Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Kidney and heart failure outcomes associated with SGLT2 inhibitor use

Abstract

Chronic kidney disease (CKD) and heart failure affect many people worldwide. Despite the availability of pharmacological treatments, both diseases remain associated with considerable morbidity and mortality. After observations that sodium–glucose co-transporter 2 (SGLT2) inhibitors — originally developed as glucose-lowering agents — improved cardiovascular and renal outcomes in patients with type 2 diabetes, dedicated trials were initiated to evaluate the cardiovascular and kidney protective effects in patients with CKD or heart failure. The results of these clinical trials and subsequent detailed analyses have shown that the benefits of SGLT2 inhibitors are consistent across many patient subgroups, including those with and without type 2 diabetes, at different stages of CKD, and in patients with heart failure with preserved or reduced ejection fraction. In addition, post-hoc analyses revealed that SGLT2 inhibitors reduce the risk of anaemia and hyperkalaemia in patients with CKD. With respect to their safety, SGLT2 inhibitors are generally well tolerated. More specifically, no increased risk of hypoglycaemia has been observed in patients with CKD or heart failure without diabetes and they do not increase the risk of acute kidney injury. SGLT2 inhibitors therefore provide clinicians with an exciting new treatment option for patients with CKD and heart failure.

Key points

  • Individuals with chronic kidney disease (CKD) are at an increased risk of heart failure; conversely, kidney function decline is common in individuals with heart failure.

  • Sodium–glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of kidney disease progression and hospitalization for heart failure, both in patients with CKD and in patients with heart failure.

  • The beneficial effects of SGLT2 inhibitors on kidney function and heart failure are consistent across stages of CKD and independent of the severity of heart failure.

  • SGLT2 inhibitors reduce the risk of anaemia and hyperkalaemia, which are common complications in patients with CKD or heart failure.

  • The characteristic decline in estimated glomerular filtration rate after initiation of SGLT2 inhibitors reflects their renal haemodynamic effects and is not associated with an increased risk of acute kidney injury or accelerated loss of kidney function.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Association between CKD and heart failure.
Fig. 2: Effect of SGLT2 inhibitors on kidney failure.
Fig. 3: Risk of acute kidney injury with SGLT2i use.
Fig. 4: Effect of SGLT2i on heart failure end points according to baseline kidney function.

References

  1. White, J. R. Apple trees to sodium glucose co-transporter inhibitors: a review of SGLT2 inhibition. Clin. Diabetes 28, 5–10 (2010).

    Article  Google Scholar 

  2. Chasis, H., Jolliffe, N. & Smith, H. W. The action of phlorizin on the excretion of glucose, xylose, sucrose, creatinine and urea by man. J. Clin. Invest. 12, 1083–1090 (1933).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Heerspink, H. J. L., Perkins, B. A., Fitchett, D. H., Husain, M. & Cherney, D. Z. I. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation 134, 752–772 (2016).

    CAS  Article  PubMed  Google Scholar 

  4. Heerspink, H. J. L., Kosiborod, M., Inzucchi, S. E. & Cherney, D. Z. I. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int. 94, 26–39 (2018).

    CAS  Article  PubMed  Google Scholar 

  5. Lee, W. S., Kanai, Y., Wells, R. G. & Hediger, M. A. The high affinity Na+/glucose cotransporter. Re-evaluation of function and distribution of expression. J. Biol. Chem. 269, 12032–12039 (1994).

    CAS  Article  PubMed  Google Scholar 

  6. Abdul-Ghani, M. A. & DeFronzo, R. A. Inhibition of renal glucose reabsorption: a novel strategy for achieving glucose control in type 2 diabetes mellitus. Endocr. Pract. 14, 782–790 (2008).

    Article  PubMed  Google Scholar 

  7. Tsujihara, K. et al. Na+-glucose cotransporter inhibitors as antidiabetics. I. Synthesis and pharmacological properties of 4’-dehydroxyphlorizin derivatives based on a new concept. Chem. Pharm. Bull. 44, 1174–1180 (1996).

