Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Note: This list includes important publications related to incretin-based therapy, including some that are not cited in the activity “Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes.”

General Agency for Healthcare Research and Quality. National Healthcare Quality Report 2011. Rockville, MD: Agency for Healthcare Research and Quality; 2012. American Diabetes Association. Standards of medical care in diabetes—2013. Diabetes Care. 2013;36(Suppl 1):S11–S66. Arnolds S, Dellweg S, Clair J, et al. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. Diabetes Care. 2010;33:1509–1515. Campbell RK. Clarifying the role of incretin-based therapies in the treatment of type 2 diabetes mellitus. Clin Ther. 2011;33:511–527. Casagrande SS, Fradkin JE, Saydah SH, et al. The prevalence of meeting A1C, blood pressure, and LDL goals among people with diabetes, 1998–2010. Diabetes Care. 2013 Feb 15 [Epub ahead of print]. Centers for Disease Control and Prevention. National diabetes fact sheet: national estimates and general information on diabetes and prediabetes in the United States, 2011. Atlanta: Centers for Disease Control and Prevention, 2011. Cornell S. Differentiating among incretin therapies: a multiple-target approach to type 2 diabetes. J Clin Pharm Ther. 2012;37:510–524. Cramer JA. A systematic review of adherence with medications for diabetes. Diabetes Care. 2004;27:1218–1224. Davidson JA. Incorporating incretin-based therapies into clinical practice: differences between glucagon-like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors. Mayo Clin Proc. 2010;85(Suppl):S27–S37. Davies M, Pratley R, Hammer M, et al. Liraglutide improves treatment satisfaction in people with type 2 diabetes compared with sitagliptin, each as an add on to metformin. Diabet Med. 2011;28:333–337. DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am. 2004;88:787–835, ix.

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Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Drucker DJ. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol Endocrinol. 2003;17:161–171. 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. Egede LE, Gebregziabher M, Dismuke CE, et al. Medication nonadherence in diabetes: longitudinal effects on costs and potential cost savings from improvement. Diabetes Care. 2012;35:2533–2539 Elrick H, Stimmler L, Hlad CJ Jr, et al. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076–1082. Freeman JS. Role of the incretin pathway in the pathogenesis of type 2 diabetes mellitus. Cleve Clin J Med. 2009;76(Suppl 5):S12–S19. Gallwitz B. The evolving place of incretin-based therapies in type 2 diabetes. Pediatr Nephrol. 2010;25:1207–1217. 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. Gonzalez-Perez A, Schlienger RG, García Rodríguez LA. Acute pancreatitis in association with type 2 diabetes and antidiabetic drugs: a population-based cohort study. Diabetes Care. 2010;33:2580–2585. Hauber AB, Mohamed AF, Johnson FR, et al. Treatment preferences and medication adherence of people with type 2 diabetes using oral glucose-lowering agents. Diabet Med. 2009;26:416–424. Ho PM, Rumsfeld JS, Masoudi FA, et al. Effect of medication nonadherence on hospitalization and mortality among patients with diabetes mellitus. Arch Intern Med. 2006;166:1836–1841. Inkster B, Zammitt NN, Frier BM. Drug-induced hypoglycemia in type 2 diabetes. Expert Opin Drug Saf. 2012;11:597–614. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach. Diabetes Care. 2012;35:1364–1379. Kirkman MS, Briscoe VJ, Clark N, et al. Diabetes in older adults. Diabetes Care. 2012;35:2650–2664. Madsbad S, Dipeptidyl peptidase-4 (DPP-4) inhibitors are favourable to glucagon-like peptide-1 (GLP-1) agonists: no. Eur J Intern Med. 2012;23:132–136. IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Meier JJ, Nauck MA. Is the diminished incretin effect in type 2 diabetes just an epiphenomenon of impaired β-cell function? Diabetes. 2010;59:1117–1125. Mudaliar S, Henry RR. The incretin hormones: from scientific discovery to practical therapeutics. Diabetologia. 2012;55:1865–1868. Muscelli E, Mari A, Casolaro A, et al. Separate impact of obesity and glucose tolerance on the incretin effect in normal subjects and type 2 diabetic patients. Diabetes. 2008;57:1340–1348. 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. Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications. Am J Med. 2011;124(1 Suppl):S3–S18. Nauck MA, Homberger E, Siegel EG, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492–498. Nauck MA, Kleine N, Ørskov C, et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7-36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia. 1993;36:741–744. Nauck MA, Schmidt WE, Meier JJ. The incretin modulators – incretin mimetics (GLP-1 receptor agonists) and incretin enhancers (DPP-4 inhibitors). In: Mogensen CE, ed. Pharmacotherapy of Diabetes: New Developments: Improving Life and Prognosis for Diabetic Patients. New York, NY: Springer; 2007:111–141. Nauck M, Stöckmann F, Ebert R, et al. Reduced insulin effect in type 2 (non-insulindependent) diabetes. Diabetologia. 1986;29:46–52. Nauck MA, Vardarli I, Deacon CF, et al. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia. 2011;54:10–18. Neumiller JJ. Differential chemistry (structure), mechanism of action, and pharmacology of the GLP-1 receptor agonists and DPP-4 inhibitors. J Am Pharm Assoc. 2009;49(Suppl 1):S16–S29. Phillips LK, Prins JB. Update on incretin hormones. Ann N Y Acad Sci. 2011;1243:E55– E74.

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Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Pladevall M, Williams LK, Potts LA, et al. Clinical outcomes and adherence to medications measured by claims data in patients with diabetes. Diabetes Care. 2004;27:2800–2805. Pratley RE. Overview of glucagon-like peptide-1 analogs and dipeptidyl peptidase-4 inhibitors for type 2 diabetes. Medscape J Med. 2008;10:171. Pratley RE. GIP: an inconsequential incretin or not? Diabetes Care. 2010;33:1691– 1692. Pratley RE, Gilbert M. Targeting incretins in type 2 diabetes: role of GLP-1 receptor agonists and DPP-4 inhibitors. Rev Diabet Stud. 2008;5:73–94. Rubin RR. Adherence to pharmacologic therapy in patients with type 2 diabetes mellitus. Am J Med. 2005;118:27S–34S. 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 populationbased matched case-control study. JAMA Intern Med. 2013 Feb 25 [Epub ahead of print]. Sinha A, Rajan M, Hoerger T, et al. Costs and consequences associated with newer medications for glycemic control in type 2 diabetes. Diabetes Care. 2010;33:695–700. US Food and Drug Administration. Orange Book: Approved Drug Products with Therapeutic Equivalence Evaluations. Available at: http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. Accessed January 14, 2013. Yang L, He Z, Tang X, et al. Type 2 diabetes mellitus and the risk of acute pancreatitis: a meta-analysis. Eur J Gastroenterol Hepatol. 2013;25:225–231. GLP-1 Agonists General Aroda VR, DeYoung MB. Clinical implications of exenatide as a twice-daily or onceweekly therapy for type 2 diabetes. Postgrad Med. 2011;123:228–238. Balena R, Hensley IE, Miller S, et al. Combination therapy with GLP-1 receptor agonists and basal insulin: a systematic review of the literature. Diabetes Obes Metab. 