Cardiac, renal, and metabolic effects of sodium-glucose co-transporter 2 inhibitors: a position paper from the European Society of Cardiology ad-hoc task force on sodium-glucose co-transporter 2 inhibitors

William G Herrington, Gianluigi Savarese, Richard Haynes, Nikolaus Marx, Linda Mellbin, Lars H Lund, Paul Dendale, Petar Seferovic, Giuseppe Rosano, Natalie Staplin, Colin Baigent, Francesco Cosentino, William G Herrington, Gianluigi Savarese, Richard Haynes, Nikolaus Marx, Linda Mellbin, Lars H Lund, Paul Dendale, Petar Seferovic, Giuseppe Rosano, Natalie Staplin, Colin Baigent, Francesco Cosentino

Abstract

In 2015, the first large-scale placebo-controlled trial designed to assess cardiovascular safety of glucose-lowering with sodium-glucose co-transporter 2 (SGLT2) inhibition in type 2 diabetes mellitus raised hypotheses that the class could favourably modify not only risk of atherosclerotic cardiovascular disease, but also hospitalization for heart failure, and the development or worsening of nephropathy. By the start of 2021, results from 10 large SGLT2 inhibitor placebo-controlled clinical outcome trials randomizing ∼71 000 individuals have confirmed that SGLT2 inhibitors can provide clinical benefits for each of these types of outcome in a range of different populations. The cardiovascular and renal benefits of SGLT2 inhibitors appear to be larger than their comparatively modest effect on glycaemic control or glycosuria alone would predict, with three trials recently reporting that clinical benefits extend to individuals without diabetes mellitus who are at risk due to established heart failure, or albuminuric chronic kidney disease. This European Society of Cardiology position paper summarizes reported results from these 10 large clinical outcome trials considering separately each of the different types of cardiorenal benefit, summarizes key molecular and pathophysiological mechanisms, and provides a synopsis of metabolic effects and safety. We also describe ongoing placebo-controlled trials among individuals with heart failure with preserved ejection fraction and among individuals with chronic kidney disease.

Keywords: Cardiovascular outcomes; Chronic kidney disease; Heart failure; Randomized controlled trials; Sodium-glucose co-transporter 2 inhibitors.

© 2021 European Society of Cardiology.

