Doms № 1 -2022

Doms № 2 -2022 (22-39 p)

Comparative efficacy of sodium-glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials
Tobias Täger, Dan Atar, Stefan Agewall, Hugo A Katus, Morten Grundtvig, John G F Cleland, Andrew L Clark, Hanna Fröhlich, Lutz Frankenstein

Abstract

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with type 2 diabetes mellitus (T2D). The comparative efficacy of individual SGLT2i remains unclear. We searched PubMed, www.clinicaltrials.gov and the Cochrane Central Register of Controlled Trials for randomised controlled trials exploring the use of canagliflozin, dapagliflozin, empagliflozin or ertugliflozin in patients with T2D. Comparators included placebo or any other active treatment. The primary endpoint was all-cause mortality. Secondary endpoints were cardiovascular mortality and worsening heart failure (HF). Evidence was synthesised using network meta-analysis (NMA). Sixty-four trials reporting on 74,874 patients were included. The overall quality of evidence was high. When compared with placebo, empagliflozin and canagliflozin improved all three endpoints, whereas dapagliflozin improved worsening HF. When compared with other SGLT2i, empagliflozin was superior for all-cause and cardiovascular mortality reduction. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Ertugliflozin had no effect on any of the three endpoints investigated. Sensitivity analyses including extension periods of trials or excluding studies with a treatment duration of < 52 weeks confirmed the main results. Similar results were obtained when restricting mortality analyses to patients included in cardiovascular outcome trials (n = 38,719). Empagliflozin and canagliflozin improved survival with empagliflozin being superior to the other SGLT2i. Empagliflozin, canagliflozin and dapagliflozin had similar effects on improving worsening HF. Prospective head-to-head comparisons would be needed to confirm these results.

Keywords: Efficacy; Heart failure; Mortality; Sodium-glucose cotransporter-2 inhibitors; Type 2 diabetes.

References

  1. Liu XY, Zhang N, Chen R, Zhao JG, Yu P (2015) Efficacy and safety of sodium-glucose cotransporter 2 inhibitors in type 2 diabetes: a meta-analysis of randomized controlled trials for 1 to 2years. J Diabetes Complicat 29(8):1295–1303. https://doi.org/10.1016/j. jdiacomp.2015.07.011
  2. Donnan JR, Grandy CA, Chibrikov E, Marra CA, Aubrey-Bassler K, Johnston K, Swab M, Hache J, Curnew D, Nguyen H, Gamble JM (2019) Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ Open 9(1):e022577. https://doi.org/10.1136/bmjo-pen-2018-022577
  3. Zelniker TA, Wiviott SD, Raz I, Im K, Goodrich EL, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Furtado RHM, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Sabatine MS (2019) SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 393(10166):31–39. https://doi.org/10.1016/S0140-6736(18)32590-X
  4. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377(7):644–657. https:// doi.org/10.1056/NEJMoa1611925
  5. Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Zelniker TA, Kuder JF, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Ruff CT, Gause-Nilsson IAM, Fredriksson M, Johans- son PA, Langkilde AM, Sabatine MS, Investigators D-T (2019) Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 380(4):347–357. https:// doi.org/10.1056/NEJMoa1812389
  6. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
  7. Nissen SE, Wolski K (2007) Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 356(24):2457–2471. https:// doi.org/10.1056/NEJMoa072761
