner A, Paz-Pacheco E, Allen E, et al. Initial combination therapy with saxagliptin and metformin provides sustained glycaemic control and is well tolerated for up to 76 weeks. Diabetes Obes Metab. 2011;13:567–576.
   PubMed Web of Science ®Google Scholar
• Gallwitz B, Rosenstock J, Rauch T, et al. 2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin: a randomised, double-blind, non-inferiority trial. Lancet. 2012;380:475–483.
   PubMed Web of Science ®Google Scholar
• Gomis R, Espadero RM, Jones R, et al. Efficacy and safety of initial combination therapy with linagliptin and pioglitazone in patients with inadequately controlled type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:653–661.
   PubMed Web of Science ®Google Scholar
• Haak T, Meinicke T, Jones R, et al. Initial combination of linagliptin and metformin improves glycaemic control in type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2012;14:565–574.
   PubMed Web of Science ®Google Scholar
• Kawamori R, Inagaki N, Araki E, et al. Linagliptin monotherapy provides superior glycaemic control versus placebo or voglibose with comparable safety in Japanese patients with type 2 diabetes: a randomized, placebo and active comparator-controlled, double-blind study. Diabetes Obes Metab. 2012;14:348–357.
   PubMed Web of Science ®Google Scholar
• DeFronzo RA, Burant CF, Fleck P, et al. Efficacy and tolerability of the DPP-4 inhibitor alogliptin combined with pioglitazone, in metformin-treated patients with type 2 diabetes. J Clin Endocrinol Metab. 2012;97:1615–1622.
   PubMed Web of Science ®Google Scholar
• Bosi E, Camisasca RP, Collober C, et al. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30:890–895.
   PubMed Web of Science ®Google Scholar
• Bosi E, Dotta F, Jia Y, et al. Vildagliptin plus metformin combination therapy provides superior glycaemic control to individual monotherapy in treatment-naive patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2009;11:506–515.
   PubMed Web of Science ®Google Scholar
• Dejager S, Razac S, Foley JE, et al. Vildagliptin in drug-naive patients with type 2 diabetes: a 24-week, double-blind, randomized, placebo-controlled, multiple-dose study. Horm Metab Res. 2007;39:218–223.
   PubMed Web of Science ®Google Scholar
• Filozof C, Gautier JF. A comparison of efficacy and safety of vildagliptin and gliclazide in combination with metformin in patients with Type 2 diabetes inadequately controlled with metformin alone: a 52-week, randomized study. Diabet Med. 2010;27:318–326.
   PubMed Web of Science ®Google Scholar
• Fonseca V, Schweizer A, Albrecht D, et al. Addition of vildagliptin to insulin improves glycaemic control in type 2 diabetes. Diabetologia. 2007;50:1148–1155.
   PubMed Web of Science ®Google Scholar
• Garber AJ, Foley JE, Banerji MA, et al. Effects of vildagliptin on glucose control in patients with type 2 diabetes inadequately controlled with a sulphonylurea. Diabetes Obes Metab. 2008;10:1047–1056.
   PubMed Web of Science ®Google Scholar
• Garber AJ, Schweizer A, Baron MA, et al. Vildagliptin in combination with pioglitazone improves glycaemic control in patients with type 2 diabetes failing thiazolidinedione monotherapy: a randomized, placebo-controlled study. Diabetes Obes Metab. 2007;9:166–174.
   PubMed Web of Science ®Google Scholar
• Goodman M, Thurston H, Penman J. Efficacy and tolerability of vildagliptin in patients with type 2 diabetes inadequately controlled with metformin monotherapy. Horm Metab Res. 2009;41:368–373.
   PubMed Web of Science ®Google Scholar
• Goke B, Hershon K, Kerr D, et al. Efficacy and safety of vildagliptin monotherapy during 2-year treatment of drug-naive patients with type 2 diabetes: comparison with metformin. Horm Metab Res. 2008;40:892–895.
   PubMed Web of Science ®Google Scholar
• Hassanein M, Abdallah K, Schweizer A. A double-blind, randomized trial, including frequent patient-physician contacts and Ramadan-focused advice, assessing vildagliptin and gliclazide in patients with type 2 diabetes fasting during Ramadan: the STEADFAST study. Vasc Health Risk Manag. 2014;10:319–326.
   PubMedGoogle Scholar
• Lukashevich V, Prato SD, Araga M, et al. Efficacy and safety of vildagliptin in patients with type 2 diabetes mellitus inadequately controlled with dual combination of metformin and sulphonylurea. Diabetes Obes Metab. 2014;16:403–409.
