Skip to main content

Cardiorenal Protection: Potential of SGLT2 Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes

Abstract

Recent large clinical trials on sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, with the aim of verifying cardiovascular safety, have revealed that these medications have a preventative advantage on adverse cardiovascular outcomes, including worsening of heart failure and deterioration of nephropathy, in patients with type 2 diabetes (T2D). These observed benefits do not seem to correlate with the glucose-lowering effect, and the underlying mechanism is being intensively investigated. Given the results from recent studies, the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that patients with T2D and clinical cardiovascular disease (CVD) with inadequate glucose control despite treatment with metformin should receive an SGLT2 inhibitor or GLP-1 receptor agonist. In this review we summarize the results of recent cardiovascular outcome trials and discuss the potential clinical advantage of SGLT2 inhibitors and GLP-1 receptor agonists. We also present practical implications of these glucose-lowering agents for reducing the risk of adverse cardiovascular events and progressive renal comorbidity in patients with T2D and CVD.

This is a preview of subscription content, access via your institution.

Fig. 1

References

  1. 1.

    Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med. 2007;356:2457–71.

    CAS  PubMed  Google Scholar 

  2. 2.

    Mahaffey KW, Hafley G, Dickerson S, et al. Results of a reevaluation of cardiovascular outcomes in the RECORD trial. Am Heart J. 2013;166(240–249):e241.

    Google Scholar 

  3. 3.

    White WB, Cannon CP, Heller SR, et al. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369:1327–35.

    CAS  PubMed  Google Scholar 

  4. 4.

    Green JB, Bethel MA, Armstrong PW, et al. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373:232–42.

    CAS  PubMed  Google Scholar 

  5. 5.

    Scirica BM, Bhatt DL, Braunwald E, et al. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369:1317–26.

    CAS  PubMed  Google Scholar 

  6. 6.

    Rosenstock J, Perkovic V, Johansen OE, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk The CARMELINA randomized clinical trial. JAMA. 2019;321:69–79.

    CAS  PubMed  Google Scholar 

  7. 7.

    Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.

    CAS  PubMed  Google Scholar 

  8. 8.

    Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380:347–57.

    CAS  PubMed  Google Scholar 

  9. 9.

    Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.

    CAS  PubMed  Google Scholar 

  10. 10.

    Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial. Lancet. 2018;392:1519–29.

    CAS  PubMed  Google Scholar 

  11. 11.

    Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375:311–22.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.

    CAS  PubMed  Google Scholar 

  13. 13.

    Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. Lancet. 2019;394:121–30.

    CAS  PubMed  Google Scholar 

  14. 14.

    Davies MJ, D’Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;2018(41):2669–701.

    Google Scholar 

  15. 15.

    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). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837–53.

  16. 16.

    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). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352: 854–65.

  17. 17.

    Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358:2545–59.

    CAS  PubMed  Google Scholar 

  18. 18.

    Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;24:2560–72.

    Google Scholar 

  19. 19.

    Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129–39.

    CAS  PubMed  Google Scholar 

  20. 20.

    Rahmoune H, Thompson PW, Ward JM, et al. Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes. 2005;54:3427–34.

    CAS  PubMed  Google Scholar 

  21. 21.

    Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255–70.

    CAS  PubMed  Google Scholar 

  22. 22.

    DeFronzo RA, Davidson JA, Del Prato S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes Metab. 2012;14:5–14.

    CAS  PubMed  Google Scholar 

  23. 23.

    Ferrannini E, Solini A. SGLT2 inhibition in diabetes mellitus: rationale and clinical prospects. Nat Rev Endocrinol. 2012;8:495–502.

    CAS  PubMed  Google Scholar 

  24. 24.

    Zelniker TA, Wiviott SD, Raz I, et al. 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. 2019;393:31–9.

    CAS  PubMed  Google Scholar 

  25. 25.

    Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380:2295–306.

    CAS  PubMed  Google Scholar 

  26. 26.

    Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll Cardiol. 2018;71:2628–39.

    CAS  PubMed  Google Scholar 

  27. 27.

    Solini A, Giannini L, Seghieri M, et al. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16:138.

    PubMed  PubMed Central  Google Scholar 

  28. 28.

    Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61:2108–17.

