Beyond metformin: Safety considerations in the decision-making process for selecting a second medication for type 2 diabetes management: Reflections from a diabetes care editors' expert forum

Diabetes Care

Volumn 37, Issue 9, 2014, Pages 2647-2659

  Cefalu, William T ^a   Buse, John B ^b   Del Prato, Stefano ^c   Home, Philip D ^d   LeRoith, Derek ^e   Nauck, Michael A ^f   Raz, Itamar ^g   Rosenstock, Julio ^h   Riddle, Matthew C ⁱ  

^a PENNINGTON BIOMEDICAL RESEARCH CENTER   (United States)

^b UNIVERSITY OF NORTH CAROLINA SCHOOL OF MEDICINE   (United States)

^c UNIVERSITY OF PISA   (Italy)

^d NEWCASTLE UNIVERSITY   (United Kingdom)

^e MOUNT SINAI SCHOOL OF MEDICINE   (United States)

^f DIABETESZENTRUM BAD LAUTERBERG   (Germany)

^g HADASSAH HEBREW UNIVERSITY MEDICAL CENTER   (Israel)

^h UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

ⁱ OREGON HEALTH AND SCIENCE UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CANAGLIFLOZIN; DAPAGLIFLOZIN; GLITAZONE DERIVATIVE; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; INCRETIN; INSULIN; INSULIN GLARGINE; METFORMIN; PIOGLITAZONE; PLACEBO; ROSIGLITAZONE; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SULFONYLUREA DERIVATIVE; TROGLITAZONE; 2,4 THIAZOLIDINEDIONE DERIVATIVE; ANTIDIABETIC AGENT; DIPEPTIDYL PEPTIDASE IV INHIBITOR; GLUCAGON RECEPTOR; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR;

ACUTE PANCREATITIS; ANTIDIABETIC ACTIVITY; ARTICLE; BLADDER CANCER; COMBINATION CHEMOTHERAPY; DIARRHEA; DOSE RESPONSE; DRUG CHOICE; DRUG DOSE TITRATION; DRUG EFFICACY; DRUG FORMULATION; DRUG INDICATION; DRUG INFORMATION; DRUG INTERMITTENT THERAPY; DRUG MEGADOSE; DRUG SAFETY; DRUG WITHDRAWAL; GASTROINTESTINAL DISEASE; GLYCEMIC CONTROL; HEART FAILURE; HUMAN; HYPOGLYCEMIA; HYPOTENSION; INJECTION SITE REACTION; LIVER TOXICITY; MEDICAL DECISION MAKING; MONOTHERAPY; NAUSEA; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; PANCREAS CANCER; PATIENT EDUCATION; PERSONALIZED MEDICINE; POSITIONAL DIZZINESS; THYROID ADENOMA; THYROID HYPERPLASIA; THYROID MEDULLARY CARCINOMA; URINARY TRACT INFECTION; VAGINA MYCOSIS; VOMITING; WEIGHT GAIN; AGONISTS; DIABETES MELLITUS, TYPE 2; DISEASE MANAGEMENT; EXPERT WITNESS; PATIENT CARE;

DIABETES MELLITUS, TYPE 2; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DISEASE MANAGEMENT; EXPERT TESTIMONY; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; METFORMIN; PATIENT-CENTERED CARE; RECEPTORS, GLUCAGON; SULFONYLUREA COMPOUNDS; THIAZOLIDINEDIONES;

EID: 84906711873     PISSN: 01495992     EISSN: 19355548     Source Type: Journal    
DOI: 10.2337/dc14-1395     Document Type: Article

References (146)