  8. Hutton B, Catala-Lopez F, Moher D (2016) The PRISMA statement extension for systematic reviews incorporating network meta-analysis: PRISMA-NMA. Med Clin (Barc) 147(6):262–266. https://doi.org/10.1016/j.medcli.2016.02.025
  9. Moher D, Stewart L, Shekelle P (2016) Implementing PRISMA-P: recommendations for prospective authors. Syst Rev 5:15. https://doi.org/10.1186/s13643-016-0191-y
  10. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, Group P-P (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ 349:g7647. https://doi.org/10.1136/ bmj.g7647
  11. Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Shekelle P, Stewart LA, Group P-P (2015) Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev 4:1. https://doi.org/10.1186/2046-4053-4-1
  12. Higgins J, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0 [updated March 2011]
  13. Higgins JP, Jackson D, Barrett JK, Lu G, Ades AE, White IR (2012) Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods 3(2):98–110. https://doi.org/10.1002/ jrsm.1044
  14. Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G (2013) Graphical tools for network meta-analysis in STATA. PLoS One 8(10):e76654. https://doi.org/10.1371/ journal.pone.0076654
  15. Salanti G (2012) Indirect and mixed-treatment com- parison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Res Synth Methods 3(2):80–97. https://doi.org/10.1002/jrsm.1037
  16. Salanti G, Marinho V, Higgins JP (2009) A case study of multiple-treatments meta-analysis demonstrates that covariates should be considered. J Clin Epidemiol 62(8):857–864. https://doi.org/10.1016/j.jcline-pi.2008.10.001
  17. Salanti G, Del Giovane C, Chaimani A, Caldwell DM,
    Higgins JP (2014) Evaluating the quality of evidence from a network meta-analysis. PLoS One 9(7):e99682. https:// doi.org/10.1371/journal.pone.0099682
  18. Puhan MA, Schunemann HJ, Murad MH, Li T, Brignardello-Petersen R, Singh JA, Kessels AG, Guyatt GH, Group GW (2014) A GRADE Working Group approach for rating the quality of treatment effect estimates from network meta-analysis. BMJ 349:g5630. https://doi. org/10.1136/bmj.g5630
  19. Salanti G, Ades AE, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64(2):163–171. https://doi. org/10.1016/j.jclinepi.2010.03.016
  20. Mbuagbaw L, Rochwerg B, Jaeschke R, Heels-Andsell D, Alhazzani W, Thabane L, Guyatt GH (2017) Approach- es to interpreting and choosing the best treatments in network meta-analyses. Syst Rev 6(1):79. https://doi. org/10.1186/s13643-017-0473-z
  21. Song F, Harvey I, Lilford R (2008) Adjusted indirect comparison may be less biased than direct comparison for evaluating new pharmaceutical interventions. J Clin Epidemiol 61(5):455–463. https://doi.org/10.1016/j. jclinepi.2007.06.006
  22. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF (2010) Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 375(9733):2223–2233. https://doi.org/10.1016/ S0140-6736(10)60407-2
  23. Bailey CJ, Iqbal N, T’Joen C, List JF (2012) Dapagliflozin monotherapy in drug-naive patients with diabetes: a randomized-controlled trial of low-dose range. Diabetes Obes Metab 14(10):951–959. https://doi.org/10.1111/ j.1463-1326.2012.01659.x
  24. Barnett AH, Mithal A, Manassie J, Jones R, Rattunde H, Woerle HJ, Broedl UC, investigators E-RRt (2014) Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebocontrolled trial. Lancet Diabetes Endocrinol 2(5):369–384. https://doi.org/10.1016/S2213-8587(13)70208-0
  25. Bode B, Stenlof K, Sullivan D, Fung A, Usiskin K (2013) Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp Pract (1995) 41(2):72–84. https://doi.org/10.3810/ hp.2013.04.1020
