Cardiovascular effects of new oral glucose-lowering agents DPP-4 and SGLT-2 inhibitors

Circulation Research

Volumn 122, Issue 10, 2018, Pages 1439-1459

  Scheen, André J ^a,b  

^a UNIVERSITY OF LIÈGE   (Belgium)

^b UNIVERSITY OF LIÈGE   (Belgium)

Author keywords

Empagliflozin; Heart failure; Mortality; Myocardial infarction; Stroke

Indexed keywords

ALOGLIPTIN; CANAGLIFLOZIN; DAPAGLIFLOZIN; DIPEPTIDYL PEPTIDASE IV INHIBITOR; EMPAGLIFLOZIN; ERTUGLIFLOZIN; GLIMEPIRIDE; GLUCOSE; LINAGLIPTIN; PLACEBO; SAXAGLIPTIN; SITAGLIPTIN; SODIUM; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; VILDAGLIPTIN; ANTIDIABETIC AGENT; GLUCAGON LIKE PEPTIDE 1 RECEPTOR; INCRETIN;

ALL CAUSE MORTALITY; BLOOD PRESSURE REGULATION; BODY WEIGHT LOSS; CARDIOVASCULAR DISEASE; CARDIOVASCULAR MORTALITY; CARDIOVASCULAR RISK; DRUG MECHANISM; DRUG SAFETY; GLUCOSURIA; HEART FAILURE; HEART LEFT VENTRICLE VOLUME; HEART PROTECTION; HOSPITALIZATION; HUMAN; MAJOR ADVERSE CARDIAC EVENT; MEDICAL DECISION MAKING; META ANALYSIS (TOPIC); NATRIURESIS; NON INSULIN DEPENDENT DIABETES MELLITUS; PATIENT SELECTION; PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PRIMARY PREVENTION; PRIORITY JOURNAL; REVIEW; TREATMENT DURATION; TREATMENT OUTCOME; CARDIOVASCULAR SYSTEM; CLINICAL TRIAL (TOPIC); COMPLICATION; DIABETIC CARDIOMYOPATHY; DIABETIC NEPHROPATHY; DRUG EFFECT; METABOLISM; MORTALITY; MULTICENTER STUDY (TOPIC); OBSERVATIONAL STUDY; PHARMACOLOGY; RISK;

CARDIOVASCULAR DISEASES; CARDIOVASCULAR SYSTEM; CLINICAL TRIALS AS TOPIC; DIABETES MELLITUS, TYPE 2; DIABETIC CARDIOMYOPATHIES; DIABETIC NEPHROPATHIES; DIPEPTIDYL-PEPTIDASE IV INHIBITORS; GLUCAGON-LIKE PEPTIDE-1 RECEPTOR; HOSPITALIZATION; HUMANS; HYPOGLYCEMIC AGENTS; INCRETINS; META-ANALYSIS AS TOPIC; MULTICENTER STUDIES AS TOPIC; OBSERVATIONAL STUDIES AS TOPIC; RISK; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; TREATMENT OUTCOME;

EID: 85049038376     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.117.311588     Document Type: Review

References (180)

1. Seshasai SR, Kaptoge S, Thompson A, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364:829-841.
2. Newman JD, Schwartzbard AZ, Weintraub HS, Goldberg IJ, Berger JS. Primary prevention of cardiovascular disease in diabetes mellitus. J Am Coll Cardiol. 2017;70:883-893. doi: 10.1016/j.jacc.2017.07.001.
3. Gregg EW, Li Y, Wang J, Burrows NR, Ali MK, Rolka D, Williams DE, Geiss L. Changes in diabetes-related complications in the United States, 1990-2010. N Engl J Med. 2014;370:1514-1523. doi: 10.1056/NEJMoa1310799.
4. Rawshani A, Rawshani A, Franzén S, Eliasson B, Svensson AM, Miftaraj M, McGuire DK, Sattar N, Rosengren A, Gudbjörnsdottir S. Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med. 2017;376:1407-1418. doi: 10.1056/NEJMoa1608664.
5. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia. 2009;52:2288-2298.
6. Hemmingsen B, Lund SS, Gluud C, Vaag A, Almdal TP, Hemmingsen C, Wetterslev J. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2013;11:CD008143.
7. Scheen AJ, Charbonnel B. Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: a critical reappraisal. Diabetes Metab. 2014;40:176-185. doi: 10.1016/j.diabet.2014.03.004.
8. Roussel R, Steg PG, Mohammedi K, Marre M, Potier L. Prevention of cardiovascular disease through reduction of glycaemic exposure in type 2 diabetes: a perspective on glucose-lowering interventions. Diabetes Obes Metab. 2018;20:238-244. doi: 10.1111/dom.13033.
9. Goldfine AB. Assessing the cardiovascular safety of diabetes therapies. N Engl J Med. 2008;359:1092-1095. doi: 10.1056/NEJMp0805758.
10. Zannad F, Stough WG, Lipicky RJ, et al. Assessment of cardiovascular risk of new drugs for the treatment of diabetes mellitus: risk assessment vs. risk aversion. Eur Heart J Cardiovasc Pharmacother. 2016;2:200-205. doi: 10.1093/ehjcvp/pvw007.
11. Ferrannini E, DeFronzo RA. Impact of glucose-lowering drugs on cardiovascular disease in type 2 diabetes. Eur Heart J. 2015;36:2288-2296. doi: 10.1093/eurheartj/ehv239.
12. Standl E, Schnell O, McGuire DK, Ceriello A, Rydén L. Integration of recent evidence into management of patients with atherosclerotic cardiovascular disease and type 2 diabetes. Lancet Diabetes Endocrinol. 2017;5:391-402. doi: 10.1016/S2213-8587(17)30033-5.
13. Chawla H, Tandon N. Interpreting cardiovascular endpoints in trials of antihyperglycemic drugs. Am J Cardiovasc Drugs. 2017;17:203-215. doi: 10.1007/s40256-017-0215-6.
14. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35:992-1019. doi: 10.1210/er.2014-1035.
15. Scheen AJ. A review of gliptins for 2014. Expert Opin Pharmacother. 2015;16:43-62. doi: 10.1517/14656566.2015.978289.
16. Abdul-Ghani MA, Norton L, Defronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev. 2011;32:515-531. doi: 10.1210/er.2010-0029.
17. Scheen AJ. Pharmacodynamics, efficacy and safety of sodium-glucose cotransporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs. 2015;75:33-59. doi: 10.1007/s40265-014-0337-y.
18. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm - 2018 executive summary. Endocr Pract. 2018;24:91-120. doi: 10.4158/CS-2017-0153.
19. American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care. 2018;41:S73-S85.
20. Ussher JR, Drucker DJ. Cardiovascular biology of the incretin system. Endocr Rev. 2012;33:187-215. doi: 10.1210/er.2011-1052.
21. Scheen AJ. Cardiovascular effects of gliptins. Nat Rev Cardiol. 2013;10:73-84. doi: 10.1038/nrcardio.2012.183.
22. Ussher JR, Drucker DJ. Cardiovascular actions of incretin-based therapies. Circ Res. 2014;114:1788-1803. doi: 10.1161/CIRCRESAHA.114.301958.
23. Nauck MA, Meier JJ, Cavender MA, Abd El Aziz M, Drucker DJ. Cardiovascular actions and clinical outcomes with glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Circulation. 2017;136:849-870. doi: 10.1161/CIRCULATIONAHA.117.028136.
24. Michel MC, Mayoux E, Vallon V. A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans. Naunyn Schmiedebergs Arch Pharmacol. 2015;388:801-816. doi: 10.1007/s00210-015-1134-1.
25. Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Cardiol. 2017;120:S28-S36. doi: 10.1016/j.amjcard.2017.05.013.
26. Ferrannini E. Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell Metab. 2017;26:27-38. doi: 10.1016/j.cmet.2017.04.011.
27. Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care. 2016;39(suppl 2):S165-S171. doi: 10.2337/dcS15-3006.
28. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134:752-772. doi: 10.1161/CIRCULATIONAHA.116.021887.
29. Scheen AJ, Delanaye P. Effects of reducing blood pressure on renal outcomes in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Metab. 2017;43:99-109. doi: 10.1016/j.diabet.2016.12.010.
30. Scheen AJ, Delanaye P. Renal outcomes with dipeptidyl peptidase-4 inhibitors. Diabetes Metab. 2018;44:101-111. doi: 10.1016/j.diabet.2017.07.011.
31. Coppolino G, Leporini C, Rivoli L, Ursini F, di Paola ED, Cernaro V, Arturi F, Bolignano D, Russo E, De Sarro G, Andreucci M. Exploring the effects of DPP-4 inhibitors on the kidney from the bench to clinical trials. Pharmacol Res. 2018; 129:274-294.
32. 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. doi: 10.1016/S0140-6736(06)69705-5.
33. Scheen AJ. Safety of dipeptidyl peptidase-4 inhibitors for treating type 2 diabetes. Expert Opin Drug Saf. 2015;14:505-524. doi: 10.1517/14740338.2015.1006625.
34. Scheen AJ. Pharmacokinetics and clinical use of incretin-based therapies in patients with chronic kidney disease and type 2 diabetes. Clin Pharmacokinet. 2015;54:1-21. doi: 10.1007/s40262-014-0198-2.
35. Anderluh M, Kocic G, Tomovic K, Kocic R, Deljanin-Ilic M, Smelcerovic A. Cross-talk between the dipeptidyl peptidase-4 and stromal cell-derived factor-1 in stem cell homing and myocardial repair: potential impact of dipeptidyl peptidase-4 inhibitors. Pharmacol Ther. 2016;167:100-107. doi: 10.1016/j.pharmthera.2016.07.009.
36. McCormick LM, Kydd AC, Read PA, Ring LS, Bond SJ, Hoole SP, Dutka DP. Chronic dipeptidyl peptidase-4 inhibition with sitagliptin is associated with sustained protection against ischemic left ventricular dysfunction in a pilot study of patients with type 2 diabetes mellitus and coronary artery disease. Circ Cardiovasc Imaging. 2014;7:274-281. doi: 10.1161/CIRCIMAGING.113.000785.
37. Yamada H, Tanaka A, Kusunose K, et al; PROLOGUE Study Investigators. Effect of sitagliptin on the echocardiographic parameters of left ventricular diastolic function in patients with type 2 diabetes: a subgroup analysis of the PROLOGUE study. Cardiovasc Diabetol. 2017;16:63. doi: 10.1186/s12933-017-0546-2.
38. White WB, Pratley R, Fleck P, Munsaka M, Hisada M, Wilson C, Menon V. Cardiovascular safety of the dipetidyl peptidase-4 inhibitor alogliptin in type 2 diabetes mellitus. Diabetes Obes Metab. 2013;15:668-673. doi: 10.1111/dom.12093.
39. Iqbal N, Parker A, Frederich R, Donovan M, Hirshberg B. Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials. Cardiovasc Diabetol. 2014;13:33. doi: 10.1186/1475-2840-13-33.
40. Engel SS, Golm GT, Shapiro D, Davies MJ, Kaufman KD, Goldstein BJ. Cardiovascular safety of sitagliptin in patients with type 2 diabetes mellitus: a pooled analysis. Cardiovasc Diabetol. 2013;12:3. doi: 10.1186/1475-2840-12-3.
41. Johansen OE, Neubacher D, von Eynatten M, Patel S, Woerle HJ. Cardiovascular safety with linagliptin in patients with type 2 diabetes mellitus: a pre-specified, prospective, and adjudicated meta-analysis of a phase 3 programme. Cardiovasc Diabetol. 2012;11:3. doi: 10.1186/1475-2840-11-3.