   PubMed Web of Science ®Google Scholar
• Lukashevich V, Schweizer A, Shao Q, et al. Safety and efficacy of vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: a prospective 24-week randomized placebo-controlled trial. Diabetes Obes Metab. 2011;13:947–954.
   PubMed Web of Science ®Google Scholar
• Matthews DR, Dejager S, Ahren B, et al. Vildagliptin add-on to metformin produces similar efficacy and reduced hypoglycaemic risk compared with glimepiride, with no weight gain: results from a 2-year study. Diabetes Obes Metab. 2010;12:780–789.
   PubMed Web of Science ®Google Scholar
• Pan C, Yang W, Barona JP, et al. Comparison of vildagliptin and acarbose monotherapy in patients with Type 2 diabetes: a 24-week, double-blind, randomized trial. Diabet Med. 2008;25:435–441.
   PubMed Web of Science ®Google Scholar
• Pan C, Xing X, Han P, et al. Efficacy and tolerability of vildagliptin as add-on therapy to metformin in Chinese patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2012;14:737–744.
   PubMed Web of Science ®Google Scholar
• Pi-Sunyer FX, Schweizer A, Mills D, et al. Efficacy and tolerability of vildagliptin monotherapy in drug-naive patients with type 2 diabetes. Diabetes Res Clin Pract. 2007;76:132–138.
   PubMed Web of Science ®Google Scholar
• Rosenstock J, Kim SW, Baron MA, et al. Efficacy and tolerability of initial combination therapy with vildagliptin and pioglitazone compared with component monotherapy in patients with type 2 diabetes. Diabetes Obes Metab. 2007;9:175–185.
   PubMed Web of Science ®Google Scholar
• Rosenstock J, Baron MA, Dejager S, et al. Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Care. 2007;30:217–223.
   PubMed Web of Science ®Google Scholar
• Scherbaum WA, Schweizer A, Mari A, et al. Evidence that vildagliptin attenuates deterioration of glycaemic control during 2-year treatment of patients with type 2 diabetes and mild hyperglycaemia. Diabetes Obes Metab. 2008;10:1114–1124.
   PubMed Web of Science ®Google Scholar
• Scherbaum WA, Schweizer A, Mari A, et al. Efficacy and tolerability of vildagliptin in drug-naive patients with type 2 diabetes and mild hyperglycaemia*. Diabetes Obes Metab. 2008;10:675–682.
   PubMed Web of Science ®Google Scholar
• Schweizer A, Dejager S, Bosi E. Comparison of vildagliptin and metformin monotherapy in elderly patients with type 2 diabetes: a 24-week, double-blind, randomized trial. Diabetes Obes Metab. 2009;11:804–812.
   PubMed Web of Science ®Google Scholar
• Strain WD, Lukashevich V, Kothny W, et al. Individualised treatment targets for elderly patients with type 2 diabetes using vildagliptin add-on or lone therapy (INTERVAL): a 24 week, randomised, double-blind, placebo-controlled study. Lancet. 2013;382:409–416.
   PubMed Web of Science ®Google Scholar
• DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care. 2005;28:1092–1100.
   PubMed Web of Science ®Google Scholar
• Gallwitz B, Bohmer M, Segiet T, et al. Exenatide twice daily versus premixed insulin aspart 70/30 in metformin-treated patients with type 2 diabetes: a randomized 26-week study on glycemic control and hypoglycemia. Diabetes Care. 2011;34:604–606.
   PubMed Web of Science ®Google Scholar
• Kendall DM, Riddle MC, Rosenstock J, 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;28:1083–1091.
   PubMed Web of Science ®Google Scholar
• Nauck MA, Duran S, Kim D, 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;50:259–267.
   PubMed Web of Science ®Google Scholar
• Buse JB, Bergenstal RM, Glass LC, et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann Intern Med. 2011;154:103–112.
   PubMed Web of Science ®Google Scholar
• Barnett AH, Burger J, Johns D, et al. Tolerability and efficacy of exenatide and titrated insulin glargine in adult patients with type 2 diabetes previously uncontrolled with metformin or a sulfonylurea: a multinational, randomized, open-label, two-period, crossover noninferiority trial. Clin Ther. 2007;29:2333–2348.
   PubMed Web of Science ®Google Scholar
• Buse JB, Henry RR, Han J, et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care. 2004;27:2628–2635.