    CAS  Article  Google Scholar 

  8. Pollock, C. A., Lawrence, J. R. & Field, M. J. Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. Am. J. Physiol. 260, F946–F952 (1991).

    CAS  PubMed  Google Scholar 

  9. Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).

    CAS  Article  PubMed  Google Scholar 

  10. Neal, B. et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377, 644–657 (2017).

    CAS  Article  PubMed  Google Scholar 

  11. Wiviott, S. D. et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med. 380, 347–357 (2019).

    CAS  Article  PubMed  Google Scholar 

  12. Wanner, C. et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med. 375, 323–334 (2016).

    CAS  Article  PubMed  Google Scholar 

  13. Cannon, C. P. et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N. Engl. J. Med. 383, 1425–1435 (2020).

    CAS  Article  PubMed  Google Scholar 

  14. Tuegel, C. & Bansal, N. Heart failure in patients with kidney disease. Heart Br. Card. Soc. 103, 1848–1853 (2017).

    CAS  Google Scholar 

  15. Jankowski, J., Floege, J., Fliser, D., Böhm, M. & Marx, N. Cardiovascular disease in chronic kidney disease: pathophysiological insights and therapeutic options. Circulation 143, 1157–1172 (2021).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  16. DeFronzo, R. A., Reeves, W. B. & Awad, A. S. Pathophysiology of diabetic kidney disease: impact of SGLT2 inhibitors. Nat. Rev. Nephrol. 17, 319–334 (2021).

    CAS  Article  PubMed  Google Scholar 

  17. Petrykiv, S. et al. Differential effects of dapagliflozin on cardiovascular risk factors at varying degrees of renal function. Clin. J. Am. Soc. Nephrol. 12, 751–759 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Levin, A. et al. Empagliflozin and cardiovascular and kidney outcomes across KDIGO risk categories: post hoc analysis of a randomized, double-blind, placebo-controlled, multinational trial. Clin. J. Am. Soc. Nephrol. 15, 1433–1444 (2020).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  19. Mosenzon, O. et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol. 7, 606–617 (2019).

    CAS  Article  PubMed  Google Scholar 

  20. Perkovic, V. et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 6, 691–704 (2018).

    CAS  Article  PubMed  Google Scholar 

  21. Neuen, B. L. et al. Cardiovascular and renal outcomes with canagliflozin according to baseline kidney function. Circulation 138, 1537–1550 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Neuen, B. L. et al. Effect of canagliflozin on renal and cardiovascular outcomes across different levels of albuminuria: data from the CANVAS program. J. Am. Soc. Nephrol. 30, 2229–2242 (2019).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. Neuen, B. L. et al. Relative and absolute risk reductions in cardiovascular and kidney outcomes with canagliflozin across KDIGO risk categories: findings from the CANVAS program. Am. J. Kidney Dis. 77, 23–34.e1 (2021).