42. McInnes G, Evans M, Del Prato S, Stumvoll M, Schweizer A, Lukashevich V, Shao Q, Kothny W. Cardiovascular and heart failure safety profile of vildagliptin: a meta-analysis of 17 000 patients. Diabetes Obes Metab. 2015;17:1085-1092. doi: 10.1111/dom.12548.
43. Monami M, Ahrén B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab. 2013;15:112-120. doi: 10.1111/dom.12000.
44. Xu S, Zhang X, Tang L, Zhang F, Tong N. Cardiovascular effects of dipeptidyl peptidase-4 inhibitor in diabetic patients with and without established cardiovascular disease: a meta-analysis and systematic review. Postgrad Med. 2017;129:205-215. doi: 10.1080/00325481.2017.1255537.
45. Savarese G, D'Amore C, Federici M, De Martino F, Dellegrottaglie S, Marciano C, Ferrazzano F, Losco T, Lund LH, Trimarco B, Rosano GM, Perrone-Filardi P. Effects of dipeptidyl peptidase 4 inhibitors and sodium-glucose linked cotransporter-2 inhibitors on cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis. Int J Cardiol. 2016;220:595-601. doi: 10.1016/j.ijcard.2016.06.208.
46. Elgendy IY, Mahmoud AN, Barakat AF, Elgendy AY, Saad M, Abuzaid A, Wayangankar SA, Bavry AA. Cardiovascular safety of dipeptidyl-peptidase IV inhibitors: a meta-analysis of placebo-controlled randomized trials. Am J Cardiovasc Drugs. 2017;17:143-155. doi: 10.1007/s40256-016-0208-x.
47. Mahmoud AN, Saad M, Mansoor H, Elgendy AY, Barakat AF, Abuzaid A, Mentias A, Elgendy IY. Cardiovascular safety of incretin-based therapy for type 2 diabetes: a meta-analysis of randomized trials. Int J Cardiol. 2017;230:324-326. doi: 10.1016/j.ijcard.2016.12.113.
48. Abbas AS, Dehbi HM, Ray KK. Cardiovascular and non-cardiovascular safety of dipeptidyl peptidase-4 inhibition: a meta-analysis of randomized controlled cardiovascular outcome trials. Diabetes Obes Metab. 2016;18:295-299. doi: 10.1111/dom.12595.
49. White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Cushman WC, Zannad F; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327-1335. doi: 10.1056/NEJMoa1305889.
50. 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. doi: 10.1056/NEJMoa1307684.
51. Green JB, Bethel MA, Armstrong PW, et al; for the TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232-242. doi: 10.1056/NEJMoa1501352.
52. Shimada YJ, Cannon CP, Liu Y, Wilson C, Kupfer S, Menon V, Cushman WC, Mehta CR, Bakris GL, Zannad F, White WB; EXAMINE Investigators. Ischemic cardiac outcomes and hospitalizations according to prior macrovascular disease status in patients with type 2 diabetes and recent acute coronary syndrome from the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care trial. Am Heart J. 2016;175:18-27. doi: 10.1016/j.ahj.2016.01.011.
53. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, Fleck PR, Mehta CR, Kupfer S, Wilson C, Lam H, White WB; EXAMINE Investigators. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385:2067-2076. doi: 10.1016/S0140-6736(14)62225-X.
54. White WB, Wilson CA, Bakris GL, Bergenstal RM, Cannon CP, Cushman WC, Heller SK, Mehta CR, Nissen SE, Zannad F, Kupfer S; EXAMINE Investigators. Angiotensin-converting enzyme inhibitor use and major cardiovascular outcomes in type 2 diabetes mellitus treated with the dipeptidyl peptidase 4 inhibitor alogliptin. Hypertension. 2016;68:606-613. doi: 10.1161/HYPERTENSIONAHA.116.07797.
55. Devin JK, Pretorius M, Nian H, Yu C, Billings FT IV, Brown NJ. Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition. Hypertension. 2014;63:951-957. doi: 10.1161/HYPERTENSIONAHA.113.02767.
56. Leiter LA, Teoh H, Braunwald E, Mosenzon O, Cahn A, Kumar KM, Smahelova A, Hirshberg B, Stahre C, Frederich R, Bonnici F, Scirica BM, Bhatt DL, Raz I; SAVOR-TIMI 53 Steering Committee and Investigators. Efficacy and safety of saxagliptin in older participants in the SAVOR-TIMI 53 trial. Diabetes Care. 2015;38:1145-1153. doi: 10.2337/dc14-2868.
57. Cavender MA, Scirica BM, Raz I, Steg PG, McGuire DK, Leiter LA, Hirshberg B, Davidson J, Cahn A, Mosenzon O, Im K, Braunwald E, Bhatt DL. Cardiovascular outcomes of patients in SAVOR-TIMI 53 by baseline hemoglobin A1c. Am J Med. 2016;129:340.e1-340.e8. doi: 10.1016/j.amjmed.2015.09.022.
58. Scirica BM, Braunwald E, Raz I, et al; SAVOR-TIMI 53 Steering Committee and Investigators*. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130:1579-1588. doi: 10.1161/CIRCULATIONAHA.114.010389.
59. Scott LJ. Sitagliptin: a review in type 2 diabetes. Drugs. 2017;77:209-224. doi: 10.1007/s40265-016-0686-9.
60. Sharma A, Green JB, Dunning A, et al; TECOS Study Group. Causes of death in a contemporary cohort of patients with type 2 diabetes and atherosclerotic cardiovascular disease: insights from the TECOS trial. Diabetes Care. 2017;40:1763-1770. doi: 10.2337/dc17-1091.