  26. Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S (2012) Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab 97(3):1020–1031. https://doi. org/10.1210/jc.2011-2260
  27. Bolinder J, Ljunggren O, Johansson L, Wilding J, Lang- kilde AM, Sjostrom CD, Sugg J, Parikh S (2014) Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab 16(2):159–169. https://doi. org/10.1111/dom.12189
  28. Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, Balis DA, Canovatchel W, Meininger G (2013) Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 382(9896):941–950. https://doi.org/10.1016/ S0140-6736(13)60683-2
  29. Cefalu WT, Leiter LA, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ (2015) Dapagliflozin’s effects on glycemia and cardiovascular risk factors in high-risk patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. Diabetes Care 38(7):1218–1227. https://doi.org/10.2337/dc14-0315
  30. Dagogo-Jack S, Liu J, Eldor R, Amorin G, Johnson J, Hille D, Liao Y, Huyck S, Golm G, Terra SG, Mancuso JP, Engel SS, Lauring B (2018) Efficacy and safety of the addition of ertugliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sitagliptin: the VERTIS SITA2 placebo-controlled randomized study. Diabetes Obes Metab 20(3):530–540. https://doi.org/10.1111/dom.13116
  31. DeFronzo RA, Lewin A, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC (2015) Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care 38(3):384–393. https://doi.org/10.2337/dc14-2364
  32. Ferdinand KC, Izzo JL, Lee J, Meng L, George J, Salsali A, Seman L (2019) Antihyperglycemic and blood pressure effects of empagliflozin in African Americans with type 2 diabetes and hypertension. Circulation. https://doi. org/10.1161/CIRCULATIONAHA.118.036568
  33. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF (2010) 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(10):2217–2224. https:// doi.org/10.2337/dc10-0612
  34. Fioretto P, Del Prato S, Buse JB, Goldenberg R, Giorgino F, Reyner D, Langkilde AM, Sjostrom CD, Sartipy P, Investigators DS (2018) Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): the DERIVE Study. Diabetes Obes Metab 20(11):2532–2540. https:// doi.org/10.1111/dom.13413
  35. Forst T, Guthrie R, Goldenberg R, Yee J, Vijapurkar U, Meininger G, Stein P (2014) Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab 16(5):467–477. https://doi.org/10.1111/dom.12273
  36. Frias JP, Guja C, Hardy E, Ahmed A, Dong F, Ohman P, Jabbour SA (2016) Exenatide once weekly plus dapagliflozin once daily versus exenatide 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 4(12):1004– 1016. https://doi.org/10.1016/S2213-8587(16)30267-4
  37. Jabbour SA, Frias JP, Hardy E, Ahmed A, Wang H, Ohman P, Guja C (2018) Safety and efficacy of exenatide once weekly plus dapagliflozin once daily versus exenatide or dapa- gliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy: 52-week results of the DURATION-8 randomized controlled trial. Diabetes Care 41(10):2136–2146. https://doi.org/10.2337/dc18-0680
  38. Grunberger G, Camp S, Johnson J, Huyck S, Terra SG, Mancuso JP, Jiang ZW, Golm G, Engel SS, Lauring B (2018) Ertugliflozin in patients with stage 3 chronic kidney disease and type 2 diabetes mellitus: the VERTIS RENAL randomized study. Diabetes Ther 9(1):49–66. https://doi.org/10.1007/s13300-017-0337-5
  39. Hadjadj S, Rosenstock J, Meinicke T, Woerle HJ, Broedl UC (2016) Initial combination of empagliflozin and metformin in patients with type 2 diabetes. Diabetes Care 39(10):1718–1728. https://doi.org/10.2337/dc16-0522