    CAS  PubMed  Google Scholar 

  29. 29.

    Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129:587–97.

    CAS  PubMed  Google Scholar 

  30. 30.

    Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375:323–34.

    CAS  PubMed  Google Scholar 

  31. 31.

    Cherney DZI, Zinman B, Inzucchi SE, et al. Effects of empagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes and established cardiovascular disease: an exploratory analysis from the EMPA-REG OUTCOME randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2017;5:610–21.

    CAS  PubMed  Google Scholar 

  32. 32.

    Holtkamp FA, de Zeeuw D, Thomas MC, et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int. 2011;80:282–7.

    CAS  PubMed  Google Scholar 

  33. 33.

    Cruzado JM, Rico J, Grinyo JM. The renin angiotensin system blockade in kidney transplantation: pros and cons. Transpl Int. 2008;21:304–13.

    CAS  PubMed  Google Scholar 

  34. 34.

    Chu C, Lu YP, Yin L, et al. The SGLT2 inhibitor empagliflozin might be a new approach for the prevention of acute kidney injury. Kidney Blood Press Res. 2019;44:149–57.

    CAS  PubMed  Google Scholar 

  35. 35.

    Tang H, Li D, Zhang J, et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: A network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2017;19:1106–15.

    CAS  PubMed  Google Scholar 

  36. 36.

    Ferrannini E, Baldi S, Frascerra S, et al. 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;65:1190–5.

    CAS  PubMed  Google Scholar 

  37. 37.

    Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21:512–7.

    CAS  PubMed  Google Scholar 

  38. 38.

    Kuhre RE, Ghiasi SM, Adriaenssens AE, et al. No direct effect of SGLT2 activity on glucagon secretion. Diabetologia. 2019;62:1011–23.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39:1108–14.

    PubMed  Google Scholar 

  40. 40.

    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;39:1115–22.

    CAS  PubMed  Google Scholar 

  41. 41.

    Lambers Heerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15:853–62.

    CAS  PubMed  Google Scholar 

  42. 42.

    Liu J, Li L, Li S, et al. Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep. 2017;7:2824.

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Zhang XL, Zhu QQ, Chen YH, et al. Cardiovascular safety, long-term noncardiovascular safety, and efficacy of sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes mellitus: a systemic review and meta-analysis with trial sequential analysis. J Am Heart Assoc 2018;7(2):e007165. https://doi.org/10.1161/JAHA.117.007165.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Tang H, Li D, Wang T, et al. Effect of sodium-glucose cotransporter 2 inhibitors on diabetic ketoacidosis among patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Diabetes Care. 2016;39:e123–4.

    CAS  PubMed  Google Scholar 

  45. 45.

    Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38:1687–93.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Hayami T, Kato Y, Kamiya H, et al. Case of ketoacidosis by a sodium-glucose cotransporter 2 inhibitor in a diabetic patient with a low-carbohydrate diet. J Diabetes Investig. 2015;6:587–90.

    PubMed  PubMed Central  Google Scholar 

  47. 47.

    Ogawa W, Sakaguchi K. Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig. 2016;7:135–8.

    CAS  PubMed  Google Scholar 

  48. 48.

    Hine J, Paterson H, Abrol E, et al. SGLT inhibition and euglycaemic diabetic ketoacidosis. Lancet Diabetes Endocrinol. 2015;3:503–4.

    CAS  PubMed  Google Scholar 

  49. 49.

    Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38:1638–42.

    CAS  PubMed  Google Scholar 

  50. 50.

    Matthews DR, Li Q, Perkovic V, et al. Effects of canagliflozin on amputation risk in type 2 diabetes: the CANVAS Program. Diabetologia. 2019;62:926–38.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Li D, Yang JY, Wang T, et al. Risks of diabetic foot syndrome and amputation associated with sodium glucose co-transporter 2 inhibitors: a meta-analysis of randomized controlled trials. Diabetes Metab. 2018;44:410–4.

    CAS  PubMed  Google Scholar 

  52. 52.

    Kohler S, Kaspers S, Salsali A, et al. Analysis of fractures in patients with type 2 diabetes treated with empagliflozin in pooled data from placebo-controlled trials and a head-to-head study versus glimepiride. Diabetes Care. 2018;41:1809–16.