61. Bethel MA, Engel SS, Green JB, Huang Z, Josse RG, Kaufman KD, Standl E, Suryawanshi S, Van de Werf F, McGuire DK, Peterson ED, Holman RR; TECOS Study Group. Assessing the safety of sitagliptin in older participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Diabetes Care. 2017;40:494-501. doi: 10.2337/dc16-1135.
62. McGuire DK, Van de Werf F, Armstrong PW, et al; Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS) Study Group. Association between sitagliptin use and heart failure hospitalization and related outcomes in type 2 diabetes mellitus: secondary analysis of a randomized clinical trial. JAMA Cardiol. 2016;1:126-135. doi: 10.1001/jamacardio.2016.0103.
63. Rosenstock J, Perkovic V, Alexander JH, et al; CARMELINA® investigators. Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk. Cardiovasc Diabetol. 2018;17:39. doi: 10.1186/s12933-018-0682-3.
64. Rosenstock J, Marx N, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Bluhmki E, Patel S, Johansen OE, Woerle HJ. 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. doi: 10.1177/1479164112475102.
65. Marx N, Rosenstock J, Kahn SE, Zinman B, Kastelein JJ, Lachin JM, Espeland MA, Bluhmki E, Mattheus M, Ryckaert B, Patel S, Johansen OE, Woerle HJ. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diab Vasc Dis Res. 2015;12:164-174. doi: 10.1177/1479164115570301.
66. Abdelmoneim AS, Eurich DT, Light PE, Senior PA, Seubert JM, Makowsky MJ, Simpson SH. Cardiovascular safety of sulphonylureas: over 40 years of continuous controversy without an answer. Diabetes Obes Metab. 2015;17:523-532. doi: 10.1111/dom.12456.
67. McMurray JJV, Ponikowski P, Bolli GB, Lukashevich V, Kozlovski P, Kothny W, Lewsey JD, Krum H; VIVIDD Trial Committees and Investigators. Effects of vildagliptin on ventricular function in patients with type 2 diabetes mellitus and heart failure: a randomized placebo-controlled trial. JACC Heart Fail. 2018;6:8-17. doi: 10.1016/j.jchf.2017.08.004.
68. Williams R, de Vries F, Kothny W, Serban C, Lopez-Leon S, Chu C, Schlienger R. Cardiovascular safety of vildagliptin in patients with type 2 diabetes: a European multi-database, non-interventional post-authorization safety study. Diabetes Obes Metab. 2017;19:1473-1478. doi: 10.1111/dom.12951.
69. Scheen AJ, Paquot N. Gliptin versus a sulphonylurea as add-on to metformin. Lancet. 2012;380:450-452. doi: 10.1016/S0140-6736(12)60859-9.
70. Scheen AJ. Cardiovascular effects of dipeptidyl peptidase-4 inhibitors: from risk factors to clinical outcomes. Postgrad Med. 2013;125:7-20. doi: 10.3810/pgm.2013.05.2659.
71. Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet. 2009;373:1765-1772. doi: 10.1016/S0140-6736(09)60697-8.
72. Nauck M. Incretin therapies: highlighting common features and differences in the modes of action of glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes Obes Metab. 2016;18:203-216. doi: 10.1111/dom.12591.
73. Crowley MJ, Williams JW Jr, Kosinski AS, D'Alessio DA, Buse JB. Metformin use may moderate the effect of DPP-4 inhibitors on cardiovascular outcomes. Diabetes Care. 2017;40:1787-1789. doi: 10.2337/dc17-1528.
74. Scheen AJ. Diabetes: Metformin - a cardiovascular moderator of DPP4 inhibitors? Nat Rev Endocrinol. 2018;14:8-9. doi: 10.1038/nrendo.2017.154.
75. Tkáč I, Raz I. Combined analysis of three large interventional trials with gliptins indicates increased incidence of acute pancreatitis in patients with type 2 diabetes. Diabetes Care. 2017;40:284-286. doi: 10.2337/dc15-1707.
76. Li L, Li S, Deng K, et al. Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies. BMJ. 2016;352:i610.
77. Ou SM, Chen HT, Kuo SC, Chen TJ, Shih CJ, Chen YT. Dipeptidyl peptidase-4 inhibitors and cardiovascular risks in patients with pre-existing heart failure. Heart. 2017;103:414-420. doi: 10.1136/heartjnl-2016-309687.
78. Kongwatcharapong J, Dilokthornsakul P, Nathisuwan S, Phrommintikul A, Chaiyakunapruk N. Effect of dipeptidyl peptidase-4 inhibitors on heart failure: a meta-analysis of randomized clinical trials. Int J Cardiol. 2016;211:88-95. doi: 10.1016/j.ijcard.2016.02.146.
79. Verma S, Goldenberg RM, Bhatt DL, Farkouh ME, Quan A, Teoh H, Connelly KA, Leiter LA, Friedrich JO. Dipeptidyl peptidase-4 inhibitors and the risk of heart failure: a systematic review and meta-analysis. CMAJ Open. 2017;5:E152-E177. doi: 10.9778/cmajo.20160058.
80. Standl E, Erbach M, Schnell O. Dipeptidyl-peptidase-4 inhibitors and heart failure: class effect, substance-specific effect, or chance effect? Curr Treat Options Cardiovasc Med. 2014;16:353. doi: 10.1007/s11936-014-0353-y.
81. Cebrián-Cuenca AM, Núñez E, Núñez-Villota J, Consuegra-Sánchez L. What would be the fate of the association between saxagliptin and heart failure admission in the SAVOR-TIMI 53 trial if appropriate statistical methods should have been applied? Diabetes Res Clin Pract. 2017;126:320-321. doi: 10.1016/j.diabres.2017.02.029.
82. Cebrian Cuenca AM, Orozco Beltran D, Navarro Perez J, Alvarez-Guisasola F, Nunez Villota J, Consuegra-Sanchez L. Saxagliptin and heart failure in the SAVOR-TIMI 53 trial: reflections on the Bradford Hill criteria. Rev Esp Cardiol (Engl Ed). 2017;70:1143-1144.