  40. Haring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Woerle HJ, Broedl UC, Investigators E-RMT (2013) 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(11):3396–3404. https://doi.org/10.2337/dc12-2673
  41. Haring HU, Merker L, Seewaldt-Becker E, Weimer M, Meinicke T, Broedl UC, Woerle HJ, Investigators E-RMT (2014) Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care 37(6):1650–1659. https://doi.org/10.2337/dc13-2105
  42. Henry RR, Murray AV, Marmolejo MH, Hennicken D, Ptaszynska A, List JF (2012) Dapagliflozin, metformin XR, or both: initial pharmacotherapy for type 2 diabetes, a randomised controlled trial. Int J Clin Pract 66(5):446– 456. https://doi.org/10.1111/j.1742-1241.2012.02911.x
  43. Hollander P, Liu J, Hill J, Johnson J, Jiang ZW, Golm G, Huyck S, Terra SG, Mancuso JP, Engel SS, Lauring B (2018) Ertugliflozin compared with glimepiride in patients with type 2 diabetes mellitus inadequately con- trolled on metformin: the VERTIS SU randomized study. Diabetes Ther 9(1):193–207. https://doi.org/10.1007/ s13300-017-0354-4
  44. Hollander P, Liu J, Hill J, Johnson J, Jiang ZW, Wang D, Golm G, Huyck S, Terra S, Mancuso JP et al (2018) Safety and efficacy of ertugliflozin compared with glimepiride after 104 weeks in patients with type 2 diabetes inadequately controlled on metformin: VERTIS SU extension. Diabetologia Conference: 54th annual meeting of the European association for the study diabetes, EASD 2018 Germany 61 (Supplement 1):S304-S305. https://doi. org/10.1007/s00125-018-4693-0
  45. Inagaki N, Kondo K, Yoshinari T, Takahashi N, Susuta Y, Kuki H (2014) Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, phase III study. Expert Opin Pharmacother 15(11):1501–1515. https://doi.org/10.1517/14656566.2014.935764
  46. Jabbour SA, Hardy E, Sugg J, Parikh S, Study G (2014) Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care 37(3):740–750. https://doi.org/10.2337/ dc13-0467
  47. Ji L, Ma J, Li H, Mansfield TA, T’Joen CL, Iqbal N, Ptas- zynska A, List JF (2014) Dapagliflozin as monotherapy in drug-naive Asian patients with type 2 diabetes mellitus: a randomized, blinded, prospective phase III study. Clin Ther 36(1):84–100.e109. https://doi.org/10.1016/j. clinthera.2013.11.002
  48. Kadowaki T, Inagaki N, Kondo K, Nishimura K, Kaneko G, Maruyama N, Nakanishi N, Iijima H, Watanabe Y, Gouda M (2017) Efficacy and safety of canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes mellitus: results of a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab 19(6):874–882. https://doi.org/10.1111/dom.12898
  49. Kaku K, Kiyosue A, Inoue S, Ueda N, Tokudome T, Yang J, Langkilde AM (2014) Efficacy and safety of dapagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled by diet and exercise. Diabetes Obes Metab 16(11):1102–1110. https://doi.org/10.1111/ dom.12325
  50. Kohan DE, Fioretto P, Tang W, List JF (2014) Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int 85(4):962–971. https://doi.org/10.1038/ ki.2013.356
  51. Kovacs CS, Seshiah V, Swallow R, Jones R, Rattunde H, Woerle HJ, Broedl UC, investigators E-RPt (2014) 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(2):147–158. https://doi.org/10.1111/dom.12188
  52. Kovacs CS, Seshiah V, Merker L, Christiansen AV, Roux F, Salsali A, Kim G, Stella P, Woerle HJ, Broedl UC, investigators E-REP (2015) Empagliflozin as add-on therapy to pioglitazone with or without metformin in patients with type 2 diabetes mellitus. Clin Ther 37(8):1773–1788 e1771. https://doi.org/10.1016/j.clinthera.2015.05.511