    CAS  Article  PubMed  Google Scholar 

  24. Perkovic, V. et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med. 380, 2295–2306 (2019).

    CAS  Article  PubMed  Google Scholar 

  25. Heerspink, H. J. L. et al. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med. 383, 1436–1446 (2020).

    CAS  Article  PubMed  Google Scholar 

  26. Wheeler, D. C. et al. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol. 9, 22–31 (2021).

    CAS  Article  PubMed  Google Scholar 

  27. Bhatt, D. L. et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N. Engl. J. Med. 384, 129–139 (2021).

    CAS  Article  PubMed  Google Scholar 

  28. Jardine, M. J. et al. Renal, cardiovascular, and safety outcomes of canagliflozin by baseline kidney function: a secondary analysis of the CREDENCE randomized trial. J. Am. Soc. Nephrol. 31, 1128–1139 (2020).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Jardine, M. et al. Kidney, cardiovascular, and safety outcomes of canagliflozin according to baseline albuminuria: a CREDENCE secondary analysis. Clin. J. Am. Soc. Nephrol. 16, 384–395 (2021).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  30. Bakris, G. et al. Effects of canagliflozin in patients with baseline eGFR <30 ml/min per 1.73 m2: subgroup analysis of the randomized CREDENCE trial. Clin. J. Am. Soc. Nephrol. 15, 1705–1714 (2020).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  31. Chertow, G. et al. Effects of dapagliflozin in stage 4 chronic kidney disease. J. Am. Soc. Nephrol. 32, 2352–2361 (2021).

    CAS  Article  PubMed  Google Scholar 

  32. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03594110 (2022).

  33. Herrington, W. G. et al. The potential for improving cardio-renal outcomes by sodium-glucose co-transporter-2 inhibition in people with chronic kidney disease: a rationale for the EMPA-KIDNEY study. Clin. Kidney J. 11, 749–761 (2018).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  34. Bays, H. E., Weinstein, R., Law, G. & Canovatchel, W. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity 22, 1042–1049 (2014).

    CAS  Article  PubMed  Google Scholar 

  35. Heerspink, H. J. L. et al. Canagliflozin slows progression of renal function decline independently of glycemic effects. J. Am. Soc. Nephrol. 28, 368–375 (2017).

    CAS  Article  PubMed  Google Scholar 

  36. Sen, T. & Heerspink, H. J. L. A kidney perspective on the mechanism of action of sodium glucose co-transporter 2 inhibitors. Cell Metab. 33, 732–739 (2021).

    CAS  Article  PubMed  Google Scholar 

  37. Cherney, D. Z. I. et al. Effects of the SGLT2 inhibitor dapagliflozin on proteinuria in non-diabetic patients with chronic kidney disease (DIAMOND): a randomised, double-blind, crossover trial. Lancet Diabetes Endocrinol. 8, 582–593 (2020).

    CAS  Article  PubMed  Google Scholar 

  38. Persson, F. et al. Efficacy and safety of dapagliflozin by baseline glycemic status: a prespecified analysis from the DAPA-CKD Trial. Diabetes Care 44, 1894–1897 (2021).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. Wheeler, D. C. et al. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int. 100, 215–224 (2021).

    CAS  Article  PubMed  Google Scholar 

  40. Wheeler, D. C. et al. Effects of dapagliflozin in major adverse kidney events in patients with focal segmental glomerulosclerosis: a prespecified analysis of the DAPA-CKD trial. Lancet Diabetes Endocrinol. 9, 22–31 (2021).

    CAS  Article  PubMed  Google Scholar 

  41. Zelniker, T. A. 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 393, 31–39 (2019).

    CAS  Article  PubMed  Google Scholar 

  42. Mahaffey, K. W. et al. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation 140, 739–750 (2019).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  43. Matsushita, K. et al. Estimated glomerular filtration rate and albuminuria for prediction of cardiovascular outcomes: a collaborative meta-analysis of individual participant data. Lancet Diabetes Endocrinol. 3, 514–525 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Heerspink, H. J. L., de Zeeuw, D., Wie, L., Leslie, B. & List, J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes. Metab. 15, 853–862 (2013).

    Article  CAS  PubMed Central  Google Scholar 

  45. van Bommel, E. J. M. et al. The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial. Kidney Int. 97, 202–212 (2020).

    Article  CAS  PubMed  Google Scholar 

  46. Kraus, B. J. et al. Characterization and implications of the initial estimated glomerular filtration rate “dip” upon sodium-glucose cotransporter-2 inhibition with empagliflozin in the EMPA-REG OUTCOME trial. Kidney Int. 99, 750–762 (2021).