83. Kaneko M, Narukawa M. Assessment of the risk of hospitalization for heart failure with dipeptidyl peptidase-4 inhibitors, saxagliptin, alogliptin, and sitagliptin in patients with type 2 diabetes, using an alternative measure to the hazard ratio. Ann Pharmacother. 2017;51:570-576. doi: 10.1177/1060028017698496.
84. Pollack PS, Chadwick KD, Smith DM, Billger M, Hirshberg B, Iqbal N, Boulton DW. Nonclinical and clinical pharmacology evidence for cardiovascular safety of saxagliptin. Cardiovasc Diabetol. 2017;16:113. doi: 10.1186/s12933-017-0595-6.
85. Koyani CN, Kolesnik E, Wölkart G, et al. Dipeptidyl peptidase-4 independent cardiac dysfunction links saxagliptin to heart failure. Biochem Pharmacol. 2017;145:64-80. doi: 10.1016/j.bcp.2017.08.021.
86. Ou HT, Chang KC, Li CY, Wu JS. Comparative cardiovascular risks of dipeptidyl peptidase 4 inhibitors with other second- and third-line antidiabetic drugs in patients with type 2 diabetes. Br J Clin Pharmacol. 2017;83:1556-1570. doi: 10.1111/bcp.13241.
87. Wang F, He Y, Zhang R, Zeng Q, Zhao X. Combination therapy of metformin plus dipeptidyl peptidase-4 inhibitor versus metformin plus sulfonylurea and their association with a decreased risk of cardiovascular disease in type 2 diabetes mellitus patients. Medicine (Baltimore). 2017;96:e7638. doi: 10.1097/MD.0000000000007638.
88. Scheen AJ, Paquot N. Metabolic effects of SGLT-2 inhibitors beyond increased glucosuria: a review of the clinical evidence. Diabetes Metab. 2014;40:S4-S11. doi: 10.1016/S1262-3636(14)72689-8.
89. Scheen AJ. Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease. Clin Pharmacokinet. 2015;54:691-708. doi: 10.1007/s40262-015-0264-4.
90. Scheen AJ. SGLT2 inhibitors: benefit/risk balance. Curr Diab Rep. 2016;16:92. doi: 10.1007/s11892-016-0789-4.
91. Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, Espadero RM, Woerle HJ, Broedl UC, Johansen OE. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12:90-100. doi: 10.1177/1479164114559852.
92. Imprialos K, Faselis C, Boutari C, Stavropoulos K, Athyros V, Karagiannis A, Doumas M. SGLT-2 inhibitors and cardiovascular risk in diabetes mellitus: a comprehensive and critical review of the literature. Curr Pharm Des. 2017;23:1510-1521. doi: 10.2174/ 1381612823666170124123927.
93. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hy-perglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia. 2017;60:215-225. doi: 10.1007/s00125-016-4157-3.
94. Cai X, Ji L, Chen Y, Yang W, Zhou L, Han X, Zhang S, Ji L. Comparisons of weight changes between sodium-glucose cotransporter 2 inhibitors treatment and glucagon-like peptide-1 analogs treatment in type 2 diabetes patients: a meta-analysis. J Diabetes Investig. 2017;8:510-517. doi: 10.1111/jdi.12625.
95. Ferrannini G, Hach T, Crowe S, Sanghvi A, Hall KD, Ferrannini E. Energy balance after sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1730-1735. doi: 10.2337/dc15-0355.
96. Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of sodium-glucose co-transport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc. 2017;6:e004007. doi: 10.1161/JAHA.116.004007.
97. Baker WL, Buckley LF, Kelly MS, Bucheit JD, Parod ED, Brown R, Carbone S, Abbate A, Dixon DL. Effects of sodium-glucose cotransporter 2 inhibitors on 24-hour ambulatory blood pressure: a systematic review and meta-analysis. J Am Heart Assoc. 2017;6:e005686. doi: 10.1161/JAHA.117.005686.
98. Zhao Y, Xu L, Tian D, Xia P, Zheng H, Wang L, Chen L. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2018;20:458-462. doi: 10.1111/dom.13101.
99. Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res. 2016;8:844-847. doi: 10.14740/jocmr2760w.
100. Bays HE, Sartipy P, Xu J, Sjostrom CD, Underberg JA. Dapagliflozin in patients with type II diabetes mellitus, with and without elevated triglyceride and reduced high-density lipoprotein cholesterol levels. J Clin Lipidol. 2017;11:450 e1-458 e1.
101. Tang H, Zhang X, Zhang J, Li Y, Del Gobbo LC, Zhai S, Song Y. Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials. Diabetologia. 2016;59:2546-2551. doi: 10.1007/s00125-016-4101-6.
102. Filippatos TD, Tsimihodimos V, Liamis G, Elisaf MS. SGLT2 inhibitors-induced electrolyte abnormalities: an analysis of the associated mechanisms. Diabetes Metab Syndr. 2018;12:59-63. doi: 10.1016/j.dsx.2017.08.003.
103. Budoff MJ, Wilding JPH. Effects of canagliflozin on cardiovascular risk factors in patients with type 2 diabetes mellitus. Int J Clin Pract. 2017;71:e12948. doi: 10.1111/ijcp.12948.
104. Deeks ED, Scheen AJ. Canagliflozin: a review in type 2 diabetes. Drugs. 2017;77:1577-1592.
105. Petrykiv S, Sjöström CD, Greasley PJ, Xu J, Persson F, Heerspink HJL. Differential effects of dapagliflozin on cardiovascular risk factors at varying degrees of renal function. Clin J Am Soc Nephrol. 2017;12:751-759. doi: 10.2215/CJN.10180916.
106. Vettor R, Inzucchi SE, Fioretto P. The cardiovascular benefits of empagliflozin: SGLT2-dependent and -independent effects. Diabetologia. 2017;60:395-398. doi: 10.1007/s00125-016-4194-y.