  53. Lavalle-Gonzalez FJ, Januszewicz A, Davidson J, Tong C, Qiu R, Canovatchel W, Meininger G (2013) Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on back-ground metformin monotherapy: a randomised trial. Diabetologia 56(12):2582–2592. https://doi.org/10.1007/ s00125-013-3039-1
  54. Leiter LA, Cefalu WT, de Bruin TW, Gause-Nilsson I, Sugg J, Parikh SJ (2014) Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J Am Geriatr Soc 62(7):1252–1262. https://doi.org/10.1111/jgs.12881
  55. Lewin A, DeFronzo RA, Patel S, Liu D, Kaste R, Woerle HJ, Broedl UC (2015) Initial combination of empagliflozin and linagliptin in subjects with type 2 diabetes. Diabetes Care 38(3):394–402. https://doi.org/10.2337/ dc14-2365
  56. Mathieu C, Ranetti AE, Li D, Ekholm E, Cook W, Hirshberg B, Chen H, Hansen L, Iqbal N (2015) Randomized, double-blind, phase 3 trial of triple therapy with dapagliflozin add-on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care 38(11):2009–2017. https://doi. org/10.2337/dc15-0779
  57. Mathieu C, Herrera Marmolejo M, Gonzalez Gonzalez JG, Hansen L, Chen H, Johnsson E, Garcia-Sanchez R, Iqbal N (2016) Efficacy and safety of triple therapy with dapagliflozin add-on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes. Diabetes Obes Metab 18(11):1134–1137. https://doi.org/10.1111/ dom.12737
  58. Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S, Study G (2015) Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care 38(3):365–372. https://doi. org/10.2337/dc14-0666
  59. Muller-Wieland D, Kellerer M, Cypryk K, Skripova D, Rohwedder K, Johnsson E, Garcia-Sanchez R, Kurlyandskaya R, Sjostrom CD, Jacob S, Seufert J, Dronamraju N, Csomos K (2018) Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add-on to metformin in patients with type 2 diabetes. Diabetes Obes Metab 20(11):2598–2607. https://doi. org/10.1111/dom.13437
  60. Nauck MA, Del Prato S, Meier JJ, Duran-Garcia S, Rohwedder K, Elze M, Parikh SJ (2011) 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(9):2015– 2022. https://doi.org/10.2337/dc11-0606
  61. Perkovic V, Jardine MJ, Neal B, Bompoint S, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Cannon CP, Capuano G, Chu PL, de Zeeuw D, Greene T, Levin A, Pollock C, Wheeler DC, Yavin Y, Zhang H, Zinman B, Meininger G, Brenner BM, Mahaffey KW (2019) Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 380(24):2295–2306. https://doi.org/10.1056/NEJMoa1811744
  62. Phrommintikul A, Wongcharoen W, Kumfu S, Jaiwongkam T, Gunaparn S, Chattipakorn S, Chattipakorn N (2019) Effects of dapagliflozin vs vildagliptin on cardiometabolic parameters in diabetic patients with coronary artery disease: a randomised study. Br J Clin Pharmacol 85(6):1337–1347. https://doi.org/10.1111/bcp.13903
  63. Pollock C, Stefansson B, Reyner D, Rossing P, Sjostrom CD, Wheeler DC, Langkilde AM, Heerspink HJL (2019) Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol 7(6):429–441. https://doi. org/10.1016/S2213-8587(19)30086-5
  64. Pratley RE, Eldor R, Raji A, Golm G, Huyck SB, Qiu Y, Sunga S, Johnson J, Terra SG, Mancuso JP, Engel SS, Lauring B (2018) Ertugliflozin plus sitagliptin versus either individual agent over 52 weeks in patients with type 2 diabetes mellitus inadequately controlled with metformin: the VER- TIS FACTORIAL randomized trial. Diabetes Obes Metab 20(5):1111–1120. https://doi.org/10.1111/dom.13194 CAS Article PubMed PubMed Central Google Scholar
  65. Ridderstrale M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC, investigators E-RHHSt (2014) 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(9):691–700. https:// doi.org/10.1016/S2213-8587(14)70120-2