1. Inzucchi SE, Bergenstal RM, Buse JB, et al.; American Diabetes Association (ADA); European Association for the Study of Diabetes (EASD). 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
2. Garber AJ, Abrahamson MJ, Barzilay JI, et al.; American Association of Clinical Endocrinologists. AACE comprehensive diabetes management algorithm 2013. Endocr Pract 2013;19: 327-336
3. Home P, Riddle M, Cefalu WT, et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges? Diabetes Care 2014;37: 1499-1508
4. Zilov AV, Wenying Y, Gonzalez-Galvez G, et al. Prevalence of complications of diabetes in people with type 2 diabetes: data from Asia, Europe and Latin America from the A1chieve study. Diabetes 2011;60(Suppl. 1):A656
5. Horvath K, Jeitler K, Berghold A, et al. Longacting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus. Cochrane Database Syst Rev 2007;2:CD005613
6. Siebenhofer A, Plank J, Berghold A, et al. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. Cochrane Database Syst Rev 2006;2: CD003287
7. Holman RR, Thorne KI, Farmer AJ, et al.; 4-T Study Group. Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes. N Engl J Med 2007;357:1716-1730
8. Gamble JM, Simpson SH, Eurich DT, Majumdar SR, Johnson JA. Insulin use and increased risk of mortality in type 2 diabetes: A cohort study. Diabetes Obes Metab 2010;12:47-53
9. Gerstein HC, Bosch J, Dagenais GR, et al.; ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med 2012;367:319-328
10. Mellbin LG, Rydén L, Riddle MC, et al.; ORIGIN Trial Investigators. Does hypoglycaemia increase the risk of cardiovascular events? A report from the ORIGIN trial. Eur Heart J 2013;34: 3137-3144
11. Yang YX, Hennessy S, Lewis JD. Insulin therapy and colorectal cancer risk among type 2 diabetes mellitus patients. Gastroenterology 2004;127:1044-1050
12. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006;29:254-258
13. Currie CJ, Poole CD, Gale EA. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 2009;52:1766-1777
14. Kramer CK, Zinman B, Retnakaran R. Shortterm intensive insulin therapy in type 2 diabetes mellitus: A systematic review and meta-analysis. Lancet Diabetes Endocrinol 2013;1:28-34
15. Lebovitz HE, Feinglos MN. Sulfonylurea drugs: mechanism of antidiabetic action and therapeutic usefulness. Diabetes Care 1978;1: 189-198
16. ReavenGM. Effect of glipizide treatment on various aspects of glucose, insulin, and lipid metabolism in patients with noninsulin-dependent diabetes mellitus. Am J Med 1983;75:8-14
17. Lebovitz HE. Clinical utility of oral hypoglycemic agents in the management of patients with noninsulin-dependent diabetes mellitus. Am J Med 1983;75(Suppl. 5B):94-99
18. Kennedy DL, Piper JM, Baum C. Trends in use of oral hypoglycemic agents 1964-1986. Diabetes Care 1988;11:558-562
19. Melander A, Lebovitz HE, Faber OK. Sulfonylureas. Why, which, and how? Diabetes Care 1990;13(Suppl. 3):18-25
20. Bryan J, Crane A, Vila-Carriles WH, Babenko AP, Aguilar-Bryan L. Insulin secretagogues, sulfonylurea receptors and K(ATP) channels. Curr Pharm Des 2005;11:2699-2716
21. Desai NR, Shrank WH, Fischer MA, et al. Patterns of medication initiation in newly diagnosed diabetes mellitus: quality and cost implications. Am J Med 2012;125:e1-e7
22. ZellerM, Danchin N, Simon D, et al.; French Registry of Acute ST-Elevation and Non-STElevation Myocardial Infarction investigators. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab 2010;95:4993-5002
23. Goldner MG, Knatterud GL, Prout TE. Effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes Clinical implications of UGDP results. JAMA 1971;218:1400-1410
24. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): Prospective observational study. BMJ 2000;321:412-419
25. Riddle MC. More reasons to say goodbye to glyburide. J Clin Endocrinol Metab 2010;95: 4867-4870
26. Lee T-M, Chou T-F. Impairment of myocardial protection in type 2 diabetic patients. J Clin Endocrinol Metab 2003;88:531-537