    CAS  Article  PubMed  Google Scholar 

  47. Oshima, M. et al. Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice. Kidney Int. 99, 999–1009 (2021).

    CAS  Article  PubMed  Google Scholar 

  48. Neuen, B. L. et al. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 7, 845–854 (2019).

    CAS  Article  PubMed  Google Scholar 

  49. Menne, J., Dumann, E., Haller, H. & Schmidt, B. M. W. Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: a systematic review and meta-analysis. PLoS Med. 16, e1002983 (2019).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Donnan, J. R. et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ Open 9, e022577 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  51. Cahn, A., Melzer-Cohen, C., Pollack, R., Chodick, G. & Shalev, V. Acute renal outcomes with sodium-glucose co-transporter-2 inhibitors: real-world data analysis. Diabetes Obes. Metab. 21, 340–348 (2019).

    CAS  Article  PubMed  Google Scholar 

  52. Iskander, C. et al. Use of sodium-glucose cotransporter-2 inhibitors and risk of acute kidney injury in older adults with diabetes: a population-based cohort study. CMAJ 192, E351–E360 (2020).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  53. Rampersad, C. et al. Acute kidney injury events in patients with type 2 diabetes using SGLT2 inhibitors versus other glucose-lowering drugs: a retrospective cohort study. Am. J. Kidney 76, 471–479.e1 (2020).

    CAS  Article  Google Scholar 

  54. Heerspink, H. J. L. et al. Canagliflozin and kidney-related adverse events in type 2 diabetes and CKD: findings from the randomized CREDENCE trial. Am. J. Kidney Dis. 79, 244–256.e1 (2022).

    CAS  Article  PubMed  Google Scholar 

  55. Heerspink, H. J. L. et al. Effects of dapagliflozin on the incidence of abrupt declines in kidney function: a pre-specified analysis of the DAPA-CKD randomized controlled trial. Kidney Int. 101, 174–184 (2021).

    Article  CAS  PubMed  Google Scholar 

  56. Heerspink, H. J. L. & Cherney, D. Z. I. Clinical implications of an acute dip in eGFR after SGLT2 inhibitor initiation. Clin. J. Am. Soc. Nephrol. 16, 1278–1280 (2021).

    Article  PubMed  Google Scholar 

  57. Ku, E., Lee, B. J., Wei, J. & Weir, M. R. Hypertension in CKD: core curriculum 2019. Am. J. Kidney Dis. 74, 120–131 (2019).

    Article  PubMed  Google Scholar 

  58. Mazidi, M., Rezaie, P., Gao, H. K. & Kengne, A. P. Effect of sodium-glucose cotransport-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. 6, e004007 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  59. Ye, N. et al. Blood pressure effects of canagliflozin and clinical outcomes in type 2 diabetes and chronic kidney disease: insights from the CREDENCE trial. Circulation 143, 1735–1749 (2021).

    CAS  Article  PubMed  Google Scholar 

  60. Scholtes, R. A. et al. Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: results of the DAPASALT Trial. Diabetes Care 44, 440–447 (2021).

    CAS  Article  PubMed  Google Scholar 

  61. Ghanim, H. et al. Dapagliflozin reduces systolic blood pressure and modulates vasoactive factors. Diabetes Obes. Metab. 23, 1614–1623 (2021).

    CAS  Article  PubMed  Google Scholar 

  62. Sano, M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J. Cardiol. 71, 471–476 (2018).

    Article  PubMed  Google Scholar 

  63. El-Achkar, T. M. et al. Higher prevalence of anemia with diabetes mellitus in moderate kidney insufficiency: the Kidney Early Evaluation Program. Kidney Int. 67, 1483–1488 (2005).

    Article  PubMed  Google Scholar 

  64. Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int. Suppl. 2, 279–335 (2012).

    Article  Google Scholar 

  65. Pfeffer, M. A. et al. A trial of darbepoetin alfa in type 2 diabetes and chronic kidney disease. N. Engl. J. Med. 361, 2019–2032 (2009).