    CAS  PubMed  Google Scholar 

  53. 53.

    The American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2019. Diabetes Care 2019;42:S90-S102.

  54. 54.

    Cherney DZI, Cooper ME, Tikkanen I, et al. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int. 2018;93:231–44.

    CAS  PubMed  Google Scholar 

  55. 55.

    Das SR, Everett BM, Birtcher KK, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Decision Pathways. J Am Coll Cardiol. 2018;72:3200–23.

    PubMed  Google Scholar 

  56. 56.

    Perry RJ, Rabin-Court A, Song JD, et al. Dehydration and insulinopenia are necessary and sufficient for euglycemic ketoacidosis in SGLT2 inhibitor-treated rats. Nat Commun. 2019;10:548.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. 57.

    Anandhakrishnan A, Korbonits M. Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical obesity. World J Diabetes. 2016;7:572–98.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8:728–42.

    CAS  PubMed  Google Scholar 

  59. 59.

    Holman RR, Bethel MA, Mentz RJ, et al. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377:1228–39.

    CAS  PubMed  Google Scholar 

  60. 60.

    Pfeffer MA, Claggett B, Diaz R, et al. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373:2247–57.

    CAS  PubMed  Google Scholar 

  61. 61.

    Kaul S. Mitigating cardiovascular risk in type 2 diabetes with antidiabetes drugs: a review of principal cardiovascular outcome results of EMPA-REG OUTCOME, LEADER, and SUSTAIN-6 trials. Diabetes Care. 2017;40:821–31.

    CAS  PubMed  Google Scholar 

  62. 62.

    Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med. 2017;377:839–48.

    CAS  PubMed  Google Scholar 

  63. 63.

    Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial. Lancet Diabetes Endocrinol. 2018;6:605–17.

    CAS  PubMed  Google Scholar 

  64. 64.

    Gerstein HC, Colhoun HM, Dagenais GR, et al. Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial. Lancet. 2019;394:131–8.

    CAS  PubMed  Google Scholar 

  65. 65.

    Bruen R, Curley S, Kajani S, et al. Liraglutide dictates macrophage phenotype in apolipoprotein E null mice during early atherosclerosis. Cardiovasc Diabetol. 2017;16:143.

    PubMed  PubMed Central  Google Scholar 

  66. 66.

    Skov J, Pedersen M, Holst JJ, et al. Short-term effects of liraglutide on kidney function and vasoactive hormones in type 2 diabetes: a randomized clinical trial. Diabetes Obes Metab. 2016;18:581–9.

    CAS  PubMed  Google Scholar 

  67. 67.

    Farah LX, Valentini V, Pessoa TD, et al. The physiological role of glucagon-like peptide-1 in the regulation of renal function. Am J Physiol Renal Physiol. 2016;310:F123–7.

    CAS  PubMed  Google Scholar 

  68. 68.

    Tonneijck L, Smits MM, Muskiet MHA, et al. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial. Diabetologia. 2016;59:1412–21.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Fujita H, Morii T, Fujishima H, et al. The protective roles of GLP-1R signaling in diabetic nephropathy: possible mechanism and therapeutic potential. Kidney Int. 2014;85:579–89.

    CAS  PubMed  Google Scholar 

  70. 70.

    Ceriello A, Novials A, Ortega E, et al. Glucagon-like peptide 1 reduces endothelial dysfunction, inflammation, and oxidative stress induced by both hyperglycemia and hypoglycemia in type 1 diabetes. Diabetes Care. 2013;36:2346–50.

    CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Hasan AA, von Websky K, Reichetzeder C, et al. Mechanisms of GLP-1 receptor-independent renoprotective effects of the dipeptidyl peptidase type 4 inhibitor linagliptin in GLP-1 receptor knockout mice with 5/6 nephrectomy. Kidney Int. 2019;95:1373–88.

    CAS  PubMed  Google Scholar 

  72. 72.

    Hasan AA, Hocher B. Role of soluble and membrane-bound dipeptidyl peptidase-4 in diabetic nephropathy. J Mol Endocrinol. 2017;59:R1–10.

    CAS  PubMed  Google Scholar 

  73. 73.