   PubMed Web of Science ®Google Scholar
• Gallwitz B, Guzman J, Dotta F, et al. Exenatide twice daily versus glimepiride for prevention of glycaemic deterioration in patients with type 2 diabetes with metformin failure (EUREXA): an open-label, randomised controlled trial. Lancet. 2012;379:2270–2278.
   PubMed Web of Science ®Google Scholar
• Liutkus J, Rosas GJ, Norwood P, et al. A placebo-controlled trial of exenatide twice-daily added to thiazolidinediones alone or in combination with metformin. Diabetes Obes Metab. 2010;12:1058–1065.
   PubMed Web of Science ®Google Scholar
• Apovian CM, Bergenstal RM, Cuddihy RM, et al. Effects of exenatide combined with lifestyle modification in patients with type 2 diabetes. Am J Med. 2010;123:468–17.
   PubMed Web of Science ®Google Scholar
• Bergenstal R, Lewin A, Bailey T, et al. Efficacy and safety of biphasic insulin aspart 70/30 versus exenatide in subjects with type 2 diabetes failing to achieve glycemic control with metformin and a sulfonylurea. Curr Med Res Opin. 2009;25:65–75.
   PubMed Web of Science ®Google Scholar
• Blonde L, Klein EJ, Han J, et al. Interim analysis of the effects of exenatide treatment on A1C, weight and cardiovascular risk factors over 82 weeks in 314 overweight patients with type 2 diabetes. Diabetes Obes Metab. 2006;8:436–447.
   PubMed Web of Science ®Google Scholar
• Riddle MC, Henry RR, Poon TH, et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev. 2006;22:483–491.
   PubMed Web of Science ®Google Scholar
• Inagaki N, Atsumi Y, Oura T, et al. Efficacy and safety profile of exenatide once weekly compared with insulin once daily in Japanese patients with type 2 diabetes treated with oral antidiabetes drug(s): results from a 26-week, randomized, open-label, parallel-group, multicenter, noninferiority study. Clin Ther. 2012;34:1892–1908.
   PubMed Web of Science ®Google Scholar
• Seino Y, Rasmussen MF, Nishida T, et al. Efficacy and safety of the once-daily human GLP-1 analogue, liraglutide, vs glibenclamide monotherapy in Japanese patients with type 2 diabetes. Curr Med Res Opin. 2010;26:1013–1022.
   PubMed Web of Science ®Google Scholar
• DeVries JH, Bain SC, Rodbard HW, et al. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets. Diabetes Care. 2012;35:1446–1454.
   PubMed Web of Science ®Google Scholar
• Garber A, Henry RR, Ratner R, et al. Liraglutide, a once-daily human glucagon-like peptide 1 analogue, provides sustained improvements in glycaemic control and weight for 2 years as monotherapy compared with glimepiride in patients with type 2 diabetes. Diabetes Obes Metab. 2011;13:348–356.
   PubMed Web of Science ®Google Scholar
• Kaku K, Rasmussen MF, Clauson P, et al. Improved glycaemic control with minimal hypoglycaemia and no weight change with the once-daily human glucagon-like peptide-1 analogue liraglutide as add-on to sulphonylurea in Japanese patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:341–347.
   PubMed Web of Science ®Google Scholar
• MedDRA Terms. NCBO BioPortal. 2013.
   Google Scholar
• Scirica BM, Braunwald E, Raz I, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130:1579–1588.
   PubMed Web of Science ®Google Scholar
• Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–1326.
   Google Scholar
• Weir DL, McAlister FA, Senthilselvan A, et al. Sitagliptin use in patients with diabetes and heart failure: a population-based retrospective cohort study. JACC Heart Fail. 2014;2:573–582.
   PubMed Web of Science ®Google Scholar
• McMurray J. The Vildagliptin in Ventricular Dysfunction Diabetes trial (VIVIDD). Amsterdam: European Society of Cardiology Heart Failure Association; 2013.
   Google Scholar
• Gonzalez-Perez A, Schlienger RG, Rodriguez LA. Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study. Diabetes Care. 2010;33:2580–2585.
   PubMed Web of Science ®Google Scholar
• Astra Zeneca. Bydureon SmPC. 2015. Accessed 2015 Aug 04. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002020/WC500108241.pdf.
   Google Scholar
• Van CJ, Sloth B, Jensen CB, et al. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond). 2014;38:784–793.
   PubMed Web of Science ®Google Scholar
• EMA. Assessment report:Lyxumia. EMA. Accessed 2015 Aug 04. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002445/WC500140449.pdf.