27. MonamiM, Luzzi C, Lamanna C, et al. Threeyear mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin. Diabetes Metab Res Rev 2006; 22:477-482
28. Holstein A, Plaschke A, Egberts E-H. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Metab Res Rev 2001;17:467-473
29. Hirst JA, Farmer AJ, Dyar A, Lung TWC, Stevens RJ. Estimating the effect of sulfonylurea on HbA1c in diabetes: A systematic review and meta-analysis. Diabetologia 2013;56:973-984
30. Zhang Y, McCoy RG, Mason JE, Smith SA, Shah ND, Denton BT. Second-line agents for glycemic control for type 2 diabetes: Are newer agents better? Diabetes Care 2014;37:1338-1345
31. Canaglifozin (Invokana) for type 2 diabetes. Med Lett Drugs Ther 2013;55:37-39
32. Campbell IW. Comparing the actions of older and newer therapies on body weight: To what extent should these effects guide the selection of antidiabetic therapy? Int J Clin Pract 2010;64:791-801
33. Cleveland JC Jr, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral sulfonylurea hypoglycemic agents prevent ischemic preconditioning in human myocardium. Two paradoxes revisited. Circulation 1997;96:29-32
34. University Group Diabetes Program. A study of the effects of hypoglycemia agents on vascular complications in patients with adult-onset diabetes. Diabetes 1970;19(Suppl. 2):747-830
35. American Diabetes Association. American diabetes association policy statement: The UGDP controversy. Diabetes Care 1979;2:1-3
36. Rytter L, Troelsen S, Beck-Nielsen H. Prevalence and mortality of acute myocardial infarction in patients with diabetes. Diabetes Care 1985;8:230-234
37. Aronow WS, Ahn C. Incidence of new coronary events in older persons with diabetes mellitus and prior myocardial infarction treated with sulfonylureas, insulin, metformin, and diet alone. Am J Cardiol 2001;88:556-557
38. Danchin N, Charpentier G, Ledru F, et al. Role of previous treatment with sulfonylureas in diabetic patients with acute myocardial infarction: results from a nationwide French registry. Diabetes Metab Res Rev 2005;21:143-149
39. Halkin A, Roth A, Jonas M, Behar S. Sulfonylureas are not associated with increased mortality in diabetics treated with thrombolysis for acute myocardial infarction. J Thromb Thrombolysis 2001;12:177-184
40. Davis TM, Parsons RW, Broadhurst RJ, Hobbs MS, Jamrozik K. Arrhythmias and mortality after myocardial infarction in diabetic patients. Relationship to diabetes treatment. Diabetes Care 1998;21:637-640
41. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853
42. Patel A, MacMahon S, Chalmers J, et al.; ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-2572
43. Home PD, Pocock SJ, Beck-Nielsen H, et al.; RECORD Study Team. Rosiglitazone Evaluated for Cardiovascular Outcomes in Oral Agent Combination Therapy for Type 2 Diabetes (RECORD): A multicentre, randomised, open-label trial. Lancet 2009;373:2125-2135
44. Kahn SE, Haffner SM, Heise MA, et al.; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-2443
45. Monami M, Genovese S, Mannucci E. Cardiovascular safety of sulfonylureas: A metaanalysis of randomized clinical trials. Diabetes Obes Metab 2013;15:938-953
46. Nagendran J, Oudit GY, Bakal JA, Light PE, Dyck JRB, McAlister FA. Are users of sulphonylureas at the time of an acute coronary syndrome at risk of poorer outcomes? Diabetes Obes Metab 2013;15:1022-1028
47. Hirsch I. First, do no harm. Clin Diabetes 2000;18:97-99
48. Hannele Y-J. Thiazolidinediones. N Engl J Med 2004;351:1106-1118
49. Mazzone T, Meyer PM, Feinstein SB, et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: A randomized trial. JAMA 2006;296: 2572-2581
50. Hanefeld M, Pfützner A, Forst T, Lübben G. Glycemic control and treatment failure with pioglitazone versus glibenclamide in type 2 diabetes mellitus: A 42-month, open-label, observational, primary care study. Curr Med Res Opin 2006;22:1211-1215