2012 Oct 15 [Epub ahead of print]. Berlie H, Hurren KM, Pinelli NR. Glucagon-like peptide-1 receptor agonists as add-on therapy to basal insulin in patients with type 2 diabetes: a systematic review. Diabetes Metab Syndr Obes. 2012;5:165–174. IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Best JH, Boye KS, Rubin RR, et al. Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily. Diabet Med. 2009;26:722–728. Gallwitz B. Glucagon-like peptide-1 analogues for type 2 diabetes mellitus: current and emerging agents. Drugs. 2011;71:1675–1688. Garg SK. The role of basal insulin and glucagon-like peptide-1 agonists in the therapeutic management of type 2 diabetes—a comprehensive review. Diabetes Technol Ther. 2010;12:11–24. Hansen KB, Vilsbøll T, Knop FK. Incretin mimetics: a novel therapeutic option for patients with type 2 diabetes–a review. Diabetes Metab Syndr Obes. 2010;3:155–163. Lorber D. GLP-1 receptor agonists: effects on cardiovascular risk reduction. Cardiovasc Ther. 2012 Jul 30 [E-pub before print]. Montanya E. A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2012;13:1451–1467. Mundil D, Cameron-Vendrig A, Husain M. GLP-1 receptor agonists: a clinical perspective on cardiovascular effects. Diabetes Vasc Dis Res. 2012;9:95–108. Okerson T, Chilton RJ. The cardiovascular effects of GLP-1 receptor agonists. Cardiovasc Ther. 2012;30:e146–e155. Ridge T, Moretto T, MacConell L, et al. Comparison of safety and tolerability with continuous (exenatide once weekly) or intermittent (exenatide twice daily) GLP-1 receptor agonism in patients with type 2 diabetes. Diabetes Obes Metab. 2012;14:1097–1103. Tzefos M, Olin JL. Glucagon-like peptide-1 analog and insulin combination therapy in the management of adults with type 2 diabetes mellitus. Ann Pharmacother. 2010;44:1294–1300. Wilding JP, Hardy K. Glucagon-like peptide-1 analogues for type 2 diabetes. BMJ. 2011;342:d410. Exenatide Twice Daily Amylin Pharmaceuticals, Inc. Byetta® (exenatide injection) medication guide. December 2011. Available at: http://documents.byetta.com/Byetta_Medication_Guide.pdf. Accessed January 15, 2013. Amylin Pharmaceuticals, Inc. Byetta® (exenatide injection) 5 mcg pen user manual. December 2011. Available at: http://documents.byetta.com/Byetta5_User_Manual.pdf. IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Accessed January 15, 2013. Amylin Pharmaceuticals, Inc. Byetta® (exenatide injection) 10 mcg pen user manual. December 2011. Available at: http://documents.byetta.com/Byetta10_User_Manual.pdf. Accessed January 15, 2013. Amylin Pharmaceuticals, Inc. Quick start guide: a handy step-by-step guide on how to use the Byetta pen. December 2011. Available at: http://www.byetta.com/Content/pdf/BYETTA-quick-start.pdf. Accessed January 15, 2013. Best JH, Hoogwerf BJ, Herman WH, et al. Risk of cardiovascular disease events in patients with type 2 diabetes prescribed the glucagon-like peptide 1 (GLP-1) receptor agonist exenatide twice daily or other glucose-lowering therapies: a retrospective analysis of the LifeLink database. Diabetes Care. 2011;34:90–95. 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. Buse JB, Henry RR, Han J, et al; 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;27:2628–2635. Byetta® (exenatide) injection. Prescribing information. San Diego: Amylin Pharmaceuticals, Inc.; December 2011. 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. Fabunmi R, Nielsen LL, Quimbo R, et al. Patient characteristics, drug adherence patterns, and hypoglycemia costs for patients with type 2 diabetes mellitus newly initiated on exenatide or insulin glargine. Curr Med Res Opin. 2009;25:777–786. 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. 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.