  66. Ridderstrale M, Rosenstock J, Andersen KR, Woerle HJ, Salsali A, investigators E-RHHSt (2018) Empagliflozin compared with glimepiride in metformin-treated patients with type 2 diabetes: 208-week data from a masked randomized controlled trial. Diabetes Obes Metab 20(12):2768–2777. https://doi.org/10.1111/dom.13457
  67. Rodbard HW, Seufert J, Aggarwal N, Cao A, Fung A, Pfeifer M, Alba M (2016) Efficacy and safety of titrated canagliflozin in patients with type 2 diabetes mellitus inadequately con- trolled on metformin and sitagliptin. Diabetes Obes Metab 18(8):812–819. https://doi.org/10.1111/dom.12684
  68. Roden M, Weng J, Eilbracht J, Delafont B, Kim G, Woerle HJ, Broedl UC, investigators E-RMt (2013) 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(3):208–219. https://doi.org/10.1016/S2213- 8587(13)70084-6
  69. Roden M, Merker L, Christiansen AV, Roux F, Salsali A, Kim G, Stella P, Woerle HJ, Broedl UC, investigators E-REM (2015) Safety, tolerability and effects on cardio-metabolic risk factors of empagliflozin monotherapy in drugnaive patients with type 2 diabetes: a double-blind extension of a phase III randomized controlled trial. Cardiovasc Diabetol 14:154. https://doi.org/10.1186/ s12933-015-0314-0
  70. Rosenstock J, Vico M, Wei L, Salsali A, List JF (2012) Ef- fects of dapagliflozin, an SGLT2 inhibitor, on HbA(1c), body weight, and hypoglycemia risk in patients with type 2 diabetes inadequately controlled on pioglitazone monotherapy. Diabetes Care 35(7):1473–1478. https:// doi.org/10.2337/dc11-1693
  71. Rosenstock J, Hansen L, Zee P, Li Y, Cook W, Hirshberg B, Iqbal N (2015) Dual add-on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double-blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care 38(3):376–383. https://doi.org/10.2337/dc14-1142
  72. Rosenstock J, Jelaska A, Zeller C, Kim G, Broedl UC, Woerle HJ, investigators E-RBt (2015) 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(10):936–948. https://doi.org/10.1111/ dom.12503
  73. Rosenstock J, Chuck L, Gonzalez-Ortiz M, Merton K, Craig J, Capuano G, Qiu R (2016) Initial combination therapy with canagliflozin plus metformin versus each component as monotherapy for drug-naive type 2 diabetes. Diabetes Care 39(3):353–362. https://doi. org/10.2337/dc15-1736
  74. Rosenstock J, Frias J, Pall D, Charbonnel B, Pascu R, Saur D, Darekar A, Huyck S, Shi H, Lauring B, Terra SG (2018) Effect of ertugliflozin on glucose control, body weight, blood pressure and bone density in type 2 diabetes mellitus inadequately controlled on metformin monotherapy (VERTIS MET). Diabetes Obes Metab 20(3):520–529. https://doi.org/10.1111/dom.13103
  75. Schernthaner G, Gross JL, Rosenstock J, Guarisco M, Fu M, Yee J, Kawaguchi M, Canovatchel W, Meininger G (2013) Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52- week randomized trial. Diabetes Care 36(9):2508–2515. https://doi.org/10.2337/dc12-2491
  76. Scott R, Morgan J, Zimmer Z, Lam RLH, O’Neill EA, Kaufman KD, Engel SS, Raji A (2018) A randomized clinical trial of the efficacy and safety of sitagliptin compared with dapagliflozin in patients with type 2 diabetes mellitus and mild renal insufficiency: the CompoSIT-R study. Diabetes Obes Metab 20(12):2876–2884. https:// doi.org/10.1111/dom.13473
  77. Softeland E, Meier JJ, Vangen B, Toorawa R, Maldonado- Lutomirsky M, Broedl UC (2017) Empagliflozin as add-on therapy in patients with type 2 diabetes inadequately