   Google Scholar
• Steinberg WM, Nauck MA, Zinman B, et al. LEADER 3–lipase and amylase activity in subjects with type 2 diabetes: baseline data from over 9000 subjects in the LEADER Trial. Pancreas. 2014;43:1223–1231.
   PubMed Web of Science ®Google Scholar
• Buse JB, Garber A, Rosenstock J, et al. Liraglutide treatment is associated with a low frequency and magnitude of antibody formation with no apparent impact on glycemic response or increased frequency of adverse events: results from the Liraglutide Effect and Action in Diabetes (LEAD) trials. J Clin Endocrinol Metab. 2011;96:1695–1702.
   PubMed Web of Science ®Google Scholar
• Violante R, Oliveira JH, Yoon KH, et al. A randomized non-inferiority study comparing the addition of exenatide twice daily to sitagliptin or switching from sitagliptin to exenatide twice daily in patients with type 2 diabetes experiencing inadequate glycaemic control on metformin and sitagliptin. Diabet Med. 2012;29:e417–e424.
   Google Scholar
• Yan S, Marguet D, Dobers J, et al. Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen. Eur J Immunol. 2003;33:1519–1527.
   PubMed Web of Science ®Google Scholar
• Vora KA, Porter G, Peng R, et al. Genetic ablation or pharmacological blockade of dipeptidyl peptidase IV does not impact T cell-dependent immune responses. BMC Immunol. 2009;10:19.
   PubMed Web of Science ®Google Scholar
• Stulc T, Sedo A. Inhibition of multifunctional dipeptidyl peptidase-IV: is there a risk of oncological and immunological adverse effects? Diabetes Res Clin Pract. 2010;88:125–131.
   PubMed Web of Science ®Google Scholar
• Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696–1705.
   PubMed Web of Science ®Google Scholar
• Tang-Christensen M, Cowley MA. GLP-1 analogs: satiety without malaise? Am J Physiol Regul Integr Comp Physiol. 2007;293:R981–R982.
   PubMed Web of Science ®Google Scholar
• Rosenstock J, Reusch J, Bush M, et al. Potential of albiglutide, a long-acting GLP-1 receptor agonist, in type 2 diabetes: a randomized controlled trial exploring weekly, biweekly, and monthly dosing. Diabetes Care. 2009;32:1880–1886.
   PubMed Web of Science ®Google Scholar
• Sun F, Yu K, Yang Z, et al. Impact of GLP-1 receptor agonists on major gastrointestinal disorders for type 2 diabetes mellitus: a mixed treatment comparison meta-analysis. Exp Diabetes Res. 2012;2012:230624.
   PubMed Web of Science ®Google Scholar
• Degn KB, Brock B, Juhl CB, et al. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes. 2004;53:2397–2403.
   PubMed Web of Science ®Google Scholar
• Brown NJ, Byiers S, Carr D, et al. Dipeptidyl peptidase-IV inhibitor use associated with increased risk of ACE inhibitor-associated angioedema. Hypertension. 2009;54(3):516–523.
   Google Scholar
• Chilton R, Wyatt J, Nandish S, et al. Cardiovascular comorbidities of type 2 diabetes mellitus: defining the potential of glucagonlike peptide-1-based therapies. Am J Med. 2011;124:S35–S53.
   PubMed Web of Science ®Google Scholar
• Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589.
   PubMed Web of Science ®Google Scholar
• Masoudi FA, Inzucchi SE, Wang Y, et al. Thiazolidinediones, metformin, and outcomes in older patients with diabetes and heart failure: an observational study. Circulation. 2005;111:583–590.
   PubMed Web of Science ®Google Scholar
• UKPDS. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854–865.
   Google Scholar
• Zarich SW. Antidiabetic agents and cardiovascular risk in type 2 diabetes. Nat Rev Endocrinol. 2009;5:500–506.
   PubMed Web of Science ®Google Scholar
• Phung OJ, Schwartzman E, Allen RW, et al. Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis. Diabet Med. 2013;30:1160–1171.
   PubMed Web of Science ®Google Scholar
• Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–2471.
   PubMed Web of Science ®Google Scholar
• Zou C, Honglin H. Use of pioglitazone in the treatment of diabetes: effect on cardiovascular risk. Vasc Health Risk Manag. 2013;9:429–433.
   PubMedGoogle Scholar
• Klonoff DC, Buse JB, Nielsen LL, et al. 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;24:275–286.