51. Tan MH, Baksi A, Krahulec B, et al.; GLAL Study Group. Comparison of pioglitazone and gliclazide in sustaining glycemic control over 2 years in patients with type 2 diabetes. Diabetes Care 2005;28:544-550
52. Nissen SE, Nicholls SJ, Wolski K, et al.; PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: The PERISCOPE randomized controlled trial. JAMA 2008;299:1561-1573
53. U.S. Food and Drug Administration. Rezulin to be withdrawn from the market [press release] March 21, 2000. Available from http:// www.fda.gov/ohrms/dockets/ac/00/backgrd/ 3634b1a-tab6c.htm. Accessed 19 November 2013
54. U.S. Food and Drug Administration. FDA Drug Safety Communication: updated risk evaluation and mitigation strategy (REMS) to restrict access to rosiglitazone-containing medicines including Avandia, Avandamet, and Avandaryl. May 18, 2011. Available from http://www.fda .gov/Drugs/DrugSafety/ucm255005.htm. Accessed 19 November 2013
55. Mahaffey KW, Hafley G, Sickerson S, et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J 2013; 166:240-249.e1
56. Tucker ME. FDA lifts rosiglitazone prescribing restrictions. Medscape Medical News. 25 November 2013. Available from http://www .medscape.com/ viewarticle/814964. Accessed 17 February 2014
57. Dormandy JA, Charbonnel B, Eckland DJA, et al.; PROactive Investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive study: A randomised controlled trial. Lancet 2005; 366:1279-1289
58. Takeda Pharmaceuticals America. Actos Prescribing Information. Deerfield, Ill., Takeda Pharmaceuticals America, 2013
59. GlaxoSmithKline. Avandia Prescribing Information. Research Triangle Park, NC, GlaxoSmithKline, 2008
60. Kahn SE, Zinman B, Lachin JM, et al.; Diabetes Outcome Progression Trial (ADOPT) Study Group. Rosiglitazone-associated fractures in type 2 diabetes: An analysis from A Diabetes Outcome Progression Trial (ADOPT). Diabetes Care 2008;31:845-851
61. Aubert RE, Herrera V, Chen W, Haffner SM, Pendergrass M. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab 2010;12: 716-721
62. Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in patients with prediabetes and type 2 diabetes given thiazolidinediones: A meta-analysis of randomised clinical trials. Lancet 2007;370: 1129-1136
63. Idris I, Warren G, Donnelly R. Association between thiazolidinedione treatment and risk of macular edema among patients with type 2 diabetes. Arch Intern Med 2012;172:1005-1011
64. Ambrosius WT, Danis RP, Goff DC Jr, et al.; ACCORD Study Group. Lack of association between thiazolidinediones and macular edema in type 2 diabetes: The ACCORD eye substudy. Arch Ophthalmol 2010;128:312-318
65. Sanyal AJ, Chalasani N, Kowdley KV, et al.; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010;362:1675-1685
66. Cohen SM. Effects of PPARgamma and combined agonists on the urinary tract of rats and other species. Toxicol Sci 2005;87:322-327
67. Lewis JD, Ferrara A, Peng T, et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: Interim report of a longitudinal cohort study. Diabetes Care 2011;34:916-922
68. Lewis JD, Strom BL, Bilker W, et al. Cohort study of pioglitazone and bladder cancer in patients with diabetes: fourth interim analysis (8- year) report with data from January 1997 to December 31, 2010 [Online Report, 2012]. Available from http://general.takedapharm .com/Trial-Disclosure/01-03-TL-OPI- 524-8-year- Interim-Report.pdf. Accessed 13 March 2014
69. Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:153-165
70. 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
71. Nauck MA. Incretin-based therapies for type 2 diabetes mellitus: Properties, functions, and clinical implications. Am J Med 2011;124 (Suppl.):S3-S18
72. Deacon CF. Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab 2007;9(Suppl. 1):23-31
73. Cobble M. Differentiating among incretinbased therapies in the management of patients with type 2 diabetes mellitus. Diabetol Metab Syndr 2012;4:8
74. Scirica BM, Bhatt DL, Braunwald E, et al.; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med 2013;369:1317-1326
75. White WB, Cannon CP, Heller SR, et al.; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med 2013;369:1327-1335
76. Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: An algorithm for glycemic control. Endocr Pract 2009;15:540-559
77. Garber A, Henry R, Ratner R, et al.; LEAD-3 (Mono) Study Group. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): A randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 2009;373: 473-481
78. 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
79. 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 randomised, parallel-group, multinational, open-label trial (LEAD-6). Lancet 2009; 374:39-47
80. 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
81. 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, open-label, non-inferiority study. Lancet 2008;372:1240-1250
82. 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;10:7
83. Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch CL. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database Syst Rev 2008;2:CD006739
84. Rosenstock J, Sankoh S, List JF. Glucoselowering activity of the dipeptidyl peptidase-4 inhibitor saxagliptin in drug-naive patients with type 2 diabetes. Diabetes Obes Metab 2008;10: 376-386
85. 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, parallelgroup study. Clin Ther 2008;30:1448-1460
86. Nelson P, Poon T, Guan X, Schnabel C, Wintle M, Fineman M. The incretin mimetic exenatide as a monotherapy in patients with type 2 diabetes. Diabetes Technol Ther 2007;9:317-326
87. Hanefeld M, Herman GA, Wu M, Mickel C, Sanchez M, Stein PP; Sitagliptin Study 014 Investigators. Once-daily sitagliptin, a dipeptidyl peptidase-4 inhibitor, for the treatment of patients with type 2 diabetes. Curr Med Res Opin 2007;23:1329-1339
88. Scott R, Wu M, Sanchez M, Stein P. Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes. Int J Clin Pract 2007;61:171-180
89. 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
90. Del Prato S, Barnett AH, Huisman H, Neubacher D, Woerle HJ, Dugi KA. Effect of linagliptin monotherapy on glycaemic control and markers of b-cell function in patients with inadequately controlled type 2 diabetes: A randomized controlled trial. Diabetes Obes Metab 2011;13:258-267
91. Raz I, Hanefeld M, Xu L, Caria C, Williams- Herman D, Khatami H; 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
92. Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; 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
93. 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;146:477-485
94. Zinman B, Gerich J, Buse JB, et al.; LEAD-4 Study Investigators. 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 Met1TZD). Diabetes Care 2009;32: 1224-1230
95. 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
96. Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R; CV181-040 Investigators. Saxagliptin added to a submaximal dose of sulphonylurea improves glycaemic control compared with uptitration of sulphonylurea in patients with type 2 diabetes: A randomised controlled trial. Int J Clin Pract 2009;63:1395-1406
97. Charbonnel B, Karasik A, Liu J, Wu M, Meininger G; Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29:2638-2643
98. DeFronzo RA, Ratner RE, Han J, Kim DD, Fineman MS, Baron AD. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005;28: 1092-1100
99. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD; Exenatide-113 Clinical Study Group. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylureatreated patients with type 2 diabetes. Diabetes Care 2004;27:2628-2635
100. Nauck MA. A critical analysis of the clinical use of incretin-based therapies: The benefits by far outweigh the potential risks. Diabetes Care 2013;36:2126-2132
101. Butler PC, Elashoff M, Elashoff R, Gale EAM. A critical analysis of the clinical use of incretin-based therapies: Are the GLP-1 therapies safe? Diabetes Care 2013;36:2118-2125