  78. controlled with linagliptin and metformin: a 24-week randomized, double-blind, parallel-group trial. Diabetes Care 40(2):201–209. https://doi.org/10.2337/dc16-1347
  79. Stenlof K, Cefalu WT, Kim KA, Alba M, Usiskin K, Tong C, Canovatchel W, Meininger G (2013) Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes Metab 15(4):372–382. https://doi. org/10.1111/dom.12054
  80. Strojek K, Yoon KH, Hruba V, Elze M, Langkilde AM, Parikh S (2011) Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with glimepiride: a randomized, 24-week, double-blind, placebo-controlled trial. Diabetes Obes Metab 13(10):928–938. https://doi.org/10.1111/j.1463- 1326.2011.01434.x
  81. Strojek K, Yoon KH, Hruba V, Sugg J, Langkilde AM, Parikh S (2014) Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss over 48 weeks: a randomized, double-blind, parallel-group, placebo-controlled trial. Diabetes Ther 5(1):267–283. https://doi.org/10.1007/ s13300-014-0072-0
  82. Terra SG, Focht K, Davies M, Frias J, Derosa G, Darekar A, Golm G, Johnson J, Saur D, Lauring B, Dagogo-Jack S (2017) Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab 19(5):721–728. https://doi. org/10.1111/dom.12888
  83. Wilding JP, Woo V, Soler NG, Pahor A, Sugg J, Rohwedder K, Parikh S, Dapagliflozin 006 Study G (2012) Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann Intern Med 156(6):405–415. https://doi. org/10.7326/0003-4819-156-6-201203200-00003
  84. Wilding JP, Woo V, Rohwedder K, Sugg J, Parikh S, Dapagliflozin 006 Study G (2014) Dapagliflozin in patients with type 2 diabetes receiving high doses of insulin: efficacy and safety over 2 years. Diabetes Obes Metab 16(2):124–136. https://doi.org/10.1111/dom.12187
  85. Wilding JP, Charpentier G, Hollander P, Gonzalez-Galvez G, Mathieu C, Vercruysse F, Usiskin K, Law G, Black S, Canovatchel W, Meininger G (2013) Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus in-adequately controlled with metformin and sulphonylurea: a randomised trial. Int J Clin Pract 67(12):1267–1282. https://doi.org/10.1111/ijcp.12322
  86. Yale JF, Bakris G, Cariou B, Yue D, David-Neto E, Xi L, Figueroa K, Wajs E, Usiskin K, Meininger G (2013) Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab 15(5):463–473. https://doi.org/10.1111/dom.12090
  87. Yang W, Han P, Min KW, Wang B, Mansfield T, T’Joen C, Iqbal N, Johnsson E, Ptaszynska A (2016) Efficacy and safety of dapagliflozin in Asian patients with type 2 diabetes after metformin failure: a randomized controlled trial. J Diabetes 8(6):796–808. https://doi.org/10.1111/1753-0407.12357
  88. Yang W, Ma J, Li Y, Zhou Z, Kim JH, Zhao J, Ptaszynska A (2018) Dapagliflozin as add-on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: a randomized controlled trial. J Diabetes(no pagination). https:// doi.org/10.1111/1753-0407.12634
  89. Schernthaner G, Khunti K, Lotan C, Burnier M, Drexel H, Prazny M (2017) Relevance of positive cardiovascular outcome trial results in clinical practice: perspectives from the Academy for Cardiovascular Risk, Outcomes and Safety Studies in Type 2 Diabetes (ACROSS T2D). Ther Clin Risk Manag 13:1569–1576. https://doi. org/10.2147/tcrm.s144362
  90. Scheen AJ (2015) Pharmacodynamics, efficacy and safety of sodium-glucose co-transporter type 2 (SGLT2) inhibitors for the treatment of type 2 diabetes mellitus. Drugs 75(1):33–59. https://doi.org/10.1007/s40265-014-0337-y
  91. Scheen AJ (2014) Evaluating SGLT2 inhibitors for type 2 diabetes: pharmacokinetic and toxicological considerations. Expert Opin Drug Metab Toxicol 10(5):647–663. https://doi.org/10.1517/17425255.2014.873788