    Article  PubMed  Google Scholar 

  66. Sano, M. & Goto, S. Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation 139, 1985–1987 (2019).

    CAS  Article  PubMed  Google Scholar 

  67. Maruyama, T. et al. Canagliflozin improves erythropoiesis in diabetes patients with anemia of chronic kidney disease. Diabetes Technol. Ther. 21, 713–720 (2019).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  68. Oshima, M. et al. Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol. 8, 903–914 (2020).

    CAS  Article  PubMed  Google Scholar 

  69. Mazer, C. D. et al. Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation 141, 704–707 (2020).

    Article  PubMed  Google Scholar 

  70. Ghanim, H. et al. Dapagliflozin suppresses hepcidin and increases erythropoiesis. J. Clin. Endocrinol. Metab. 105, dgaa057 (2020).

    Article  PubMed  Google Scholar 

  71. US Food and Drug Administration. INVOKANA (canagliflozin) tablets (FDA, 2016).

  72. Yavin, Y. et al. Effect of the SGLT2 inhibitor dapagliflozin on potassium levels in patients with type 2 diabetes mellitus: a pooled analysis. Diabetes Ther. 7, 125–137 (2016).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  73. Weir, M. R. et al. Effects of canagliflozin on serum potassium in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. Clin. Kidney J. 14, 1396–1402 (2021).

    CAS  Article  PubMed  Google Scholar 

  74. Neuen, B. L. et al. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: the CREDENCE trial. Eur. Heart J. 42, 4891–4901 (2021).

    CAS  Article  PubMed  Google Scholar 

  75. Bakris, G. L. et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes. N. Engl. J. Med. 383, 2219–2229 (2020).

    CAS  Article  PubMed  Google Scholar 

  76. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT04595370 (2021).

  77. Provenzano M., et al. Study design of the rotation for optimal targeting of albuminuria and treatment evaluation (ROTATE-3): a rotation study of different albuminuria lowering drugs classes to study individual drug response in diabetic and non-diabetic CKD. Nephrol. Dial. Transpl. 35 (Suppl. 3), gfaa142.P1003 (2020).

    Article  Google Scholar 

  78. Groenewegen, A., Rutten, F. H., Mosterd, A. & Hoes, A. W. Epidemiology of heart failure. Eur. J. Heart Fail. 22, 1342–1356 (2020).

    Article  PubMed  Google Scholar 

  79. Damman, K. & Testani, J. M. The kidney in heart failure: an update. Eur. Heart J. 36, 1437–1444 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Ishigami, J. et al. Acceleration of kidney function decline after incident hospitalization with cardiovascular disease: the Stockholm CREAtinine Measurements (SCREAM) project. Eur. J. Heart Fail. 22, 1790–1799 (2020).

    CAS  Article  PubMed  Google Scholar 

  81. McMurray, J. J. & Stewart, S. Epidemiology, aetiology, and prognosis of heart failure. Heart 83, 596–602 (2000).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. Hallow, K. M., Helmlinger, G., Greasley, P. J., McMurray, J. J. V. & Boulton, D. W. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes. Metab. 20, 479–487 (2018).

    CAS  Article  PubMed  Google Scholar 

  83. Joshi, S. S., Singh, T., Newby, D. E. & Singh, J. Sodium-glucose co-transporter 2 inhibitor therapy: mechanisms of action in heart failure. Heart 107, 1032–1038 (2021).

    CAS  Article  Google Scholar 

  84. de Leeuw, A. E. & de Boer, R. A. Sodium-glucose cotransporter 2 inhibition: cardioprotection by treating diabetes — a translational viewpoint explaining its potential salutary effects. Eur. Heart J. Cardiovasc. Pharmacother. 2, 244–255 (2016).

    Article  CAS  PubMed  Google Scholar 

  85. Arnold, J. M. O. et al. Prevention of heart failure in patients in the heart outcomes prevention evaluation (HOPE) study. Circulation 107, 1284–1290 (2003).