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Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Misurski D, Lage MJ, Fabunmi R, et al. A comparison of costs among patients with type 2 diabetes mellitus who initiated therapy with exenatide or insulin glargine. Appl Health Econ Health Policy. 2009;7:245–254. Moretto TJ, Milton DR, Ridge TD, et al. Efficacy and tolerability of exenatide monotherapy over 24 weeks in antidiabetic drug-naive patients with type 2 diabetes: a randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2008;30:1448–1460. Nelson P, Poon T, Guan X, et al. The incretin mimetic exenatide as a monotherapy in patients with type 2 diabetes. Diabetes Technol Ther. 2007;9:317–326. Rosenstock J, Shenouda SK, Bergenstal RM, et al. Baseline factors associated with glycemic control and weight loss when exenatide twice daily is added to optimized insulin glargine in patients with type 2 diabetes. Diabetes Care. 2012;35:955–958. Tzefos M, Olin JL. Glucagon-like peptide-1 analog and insulin combination therapy in the management of adults with type 2 diabetes mellitus. Ann Pharmacother. 2010;44:1294–1300. Zander M, Madsbad S, Madsen JL. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet. 2002;359:824–830. Zinman B, Hoogwerf BJ, Durán García S, et al. The effect of adding exenatide to a thiazolidinedione in suboptimally controlled type 2 diabetes: a randomized trial. Ann Intern Med. 2007;30:477–485. Liraglutide Armstrong MJ, Houlihan DD, Rowe IA, et al. Safety and efficacy of liraglutide in patients with type 2 diabetes and elevated liver enzymes: individual patient data meta-analysis of the LEAD program. Aliment Pharmacol Ther. 2013;37:234–242. Barnett AH. The role of GLP-1 mimetics and basal insulin analogues in type 2 diabetes mellitus: guidance from studies of liraglutide. Diabetes Obes Metab. 2012;14:304–314. Blonde L, Montanya E. Comparison of liraglutide versus other incretin-related antihyperglycaemic agents. Diabetes Obes Metab. 2012;14(Suppl 2):20–32. Bode B. An overview of the pharmacokinetics, efficacy and safety of liraglutide. Diabetes Res Clin Pract. 2012;97:27–42. Buse JB, Rosenstock J, Sesti G, et al; LEAD-6 Study Group. Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomized, parallel-group, IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References multinational, open-label trial (LEAD-6). Lancet. 2009;374:39–47. DeVries JH, Bain SC, Rodbard HW, et al; Liraglutide-Detemir Study Group. 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. Garber A, Henry R, Ratner R, et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, paralleltreatment trial. Lancet. 2009;373:473–481. Garber A, Henry RR, Ratner R, et al. LEAD-3 (Mono) Study Group. Liraglutide, a oncedaily 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. Lane W, Weinrib S, Rappaport J. The effect of liraglutide added to U-500 insulin in patients with type 2 diabetes and high insulin requirements. Diabetes Technol Ther. 2011;13:592–595. Madsbad S, Schmitz O, Ranstam J, et al. Improved glycemic control with no weight increase in patients with type 2 diabetes after once-daily treatment with the long-acting glucagon-like peptide 1 analog liraglutide (NN2211): a 12-week, double-blind, randomized, controlled trial. Diabetes Care. 2004;27(6):1335–1342. Marre M, Shaw J, Brändle 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. Morrow L, Hompesch M, Guthrie H, et al. Co-administration of liraglutide with insulin detemir demonstrates additive pharmacodynamic effects with no pharmacokinetic interaction. Diabetes Obes Metab. 2011;13:75–80. Nauck MA. The design of the liraglutide clinical trial programme. Diabetes Obes Metab. 2012;14(Suppl 2):4–12. Nauck M, Frid A, Hermansen K, et al; 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;32:84–90. Novo Nordisk Inc. Victoza® (liraglutide [rDNA origin]) injection. Medication guide. Princeton: Novo Nordisk Inc.; January 2013.