  92. Bloomgarden Z (2018) The kidney and cardiovascular outcome trials. J Diabetes 10(2):88–89. https://doi. org/10.1111/1753-0407.12616
  93. Cannon CP, McGuire DK, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Charbonnel B, Shih WJ, Gallo S, Masiukiewicz U, Golm G, Cosentino F, Lauring B, Terra SG (2018) Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV). Am Heart J 206:11–23. https://doi.org/10.1016/j.ahj.2018.08.016
  94. Fitchett D, Butler J, van de Borne P, Zinman B, Lachin JM, Wanner C, Woerle HJ, Hantel S, George JT, Johansen OE, Inzucchi SE (2018) Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA- REG OUTCOME(R) trial. Eur Heart J 39(5):363–370. https://doi.org/10.1093/eurheartj/ehx511
  95. Radholm K, Figtree G, Perkovic V, Solomon SD, Mahaffey KW, de Zeeuw D, Fulcher G, Barrett TD, Shaw W, Desai M, Matthews DR, Neal B (2018) Canagliflozin and heart failure in type 2 diabetes mellitus. Circulation 138(5):458–468. https://doi.org/10.1161/circulationaha.118.034222
  96. Kato ET, Silverman MG, Mosenzon O, Zelniker TA, Cahn A, Furtado RHM, Kuder J, Murphy SA, Bhatt DL, Leiter LA, McGuire DK, Wilding JPH, Bonaca MP, Ruff CT, De- sai AS, Goto S, Johansson PA, Gause-Nilsson I, Johanson P, Langkilde AM, Raz I, Sabatine MS, Wiviott SD (2019) Effect of dapagliflozin on heart failure and mortality in type 2 diabetes mellitus. Circulation 139(22):2528–2536. https://doi.org/10.1161/circulationaha.119.040130
  97. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, investigators E-ROt (2016) Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J 37(19):1526–1534. https://doi.org/10.1093/eurheartj/ehv728
  98. Psaty BM, Lumley T, Furberg CD, Schellenbaum G, Pahor M, Alderman MH, Weiss NS (2003) Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 289(19):2534–2544. https://doi.org/10.1001/ jama.289.19.2534
  99. Staels B (2017) Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Med 130(6S):S30–S39. https://doi.org/10.1016/j. amjmed.2017.04.009
  100. Marti CN, Gheorghiade M, Kalogeropoulos AP, Georgiopoulou VV, Quyyumi AA, Butler J (2012) Endothelial dysfunction, arterial stiffness, and heart failure. J Am Coll Cardiol 60(16):1455–1469. https://doi.org/10.1016/j. jacc.2011.11.082
  101. Zheng SL, Roddick AJ, Aghar-Jaffar R, Shun-Shin MJ, Francis D, Oliver N, Meeran K (2018) Association between use of sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 agonists, and dipeptidyl peptidase 4 inhibitors with all-cause mortality in patients with type 2 diabetes: a systematic review and meta-analysis. JAMA 319(15):1580–1591. https://doi.org/10.1001/ jama.2018.3024
  102. Yang DY, He X, Liang HW, Zhang SZ, Zhong XB, Luo CF, Du ZM, He JG, Zhuang XD, Liao XX (2019) Comparative outcomes of heart failure among existent classes of anti-diabetic agents: a network meta-analysis of 171,253 participants from 91 randomized controlled trials. Cardiovasc Diabetol 18(1):47. https://doi.org/10.1186/ s12933-019-0853-x
  103. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosi- borod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM, Committees D-HT, Investigators (2019) Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. https://doi.org/10.1056/NEJMoa1911303

 

Originally published: Täger, T., Atar, D., Agewall, S. et al. Comparative efficacy of sodium- glucose cotransporter-2 inhibitors (SGLT2i) for cardiovascular outcomes in type 2 diabetes: a systematic review and network meta-analysis of randomised controlled trials. Heart Fail Rev 26, 1421–1435 (2021). https://doi.org/10.1007/ s10741-020-09954-8

CC Attribution-ShareAlike 4.0 International.