102. Green JB, Bethel MA, Paul SK, et al. Rationale, design, and organization of a randomized, controlled Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) in patients with type 2 diabetes and established cardiovascular disease. Am Heart J 2013;166:983-989.e7
103. Rosenstock J, Marx N, Kahn SE, et al. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab Vasc Dis Res 2013;10:289-301
104. Nachnani JS, Bulchandani DG, Nookala A, et al. Biochemical and histological effects of exendin-4 (exenatide) on the rat pancreas. Diabetologia 2010;53:153-159
105. Gier B, Matveyenko AV, Kirakossian D, Dawson D, Dry SM, Butler PC. 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
106. Nyborg NC, Mølck AM, Madsen LW, Knudsen LB. The human GLP-1 analog liraglutide and the pancreas: Evidence for the absence of structural pancreatic changes in three species. Diabetes 2012;61:1243-1249
107. Matveyenko AV, Dry S, Cox HI, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: Interactions with metformin. Diabetes 2009; 58:1604-1615
108. Ahmad SR, Swann J. Exenatide and rare adverse events. N Engl J Med 2008;358:1970- 1971; discussion 1971-1972
109. Tatarkiewicz K, Smith PA, Sablan EJ, et al. Exenatide does not evoke pancreatitis and attenuates chemically induced pancreatitis in normal and diabetic rodents. Am J Physiol Endocrinol Metab 2010;299:E1076-E1086
110. Koehler JA, Baggio LL, Lamont BJ, Ali S, Drucker DJ. Glucagon-like peptide-1 receptor activation modulates pancreatitis-associated gene expression but does not modify the susceptibility to experimental pancreatitis in mice. Diabetes 2009;58:2148-2161
111. Parks M, Rosebraugh C. Weighing risks and benefits of liraglutidedthe FDA's review of a new antidiabetic therapy. N Engl J Med 2010;362:774-777
112. 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
113. Dore DD, Seeger JD, Arnold Chan K. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide. Curr Med Res Opin 2009; 25:1019-1027
114. 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
115. Wenten M, Gaebler JA, Hussein M, et al. Relative risk of acute pancreatitis in initiators of exenatide twice daily compared with other antidiabetic medication: A follow-up study. Diabet Med 2012;29:1412-1418
116. Pendergrass M, Chen W. Association between diabetes, exenatide, sitagliptin and acute pancreatitis. Diabetes 2010;59(Suppl. 1):A160
117. Elashoff M, Matveyenko AV, Gier B, Elashoff R, Butler PC. Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide- 1-based therapies. Gastroenterology 2011;141: 150-156
118. Singh S, Chang H-Y, Richards TM, Weiner JP, Clark JM, Segal JB. 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
119. Steinberg W, Rosenstock J, De Vries H, Bloch Thomsen A, Svendsen CB, Wadden TA. Elevated serum lipase activity in adults with type 2 diabetes and no gastrointestinal symptoms. Gastroenterology 2012;142(Suppl. 1): S93-S94
120. Cefalu WT, Rosenstock J, Henry RR, Riddle M. Signals and noise in drug safety analyses: The incretin therapy debate provides the rationale for revamping epidemiologic pharmacovigilance. Diabetes Care 2013;36:1804-1806
121. Butler AE, Campbell-Thompson M, Gurlo T, Dawson DW, Atkinson M, Butler PC. 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
122. Bonner-Weir S, In't Veld PA, Weir GC. Reanalysis of study of pancreatic effects of incretin therapy: methodological deficiencies. Diabetes Obes Metab. 8 January 2014 [Epub ahead of print]
123. In't Veld P, De Munck N, Van Belle K, et al. Beta-cell replication is increased in donor organs from young patients after prolonged life support. Diabetes 2010;59:1702-1708
124. Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467: 1114-1117
125. Bjerre Knudsen L, Madsen LW, Andersen S, 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
126. Hegedüs L, Moses AC, Zdravkovic M, Le Thi T, Daniels GH. 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