107. Food and Drug Administration: Center for Drug Evaluation and Research. Canagliflozin (Invokana): Summary Review (Application Number: 204042Orig1s000). https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204042Orig1s000ClinPharmR.pdf. 2013. Accessed April 19, 2018.
108. Tang H, Fang Z, Wang T, Cui W, Zhai S, Song Y. Meta-analysis of effects of sodium-glucose cotransporter 2 inhibitors on cardiovascular outcomes and all-cause mortality among patients with type 2 diabetes mellitus. Am J Cardiol. 2016;118:1774-1780. doi: 10.1016/j.amjcard. 2016.08.061.
109. Sonesson C, Johansson PA, Johnsson E, Gause-Nilsson I. Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovasc Diabetol. 2016;15:37. doi: 10.1186/s12933-016-0356-y.
110. Salsali A, Kim G, Woerle HJ, Broedl UC, Hantel S. Cardiovascular safety of empagliflozin in patients with type 2 diabetes: a meta-analysis of data from randomized placebo-controlled trials. Diabetes Obes Metab. 2016;18:1034-1040. doi: 10.1111/dom.12734.
111. Wu JH, Foote C, Blomster J, Toyama T, Perkovic V, Sundström J, Neal B. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016;4:411-419. doi: 10.1016/S2213-8587(16)00052-8.
112. Monami M, Dicembrini I, Mannucci E. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetol. 2017;54:19-36. doi: 10.1007/s00592-016-0892-7.
113. Saad M, Mahmoud AN, Elgendy IY, Abuzaid A, Barakat AF, Elgendy AY, Al-Ani M, Mentias A, Nairooz R, Bavry AA, Mukherjee D. Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: a meta-analysis of placebo-controlled randomized trials. Int J Cardiol. 2017;228:352-358. doi: 10.1016/j.ijcard.2016.11.181.
114. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117-2128. doi: 10.1056/NEJMoa1504720.
115. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME® Trial Investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37:1526-1534. doi: 10.1093/eurheartj/ehv728.
116. Fitchett D, Butler J, van de Borne P, Zinman B, Lachin JM, Wanner C, Woerle HJ, Hantel S, George JT, Johansen OE, Inzucchi SE; EMPA-REG OUTCOME® Trial Investigators. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial. Eur Heart J. 2018;39:363-370. doi: 10.1093/eurheartj/ehx511.
117. Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 Inhibition and cardiovascular events: why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia. 2016;59:1333-1339. doi: 10.1007/s00125-016-3956-x.
118. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323-334. doi: 10.1056/NEJMoa1515920.
119. Scheen AJ. Effects of reducing blood pressure on cardiovascular outcomes and mortality in patients with type 2 diabetes: focus on SGLT2 inhibitors and EMPA-REG OUTCOME. Diabetes Res Clin Pract. 2016;121:204-214. doi: 10.1016/j.diabres.2016.09.016.
120. Zinman B, Inzucchi SE, Lachin JM, Wanner C, Fitchett D, Kohler S, Mattheus M, Woerle HJ, Broedl UC, Johansen OE, Albers GW, Diener HC; EMPA-REG OUTCOME Investigators (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients). Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke. 2017;48:1218-1225. doi: 10.1161/STROKEAHA.116.015756.
121. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644-657. doi: 10.1056/NEJMoa1611925.
122. Neal B, Perkovic V, Mahaffey KW, Fulcher G, Erondu N, Desai M, Shaw W, Law G, Walton MK, Rosenthal N, de Zeeuw D, Matthews DR; CANVAS Program Collaborative Group. Optimizing the analysis strategy for the CANVAS Program: a prespecified plan for the integrated analyses of the CANVAS and CANVAS-R trials. Diabetes Obes Metab. 2017;19:926-935. doi: 10.1111/dom.12924.
123. Raz I, Mosenzon O, Bonaca MP, Cahn A, Kato ET, Silverman MG, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Gause-Nilsson IAM, Langkilde AM, Johansson PA, Sabatine MS, Wiviott SD. DECLARE-TIMI 58: participants' baseline characteristics. Diabetes Obes Metab. 2018;20:1102-1110. doi: 10.1111/dom.13217.
124. Avogaro A, Giaccari A, Fioretto P, Genovese S, Purrello F, Giorgino F, Del Prato S. A consensus statement for the clinical use of the renal sodium-glucose co-transporter-2 inhibitor dapagliflozin in patients with type 2 diabetes mellitus. Expert Rev Clin Pharmacol. 2017;10:763-772. doi: 10.1080/17512433.2017.1322507.
125. Cinti F, Moffa S, Impronta F, Cefalo CM, Sun VA, Sorice GP, Mezza T, Giaccari A. Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther. 2017;11:2905-2919. doi: 10.2147/DDDT.S114932.
126. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jørgensen ME, Thuresson M, Arya N, Bodegård J, Hammar N, Fenici P; CVD-REAL Investigators and Study Group*. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors). Circulation. 2017;136:249-259. doi: 10.1161/CIRCULATIONAHA.117.029190.
127. Kosiborod M, Birkeland KI, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Jørgensen ME, Wittbrodt ET, Thuresson M, Bodegård J, Hammar N, Fenici P; CVD-REAL Investigators and Study Group. Rates of myocardial infarction and stroke in patients initiated on SGLT2-inhibitors versus other glucose-lowering agents in real-world clinical practice: results from the CVD-REAL study [published online ahead of print March 22, 2018]. Diabetes Obes Metab. doi: 10.1111/dom.13299. https://onlinelibrary.wiley.com/doi/epdf/10.1111/dom.13299.