    CAS  Article  PubMed  Google Scholar 

  86. NAVIGATOR Study Group, McMurray, J. J. et al. Effect of valsartan on the incidence of diabetes and cardiovascular events. N. Engl. J. Med. 362, 1477–1490 (2010).

    Article  Google Scholar 

  87. McMurray, J. J. V. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 381, 1995–2008 (2019).

    CAS  Article  PubMed  Google Scholar 

  88. Petrie, M. C. et al. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA 323, 1353–1368 (2020).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. Inzucchi, S. E. et al. Dapagliflozin and the incidence of type 2 diabetes in patients with heart failure and reduced ejection fraction: an exploratory analysis from DAPA-HF. Diabetes Care 44, 586–594 (2021).

    CAS  Article  PubMed  Google Scholar 

  90. Packer, M. et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383, 1413–1424 (2020).

    CAS  Article  PubMed  Google Scholar 

  91. Zannad, F. et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 396, 819–829 (2020).

    Article  PubMed  Google Scholar 

  92. Anker, S. D. et al. Empagliflozin in heart failure with a preserved ejection fraction. N. Engl. J. Med. 385, 1451–1461 (2021).

    CAS  Article  PubMed  Google Scholar 

  93. Szarek, M. et al. Effect of sotagliflozin on total hospitalizations in patients with type 2 diabetes and worsening heart failure: a randomized trial. Ann. Intern. Med. 174, 1065–1072 (2021).

    Article  PubMed  Google Scholar 

  94. Jhund, P. S. et al. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction: results of DAPA-HF. Circulation 143, 298–309 (2021).

    CAS  Article  PubMed  Google Scholar 

  95. Zannad, F. et al. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-reduced. Circulation 143, 310–321 (2021).

    CAS  Article  PubMed  Google Scholar 

  96. McMurray, J. J. V. et al. Effects of dapagliflozin in patients with kidney disease, with and without heart failure. JACC Heart Fail. 9, 807–820 (2021).

    Article  PubMed  Google Scholar 

  97. Jackson, A. M. et al. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation 142, 1040–1054 (2020).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. Solomon, S. D. et al. Effect of dapagliflozin in patients with HFrEF treated with sacubitril/valsartan: the DAPA-HF Trial. JACC Heart Fail. 8, 811–818 (2020).

    Article  PubMed  Google Scholar 

  99. Shen, L. et al. Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail. 9, 254–264 (2021).

    Article  PubMed  Google Scholar 

  100. Packer, M. et al. Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: the EMPEROR-Reduced trial. Eur. Heart J. 42, 671–680 (2021).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  101. Ferreira, J. P. et al. Interplay of mineralocorticoid receptor antagonists and empagliflozin in heart failure: EMPEROR-reduced. J. Am. Coll. Cardiol. 77, 1397–1407 (2021).

    CAS  Article  PubMed  Google Scholar 

  102. Docherty, K. F. et al. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur. Heart J. 41, 2379–2392 (2020).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  103. Pieske, B. et al. How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur. Heart J. 40, 3297–3317 (2019).

    Article  PubMed  Google Scholar 

  104. Ter Maaten, J. M. et al. Connecting heart failure with preserved ejection fraction and renal dysfunction: the role of endothelial dysfunction and inflammation. Eur. J. Heart Fail. 18, 588–598 (2016).

    Article  PubMed  Google Scholar 

  105. Bhatt, D. L. et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N. Engl. J. Med. 384, 117–128 (2021).

    CAS  Article  PubMed  Google Scholar 

  106. Singh, A. K. & Singh, R. Cardiovascular outcomes with SGLT-2 inhibitors in patients with heart failure with or without type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Metab. Syndr. 15, 351–359 (2021).