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Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Novo Nordisk Inc. Understanding your Victoza® pen. September 2012. Available at: http://www.victoza.com/starting/using-your-pen.aspx. Accessed January 15, 2013. Pratley RE, Nauck M, Bailey T, et al; 1860-LIRA-DPP-4 Study Group. 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. Pratley R, Nauck M, Bailey T, et al; 1860-LIRA-DPP-4 Study Group. One year of liraglutide treatment offers sustained and more effective glycaemic control and weight reduction compared with sitagliptin, both in combination with metformin, in patients with type 2 diabetes: a randomised, parallel-group, open-label trial. Int J Clin Pract. 2011;65:397–407. Russell-Jones D, Vaag A, Schmitz O, et al; Liraglutide Effect and Action in Diabetes 5 (LEAD-5) met+SU Study Group. Liraglutide vs insulin glargine and placebo in combination with metformin and sulfonylurea therapy in type 2 diabetes mellitus (LEAD5 met+SU): a randomised controlled trial. Diabetologia. 2009;52:2046–2055. Victoza® (liraglutide [rDNA origin]) injection. Prescribing information. Princeton: Novo Nordisk Inc.; December 2012. Zinman B, Gerich J, Buse JB, et al; LEAD-4 Study Investigators. Efficacy and safety of the human GLP-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. Exenatide Once Weekly Amylin Pharmaceuticals, Inc. Dosing and administration of Bydureon™ diabetes medication. 2012. Available at: http://www.bydureonhcp.com/getting-patientsstarted/dosing-and-administration. Accessed January 15, 2013. Amylin Pharmaceuticals, Inc. Instructions for use: once-weekly Bydureon™ exenatide extended-release for injectable suspension. 2012. Available at: http://documents.bydureon.com/Bydureon_Patient_Instructions_Use.pdf. Accessed January 15, 2013. Bergenstal RM, Li Y, Booker Porter TK, et al. Exenatide once weekly improved glycaemic control, cardiometabolic risk factors and a composite index of an HbA1c < 7%, without weight gain or hypoglycaemia, over 52 weeks. Diabetes Obes Metab. 2013;15:264–271. Bergenstal RM, Wysham C, MacConell L, et al; DURATION-2 Study Group. Efficacy IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References 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. Best JH, Boye KS, Rubin RR, et al. Improved treatment satisfaction and weight-related quality of life with exenatide once weekly or twice daily. Diabet Med. 2009;26:722–728. Bischoff LA, Jabbour SA, Miller JL. Exenatide once weekly in type 2 diabetes mellitus. Expert Opin Pharmacother. 2011;12:1297–1303. Blevins T, Pullman J, Malloy J, 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;96:1301–1310. Buse JB, Drucker DJ, Taylor KL, et al; DURATION-1 Study Group. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care. 2010;33:1255–1261. 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. Bydureon™ (exenatide extended-release for injectable suspension). Prescribing information. San Diego: Amylin Pharmaceuticals, Inc.; January 2012. Diamant M, Van Gaal G, 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. Diamant M, Van Gaal L, 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. Drucker DJ, Buse JB, Taylor K, et al; DURATION-1 Study Group. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, openlabel, non-inferiority study. Lancet. 2008;372:1240–1250. Russell-Jones D, Cuddihy RM, Hanefeld M, et al; DURATION-4 Study Group. 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). Diabetes Care. 2012;35:252–258. Zinman B, Gerich J, Buse JB, et al; LEAD-4 Study Investigators. Efficacy and safety of the human GLP-1 analog liraglutide in combination with metformin and thiazolidinedione

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Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References in patients with type 2 diabetes (LEAD-4 Met+TZD). Diabetes Care. 2009;32:1224– 1230. Lixisenatide [Not approved for use in the United States when this document was prepared] Fonseca VA, Alvarado-Ruiz R, Raccah D, et al; EFC6018 GetGoal-Mono Study Investigators. Efficacy and safety of the once-daily GLP-1 receptor agonist lixisenatide in monotherapy: a randomized, double-blind, placebo-controlled trial in patients with type 2 diabetes (GetGoal-Mono). Diabetes Care. 2012;35:1225–1231. Horowitz M, Rayner CK, Jones KL. Mechanisms and clinical efficacy of lixisenatide for the management of type 2 diabetes. Adv Ther. 2013 Feb 13 [Epub ahead of print]. Kapitza C, Forst T, Coester HV, et al. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab. 2013 Jan 31 [Epub ahead of print]. Ratner RE, Rosenstock J, Boka G; DRI6012 Investigators. Dose-dependent effects of the once-daily GLP-1 receptor agonist lixisenatide in patients with type 2 diabetes inadequately controlled with metformin: a randomized, double-blind, placebo-controlled trial. Diabet Med. 2010;27:1024–1032. Sanofi. Once-daily Lyxumia® (lixisenatide) approved for treatment type 2 diabetes in Europe. Press release. February 4, 2013. Available at: http://en.sanofi.com/Images/31826_20130204_LYXUMIA-EC-APPROVAL_en.pdf. Accessed March 6, 2013. Sanofi. Sanofi New Drug Application for lixisenatide accepted for review by FDA. Press release. February 19, 2013. Available at: http://en.sanofi.com/Images/31904_20130219_LIXISENATIDE_en.pdf. Accessed March 6, 2013. Seino Y, Min KW, Niemoeller E, et al; EFC10887 GETGOAL-L Asia Study Investigators. 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.