    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;18:203–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Vilsboll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018;20:889–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Bethel MA, Patel RA, Merrill P, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a meta-analysis. Lancet Diabetes Endocrinol. 2018;6:105–13.

    PubMed  Google Scholar 

  76. 76.

    Margulies KB, Hernandez AF, Redfield MM, et al. Effects of liraglutide on clinical stability among patients with advanced heart failure and reduced ejection fraction: a randomized clinical trial. JAMA. 2016;316:500–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Jorsal A, Kistorp C, Holmager P, et al. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE)—a multicentre, double-blind, randomised, placebo-controlled trial. Eur J Heart Fail. 2017;19:69–77.

    CAS  PubMed  Google Scholar 

  78. 78.

    Owens DR, Monnier L, Barnett AH. Future challenges and therapeutic opportunities in type 2 diabetes: changing the paradigm of current therapy. Diabetes Obes Metab. 2017;19:1339–52.

    CAS  PubMed  PubMed Central  Google Scholar 

  79. 79.

    Meier JJ, Rosenstock J, Hincelin-Mery A, 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. 2015;38:1263–73.

    CAS  PubMed  Google Scholar 

  80. 80.

    Dalsgaard NB, Vilsboll T, Knop FK. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk factors: a narrative review of head-to-head comparisons. Diabetes Obes Metab. 2018;20:508–19.

    CAS  PubMed  Google Scholar 

  81. 81.

    Drucker DJ, Buse JB, Taylor K, et al. Exenatide once weekly versus twice daily for the treatment of type 2 diabetes: a randomised, open-label, non-inferiority study. Lancet. 2008;372:1240–50.

    CAS  PubMed  Google Scholar 

  82. 82.

    Blevins T, Pullman J, Malloy J, et al. DURATION-5: exenatide once weekly resulted in greater improvements in glycemic control compared with exenatide twice daily in patients with type 2 diabetes. J Clin Endocrinol Metab. 2011;96:1301–10.

    CAS  PubMed  Google Scholar 

  83. 83.

    Buse JB, Rosenstock J, Sesti G, 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. 2009;374:39–47.

    CAS  PubMed  Google Scholar 

  84. 84.

    Wysham C, Blevins T, Arakaki R, 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. 2014;37:2159–67.

    CAS  PubMed  Google Scholar 

  85. 85.

    Nauck M, Rizzo M, Johnson A, et al. Once-daily liraglutide versus lixisenatide as add-on to metformin in type 2 diabetes: a 26-week randomized controlled clinical trial. Diabetes Care. 2016;39:1501–9.

    CAS  PubMed  Google Scholar 

  86. 86.

    Kapitza C, Forst T, Coester HV, et al. Pharmacodynamic characteristics of lixisenatide once daily versus liraglutide once daily in patients with type 2 diabetes insufficiently controlled on metformin. Diabetes Obes Metab. 2013;15:642–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Buse JB, Nauck M, Forst T, et al. Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised, open-label study. Lancet. 2013;381:117–24.

    CAS  PubMed  Google Scholar 

  88. 88.

    Dungan KM, Povedano ST, Forst T, 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. 2014;384:1349–57.

    CAS  PubMed  Google Scholar 

  89. 89.

    Nauck MA, Petrie JR, Sesti G, 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. 2016;39:231–41.

    CAS  PubMed  Google Scholar 

  90. 90.

    Ahmann AJ, Capehorn M, Charpentier G, et al. Efficacy and safety of once-weekly semaglutide versus exenatide ER in subjects with type 2 diabetes (SUSTAIN 3): a 56-week, open-label, randomized clinical trial. Diabetes Care. 2018;41:258–66.

    CAS  PubMed  Google Scholar 

  91. 91.

    Singh S, Wright EE Jr, Kwan AY, et al. Glucagon-like peptide-1 receptor agonists compared with basal insulins for the treatment of type 2 diabetes mellitus: a systematic review and meta-analysis. Diabetes Obes Metab. 2017;19:228–38.

    CAS  PubMed  Google Scholar 

  92. 92.

    Inzucchi SE, Bergenstal RM, Buse JB, 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. 2015;38:140–9.

    PubMed  Google Scholar 

  93. 93.