   PubMed Web of Science ®Google Scholar
• Vilsbøll T, Zdravkovic M, Le-Thi T, 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;30:1608–1610.
   PubMed Web of Science ®Google Scholar
• Monami M, Cremasco F, Lamanna C, et al. Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. Exp Diabetes Res. 2011;2011:215764.
   PubMedGoogle Scholar
• Monami M, Ahren B, Dicembrini I, et al. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15:112–120.
   PubMed Web of Science ®Google Scholar
• Noel RA, Braun DK, Patterson RE, et al. Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study. Diabetes Care. 2009;32:834–838.
   PubMed Web of Science ®Google Scholar
• Raschi E, Piccinni C, Poluzzi E, et al. The association of pancreatitis with antidiabetic drug use: gaining insight through the FDA pharmacovigilance database. Acta Diabetol. 2013;50:569–577.
   PubMed Web of Science ®Google Scholar
• Dore DD, Seeger JD, Arnold CK. 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;25:1019–1027.
   PubMed Web of Science ®Google Scholar
• Dore DD, Bloomgren GL, Wenten M, et al. A cohort study of acute pancreatitis in relation to exenatide use. Diabetes Obes Metab. 2011;13:559–566.
   PubMed Web of Science ®Google Scholar
• 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;33:2349–2354.
   PubMed Web of Science ®Google Scholar
• Gier B, Matveyenko AV, Kirakossian D, et al. Chronic GLP-1 receptor activation by exendin-4 induces expansion of pancreatic duct glands in rats and accelerates formation of dysplastic lesions and chronic pancreatitis in the Kras(G12D) mouse model. Diabetes. 2012;61:1250–1262.
   PubMed Web of Science ®Google Scholar
• Nakamura T, Ito T, Uchida M, et al. PSCs and GLP-1R: occurrence in normal pancreas, acute/chronic pancreatitis and effect of their activation by a GLP-1R agonist. Lab Invest. 2014;94:63–78.
   Web of Science ®Google Scholar
• Busch SJ, Hoffmann P, Sahota P, et al. Studies in rodents with the dipeptidyl peptidase-4 inhibitor vildagliptin to evaluate possible drug-induced pancreatic histological changes that are predictive of pancreatitis and cancer development in man. Diabetes Obes Metab. 2013;15:72–76.
   PubMed Web of Science ®Google Scholar
• Ellenbroek JH, Tons HA, Westerouen Van Meeteren MJ, et al. Glucagon-like peptide-1 receptor agonist treatment reduces beta cell mass in normoglycaemic mice. Diabetologia. 2013;56:1980–1986.
   PubMed Web of Science ®Google Scholar
• Holst JJ. Pancreatic safety of GLP-1-based therapeutic agents: further insights from rodent studies? Diabetologia. 2013;56:1869–1872.
   PubMed Web of Science ®Google Scholar
• Faillie JL, Azoulay L, Patenaude V, et al. Incretin based drugs and risk of acute pancreatitis in patients with type 2 diabetes: cohort study. Bmj. 2014;348:g2780.
   PubMed Web of Science ®Google Scholar
• Li L, Shen J, Bala MM, et al. Incretin treatment and risk of pancreatitis in patients with type 2 diabetes mellitus: systematic review and meta-analysis of randomised and non-randomised studies. Bmj. 2014;348:g2366.
   PubMed Web of Science ®Google Scholar
• Ryder RE. The potential risks of pancreatitis and pancreatic cancer with GLP-1-based therapies are far outweighed by the proven and potential (cardiovascular) benefits. Diabet Med. 2013;30:1148–1155.
   PubMed Web of Science ®Google Scholar
• Hegedus L, Moses AC, Zdravkovic M, et al. GLP-1 and calcitonin concentration in humans: lack of evidence of calcitonin release from sequential screening in over 5000 subjects with type 2 diabetes or nondiabetic obese subjects treated with the human GLP-1 analog, liraglutide. J Clin Endocrinol Metab. 2011;96:853–860.
   PubMed Web of Science ®Google Scholar
• Nathan DM, Buse JB, Davidson MB, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203.
   PubMed Web of Science ®Google Scholar
• Garber AJ, Abrahamson MJ, Barzilay JI, et al. AACE comprehensive diabetes management algorithm 2013. Endocr Pract. 2013;19:327–336.
   PubMed Web of Science ®Google Scholar
• Inzucchi SE, Bergenstal RM, Buse JB, 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;35:1364–1379.
   PubMed Web of Science ®Google Scholar