128. Kosiborod M, Lam CSP, Kohsaka S, Kim DJ, Karasik A, Shaw J, Tangri N, Goh SY, Thuresson M, Chen H, Surmont F, Hammar N, Fenici P; CVD-REAL Investigators and Study Group. Lower cardiovascular risk associated with SGLT-2i in >400,000 patients: the CVD-REAL 2 Study [published online ahead of print March 7, 2018]. J Am Coll Cardiol. doi: 10.1016/j.jacc.2018.03.009. https://www.sciencedirect.com/science/article/pii/S0735109718335289?via%3Dihub.
129. Birkeland KI, Jørgensen ME, Carstensen B, Persson F, Gulseth HL, Thuresson M, Fenici P, Nathanson D, Nyström T, Eriksson JW, Bodegård J, Norhammar A. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol. 2017;5:709-717. doi: 10.1016/S2213-8587(17)30258-9.
130. Persson F, Nyström T, Jørgensen ME, Carstensen B, Gulseth HL, Thuresson M, Fenici P, Nathanson D, Eriksson JW, Norhammar A, Bodegard J, Birkeland KI. Dapagliflozin is associated with lower risk of cardiovascular events and all-cause mortality in people with type 2 diabetes (CVD-REAL Nordic) when compared with dipeptidyl peptidase-4 inhibitor therapy: a multinational observational study. Diabetes Obes Metab. 2018;20:344-351. doi: 10.1111/dom.13077.
131. Suissa S. Lower risk of death with SGLT2 inhibitors in observational studies: real or bias? Diabetes Care. 2018;41:6-10. doi: 10.2337/dc17-1223.
132. Scheen AJ. Diabetes: time for reconciliation between cardiologists and diabetologists. Nat Rev Cardiol. 2016;13:509-510. doi: 10.1038/nrcardio.2016.113.
133. Pham SV, Chilton R. EMPA-REG OUTCOME: the cardiologist's point of view. Am J Med. 2017;130:S57-S62. doi: 10.1016/j.amjmed.2017.04.006.
134. Scheen AJ. Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab. 2016;42:71-76. doi: 10.1016/j.diabet.2015.12.005.
135. Perreault L. EMPA-REG OUTCOME: the endocrinologist's point of view. Am J Cardiol. 2017;120:S48-S52. doi: 10.1016/j.amjcard.2017.05.010.
136. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME Study? a unifying hypothesis. Diabetes Care. 2016;39:1115-1122. doi: 10.2337/dc16-0542.
137. McMurray J. EMPA-REG - the “diuretic hypothesis”. J Diabetes Complications. 2016;30:3-4. doi: 10.1016/j.jdiacomp.2015.10.012.
138. Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: comparison with classic diuretics. Diabetes Metab. 2016;42:224-233. doi: 10.1016/j.diabet.2016.05.006.
139. Hallow KM, Helmlinger G, Greasley PJ, McMurray JJV, Boulton DW. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obesity Metab. 2018;20:479-487.
140. Lytvyn Y, Bjornstad P, Udell JA, Lovshin JA, Cherney DZI. Sodium glucose cotransporter-2 inhibition in heart failure: potential mechanisms, clinical applications, and summary of clinical trials. Circulation. 2017;136:1643-1658.
141. Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME Trial. Diabetes Care. 2018;41:356-363. doi: 10.2337/dc17-1096.
142. Ceriello A, Genovese S, Mannucci E, Gronda E. Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol. 2015;3:929-930. doi: 10.1016/S2213-8587(15)00426-X.
143. Ceriello A, Genovese S, Mannucci E, Gronda E. Glucagon and heart in type 2 diabetes: new perspectives. Cardiovasc Diabetol. 2016;15:123. doi: 10.1186/s12933-016-0440-3.
144. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME Trial: a “Thrifty Substrate” hypothesis. Diabetes Care. 2016;39:1108-1114. doi: 10.2337/dc16-0330.
145. Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, Mari A, Pieber TR, Muscelli E. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65:1190-1195. doi: 10.2337/db15-1356.
146. Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol. 2017;2:1025-1029. doi: 10.1001/jamacardio.2017.2275.
147. Scheen AJ. SGLT2 inhibition: efficacy and safety in type 2 diabetes treatment. Expert Opin Drug Saf. 2015;14:1879-1904. doi: 10.1517/14740338.2015.1100167.
148. Qiu R, Balis D, Xie J, Davies MJ, Desai M, Meininger G. Longer-term safety and tolerability of canagliflozin in patients with type 2 diabetes: a pooled analysis. Curr Med Res Opin. 2017;33:553-562. doi: 10.1080/03007995.2016.1271780.
149. Jabbour S, Seufert J, Scheen A, Bailey CJ, Karup C, Langkilde AM. Dapagliflozin in patients with type 2 diabetes mellitus: a pooled analysis of safety data from phase IIb/III clinical trials. Diabetes Obes Metab. 2018;20:620-628. doi: 10.1111/dom.13124.
150. Kohler S, Zeller C, Iliev H, Kaspers S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. Adv Ther. 2017;34:1707-1726. doi: 10.1007/s12325-017-0573-0.
151. Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may predispose to ketoacidosis. J Clin Endocrinol Metab. 2015;100:2849-2852. doi: 10.1210/jc.2015-1884.
152. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638-1642. doi: 10.2337/dc15-1380.
153. Monami M, Nreu B, Zannoni S, Lualdi C, Mannucci E. Effects of SGLT-2 inhibitors on diabetic ketoacidosis: a meta-analysis of randomised controlled trials. Diabetes Res Clin Pract. 2017;130:53-60. doi: 10.1016/j.diabres.2017.04.017.
154. Fralick M, Schneeweiss S, Patorno E. Risk of diabetic ketoacidosis after initiation of an SGLT2 inhibitor. N Engl J Med. 2017;376:2300-2302. doi: 10.1056/NEJMc1701990.
155. Fadini GP, Bonora BM, Avogaro A. SGLT2 inhibitors and diabetic ketoacidosis: data from the FDA Adverse Event Reporting System. Diabetologia. 2017;60:1385-1389. doi: 10.1007/s00125-017-4301-8.