    Carris NW, Taylor JR, Gums JG. Combining a GLP-1 receptor agonist and basal insulin: study evidence and practical considerations. Drugs. 2014;74:2141–52.

    CAS  PubMed  Google Scholar 

  94. 94.

    Frias JP, Guja C, Hardy E, et al. 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. 2016;4:1004–16.

    CAS  PubMed  Google Scholar 

  95. 95.

    Ludvik B, Frias JP, Tinahones FJ, et al. Dulaglutide as add-on therapy to SGLT2 inhibitors in patients with inadequately controlled type 2 diabetes (AWARD-10): a 24-week, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6:370–81.

    CAS  PubMed  Google Scholar 

  96. 96.

    DeFronzo RA. Combination therapy with GLP-1 receptor agonist and SGLT2 inhibitor. Diabetes Obes Metab. 2017;19:1353–62.

    CAS  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Harashima SI, Inagaki N, Kondo K, et al. Efficacy and safety of canagliflozin as add-on therapy to a glucagon-like peptide-1 receptor agonist in Japanese patients with type 2 diabetes mellitus: a 52-week, open-label, phase IV study. Diabetes Obes Metab. 2018;20:1770–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Ishihara H, Yamaguchi S, Nakao I, et al. Ipragliflozin add-on therapy to a GLP-1 receptor agonist in Japanese patients with type 2 diabetes (AGATE): a 52-week open-label study. Diabetes Ther Res Treat Educ Diabetes Rel Disorders. 2018;9:1549–67.

    CAS  Google Scholar 

  99. 99.

    Seino Y, Yabe D, Sasaki T, et al. Sodium-glucose cotransporter-2 inhibitor luseogliflozin added to glucagon-like peptide 1 receptor agonist liraglutide improves glycemic control with bodyweight and fat mass reductions in Japanese patients with type 2 diabetes: a 52-week, open-label, single-arm study. J Diabetes Investig. 2018;9:332–40.

    CAS  PubMed  Google Scholar 

  100. 100.

    Raz I, Wiviott SD, Yanuv I, et al. 244-OR: effects of dapagliflozin on the urinary albumin-to-creatinine ratio in patients with type 2 diabetes: a predefined analysis from the DECLARE-TIMI 58 randomised, placebo-controlled trial. Diabetes. 2019;68[Suppl 1]:244-OR.

    Google Scholar 

  101. 101.

    Bethel MA, Mentz RJ, Merrill P, et al. Renal outcomes in the EXenatide Study of Cardiovascular Event Lowering (EXSCEL). Diabetes. 2018;67[Suppl 1]:522-P.

    Google Scholar 

  102. 102.

    Husain M, Birkenfeld AL, Donsmark M, et al. Oral semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2019. https://doi.org/10.1056/nejmoa1901118.

    Article  PubMed  Google Scholar 

  103. 103.

    Muskiet MHA, Tonneijck L, Huang Y, et al. Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. Lancet Diabetes Endocrinol. 2018;6:859–69.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Dr. Wendy Gray, self-employed, for editing the manuscript.

Funding

No funding or sponsorship was received for this study or publication of this article. Publication fee of this article was waived by the publisher.

Authorship

All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Disclosures

Yoshifumi Saisho received honoraria from Takeda Pharmaceutical Co. Ltd., Japan and Nippon Boehringer Ingelheim Co. Ltd., Japan and a grant from AstraZeneca K.K., Japan not related to the submitted work. Taichi Nagahisa has nothing to disclose.

Compliance with Ethics Guidelines

This article is based on previously conducted studies and does not contain any studies with human participants or animals performed by any of the authors.

Data Availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study.

Open Access

This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yoshifumi Saisho.

Additional information

Enhanced Digital Features

To view enhanced digital features for this article go to https://doi.org/10.6084/m9.figshare.9332171.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nagahisa, T., Saisho, Y. Cardiorenal Protection: Potential of SGLT2 Inhibitors and GLP-1 Receptor Agonists in the Treatment of Type 2 Diabetes. Diabetes Ther 10, 1733–1752 (2019). https://doi.org/10.1007/s13300-019-00680-5

Download citation

Keywords

  • Cardiovascular outcome
  • Glucagon-like peptide-1
  • Sodium-glucose cotransporter-2
  • Type 2 diabetes