    Article  PubMed  Google Scholar 

  107. Cardoso, R. et al. SGLT2 inhibitors decrease cardiovascular death and heart failure hospitalizations in patients with heart failure: a systematic review and meta-analysis. EClinicalMedicine 36, 100933 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  108. Solomon, S. D. et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction: rationale and design of the DELIVER trial. Eur. J. Heart Fail. 23, 1217–1225 (2021).

    CAS  Article  PubMed  Google Scholar 

  109. Boer, I. H. et al. KDIGO 2020 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 98, S1–S115 (2020).

    Article  Google Scholar 

  110. Das, S. R. et al. 2020 expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes. J. Am. Coll. Cardiol. 76, 1117–1145 (2020).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  111. McDonagh, T. A. et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 42, 3599–3726 (2021).

    CAS  Article  PubMed  Google Scholar 

  112. AlKindi, F. et al. Outcomes of SGLT2 inhibitors use in diabetic renal transplant patients. Transpl. Proc. 52, 175–178 (2020).

    CAS  Article  Google Scholar 

  113. Halden, T. A. S. et al. Efficacy and safety of empagliflozin in renal transplant recipients with posttransplant diabetes mellitus. Diabetes Care 42, 1067–1074 (2019).

    CAS  Article  PubMed  Google Scholar 

  114. Oikonomaki, D., Dounousi, E., Duni, A., Roumeliotis, S. & Liakopoulos, V. Incretin based therapies and SGLT-2 inhibitors in kidney transplant recipients with diabetes: a systematic review and meta-analysis. Diabetes Res. Clin. Pract. 172, 108604 (2021).

    CAS  Article  PubMed  Google Scholar 

  115. Sarraju, A. et al. Effects of canagliflozin on cardiovascular, renal, and safety outcomes in participants with type 2 diabetes and chronic kidney disease according to history of heart failure: results from the CREDENCE trial. Am. Heart J. 233, 141–148 (2021).

    CAS  Article  PubMed  Google Scholar 

  116. Packer, M. et al. Effect of empagliflozin on worsening heart failure events in patients with heart failure and a preserved ejection fraction: the EMPEROR-preserved trial. Circulation 144, 1284–1294 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Ferreira, J. P. et al. Cardio/kidney composite end points: a post hoc analysis of the EMPA-REG OUTCOME Trial. J. Am. Heart Assoc. 10, e020053 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Packer, M. et al. Empagliflozin and major renal outcomes in heart failure. N. Engl. J. Med. 385, 1531–1533 (2021).

    Article  PubMed  Google Scholar 

  119. Cherney, D. Z. I. et al. Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial. Diabetologia 64, 1256–1267 (2021).

    CAS  Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Hiddo J. L. Heerspink.

Ethics declarations

Competing interests

R.A.d.B has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis and Roche, is on the Executive Committee of the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) trial, sponsored by AstraZeneca, and is a study group member of the Dapagliflozin Effect on Exercise Capacity Using a 6-minute Walk Test in Patients With Heart Failure With Reduced Ejection Fraction and Preserved Ejection Fraction (DETERMINE Reduced & Preserved) trials, sponsored by AstraZeneca. H.J.L.H. has consulting relationships with AbbVie, AstraZeneca, Bayer, Boehringer Ingelheim, CSL Pharma, Chinook, Dimerix, Gilead, Janssen, Merck, Mitsubishi Tanabe, Mundi Pharma, NovoNordisk and Travere. A.B.v.d.A.-v.d.B. declares no competing interests.

Peer review

Peer review information

Nature Reviews Nephrology thanks Fan Fan Hou; Joshua Neumiller; and Sean Virani, who co-reviewed with Nima Moghaddam, for their contribution to the peer review of this work.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

van der Aart-van der Beek, A.B., de Boer, R.A. & Heerspink, H.J.L. Kidney and heart failure outcomes associated with SGLT2 inhibitor use. Nat Rev Nephrol 18, 294–306 (2022). https://doi.org/10.1038/s41581-022-00535-6

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41581-022-00535-6

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing