Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus

Nature Reviews Endocrinology

Volumn 12, Issue 10, 2016, Pages 566-592

  Tahrani, Abd A ^a,b   Barnett, Anthony H ^a,b   Bailey, Clifford J ^c  

^a UNIVERSITY OF BIRMINGHAM   (United Kingdom)

^b UNIVERSITY HOSPITALS BIRMINGHAM NHS FOUNDATION TRUST   (United Kingdom)

^c ASTON UNIVERSITY   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

2,4 THIAZOLIDINEDIONE DERIVATIVE; ACARBOSE; ANTIDIABETIC AGENT; BILE ACID SEQUESTRANT; BROMOCRIPTINE; CANAGLIFLOZIN; DAPAGLIFLOZIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EMPAGLIFLOZIN; GLUCAGON LIKE PEPTIDE 1 RECEPTOR AGONIST; INSULIN; METFORMIN; NATEGLINIDE; PRAMLINTIDE; REPAGLINIDE; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SULFONYLUREA; BENZAMIDE DERIVATIVE; BIGUANIDE DERIVATIVE; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; GLYCOSIDASE INHIBITOR; MEGLITINIDE; SULFONYLUREA DERIVATIVE;

ABDOMINAL DISCOMFORT; ACUTE PANCREATITIS; BLOOD PRESSURE; BODY WEIGHT; BONE DENSITY; CEREBROVASCULAR ACCIDENT; DIABETIC KETOACIDOSIS; DIARRHEA; DRUG BIOAVAILABILITY; DRUG MECHANISM; DRUG SAFETY; EDEMA; FLATULENCE; FRACTURE; GASTROINTESTINAL SYMPTOM; GENITAL TRACT INFECTION; GLYCEMIC CONTROL; HEART INFARCTION; HUMAN; HYPOGLYCEMIA; INJECTION SITE REACTION; MAXIMUM PLASMA CONCENTRATION; META ANALYSIS (TOPIC); NAUSEA; NAUSEA AND VOMITING; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OSMOTIC DIURESIS; PANCREATITIS; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIORITY JOURNAL; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; SIDE EFFECT; URINARY TRACT INFECTION; AGONISTS; COMBINATION DRUG THERAPY;

BENZAMIDES; BIGUANIDES; DIABETES MELLITUS, TYPE 2; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; DRUG THERAPY, COMBINATION; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; GLYCOSIDE HYDROLASE INHIBITORS; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; SULFONYLUREA COMPOUNDS; THIAZOLIDINEDIONES;

EID: 84976260652     PISSN: 17595029     EISSN: 17595037     Source Type: Journal    
DOI: 10.1038/nrendo.2016.86     Document Type: Review

References (359)

1. International Diabetes Federation. IDF Diabetes Atlas 7th edn http://www.diabetesatlas.org/ (2016).
2. de Groot, M., Anderson, R., Freedland, K. E., Clouse, R. E. & Lustman, P. J. Association of depression and diabetes complications: a meta-analysis. Psychosom. Med. 63, 619-630 (2001).
3. Jacobson, A. M. Impact of improved glycemic control on quality of life in patients with diabetes. Endocr. Pract. 10, 502-508 (2004).
4. Stumvoll, M., Goldstein, B. J. & van Haeften, T. W. Type 2 diabetes: principles of pathogenesis and therapy. Lancet 365, 1333-1346 (2005).
5. Kahn, S. E., Hull, R. L. & Utzschneider, K. M. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature 444, 840-846 (2006).
6. Mulder, H., Nagorny, C. L., Lyssenko, V. & Groop, L. Melatonin receptors in pancreatic islets: good morning to a novel type 2 diabetes gene. Diabetologia 52, 1240-1249 (2009).
7. Drucker, D. J. & Nauck, M. A. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368, 1696-1705 (2006).
8. Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111-1119 (2005).
9. Yang, Q. et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 436, 356-362 (2005).
10. Rui, L., Yuan, M., Frantz, D., Shoelson, S. & White, M. F. SOCS-1 and SOCS-3 block insulin signaling by ubiquitin-mediated degradation of IRS1 and IRS2. J. Biol. Chem. 277, 42394-42398 (2002).
11. Marcheva, B. et al. Disruption of the clock components CLOCK and BMAL1 leads to hypoinsulinaemia and diabetes. Nature 466, 627-631 (2010).
12. Yang, C. S. et al. Hypothalamic AMP-activated protein kinase regulates glucose production. Diabetes 59, 2435-2443 (2010).
13. Marchetti, P. et al. in The Islets of Langerhans (ed. Islam, M. S.) 501-514 (Springer Netherlands, 2010).
14. Campbell, J. E. & Drucker, D. J. Islet α cells and glucagon - critical regulators of energy homeostasis. Nat. Rev. Endocrinol. 11, 329-338 (2015).
15. Kahn, S. E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355, 2427-2443 (2006).
16. Defronzo, R. A. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58, 773-795 (2009).
17. Bailey, C. J. Treating insulin resistance: future prospects. Diab. Vasc. Dis. Res. 4, 20-31 (2007).
18. Altaf, Q. A., Barnett, A. H. & Tahrani, A. A. Novel therapeutics for type 2 diabetes: insulin resistance. Diabetes Obes. Metab. 17, 319-334 (2015).
19. Samuel, V. T. & Shulman, G. I. Mechanisms for insulin resistance: common threads and missing links. Cell 148, 852-871 (2012).
20. Meier, B. C. & Wagner, B. K. Inhibition of HDAC3 as a strategy for developing novel diabetes therapeutics. Epigenomics 6, 209-214 (2014).
21. Brownlee, M. The pathobiology of diabetic complications: a unifying mechanism. Diabetes 54, 1615-1625 (2005).
22. 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 352, 837-853 (1998).
23. Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R. & Neil, H. A. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577-1589 (2008).
24. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329, 977-986 (1993).
25. Hayward, R. A. et al. Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 372, 2197-2206 (2015).
26. Tahrani, A. A., Bailey, C. J., Del Prato, S. & Barnett, A. H. Management of type 2 diabetes: new and future developments in treatment. Lancet 378, 182-197 (2011).
27. Tahrani, A. A., Piya, M. K., Kennedy, A. & Barnett, A. H. Glycaemic control in type 2 diabetes: targets and new therapies. Pharmacol. Ther. 125, 328-361 (2010).
28. Bailey, C. J. The current drug treatment landscape for diabetes and perspectives for the future. Clin. Pharmacol. Ther. 98, 170-184 (2015).
29. Maruthur, N. M. et al. The pharmacogenetics of type 2 diabetes: a systematic review. Diabetes Care 37, 876-886 (2014).
30. Home, P. et al. Insulin therapy in people with type 2 diabetes: opportunities and challenges? Diabetes Care 37, 1499-1508 (2014).
31. Ohkubo, Y. et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res. Clin. Pract. 28, 103-117 (1995).
32. Dormandy, J. A. et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 366, 1279-1289 (2005).
33. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358, 2545-2559 (2008).
34. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358, 2560-2572 (2008).
35. Duckworth, W. et al. Glucose control and vascular complications in veterans with type 2 diabetes. N. Engl. J. Med. 360, 129-139 (2009).
36. Inzucchi, S. E. et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38, 140-149 (2015).
37. Krentz, A. J. & Bailey, C. J. Oral antidiabetic agents: current role in type 2 diabetes mellitus. Drugs 65, 385-411 (2005).
38. Tahrani, A. A., Varughese, G. I., Scarpello, J. H. & Hanna, F. W. F. Metformin, heart failure, and lactic acidosis: is metformin absolutely contraindicated? BMJ 335, 508-512 (2007).
39. Bailey, C. J. & Turner, R. C. Metformin. N. Engl. J. Med. 334, 574-579 (1996).
40. Ferrannini, E. The target of metformin in type 2 diabetes. N. Engl. J. Med. 371, 1547-1548 (2014).
41. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167-1174 (2001).
42. Viollet, B. et al. Cellular and molecular mechanisms of metformin: an overview. Clin. Sci. (Lond.) 122, 253-270 (2012).
43. Bailey, C. J., Wilcock, C. & Scarpello, J. H. Metformin and the intestine. Diabetologia 51, 1552-1553 (2008).
44. Madiraju, A. K. et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510, 542-546 (2014).
45. Buse, J. B. et al. The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 39, 198-205 (2016).
46. Lindsay, J. R. et al. Inhibition of dipeptidyl peptidase IV activity by oral metformin in type 2 diabetes. Diabet. Med. 22, 654-657 (2005).
47. Mannucci, E. et al. Effect of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels in obese nondiabetic subjects. Diabetes Care 24, 489-494 (2001).
48. Mannucci, E. et al. Effects of metformin on glucagon-like peptide-1 levels in obese patients with and without type 2 diabetes. Diabetes Nutr. Metab. 17, 336-342 (2004).
49. Maida, A., Lamont, B. J., Cao, X. & Drucker, D. J. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-α in mice. Diabetologia 54, 339-349 (2011).
50. Cho, Y. M. & Kieffer, T. J. New aspects of an old drug: metformin as a glucagon-like peptide 1 (GLP-1) enhancer and sensitiser. Diabetologia 54, 219-222 (2011).
51. Mulherin, A. J. et al. Mechanisms underlying metformin-induced secretion of glucagon-like peptide-1 from the intestinal L cell. Endocrinology 152, 4610-4619 (2011).
52. Um, J. H. et al. Activation of 5'-AMP-activated kinase with diabetes drug metformin induces casein kinase Iϵ (CKIϵ)-dependent degradation of clock protein mPer2. J. Biol. Chem. 282, 20794-20798 (2007).
53. Barnea, M. et al. Metformin affects the circadian clock and metabolic rhythms in a tissue-specific manner. Biochim. Biophys. Acta 1822, 1796-1806 (2012).
54. Scheen, A. J. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet. 30, 359-371 (1996).
55. Grant, P. J. Beneficial effects of metformin on haemostasis and vascular function in man. Diabetes Metab. 29, 6S44-6S52 (2003).
56. Del Prato, S., Bianchi, C. & Marchetti, P. β-cell function and anti-diabetic pharmacotherapy. Diabetes Metab. Res. Rev. 23, 518-527 (2007).
57. Dujic, T. et al. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes 64, 1786-1793 (2015).
58. Heaf, J. Metformin in chronic kidney disease: time for a rethink. Perit. Dial. Int. 34, 353-357 (2014).
59. Scheen, A. J. & Paquot, N. Metformin revisited: a critical review of the benefit-risk balance in at-risk patients with type 2 diabetes. Diabetes Metab. 39, 179-190 (2013).
60. Eurich, D. T. et al. Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34, 000 patients. Circ. Heart Fail. 6, 395-402 (2013).
61. Hitchings, A. W., Archer, J. R. Srivastava, S. A. & Baker, E. H. Safety of metformin in patients with chronic obstructive pulmonary disease and type 2 diabetes mellitus. COPD 12, 126-131 (2015).
62. Hung, S. C. et al. Metformin use and mortality in patients with advanced chronic kidney disease: national, retrospective, observational, cohort study. Lancet Diabetes Endocrinol. 3, 605-614 (2015).
63. Salpeter, S. R., Greyber, E., Pasternak, G. A. & Salpeter, E. E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst. Rev. 4, CD002967 (2010).
64. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352, 854-865 (1998).
65. Ferrannini, E. & DeFronzo, R. A. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur. Heart J. 36, 2288-2296 (2015).
66. Henquin, J. C. The fiftieth anniversary of hypoglycaemic sulphonamides. How did the mother compound work? Diabetologia 35, 907-912 (1992).
67. Ashcroft, F. M. & Gribble, F. M. ATP-sensitive K+ channels and insulin secretion: their role in health and disease. Diabetologia 42, 903-919 (1999).
68. Groop, L. C. Sulfonylureas in NIDDM. Diabetes Care 15, 737-754 (1992).
69. Lebovitz, H. E. Insulin secretagogues: old and new. Diabetes Rev. 7, 139-153 (1999).
70. Rendell, M. The role of sulphonylureas in the management of type 2 diabetes mellitus. Drugs 64, 1339-1358 (2004).
71. Abe, M., Okada, K. & Soma, M. Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. Curr. Drug Metab. 12, 57-69 (2011).
72. Scheen, A. J. Pharmacokinetic considerations for the treatment of diabetes in patients with chronic kidney disease. Expert Opin. Drug Metab. Toxicol. 9, 529-550 (2013).
73. Arnouts, P. et al. Glucose-lowering drugs in patients with chronic kidney disease: a narrative review on pharmacokinetic properties. Nephrol. Dial. Transplant. 29, 1284-1300 (2014).
74. Schernthaner, G. et al. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Eur. J. Clin. Invest. 34, 535-542 (2004).
75. Carlson, R. F., Isley, W. L., Ogrinc, F. G. & Klobucar, T. R. Efficacy and safety of reformulated, micronized glyburide tablets in patients with non-insulin-dependent diabetes mellitus: a multicenter, double-blind, randomized trial. Clin. Ther. 15, 788-796 (1993).
76. Chung, M. et al. Pharmacokinetics and pharmacodynamics of extended-release glipizide GITS compared with immediate-release glipizide in patients with type II diabetes mellitus. J. Clin. Pharmacol. 42, 651-657 (2002).
77. UK Hypoglycaemia Study Group. Risk of hypoglycaemia in types 1 and 2 diabetes: effects of treatment modalities and their duration. Diabetologia 50, 1140-1147 (2007).
78. Barnett, A. H. et al. The efficacy of self-monitoring of blood glucose in the management of patients with type 2 diabetes treated with a gliclazide modified release-based regimen. A multicentre, randomized, parallel-group, 6-month evaluation (DINAMIC 1 study). Diabetes Obes. Metab. 10, 1239-1247 (2008).
79. Meinert, C. L., Knatterud, G. L., Prout, T. E. & Klimt, C. R. A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes 19 (Suppl.), 789-830 (1970).
80. US National Library of Science. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01243424 (2016).
81. Campbell, I. W. Nateglinide - current and future role in the treatment of patients with type 2 diabetes mellitus. Int. J. Clin. Pract. 59, 1218-1228 (2005).
82. Dornhorst, A. Insulinotropic meglitinide analogues. Lancet 358, 1709-1716 (2001).
83. Guardado-Mendoza, R., Prioletta, A., Jiménez-Ceja, L. M., Sosale, A. & Folli, F. The role of nateglinide and repaglinide, derivatives of meglitinide, in the treatment of type 2 diabetes mellitus. Arch. Med. Sci. 9, 936-943 (2013).
84. Scheen, A. J. Drug-drug and food-drug pharmacokinetic interactions with new insulinotropic agents repaglinide and nateglinide. Clin. Pharmacokinet. 46, 93-108 (2007).
85. Panelo, A. & Wing, J. R. Repaglinide/bedtime NPH insulin is comparable to twice-daily NPH insulin. Diabetes Care 28, 1789-1790 (2005).
86. Lund, S. S. et al. Combining insulin with metformin or an insulin secretagogue in non-obese patients with type 2 diabetes: 12 month, randomised, double blind trial. BMJ 339, b4324 (2009).
87. Rosenstock, J. et al. Repaglinide versus nateglinide monotherapy: a randomized, multicenter study. Diabetes Care 27, 1265-1270 (2004).
88. Madsbad, S., Kilhovd, B., Lager, I., Mustajoki, P. & Dejgaard, A. Comparison between repaglinide and glipizide in type 2 diabetes mellitus: a 1-year multicentre study. Diabet. Med. 18, 395-401 (2001).
89. Marbury, T., Huang, W. C., Strange, P. & Lebovitz, H. Repaglinide versus glyburide: a one-year comparison trial. Diabetes Res. Clin. Pract. 43, 155-166 (1999).
90. Meneilly, G. S. Effect of repaglinide versus glyburide on postprandial glucose and insulin values in elderly patients with type 2 diabetes. Diabetes Technol. Ther. 13, 63-65 (2011).
91. Schwarz, S. L. et al. Nateglinide, alone or in combination with metformin, is effective and well tolerated in treatment naïve elderly patients with type 2 diabetes. Diabetes Obes. Metab. 10, 652-660 (2008).
92. Bellomo Damato, A., Stefanelli, G., Laviola, L., Giorgino, R. & Giorgino, F. Nateglinide provides tighter glycaemic control than glyburide in patients with type 2 diabetes with prevalent postprandial hyperglycaemia. Diabet. Med. 28, 560-566 (2011).
93. Hu, S. et al. Pancreatic ß-cell K(ATP) channel activity and membrane-binding studies with nateglinide: a comparison with sulfonylureas and repaglinide. J. Pharmacol. Exp. Ther. 293, 444-452 (2000).
94. NAVIGATOR Study Group et al. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N. Engl. J. Med. 362, 1463-1476 (2010).
95. Huang, Y., Abdelmoneim, A. S., Light, P., Qiu, W. & Simpson, S. H. Comparative cardiovascular safety of insulin secretagogues following hospitalization for ischemic heart disease among type 2 diabetes patients: a cohort study. J. Diabetes Compl. 29, 196-202 (2015).
96. Bailey, C. J. Diabetes Therapies: Treating Hyperglycaemia 77-82 (MedEd UK Limited, 2009).
97. Ueno, H. et al. Effects of miglitol, acarbose, and sitagliptin on plasma insulin and gut peptides in type 2 diabetes mellitus: a crossover study. Diabetes Ther. 6, 187-196 (2015).
98. Joshi, S. R. et al. Therapeutic potential of α-glucosidase inhibitors in type 2 diabetes mellitus: an evidence-based review. Expert Opin. Pharmacother. 16, 1959-1981 (2015).
99. Yang, W. et al. Acarbose compared with metformin as initial therapy in patients with newly diagnosed type 2 diabetes: an open-label, non-inferiority randomised trial. Lancet Diabetes Endocrinol. 2, 46-55 (2014).
100. van de Laar, F. A. et al. Is acarbose equivalent to tolbutamide as first treatment for newly diagnosed type 2 diabetes in general practice? A randomised controlled trial. Diabetes Res. Clin. Pract. 63, 57-65 (2004).
101. Chiasson, J. L. et al. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Lancet 359, 2072-2077 (2002).
102. Chiasson, J. L. et al. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. JAMA 290, 486-494 (2003).
103. Holman, R. R. et al. Rationale for and design of the Acarbose Cardiovascular Evaluation (ACE) trial. Am. Heart J. 168, 23-29 (2014).
104. Yki-Järvinen, H. Thiazolidinediones. N. Engl. J. Med. 351, 1106-1118 (2004).
105. Hauner, H. The mode of action of thiazolidinediones. Diabetes Metab. Res. Rev. 18, S10-S15 (2002).
106. Scheen, A. J. Pharmacokinetic interactions with thiazolidinediones. Clin. Pharmacokinet. 46, 1-12 (2007).
107. Rosenstock, J., Einhorn, D., Hershon, K., Glazer, N. B. & Yu, S. Efficacy and safety of pioglitazone in type 2 diabetes: a randomised, placebo-controlled study in patients receiving stable insulin therapy. Int. J. Clin. Pract. 56, 251-257 (2002).
108. Charbonnel, B. et al. Long-term efficacy and tolerability of add-on pioglitazone therapy to failing monotherapy compared with addition of gliclazide or metformin in patients with type 2 diabetes. Diabetologia 48, 1093-1104 (2005).
109. Punthakee, Z. et al. Impact of rosiglitazone on body composition, hepatic fat, fatty acids, adipokines and glucose in persons with impaired fasting glucose or impaired glucose tolerance: a sub-study of the DREAM trial. Diabet. Med. 31, 1086-1092 (2014).
110. Loke, Y. K., Singh, S. & Furberg, C. D. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ 180, 32-39 (2009).
111. Schwartz, A. V. et al. Effects of TZD use and discontinuation on fracture rates in ACCORD bone study. J. Clin. Endocrinol. Metab. 100, 4059-4066 (2015).
112. Billington, E. O., Grey, A. & Bolland, M. J. The effect of thiazolidinediones on bone mineral density and bone turnover: systematic review and meta-analysis. Diabetologia 58, 2238-2246 (2015).
113. Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457-2471 (2007).
114. Mahaffey, K. W. et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am. Heart J. 166, 240-249.e1 (2013).
115. Winkler, K. et al. Pioglitazone reduces atherogenic dense LDL particles in nondiabetic patients with arterial hypertension. Diabetes Care 26, 2588-2594 (2003).
116. Erdmann, E. et al. The effect of pioglitazone on recurrent myocardial infarction in 2, 445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study. J. Am. Coll. Cardiol. 49, 1772-1780 (2007).
117. Wilcox, R. et al. Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04). Stroke 38, 865-873 (2007).
118. Pfister, R., Cairns, R., Erdmann, E. & Schneider, C. A. A clinical risk score for heart failure in patients with type 2 diabetes and macrovascular disease: an analysis of the PROactive study. Int. J. Cardiol. 162, 112-116 (2013).
119. Nissen, S. E. et al. Comparison of pioglitazone versus glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 299, 1561-1573 (2008).
120. Mazzone, T. et al. Effect of pioglitazone compared with glimepiride on carotid intima-media thickness in type 2 diabetes: a randomized trial. JAMA 296, 2572-2581 (2006).
121. Hughes, A. D. et al. A randomized placebo controlled double blind crossover study of pioglitazone on left ventricular diastolic function in type 2 diabetes. Int. J. Cardiol. 167, 1329-1332 (2013).
122. Straznicky, N. E. et al. A randomized controlled trial of the effects of pioglitazone treatment on sympathetic nervous system activity and cardiovascular function in obese subjects with metabolic syndrome. J. Clin. Endocrinol. Metab. 99, E1701-E1707 (2014).
123. Palalau, A. I., Tahrani, A. A., Piya, M. K. & Barnett, A. H. DPP-4 inhibitors in clinical practice. Postgrad. Med. 121, 70-100 (2009).
124. McKeage, K. Trelagliptin: first global approval. Drugs 75, 1161-1164 (2015).
125. Burness, C. B. Omarigliptin: first global approval. Drugs 75, 1947-1952 (2015).
126. Elrick, H., Stimmler, L., Hlad, C. J. & Arai, Y. Plasma insulin response to oral and intravenous glucose administration. J. Clin. Endocrinol. Metab. 24, 1076-1082 (1964).
127. Nauck, M. A. et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J. Clin. Endocrinol. Metab. 63, 492-498 (1986).
128. Baggio, L. L. & Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131-2157 (2007).
129. Fehmann, H. C., Ge, R. & Ge, B. Cell and molecular biology of the incretin hormones glucagon-like peptide-I and glucose-dependent insulin releasing polypeptide. Endocr. Rev. 16, 390-410 (1995).
130. Gautier, J. F., Choukem, S. P. & Girard, J. Physiology of incretins (GIP and GLP-1) and abnormalities in type 2 diabetes. Diabetes Metab. 34, S65-S72 (2008).
131. Dupre, J., Ross, S. A., Watson, D. & Brown, J. C. Stimulation of insulin secretion by gastric inhibitory polypeptide in man. J. Clin. Endocrinol. Metab. 37, 826-828 (1973).
132. Trper, A. et al. Glucose-dependent insulinotropic polypeptide is a growth factor for β (INS-1) cells by pleiotropic signaling. Mol. Endocrinol. 15, 1559-1570 (2001).
133. Yip, R. G. & Wolfe, M. M. GIP biology and fat metabolism. Life Sci. 66, 91-103 (2000).
134. Ahr, B. Gut peptides and type 2 diabetes mellitus treatment. Curr. Diab. Rep. 3, 365-372 (2003).
135. Barnett, A. H. New treatments in type 2 diabetes: a focus on the incretin-based therapies. Clin. Endocrinol. (Oxf.) 70, 343-353 (2009).
136. Drucker, D. J., Philippe, J., Mojsov, S., Chick, W. L. & Habener, J. F. Glucagon-like peptide I stimulates insulin gene expression and increases cyclic AMP levels in a rat islet cell line. Proc. Natl Acad. Sci. USA 84, 3434-3438 (1987).
137. Drucker, D. J. Glucagon-like peptides: regulators of cell proliferation, differentiation, and apoptosis. Mol. Endocrinol. 17, 161-171 (2003).
138. Malmgren, S. & Ahr, B. DPP-4 inhibition contributes to the prevention of hypoglycaemia through a GIP-glucagon counterregulatory axis in mice. Diabetologia 58, 1091-1099 (2015).
139. Farngren, J., Persson, M., Schweizer, A., Foley, J. E. & Ahr, B. Vildagliptin reduces glucagon during hyperglycemia and sustains glucagon counterregulation during hypoglycemia in type 1 diabetes. J. Clin. Endocrinol. Metab. 97, 3799-3806 (2012).
140. Hansen, L., Deacon, C. F., Orskov, C. & Holst, J. J. Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine. Endocrinology 140, 5356-5363 (1999).
141. Deacon, C. F., Johnsen, A. H. & Holst, J. J. Degradation of glucagon-like peptide-1 by human plasma in vitro yields an N-terminally truncated peptide that is a major endogenous metabolite in vivo. J. Clin. Endocrinol. Metab. 80, 952-957 (1995).
142. Mentlein, R. Dipeptidyl-peptidase IV (CD26) - role in the inactivation of regulatory peptides. Regul. Pept. 85, 9-24 (1999).
143. He, Y. L. et al. Pharmacokinetics and pharmacodynamics of vildagliptin in patients with type 2 diabetes mellitus. Clin. Pharmacokinet. 46, 577-588 (2007).
144. Herman, G. A. et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin. Pharmacol. Ther. 78, 675-688 (2005).
145. Nauck, M. A. & El-Ouaghlidi, A. The therapeutic actions of DPP-IV inhibition are not mediated by glucagon-like peptide-1. Diabetologia 48, 608-611 (2005).
146. Mearns, E. S. et al. Comparative efficacy and safety of antidiabetic drug regimens added to metformin monotherapy in patients with type 2 diabetes: a network meta-analysis. PLoS ONE 10, e0125879 (2015).
147. Day, C. & Bailey, C. J. Pharmacotherapies to manage diabesity: an update. Diabes. Pract. 4, 14-23 (2015).
148. Tahrani, A. A., Piya, M. K. & Barnett, A. H. Saxagliptin: a new DPP-4 inhibitor for the treatment of type 2 diabetes mellitus. Adv. Ther. 26, 249-262 (2009).
149. Tahrani, A. A., Piya, M. K. & Barnett, A. H. Drug evaluation: vildagliptin-metformin single-tablet combination. Adv. Ther. 26, 138-154 (2009).
150. Deacon, C. F. & Lebovitz, H. E. Comparative review of dipeptidyl peptidase-4 inhibitors and sulphonylureas. Diabetes Obes. Metab. 18, 333-347 (2016).
151. Deacon, C. F. Dipeptidyl peptidase-4 inhibitors in the treatment of type 2 diabetes: a comparative review. Diabetes Obes. Metab. 13, 7-18 (2011).
152. Scheen, A. J. Dipeptidylpeptidase-4 inhibitors (gliptins). Clin. Pharmacokinet. 49, 573-588 (2010).
153. Esposito, K. et al. A nomogram to estimate the HbA1c response to different DPP-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of 98 trials with 24 163 patients. BMJ Open 5, e005892 (2015).
154. Karagiannis, T., Paschos, P., Paletas, K., Matthews, D. R. & Tsapas, A. Dipeptidyl peptidase-4 inhibitors for treatment of type 2 diabetes mellitus in the clinical setting: systematic review and meta-analysis. BMJ 344, e1369 (2012).
155. Zhang, Y. et al. Head-to-head comparison of dipeptidyl peptidase-IV inhibitors and sulfonylureas - a meta-analysis from randomized clinical trials. Diabetes Metab. Res. Rev. 30, 241-256 (2014).
156. Derosa, G. et al. A randomized, double-blind, comparative therapy evaluating sitagliptin versus glibenclamide in type 2 diabetes patients already treated with pioglitazone and metformin: a 3-year study. Diabetes Technol. Ther. 15, 214-222 (2013).
157. Rosenstock, J., Wilson, C. & Fleck, P. Alogliptin versus glipizide monotherapy in elderly type 2 diabetes mellitus patients with mild hyperglycaemia: a prospective, double-blind, randomized, 1-year study. Diabetes Obes. Metab. 15, 906-914 (2013).
158. Gallwitz, B. 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 380, 475-483 (2012).
159. Filozof, C. & Gautier, J. F. 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. 27, 318-326 (2010).
160. Matthews, D. R. 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. 12, 780-789 (2010).
161. Foley, J. E. & 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. 41, 905-909 (2009).
162. Arjona Ferreira, J. C. 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. 61, 579-587 (2013).
163. Arjona Ferreira, J. C. et al. Efficacy and safety of sitagliptin versus glipizide in patients with type 2 diabetes and moderate-to-severe chronic renal insufficiency. Diabetes Care 36, 1067-1073 (2013).
164. Seck, T. 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. 64, 562-576 (2010).
165. Kim, Y. G. et al. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia 56, 696-708 (2013).
166. Zimdahl, H. et al. Influence of TCF7L2 gene variants on the therapeutic response to the dipeptidylpeptidase-4 inhibitor linagliptin. Diabetologia 57, 1869-1875 (2014).
167. Esposito, K. et al. Glycaemic durability with dipeptidyl peptidase-4 inhibitors in type 2 diabetes: a systematic review and meta-analysis of long-term randomised controlled trials. BMJ Open 4, e005442 (2014).
168. Scheen, A. J., Charpentier, G., Ostgren, C. J., Hellqvist, A. & Gause-Nilsson, I. Efficacy and safety of saxagliptin in combination with metformin compared with sitagliptin in combination with metformin in adult patients with type 2 diabetes mellitus. Diabetes Metab. Res. Rev. 26, 540-549 (2010).
169. Kothny, W., Lukashevich, V., Foley, J. E., Rendell, M. S. & Schweizer, A. Comparison of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment: a randomised clinical trial. Diabetologia 58, 2020-2026 (2015).
170. Inagaki, N., Onouchi, H., Maezawa, H., Kuroda, S. & Kaku, K. Once-weekly trelagliptin versus daily alogliptin in Japanese patients with type 2 diabetes: a randomised, double-blind, phase 3, non-inferiority study. Lancet Diabetes Endocrinol. 3, 191-197 (2015).
171. Gantz, I., Okamoto, T., Ito, Y., Okuyama, K. & Engel, S. S. Effect of omarigliptin, a novel once-weekly DPP-4 inhibitor, in Japanese patients with type 2 diabetes: a placebo-and sitagliptin-controlled trial. Diabetologia 57, S55 (2014).
172. Park, H., Park, C., Kim, Y. & Rascati, K. L. Efficacy and safety of dipeptidyl peptidase-4 inhibitors in type 2 diabetes: meta-analysis. Ann. Pharmacother. 46, 1453-1469 (2012).
173. Ussher, J. R. & Drucker, D. J. Cardiovascular biology of the incretin system. Endocr. Rev. 33, 187-215 (2012).
174. Scheen, A. J. Cardiovascular effects of gliptins. Nat. Rev. Cardiol. 10, 73-84 (2013).
175. Scirica, B. M. et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med. 369, 1317-1326 (2013).
176. Udell, J. A. et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes and moderate or severe renal impairment: observations from the SAVOR-TIMI 53 trial. Diabetes Care 38, 696-705 (2015).
177. White, W. B. et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N. Engl. J. Med. 369, 1327-1335 (2013).
178. Green, J. B. et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 373, 232-242 (2015).
179. Li, L. 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 348, g2366 (2014).
180. Roshanov, P. S. & Dennis, B. B. Incretin-based therapies are associated with acute pancreatitis: meta-analysis of large randomized controlled trials. Diabetes Res. Clin. Pract. 110, e13-e17 (2015).
181. Eng, J., Kleinman, W. A., Singh, L., Singh, G. & Raufman, J. P. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J. Biol. Chem. 267, 7402-7405 (1992).
182. Barnett, A. Exenatide. Expert. Opin. Pharmacother. 8, 2593-2608 (2007).
183. Drucker, D. J. et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet 372, 1240-1250 (2008).
184. Green, B. D. & Flatt, P. R. Incretin hormone mimetics and analogues in diabetes therapeutics. Best. Pract. Res. Clin. Endocrinol. Metab. 21, 497-516 (2007).
185. Christensen, M. & Knop, F. K. Once-weekly GLP-1 agonists: how do they differ from exenatide and liraglutide? Curr. Diab. Rep. 10, 124-132 (2010).
186. Christensen, M., Knop, F. K., Holst, J. J. & Vilsboll, T. Lixisenatide, a novel GLP-1 receptor agonist for the treatment of type 2 diabetes mellitus. IDrugs 12, 503-513 (2009).
187. Jimenez-Solem, E., Rasmussen, M. H., Christensen, M. & Knop, F. K. Dulaglutide, a long-acting GLP-1 analog fused with an Fc antibody fragment for the potential treatment of type 2 diabetes. Curr. Opin. Mol. Ther. 12, 790-797 (2010).
188. Nauck, M. A., Vardarli, I., Deacon, C. F., Holst, J. J. & Meier, J. J. Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 54, 10-18 (2011).
189. Kolterman, O. G. et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am. J. Health Syst. Pharm. 62, 173-181 (2005).
190. Copley, K. et al. Investigation of exenatide elimination and its in vivo and in vitro degradation. Curr. Drug Metab. 7, 367-374 (2006).
191. Edwards, C. M. et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am. J. Physiol. Endocrinol. Metab. 281, E155-E161 (2001).
192. Simonsen, L., Holst, J. J. & Deacon, C. F. Exendin-4, but not glucagon-like peptide-1, is cleared exclusively by glomerular filtration in anaesthetised pigs. Diabetologia 49, 706-712 (2006).
193. Linnebjerg, H. et al. Effect of renal impairment on the pharmacokinetics of exenatide. Br. J. Clin. Pharmacol. 64, 317-327 (2007).
194. Jose, B., Tahrani, A. A., Piya, M. K. & Barnett, A. H. Exenatide once weekly: clinical outcomes and patient satisfaction. Patient Prefer. Adherence 4, 313-324 (2010).
195. Elbrd, B. et al. Pharmacokinetics, pharmacodynamics, safety, and tolerability of a single-dose of NN2211, a long-acting glucagon-like peptide 1 derivative, in healthy male subjects. Diabetes Care 25, 1398-1404 (2002).
196. Juhl, C. B. et al. Bedtime administration of NN2211, a long-acting GLP-1 derivative, substantially reduces fasting and postprandial glycemia in type 2 diabetes. Diabetes 51, 424-429 (2002).
197. Agers, H., Jensen, L. B., Elbrd, B., Rolan, P. & Zdravkovic, M. The pharmacokinetics, pharmacodynamics, safety and tolerability of NN2211, a new long-acting GLP-1 derivative, in healthy men. Diabetologia 45, 195-202 (2002).
198. Barnett, A. H. Lixisenatide: evidence for its potential use in the treatment of type 2 diabetes. Core Evid. 6, 67-79 (2011).
199. Matthews, J. E. et al. Pharmacodynamics, pharmacokinetics, safety, and tolerability of albiglutide, a long-acting glucagon-like peptide-1 mimetic, in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 93, 4810-4817 (2008).
200. Barrington, P. et al. A 5-week study of the pharmacokinetics and pharmacodynamics of LY2189265, a novel, long-acting glucagon-like peptide-1 analogue, in patients with type 2 diabetes. Diabetes Obes. Metab. 13, 426-433 (2011).
201. Hurren, K. M. & Pinelli, N. R. Drug-drug interactions with glucagon-like peptide-1 receptor agonists. Ann. Pharmacother. 46, 710-717 (2012).
202. Buse, J. B. et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 27, 2628-2635 (2004).
203. DeFronzo, R. A. 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 28, 1092-1100 (2005).
204. Kendall, D. M. 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 28, 1083-1091 (2005).
205. Buse, J. B. 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 374, 39-47 (2009).
206. Garber, A. et al. Liraglutide versus glimepiride monotherapy for type 2 diabetes (LEAD-3 Mono): a randomised, 52-week, phase III, double-blind, parallel-treatment trial. Lancet 373, 473-481 (2009).
207. Marre, 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. 26, 268-278 (2009).
208. Nauck, M. 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 32, 84-90 (2009).
209. Zinman, B. 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 32, 1224-1230 (2009).
210. Bolli, G. B. et al. Efficacy and safety of lixisenatide once daily versus placebo in people with Type-2 diabetes insufficiently controlled on metformin (GetGoal-F1). Diabet. Med. 31, 176-184 (2014).
211. Ahr, B., Leguizamo Dimas, A., Miossec, P., Saubadu, S. & Aronson, R. Efficacy and safety of lixisenatide once-daily morning or evening injections in type 2 diabetes inadequately controlled on metformin (GetGoal-M). Diabetes Care 36, 2543-2550 (2013).
212. Pinget, M. et al. Efficacy and safety of lixisenatide once daily versus placebo in type 2 diabetes insufficiently controlled on pioglitazone (GetGoal-P). Diabetes Obes. Metab. 15, 1000-1007 (2013).
213. Riddle, M. C. et al. Adding once-daily lixisenatide for type 2 diabetes inadequately controlled with newly initiated and continuously titrated basal insulin glargine: a 24-week, randomized, placebo-controlled study (GetGoal-Duo 1). Diabetes Care 36, 2497-2503 (2013).
214. Seino, Y., Min, K. W., Niemoeller, E. & Takami, A. 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. 14, 910-917 (2012).
215. Fonseca, V. A. et al. 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 35, 1225-1231 (2012).
216. Rosenstock, J. et al. Efficacy and safety of lixisenatide once daily versus exenatide twice daily in type 2 diabetes inadequately controlled on metformin: a 24-week, randomized, open-label, active-controlled study (GetGoal-X). Diabetes Care 36, 2945-2951 (2013).
217. Ratner, R. E., Rosenstock, J. & Boka, G. 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. 27, 1024-1032 (2010).
218. Bergenstal, R. M. 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 376, 431-439 (2010).
219. Blevins, T. 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. 96, 1301-1310 (2011).
220. Buse, J. B. et al. DURATION-1: exenatide once weekly produces sustained glycemic control and weight loss over 52 weeks. Diabetes Care 33, 1255-1261 (2010).
221. Buse, J. B. et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet 381, 117-124 (2013).
222. Diamant, M. et al. Exenatide once weekly versus insulin glargine for type 2 diabetes (DURATION-3): 3-year results of an open-label randomised trial. Lancet Diabetes Endocrinol. 2, 464-473 (2014).
223. Home, P. D. 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. 17, 179-187 (2015).
224. Weissman, P. N. 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 57, 2475-2484 (2014).
225. Reusch, J. 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. 16, 1257-1264 (2014).
226. Ahr, B. 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 37, 2141-2148 (2014).
227. Pratley, R. E. 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. 2, 289-297 (2014).
228. Reaney, M., Yu, M., Lakshmanan, M., Pechtner, V. & van Brunt, K. Treatment satisfaction in people with type 2 diabetes mellitus treated with once-weekly dulaglutide: data from the AWARD-1 and AWARD-3 clinical trials. Diabetes Obes. Metab. 17, 896-903 (2015).
229. Weinstock, R. S. et al. Safety and efficacy of once-weekly dulaglutide versus sitagliptin after 2 years in metformin-treated patients with type 2 diabetes (AWARD-5): a randomized, phase III study. Diabetes Obes. Metab. 17, 849-858 (2015).
230. Dungan, K. M. 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 384, 1349-1357 (2014).
231. Wysham, C. 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 37, 2159-2167 (2014).
232. Umpierrez, G., Tof Povedano, S., Pez Manghi, F., Shurzinske, L. & Pechtner, V. Efficacy and safety of dulaglutide monotherapy versus metformin in type 2 diabetes in a randomized controlled trial (AWARD-3). Diabetes Care 37, 2168-2176 (2014).
233. Skrivanek, Z. et al. Dose-finding results in an adaptive, seamless, randomized trial of once-weekly dulaglutide combined with metformin in type 2 diabetes patients (AWARD-5). Diabetes Obes. Metab. 16, 748-756 (2014).
234. Nauck, M. 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 37, 2149-2158 (2014).
235. Russell-Jones, D. et al. Liraglutide versus 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 52, 2046-2055 (2009).
236. Diamant, M. 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 375, 2234-2243 (2010).
237. Giorgino, F., Benroubi, M., Sun, J. H., Zimmermann, A. G. & Pechtner, V. Efficacy and safety of once-weekly dulaglutide versus insulin glargine in patients with type 2 diabetes on metformin and glimepiride (AWARD-2). Diabetes Care 38, 2241-2249 (2015).
238. Meier, J. J. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 8, 728-742 (2012).
239. Harris, K. B. & McCarty, D. J. Efficacy and tolerability of glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes mellitus. Ther. Adv. Endocrinol. Metab. 6, 3-18 (2015).
240. Klonoff, D. C. 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. 24, 275-286 (2008).
241. Aroda, V. R. et al. Efficacy of GLP-1 receptor agonists and DPP-4 inhibitors: meta-analysis and systematic review. Clin. Ther. 34, 1247-1258 (2012).
242. Buse, J. B. et al. Use of twice-daily exenatide in Basal insulin-treated patients with type 2 diabetes: a randomized, controlled trial. Ann. Intern. Med. 154, 103-112 (2011).
243. Rosenstock, J. 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 35, 955-958 (2012).
244. Deacon, C. F., Mannucci, E. & Ahr, B. Glycaemic efficacy of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors as add-on therapy to metformin in subjects with type 2 diabetes - a review and meta analysis. Diabetes Obes. Metab. 14, 762-767 (2012).
245. Henry, R. R. et al. DURATION-1 extension: efficacy and tolerability of exenatide once weekly (QW) over 6 years in patients with T2DM. Diabetes 63, A247 (2014).
246. Klein, E. et al. DURATION-1 extension: efficacy and tolerability of exenatide once weekly over 6 years in patients with type 2 diabetes mellitus. Diabetologia 57, S39 (2014).
247. Garber, A. 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. 13, 348-356 (2011).
248. Ahmann, A. et al. Efficacy and safety of liraglutide versus placebo added to basal insulin analogues (with or without metformin) in patients with type 2 diabetes: a randomized, placebo-controlled trial. Diabetes Obes. Metab. 17, 1056-1064 (2015).
249. Henry, R. R. et al. Efficacy of anthiyperglycemic therapies and the influence of baseline hemoglobin A(1C): a meta-analysis of the liraglutide development program. Endocr. Pract. 17, 906-913 (2011).
250. Tella, S. H. & Rendell, M. S. Glucagon-like polypeptide agonists in type 2 diabetes mellitus: efficacy and tolerability, a balance. Ther. Adv. Endocrinol. Metab. 6, 109-134 (2015).
251. Yu Pan, C. et al. Lixisenatide treatment improves glycaemic control in Asian patients with type 2 diabetes mellitus inadequately controlled on metformin with or without sulfonylurea: a randomized, double-blind, placebo-controlled, 24-week trial (GetGoal-M-Asia). Diabetes Metab. Res. Rev. 30, 726-735 (2014).
252. Rosenstock, J. et al. Beneficial effects of once-daily lixisenatide on overall and postprandial glycemic levels without significant excess of hypoglycemia in Type 2 diabetes inadequately controlled on a sulfonylurea with or without metformin (GetGoal-S). J. Diabetes Complications 28, 386-392 (2014).
253. Riddle, M. C. 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 36, 2489-2496 (2013).
254. Raccah, D., Gourdy, P., Sagnard, L. & Ceriello, A. Lixisenatide as add-on to oral anti-diabetic therapy: an effective treatment for glycaemic control with body weight benefits in type 2 diabetes. Diabetes Metab. Res. Rev. 30, 742-748 (2014).
255. Schmidt, L. J., Habacher, W., Augustin, T., Krahulec, E. & Semlitsch, T. A systematic review and meta-analysis of the efficacy of lixisenatide in the treatment of patients with type 2 diabetes. Diabetes Obes. Metab. 16, 769-779 (2014).
256. Ahrén, B. et al. Pronounced reduction of postprandial glucagon by lixisenatide: a meta-analysis of randomized clinical trials. Diabetes Obes. Metab. 16, 861-868 (2014).
257. Charbonnel, B., Bertolini, M., Tinahones, F. J., Domingo, M. P. & Davies, M. Lixisenatide plus basal insulin in patients with type 2 diabetes mellitus: a meta-analysis. J. Diabetes Complications 28, 880-886 (2014).
258. Russell-Jones, D. 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 35, 252-258 (2012).
259. Davies, M. et al. Once-weekly exenatide versus once- or twice-daily insulin detemir: randomized, open-label, clinical trial of efficacy and safety in patients with type 2 diabetes treated with metformin alone or in combination with sulfonylureas. Diabetes Care 36, 1368-1376 (2013).
260. Wysham, C. H. et al. Five-year efficacy and safety data of exenatide once weekly: long-term results from the DURATION-1 randomized clinical trial. Mayo Clin. Proc. 90, 356-365 (2015).
261. Rosenstock, J. 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 32, 1880-1886 (2009).
262. Karagiannis, T. et al. Efficacy and safety of once-weekly glucagon-like peptide 1 receptor agonists for the management of type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes. Metab. 17, 1065-1074 (2015).
263. Rosenstock, J. et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 37, 2317-2325 (2014).
264. Kim, Y. G., Hahn, S., Oh, T. J., Park, K. S. & Cho, Y. M. Differences in the HbA1c-lowering efficacy of glucagon-like peptide-1 analogues between Asians and non-Asians: a systematic review and meta-analysis. Diabetes Obes. Metab. 16, 900-909 (2014).
265. Vilsbøll, T., Christensen, M., Junker, A. E., Knop, F. K. & Gluud, L. L. Effects of glucagon-like peptide-1 receptor agonists on weight loss: systematic review and meta-analyses of randomised controlled trials. BMJ 344, d7771 (2012).
266. Eng, C., Kramer, C. K., Zinman, B. & Retnakaran, R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 384, 2228-2234 (2014).
267. Potts, J. E. et al. The effect of glucagon-like peptide 1 receptor agonists on weight loss in type 2 diabetes: a systematic review and mixed treatment comparison meta-analysis. PLoS ONE 10, e0126769 (2015).
268. Sun, F. et al. Effect of GLP-1 receptor agonists on waist circumference among type 2 diabetes patients: a systematic review and network meta-analysis. Endocrine 48, 794-803 (2015).
269. Katout, M. et al. Effect of GLP-1 mimetics on blood pressure and relationship to weight loss and glycemia lowering: results of a systematic meta-analysis and meta-regression. Am. J. Hypertens. 27, 130-139 (2014).
270. Sun, F. et al. Impact of GLP-1 receptor agonists on blood pressure, heart rate and hypertension among patients with type 2 diabetes: a systematic review and network meta-analysis. Diabetes Res. Clin. Pract. 110, 26-37 (2015).
271. Ferdinand, K. C. et al. Effects of the once-weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus. Hypertension 64, 731-737 (2014).
272. Sun, F. et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin. Ther. 37, 225-241 (2015).
273. Egan, A. G. et al. Pancreatic safety of incretin-based drugs - FDA and EMA assessment. N. Engl. J. Med. 370, 794-797 (2014).
274. Wang, T. et al. Using real-world data to evaluate the association of incretin-based therapies with risk of acute pancreatitis: a meta-analysis of 1, 324, 515 patients from observational studies. Diabetes Obes. Metab. 17, 32-41 (2015).
275. Giorda, C. B. et al. Incretin-based therapies and acute pancreatitis risk: a systematic review and meta-analysis of observational studies. Endocrine 48, 461-471 (2015).
276. Pfeffer, M. A. et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N. Engl. J. Med. 373, 2247-2257 (2015).
277. Lønborg, J. et al. Exenatide reduces reperfusion injury in patients with ST-segment elevation myocardial infarction. Eur. Heart J. 33, 1491-1499 (2012).
278. Gill, A. et al. Effect of exenatide on heart rate and blood pressure in subjects with type 2 diabetes mellitus: a double-blind, placebo-controlled, randomized pilot study. Cardiovasc. Diabetol. 9, 6 (2010).
279. Trujillo, J. M., Nuffer, W. & Ellis, S. L. GLP-1 receptor agonists: a review of head-to-head clinical studies. Ther. Adv. Endocrinol. Metab. 6, 19-28 (2015).
280. Owens, D. R., Monnier, L. & Bolli, G. B. Differential effects of GLP-1 receptor agonists on components of dysglycaemia in individuals with type 2 diabetes mellitus. Diabetes Metab. 39, 485-496 (2013).
281. Meier, J. J. et al. Contrasting effects of lixisenatide and liraglutide on postprandial glycemic control, gastric emptying, and safety parameters in patients with type 2 diabetes on optimized insulin glargine with or without metformin: a randomized, open-label trial. Diabetes Care 38, 1263-1273 (2015).
282. Wang, Y. et al. Glucagon-like peptide-1 receptor agonists versus insulin in inadequately controlled patients with type 2 diabetes mellitus: a meta-analysis of clinical trials. Diabetes Obes. Metab. 13, 972-981 (2011).
283. Blonde, L. et al. Once-weekly dulaglutide versus bedtime insulin glargine, both in combination with prandial insulin lispro, in patients with type 2 diabetes (AWARD-4): a randomised, open-label, phase 3, non-inferiority study. Lancet 385, 2057-2066 (2015).
284. Gough, S. C. et al. Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes. Lancet Diabetes Endocrinol. 2, 885-893 (2014).
285. Gough, S. C. et al. One-year efficacy and safety of a fixed combination of insulin degludec and liraglutide in patients with type 2 diabetes: results of a 26-week extension to a 26-week main trial. Diabetes Obes. Metab. 17, 965-973 (2015).
286. Buse, J. B. et al. Contribution of liraglutide in the fixed-ratio combination of insulin degludec and liraglutide (IDegLira). Diabetes Care 37, 2926-2933 (2014).
287. Rosenstock, J. et al. Benefits of a fixed-ratio formulation of once-daily insulin glargine/lixisenatide (LixiLan) versus glargine in type 2 diabetes inadequately controlled on metformin. Diabetologia 57, S108 (2014).
288. [no authors listed.] Sanofi reports positive top-line results in second pivotal LixiLan phase III study. SANOFI http://en.sanofi.com/NasdaQ-OMX/local/press-releases/sanofi-reports-positive-toplin-1951405-14-09-2015!07-00-00.aspx (2015).
289. Tahrani, A. A., Barnett, A. H. & Bailey, C. J. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 1, 140-151 (2013).
290. Scheen, A. J. Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 75, 33-59 (2015).
291. Wright, E. M., Hirayama, B. A. & Loo, D. F. Active sugar transport in health and disease. J. Intern. Med. 261, 32-43 (2007).
292. Thorens, B. & Mueckler, M. Glucose transporters in the 21st Century. Am. J. Physiol. Endocrinol. Metab. 298, E141-E145 (2010).
293. Bailey, C. J. & Day, C. SGLT2 inhibitors: glucuretic treatment for type 2 diabetes. Br. J. Diabetes Vasc. Dis. 10, 193-199 (2010).
294. Bailey, C. J. Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol. Sci. 32, 63-71 (2011).
295. Wright, E. M., Loo, D. D. & Hirayama, B. A. Biology of human sodium glucose transporters. Physiol. Rev. 91, 733-794 (2011).
296. Wright, E. M. Renal Na+-glucose cotransporters. Am. J. Physiol. Renal Physiol. 280, F10-F18 (2001).
297. Nauck, M. A. et al. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care 34, 2015-2022 (2011).
298. Ferrannini, G. et al. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care 38, 1730-1735 (2015).
299. Fulcher, G. et al. Efficacy and safety of canagliflozin when used in conjunction with incretin-mimetic therapy in patients with type 2 diabetes. Diabetes Obes. Metab. 18, 82-91 (2016).
300. Obermeier, M. et al. In vitro characterization and pharmacokinetics of dapagliflozin (BMS-512148), a potent sodium-glucose cotransporter type II inhibitor, in animals and humans. Drug Metab. Dispos. 38, 405-414 (2010).
301. Meng, W. et al. Discovery of dapagliflozin: a potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem. 51, 1145-1149 (2008).
302. Devineni, D. et al. Canagliflozin improves glycaemic control over 28 days in subjects with type 2 diabetes not optimally controlled on insulin. Diabetes Obes. Metab. 14, 539-545 (2012).
303. Heise, T. et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks' treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes. Metab. 15, 613-621 (2013).
304. Grempler, R. et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes. Metab. 14, 83-90 (2012).
305. Jahagirdar, V. & Barnett, A. H. Empagliflozin for the treatment of type 2 diabetes. Expert Opin. Pharmacother. 15, 2429-2441 (2014).
306. Scheen, A. J. Drug-drug interactions with sodium-glucose cotransporters type 2 (SGLT2) inhibitors, new oral glucose-lowering agents for the management of type 2 diabetes mellitus. Clin. Pharmacokinet. 53, 295-304 (2014).
307. Ferrannini, E., Ramos, S. J., Salsali, A., Tang, W. & List, J. F. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 33, 2217-2224 (2010).
308. Sun, Y. N., Zhou, Y., Chen, X., Che, W. S. & Leung, S. W. The efficacy of dapagliflozin combined with hypoglycaemic drugs in treating type 2 diabetes mellitus: meta-analysis of randomised controlled trials. BMJ Open 4, e004619 (2014).
309. Nauck, M. A. et al. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes. Metab. 16, 1111-1120 (2014).
310. Grandy, S., Hashemi, M., Langkilde, A. M., Parikh, S. & Sjöström, C. D. Changes in weight loss-related quality of life among type 2 diabetes mellitus patients treated with dapagliflozin. Diabetes Obes. Metab. 16, 645-650 (2014).
311. Merovci, A. et al. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Invest. 124, 509-514 (2014).
312. Bonner, C. et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic α cells triggers glucagon secretion. Nat. Med. 21, 512-517 (2015).