156. Tanaka A, Node K. Increased amputation risk with canagliflozin treatment: behind the large cardiovascular benefit? Cardiovasc Diabetol. 2017;16:129. doi: 10.1186/s12933-017-0611-x.
157. Fadini GP, Avogaro A. SGTL2 inhibitors and amputations in the US FDA Adverse Event Reporting System. Lancet Diabetes Endocrinol. 2017;5:680-681. doi: 10.1016/S2213-8587(17)30257-7.
158. Yuan Z, DeFalco FJ, Ryan PB, Schuemie MJ, Stang PE, Berlin JA, Desai M, Rosenthal N. Risk of lower extremity amputations in people with type 2 diabetes mellitus treated with sodium-glucose co-transporter-2 inhibitors in the USA: a retrospective cohort study. Diabetes Obes Metab. 2018;20:582-589. doi: 10.1111/dom.13115.
159. Inzucchi SE, Iliev H, Pfarr E, Zinman B. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41:e4-e5.
160. Verma S, Mazer CD, Al-Omran M, Inzucchi SE, Fitchett D, Hehnke U, George JT, Zinman B. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: a subanalysis of EMPA-REG OUTCOME. Circulation. 2018;137:405-407. doi: 10.1161/CIRCULATIONAHA.117.032031.
161. Blevins TC, Farooki A. Bone effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, in patients with type 2 diabetes mellitus. Postgrad Med. 2017;129:159-168. doi: 10.1080/00325481.2017.1256747.
162. Scheen AJ. Does lower-limb amputation concern all SGLT-2 inhibitors [published online ahead of print April 6, 2018]? Nature Rev Endocrinol. doi: 10.1038/s41574-018-0001-9.
163. Arnold SV, Inzucchi SE, Tang F, McGuire DK, Mehta SN, Maddox TM, Goyal A, Sperling LS, Einhorn D, Wong ND, Khunti K, Lam CS, Kosiborod M. Real-world use and modeled impact of glucose-lowering therapies evaluated in recent cardiovascular outcomes trials: an NCDR(R) Research to Practice project. Eur J Prev Cardiol. 2017;24:1637-1645.
164. McGovern A, Feher M, Munro N, de Lusignan S. Sodium-glucose cotransporter 2 (SGLT2) inhibitor: comparing trial data and real-world use. Diabetes Ther. 2017;8:365-376. doi: 10.1007/s13300-017-0254-7.
165. Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311-322. doi: 10.1056/NEJMoa1603827.
166. Scheen AJ. GLP-1 receptor agonists and heart failure in diabetes. Diabetes Metab. 2017;43(suppl 1):2S13-2S19.
167. DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab. 2017;19:1353-1362. doi: 10.1111/dom.12982.
168. Butler J, Hamo CE, Filippatos G, et al; EMPEROR Trials Program. The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail. 2017;19:1390-1400. doi: 10.1002/ejhf.933.
169. American Diabetes Association. Standards of medical care in diabetes - 2017. Diabetes Care. 2017;40:S1-S135.
170. Scheen AJ. SGLT2 versus DPP4 inhibitors for type 2 diabetes. Lancet Diabetes Endocrinol. 2013;1:168-170. doi: 10.1016/ S2213-8587(13)70095-0.
171. Scheen AJ. Precision medicine: the future in diabetes care? Diabetes Res Clin Pract. 2016;117:12-21. doi: 10.1016/j.diabres.2016.04.033.
172. Ismail-Beigi F, Moghissi E, Kosiborod M, Inzucchi SE. Shifting paradigms in the medical management of type 2 diabetes: reflections on recent cardiovascular outcome trials. J Gen Intern Med. 2017;32:1044-1051. doi: 10.1007/s11606-017-4061-7.
173. Ponikowski P, Voors AA, Anker SD, et al; ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2016;37:2129-2200. doi: 10.1093/eurheartj/ehw128.
174. Scheen AJ. Pharmacotherapy of 'treatment resistant' type 2 diabetes. Expert Opin Pharmacother. 2017;18:503-515. doi: 10.1080/14656566. 2017.1297424.
175. Scheen AJ. DPP-4 inhibitor plus SGLT-2 inhibitor as combination therapy for type 2 diabetes: from rationale to clinical aspects. Expert Opin Drug Metab Toxicol. 2016;12:1407-1417. doi: 10.1080/ 17425255.2016.1215427.
176. Dey J. SGLT2 inhibitor/DPP-4 inhibitor combination therapy - complementary mechanisms of action for management of type 2 diabetes mellitus. Postgrad Med. 2017;129:409-420. doi: 10.1080/00325481.2017.1307081.
177. Fadini GP, Bonora BM, Mayur S, Rigato M, Avogaro A. Dipeptidyl peptidase-4 inhibitors moderate the risk of genitourinary tract infections associated with sodium-glucose co-transporter-2 inhibitors. Diabetes Obes Metab. 2018;20:740-744. doi: 10.1111/dom.13130.
178. Frías JP, Guja C, Hardy E, Ahmed A, Dong F, Öhman P, Jabbour SA. Exenatide once weekly plus dapagliflozin once daily versus ex-enatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4:1004-1016. doi: 10.1016/ S2213-8587(16)30267-4.
179. Busch RS, Kane MP. Combination SGLT2 inhibitor and GLP-1 receptor agonist therapy: a complementary approach to the treatment of type 2 diabetes. Postgrad Med. 2017;129:686-697. doi: 10.1080/00325481.2017.1342509.
180. Nauck MA, Kahle M, Baranov O, Deacon CF, Holst JJ. Addition of a dipeptidyl peptidase-4 inhibitor, sitagliptin, to ongoing therapy with the glucagon-like peptide-1 receptor agonist liraglutide: a randomized controlled trial in patients with type 2 diabetes. Diabetes Obes Metab. 2017;19:200-207. doi: 10.1111/dom.12802.