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Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References DPP-4 Inhibitors General Byrd JS, Minor DS, Elsayed R, et al. DPP-4 inhibitors and angioedema: a cause for concern? Ann Allergy Asthma Immunol. 2011;106:436–438. Deacon CF. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes Metab. 2011;13:7–18. Dicker D. DPP-4 inhibitors: impact on glycemic control and cardiovascular risk factors. Diabetes Care. 2011;34(Suppl 2):S276–S278. Jose T, Inzucchi SE. Cardiovascular effects of the DPP-4 inhibitors. Diabetes Vasc Dis Res. 2012;9:109–116. Monami M, Ahrén 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. Monami M, Dicembrini I, Martelli D, et al. Safety of dipeptidyl peptidase-4 inhibitors: a meta-analysis of randomized clinical trials. Curr Med Res Opin. 2011;27(Suppl 3):57– 64. Patil HR, Al Badarin FJ, Al Shami HA, et al. Meta-analysis of effect of dipeptidyl peptidase-4 inhibitors on cardiovascular risk in type 2 diabetes mellitus. Am J Cardiol. 2012;110:826–833. Scheen AJ. Dipeptidylpeptidase-4 inhibitors (gliptins): focus on drug-drug interactions. Clin Pharmacokinet. 2010;49:573–588. Scheen AJ, Charpentier G, Östgren CJ, et al. Efficacy 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. Waeber B, Buclin T, Grouzmann E. [Angioedema during ACE and DPP-4 inhibition]. Rev Med Suisse. 2010;6:28–31. Sitagliptin 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.

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Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Aschner P, Katzeff HL, Guo H, et al; Sitagliptin Study 049 Group. Efficacy and safety of monotherapy of sitagliptin compared with metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2010;12:252–261. Charbonnel B, Karasik A, Liu J, et al; 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;29:2638–2643. Derosa G, Maffioli P, Salvadeo SA, et al. Effects of sitagliptin or metformin added to pioglitazone monotherapy in poorly controlled type 2 diabetes mellitus patients. Metabolism. 2010;59:887–895. Engel SS, Williams-Herman DE, Golm GT, et al. Sitagliptin: review of preclinical and clinical data regarding incidence of pancreatitis. Int J Clin Pract. 2010;64:984–990. Goldstein BJ, Feinglos MN, Lunceford JK, et al. Sitagliptin 036 Study Group. 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;30:1979–1987. Hermansen K, Kipnes M, Luo E, et al; Sitagliptin Study 035 Group. 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. Hollander P, Raslova K, Skjøth TV, et al. Efficacy and safety of insulin detemir once daily in combination with sitagliptin and metformin: the TRANSITION randomized controlled trial. Diabetes Obes Metab. 2011;13:268–275. Janumet® (sitagliptin/metformin HCl) tablets. Prescribing information. Whitehouse Station, NJ: Merck & Co., Inc.; April 2012. Janumet® XR (sitagliptin and metformin HCl extended-release) tablets. Prescribing information. Whitehouse Station, NJ: Merck & Co., Inc.; April 2012. Januvia® (sitagliptin) tablets. Prescribing information. Whitehouse Station, NJ: Merck & Co., Inc.; April 2012. Juvisync™ (sitagliptin and simvastatin) tablets. Prescribing information. Whitehouse Station, NJ: Merck & Co., Inc.; October 2012. Nauck MA, Meininger G, Sheng D, et al; Sitagliptin Study 024 Group. 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 IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205. Pérez-Monteverde A, Seck T, Xu L, et al. Efficacy and safety of sitagliptin and the fixeddose combination of sitagliptin and metformin vs. pioglitazone in drug-naïve patients with type 2 diabetes. Int J Clin Pract. 2011;65:930–938. 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. Raz I, Hanefeld M, Xu L, et al; Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia. 2006;49:2564–2571. Rosenstock J, Brazg R, Andryuk PJ, et al; 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, doubleblind, placebo-controlled, parallel-group study. Clin Ther. 2006;28:1556–1568. Vilsbøll T, Rosenstock J, Yki-Järvinen 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. 