313. Yang, X. P., Lai, D., Zhong, X. Y., Shen, H. P. & Huang, Y. L. Efficacy and safety of canagliflozin in subjects with type 2 diabetes: systematic review and meta-analysis. Eur. J. Clin. Pharmacol. 70, 1149-1158 (2014).
314. Neal, B. et al. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care 38, 403-411 (2015).
315. Stein, P. et al. Canagliflozin, a sodium glucose co-transporter 2 inhibitor, reduces post-meal glucose excursion in patients with type 2 diabetes by a non-renal mechanism: results of a randomized trial. Metabolism 63, 1296-1303 (2014).
316. Leiter, L. A. et al. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care 38, 355-364 (2015).
317. Roden, M. et al. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol. 1, 208-219 (2013).
318. Häring, H. U. et al. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 37, 1650-1659 (2014).
319. Häring, H. U. et al. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week randomized, double-blind, placebo-controlled trial. Diabetes Care 36, 3396-3404 (2013).
320. Kovacs, C. S. et al. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes. Metab. 16, 147-158 (2014).
321. Roden, M. et al. Empagliflozin (EMPA) monotherapy for ≥76 weeks in drug-naïve patients with type 2 diabetes (T2DM) [abstract 264-OR]. Diabetes 63 (Suppl. 1), A69 (2014).
322. Kovacs, C. S. et al. Empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. Clin. Ther. 37, 1773-1788 (2015).
323. Merker, L. et al. Empagliflozin as add-on to metformin in people with type 2 diabetes. Diabet. Med. 32, 1555-1567 (2015).
324. Haering, H. U. et al. Empagliflozin as add-on to metformin plus sulphonylurea in patients with type 2 diabetes. Diabetes Res. Clin. Pract. 110, 82-90 (2015).
325. Ridderstråle, M. et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2, 691-700 (2014).
326. Rosenstock, J. et al. Impact of empagliflozin added on to basal insulin in type 2 diabetes inadequately controlled on basal insulin: a 78-week randomized, double-blind, placebo-controlled trial. Diabetes Obes. Metab. 17, 936-948 (2015).
327. Rosenstock, J. et al. Improved glucose control with weight loss, lower insulin doses, and no increased hypoglycemia with empagliflozin added to titrated multiple daily injections of insulin in obese inadequately controlled type 2 diabetes. Diabetes Care 37, 1815-1823 (2014).
328. Tikkanen, I. et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 38, 420-428 (2015).
329. Barnett, A. H. et al. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2, 369-384 (2014).
330. Nyirjesy, P. et al. Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Curr. Med. Res. Opin. 30, 1109-1119 (2014).
331. Hach, T. et al. Empagliflozin improves glycemic parameters and cardiovascular risk factors in patients with type 2 diabetes (T2DM): pooled data from four pivotal Phase III trials [abstract 69-LB]. Diabetes 62 (Suppl. 1A), LB19 (2013).
332. Ptaszynska, A. et al. Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Saf. 37, 815-829 (2014).
333. Sha, S. et al. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes. Metab. 16, 1087-1095 (2014).
334. Toto, R. et al. No overall increase in volume depletion events with empagliflozin (EMPA) in a pooled analysis of more than 11, 000 patients with type 2 diabetes (T2DM) [abstract SA-PO373]. J. Am. Soc. Nephrol. 24, 711A (2013).
335. Ljunggren, Ö. et al. Dapagliflozin has no effect on markers of bone formation and resorption or bone mineral density in patients with inadequately controlled type 2 diabetes mellitus on metformin. Diabetes Obes. Metab. 14, 990-999 (2012).
336. Bilezikian, J. P. et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J. Clin. Endocrinol. Metab. 101, 44-51 (2016).
337. Watts, N. B. et al. Effects of canagliflozin on fracture risk in patients with type 2 diabetes mellitus. J. Clin. Endocrinol. Metab. 101, 157-166 (2015).
338. Kalra, S., Sahay, R. & Gupta, Y. Sodium glucose transporter 2 (SGLT2) inhibition and ketogenesis. Indian J. Endocrinol. Metab. 19, 524-528 (2015).
339. Storgaard, H., Bagger, J. I., Knop, F. K., Vilsbøll, T. & Rungby, J. Diabetic ketoacidosis in a patient with type 2 diabetes after initiation of sodium-glucose cotransporter 2 inhibitor treatment. Basic Clin. Pharmacol. Toxicol. 118, 168-170 (2016).
340. Peters, A. L. et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care 38, 1687-1693 (2015).
341. Erondu, N., Desai, M., Ways, K. & Meininger, G. Diabetic ketoacidosis and related events in the canagliflozin type 2 diabetes clinical program. Diabetes Care 38, 1680-1686 (2015).
342. Rosenstock, J. & Ferrannini, E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care 38, 1638-1642 (2015).
343. Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117-2128 (2015).
344. Holt, R. I., Barnett, A. H. & Bailey, C. J. Bromocriptine: old drug, new formulation and new indication. Diabetes Obes. Metab. 12, 1048-1057 (2010).
345. Cincotta, A. H., Meier, A. H. & Cincotta, J. M. Bromocriptine improves glycaemic control and serum lipid profile in obese Type 2 diabetic subjects: a new approach in the treatment of diabetes. Expert. Opin. Investig. Drugs 8, 1683-1707 (1999).
346. Barnett, A. H., Chapman, C., Gailer, K. & Hayter, C. J. Effect of bromocriptine on maturity onset diabetes. Postgrad. Med. J. 56, 11-14 (1980).
347. Lam, C. K., Chari, M. & Lam, T. K. CNS regulation of glucose homeostasis. Physiology (Bethesda) 24, 159-170 (2009).
348. Liang, W. et al. Efficacy and safety of bromocriptine-QR in type 2 diabetes: a systematic review and meta-analysis. Horm. Metab. Res. 47, 805-812 (2015).
349. Gaziano, J. M. et al. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Diabetes Care 33, 1503-1508 (2010).
350. Fonseca, V. A., Handelsman, Y. & Staels, B. Colesevelam lowers glucose and lipid levels in type 2 diabetes: the clinical evidence. Diabetes Obes. Metab. 12, 384-392 (2010).
351. Rosenstock, J. et al. Efficacy and safety of colesevelam in combination with pioglitazone in patients with type 2 diabetes mellitus. Horm. Metab. Res. 46, 943-949 (2014).
352. Younk, L. M., Mikeladze, M. & Davis, S. N. Pramlintide and the treatment of diabetes: a review of the data since its introduction. Expert Opin. Pharmacother. 12, 1439-1451 (2011).
353. Henry, R. R. et al. Randomized trial of continuous subcutaneous delivery of exenatide by ITCA 650 versus twice-daily exenatide injections in metformin-treated type 2 diabetes. Diabetes Care 36, 2559-2565 (2013).
354. Nauck, M. A. et al. A phase 2, randomized, dose-finding study of the novel once-weekly human GLP-1 analog, semaglutide, compared with placebo and open-label liraglutide in patients with type 2 diabetes. Diabetes Care 39, 231-241 (2016).
355. Biftu, T. et al. Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes. J. Med. Chem. 57, 3205-3212 (2014).
356. Amin, N. B. et al. Dose-ranging efficacy and safety study of ertugliflozin, a sodium-glucose co-transporter 2 inhibitor, in patients with type 2 diabetes on a background of metformin. Diabetes Obes. Metab. 17, 591-598 (2015).
357. Amin, N. B. et al. Blood pressure lowering effect of the sodium glucose co-transporter (SGLT2) inhibitor, ertugliflozin, assessed via ambulatory blood pressure monitoring (ABPM), in patients with type 2 diabetes and hypertension. Diabetes Obes. Metab. 17, 805-808 (2015).
358. van Gaal, L. & Scheen, A. Weight management in type 2 diabetes: current and emerging approaches to treatment. Diabetes Care 38, 1161-1172 (2015).
359. Bailey, C. J. Interpreting adverse signals in diabetes drug development programs. Diabetes Care 36, 2098-2106 (2013).