127. Aschebrook-Kilfoy B, Ward MH, Sabra MM, Devesa SS. Thyroid cancer incidence patterns in the United States by histologic type, 1992-2006. Thyroid 2011;21:125-134
128. Egan AG, Blind E, Dunder K, et al. Pancreatic safety of incretin-based drugsdFDA and EMA assessment. N Engl J Med 2014;370:794-797
129. Musso G, Gambino R, CassaderM, Pagano G. A novel approach to control hyperglycemia in type 2 diabetes: sodium glucose co-transport (SGLT) inhibitors: systematic review and metaanalysis of randomized trials. Ann Med 2012;44: 375-393
130. Andrianesis V, Doupis J. The role of kidney in glucose homeostasisdSGLT2 inhibitors, a new approach in diabetes treatment. Expert Rev Clin Pharmacol 2013;6:519-539
131. Nisly SA, Kolanczyk DM, Walton AM. Canagliflozin, a new sodium-glucose cotransporter 2 inhibitor, in the treatment of diabetes. Am J Health Syst Pharm 2013;70:311-319
132. Komoroski B, Vachharajani N, Feng Y, Li L, Kornhauser D, Pfister M. Dapagliflozin, a novel, selective SGLT2 inhibitor, improved glycemic control over 2 weeks in patients with type 2 diabetes mellitus. Clin Pharmacol Ther 2009; 85:513-519
133. List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care 2009;32:650-657
134. Wilding JP, Norwood P, T'joen C, Bastien A, List JF, Fiedorek FT. A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers: Applicability of a novel insulin-independent treatment. Diabetes Care 2009;32:1656-1662
135. Pharmaceuticals J. Invokana Prescribing Information. Titusville, NJ, Janssen Pharmaceuticals, 2013
136. Bristol-Myers Squibb. Farxiga Prescribing Information. Princeton, NJ, Bristol-Myers Squibb, 2014
137. List J, Ley S, Ptaszynska A, et al. Characterization of genital infections in the setting of pharmacologically induced glucosuria. Diabetes 2011;60(Suppl. 1):A270
138. Parikh SJ, Johnsson KM, Ptaszynska A, Schmitz BG, Sugg JE, List JF. Characterization of urinary tract infections in the setting of pharmacologically induced glucosuria. Diabetes 2011;60(Suppl. 1):A270
139. Inagaki N, Kondo K, Iwasaki T, et al. Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2 (SGLT2) improves glycemic control and reduces body weight in Japanese type 2 diabetes mellitus (T2DM). Diabetes 2011;60(Suppl. 1):A274
140. Rosenstock J, Aggarwal N, Polidori D, et al.; Canagliflozin DIA 2001 Study Group. Dose-ranging effects of canagliflozin, a sodiumglucose cotransporter 2 inhibitor, as add-on to metformin in subjects with type 2 diabetes. Diabetes Care 2012;35:1232-1238
141. Leiter LA, Cefalu WT, de Bruin TWA, Gause-Nilsson I, Sugg J, Parikh SJ. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: A 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc. 2 June 2014 [Epub ahead of print]
142. CefaluWT, Leiter LA, Yoon KH, et al. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results froma randomised, double-blind, phase 3 non-inferiority trial. Lancet 2013;382:941-950
143. Wilding JPH, Woo V, Pahor A, Sugg J, Langkilde A, Parikh S. Sustained effectiveness of dapagliflozin over 48 weeks in patients with type 2 diabetes poorly controlled with insulin. Diabetologia 2010;53(Suppl. 1):S348-S349
144. U.S. Food and Drug Administration. FDA approves Farxiga to treat type 2 diabetes [press release]. 8 January 2014. Available from http://www.fda.gov/ NewsEvents/Newsroom/ PressAnnouncements/ucm380829.htm. Accessed 18 February 2014
145. Henry RR, Rosenstock J, Chalamandaris A-G, Kasichayanula S, Bogle A, Griffen SC. Exploring the potential of dapagliflozin in type 1 diabetes: Phase 2a pilot study [abstract]. Presented at the 73rd Scientific Sessions of the American Diabetes Association, Chicago, IL, 21-25 June 2013
146. Perkins BA, Cherney DZ, Partridge H, et al. Sodium-glucose cotransporter 2 inhibition and glycemic control in type 1 diabetes: results of an 8-week open-label proof-of-concept trial. Diabetes Care 2014;37:1480-1483