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. Williams-Herman D, Engel SS, Round E, 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 Apr 22;10:7. 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. Williams-Herman D, Xu L, Teng R, et al. Effect of initial combination therapy with sitagliptin and metformin on β-cell function in patients with type 2 diabetes. Diabetes Obes Metab. 2012;14:67–76. Saxagliptin Barnett AH, Charbonnel B, Donovan M, et al; CV181-057 Investigators. 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– IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References 523. Chacra AR, Tan GH, Apanovich A, et al; 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 randomized controlled trial. Int J Clin Pract. 2009;63:1395–1406. DeFronzo RA, Hissa MN, Garber AJ, et al; 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;32:1649–1655. Frederich R, Alexander JH, Fiedorek FT, et al. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Postgrad Med. 2010;122:16–27. Göke B, Gallwitz B, Eriksson J, et al; D1680C00001 Investigators. Saxagliptin is noninferior 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. Hollander P, Li J, Allen E, et al; CV181-013 Investigators. 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– 4819. Jadzinsky M, Pfützner A, Paz-Pacheco E, et al; CV-181-039 Investigators. 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. Kombiglyze™ XR (saxagliptin and metformin HCl extended-release) tablets. Prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; March 2012. Neumiller JJ, Campbell RK. Saxagliptin: a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. Am J Health-Syst Pharm. 2010;67:1515–1525. 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. Onglyza® (saxagliptin) tablets. Prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; December 2011. Rosenstock J, Aguilar-Salinas C, Klein E, et al; CV181-011 Study Investigators. Effect IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References of saxagliptin monotherapy in treatment-naïve patients with type 2 diabetes. Curr Med Res Opin. 2009;25:2401–2411. Linagliptin Del Prato S, Barnett AH, Huisman H, et al. Effect of linagliptin monotherapy on glycaemic control and markers of β-cell function in patients with inadequately controlled type 2 diabetes: a randomized controlled trial. Diabetes Obes Metab. 2011;13:258–267. Forst T, Uhlig-Laske B, Ring A, et al. Linagliptin (BI 1356), a potent and selective DPP-4 inhibitor, is safe and efficacious in combination with metformin in patients with inadequately controlled type 2 diabetes. Diabet Med. 2010;27:1409–1419. Gallwitz B. Linagliptin—a novel dipeptidyl peptidase inhibitor for type 2 diabetes therapy. Clin Med Insights Endocrinol Diabetes. 2012;5:1–11. 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. 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. Gomis R, Owens DR, Taskinen MR, et al. Long-term safety and efficacy of linagliptin as monotherapy or in combination with other oral glucose-lowering agents in 2121 subjects with type 2 diabetes: up to 2 years exposure in 24-week phase III trials followed by a 78-week open-label extension. Int J Clin Pract. 2012;66:731–740. Haak T. Initial combination with linagliptin and metformin in newly diagnosed type 2 diabetes and severe hyperglycemia. Adv Ther. 2012;29:1005–1015. 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, placebocontrolled study. Diabetes Obes Metab. 2012;14:565–574. Jentadueto™ (linagliptin and metformin hydrochloride) tablets. Prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; January 2012. McGill JB. Linagliptin for type 2 diabetes mellitus: a review of the pivotal clinical trials. Ther Adv Endocrinol Metab. 2012;3:113–124. 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 IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References sulphonylurea: a 24-week randomized study. Diabet Med. 2011;28:1352–1361. Taskinen MR, Rosenstock J, Tamminen I, et al. Safety and efficacy of linagliptin as addon therapy to metformin in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Diabetes Obes Metab. 2011;13:65–74. Tradjenta® (linagliptin) tablets. Prescribing information. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; September 2012. von Eynatten M, Emser A, Cooper ME, et al. Renal safety and outcomes with linagliptin: meta-analysis of individual data for 5466 patients with type 2 diabetes. J Am Soc Nephrol. 2012;23:218A. Abstract TH-PO530. Yki-Järvinen H, Rosenstock J, Durán-Garcia S, et al. Long-term safety and efficacy of linagliptin as add-on therapy to basal insulin in patients with type 2 diabetes: a 52-week randomised, placebo-controlled trial. Oral Presentation 6. European Association for the Study of Diabetes 48th Annual Meeting; Berlin; October 1–5, 2012. Alogliptin Andukuri R, Drincic A, Rendell M. Alogliptin: a new addition to the class of DPP-4 inhibitors. Diabetes Metab Syndr Obes 2009;2:117–126. Bosi E, Ellis GC, Wilson CA, et al. Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study. Diabetes Obes Metab. 2011;13:1088–1096. DeFronzo RA, Fleck PR, Wilson CA, et al; Alogliptin Study 010 Group. 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;31:2315–2317. Nauck MA, Ellis GC, Fleck PR, et al; Alogliptin Study 008 Group. 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. Nesina™ (alogliptin) tablets. Prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; January 2013. Kazano™ (alogliptin and metformin HCl) tablets for oral administration. Prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; January 2013.

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Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References Oseni™ (alogliptin and pioglitazone) tablets. Prescribing information. Deerfield, IL: Takeda Pharmaceuticals America, Inc.; January 2013. Pratley RE, Kipnes MS, Fleck PR, et al; Alogliptin Study 007 Group. 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. Pratley RE, Reusch JE, Fleck PR, et al; Alogliptin Study 009 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor alogliptin added to pioglitazone in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Curr Med Res Opin. 2009;25:2361–2371. Rendell M, Drincic A, Andukuri R. Alogliptin benzoate for the treatment of type 2 diabetes. Expert Opin Pharmacother. 2012;13:553–563. Rosenstock J, Inzucchi SE, Seufert SE, et al. Initial combination therapy with alogliptin and pioglitazone in drug-naïve patients with type 2 diabetes. Diabetes Care. 2010;33:2406–2408. Rosenstock J, Rendell MS, Gross JL, et al. Alogliptin added to insulin therapy in patients with type 2 diabetes reduces HbA1c without causing weight gain or increased hypoglycaemia. Diabetes Obes Metab. 2009;11:1145–1152. Vildagliptin [Not approved for use in the United States] Blüher M, Kurz I, Dannenmaier S, et al. Efficacy and safety of vildagliptin in clinical practice—results of the PROVIL study. World J Diabetes. 2012;3:161–169. Cai L, Cai Y, Lu ZJ, et al. The efficacy and safety of vildagliptin in patients with type 2 diabetes: a meta-analysis of randomized clinical trials. J Clin Pham Ther. 2012;37:386– 398. Dejager S, Schweizer A, Foley JE. Evidence to support the use of vildagliptin monotherapy in the treatment of type 2 diabetes mellitus. Vasc Health Risk Manage. 2012;8:339–348. Eucreas (vildagliptin 80 mg/metformin hydrochloride 850 mg film-coated tablets). Summary of product characteristics. London: European Medicines Agency; March 2012. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000807/WC500030594.pdf. Accessed January 4, 2013. Galvus (vildagliptin 50 mg tablets). Summary of product characteristics. London: European Medicines Agency; June 2012. Available at: IBT-ETS-T2DM_Refs Scherer Clinical Communications 5/30/13

Incretin-Based Therapy: Evolving Treatment Strategies for Type 2 Diabetes References http://www.ema.europa.eu/docs/en_GB/document_library/EPAR__Product_Information/human/000771/WC500020327.pdf. Accessed January 4, 2013. Ligueros-Saylan M, Foley JE, Schweizer A, et al. An assessment of adverse effects of vildagliptin versus 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. Schweizer A, Dejager S, Foley JE. Impact of insulin resistance, body mass index, disease duration, and duration of metformin use on the efficacy of vildagliptin. Diabetes Ther. 2012;3:8.

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