References

    1. Himsworth HP. The relation of glycosuria to glycaemia and the determination of the renal threshold for glucose. Biochem J 1931;25:1128-1146.
    1. Hjarne U. A study of orthoglycaemic glycosuria with particular reference to it hereditability. Acta Med Scand 1927;67:495-571.
    1. Poulsson LT. On the mechanism of sugar elimination in phlorrhizin glycosuria. A contribution to the filtration-reabsorption theory on kidney function. J Physiol 1930;69:411-422.
    1. Lee WS, Kanai Y, Wells RG, Hediger MA. The high affinity Na+/glucose cotransporter. Re-evaluation of function and distribution of expression. J Biol Chem 1994;269:12032-12039.
    1. Song P, Onishi A, Koepsell H, Vallon V. Sodium glucose cotransporter SGLT1 as a therapeutic target in diabetes mellitus. Expert Opin Ther Targets 2016;20:1109-1125.
    1. Cefalo CMA, Cinti F, Moffa S, Impronta F, Sorice GP, Mezza T, Pontecorvi A, Giaccari A. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol 2019;18:20.
    1. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 2012;14:83-90.
    1. Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. 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 2010;33:2217-2224.
    1. Bailey CJ, Gross JL, Pieters A, Bastien A, List JF. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: a randomised, double-blind, placebo-controlled trial. Lancet 2010;375:2223-3223.
    1. US Food and Drug Administration. Guidance for Industry on Diabetes Mellitus-Evaluating Cardiovascular Risk in New Antidiabetic Therapies to Treat Type 2 Diabetes. A Notice by the Food and Drug Administration on 12/19/2008. (1 January 2021).
    1. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128.
    1. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-657.
    1. 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, Johansson PA, Langkilde AM, Sabatine MS; DECLARE-TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019;380:347-357.
    1. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Jüni P, Lettino M, Marx N, Mellbin LG, Östgren CJ, Rocca B, Roffi M, Sattar N, Seferović PM, Sousa-Uva M, Valensi P, Wheeler DC; ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J 2020;41:255-323.
    1. 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; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019;380:2295-2306.
    1. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Bělohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát 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, Sjöstrand M, Langkilde AM; DAPA-HF Trial Committees and Investigators. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019;381:1995-2008.
    1. Seferovic PM, Fragasso G, Petrie M, Mullens W, Ferrari R, Thum T, Bauersachs J, Anker SD, Ray R, Çavuşoğlu Y, Polovina M, Metra M, Ambrosio G, Prasad K, Seferović J, Jhund PS, Dattilo G, Čelutkiene J, Piepoli M, Moura B, Chioncel O, Ben Gal T, Heymans S, de Boer RA, Jaarsma T, Hill L, Lopatin Y, Lyon AR, Ponikowski P, Lainščak M, Jankowska E, Mueller C, Cosentino F, Lund L, Filippatos GS, Ruschitzka F, Coats AJS, Rosano GMC. Sodium-glucose co-transporter 2 inhibitors in heart failure: beyond glycaemic control. A position paper of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2020;22:1495-1503.
    1. Cannon CP, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Masiukiewicz U, Charbonnel B, Frederich R, Gallo S, Cosentino F, Shih WJ, Gantz I, Terra SG, Cherney DZI, McGuire DK; VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383:1425-1435.
    1. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, Jamal W, Kimura K, Schnee J, Zeller C, Cotton D, Bocchi E, Böhm M, Choi DJ, Chopra V, Chuquiure E, Giannetti N, Janssens S, Zhang J, Gonzalez Juanatey JR, Kaul S, Brunner-La Rocca HP, Merkely B, Nicholls SJ, Perrone S, Pina I, Ponikowski P, Sattar N, Senni M, Seronde MF, Spinar J, Squire I, Taddei S, Wanner C, Zannad F; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-1424.
    1. Bhatt DL, Szarek M, Steg PG, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Voors AA, Metra M, Lund LH, Komajda M, Testani JM, Wilcox CS, Ponikowski P, Lopes RD, Verma S, Lapuerta P, Pitt B; SOLOIST-WHF Trial Investigators. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021;384:117-128.
    1. Heerspink HJL, Stefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, Mann JFE, McMurray JJV, Lindberg M, Rossing P, Sjöström CD, Toto RD, Langkilde AM, Wheeler DC; DAPA-CKD Trial Committees and Investigators. Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020;383:1436-1446.
    1. Bhatt DL, Szarek M, Pitt B, Cannon CP, Leiter LA, McGuire DK, Lewis JB, Riddle MC, Inzucchi SE, Kosiborod MN, Cherney DZI, Dwyer JP, Scirica BM, Bailey CJ, Díaz R, Ray KK, Udell JA, Lopes RD, Lapuerta P, Steg PG; SCORED Investigators. Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021;384:129-139.
    1. Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER). (24 December 2020).
    1. EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved). (24 December 2020).
    1. Herrington WG, Preiss D, Haynes R, von Eynatten M, Staplin N, Hauske SJ, George JT, Green JB, Landray MJ, Baigent C, Wanner C. 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 2018;11:749-761.
    1. Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME® trial investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J 2016;37:1526-1534.
    1. McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, Pratley R, Greenberg M, Wang S, Huyck S, Gantz I, Terra SG, Masiukiewicz U, Cannon CP. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol 2021;6:148-158.
    1. Figtree GA, Radholm K, Barrett TD, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Matthews DR, Shaw W, Neal B. Effects of canagliflozin on heart failure outcomes associated with preserved and reduced ejection fraction in type 2 diabetes mellitus. Circulation 2019;139:2591-2593.
    1. Cosentino F, Cannon CP, Cherney DZI, Masiukiewicz U, Pratley R, Dagogo-Jack S, Frederich R, Charbonnel B, Mancuso J, Shih WJ, Terra SG, Cater NB, Gantz I, McGuire DK; VERTIS CV Investigators. Efficacy of ertugliflozin on heart failure-related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV trial. Circulation 2020;142:2205-2215.
    1. Cherney DZI, Cooper ME, Tikkanen I, Pfarr E, Johansen OE, Woerle HJ, Broedl UC, Lund SS. 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;93:231-244.
    1. Mahaffey KW, Jardine MJ, Bompoint S, Cannon CP, Neal B, Heerspink HJL, Charytan DM, Edwards R, Agarwal R, Bakris G, Bull S, Capuano G, de Zeeuw D, Greene T, Levin A, Pollock C, Sun T, Wheeler DC, Yavin Y, Zhang H, Zinman B, Rosenthal N, Brenner BM, Perkovic V. Canagliflozin and cardiovascular and renal outcomes in type 2 diabetes mellitus and chronic kidney disease in primary and secondary cardiovascular prevention groups. Circulation 2019;140:739-750.
    1. Zannad F, Ferreira JP, Pocock SJ, Zeller C, Anker SD, Butler J, Filippatos G, Hauske SJ, Brueckmann M, Pfarr E, Schnee J, Wanner C, Packer M. Cardiac and kidney benefits of empagliflozin in heart failure across the spectrum of kidney function: insights from EMPEROR-Reduced. Circulation 2021;143:310-321.
    1. Jhund PS, Solomon SD, Docherty KF, Heerspink HJL, Anand IS, Bohm M, Chopra V, de Boer RA, Desai AS, Ge J, Kitakaze M, Merkley B, O'Meara E, Shou M, Tereshchenko S, Verma S, Vinh PN, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Bengtsson O, Langkilde AM, Sjöstrand M, McMurray JJV. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction: results of DAPA-HF. Circulation 2021;143:298-309.
    1. Wheeler DC, Stefansson BV, Jongs N, Chertow GM, Greene T, Hou FF, McMurray JJV, Correa-Rotter R, Rossing P, Toto RD, Sjöström CD, Langkilde AM, Heerspink HJL; DAPA-CKD Trial Committees and Investigators. 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 2021;9:22-31.
    1. Docherty KF, Jhund PS, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, DeMets DL, Sabatine MS, Bengtsson O, Sjöstrand M, Langkilde AM, Desai AS, Diez M, Howlett JG, Katova T, Ljungman CEA, O'Meara E, Petrie MC, Schou M, Verma S, Vinh PN, Solomon SD, McMurray JJV. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J 2020;41:2379-2392.
    1. Docherty KF, Jhund PS, Bengtsson O, DeMets DL, Inzucchi SE, Kober L, Kosiborod MN, Langkilde AM, Martinez FA, Sabatine MS, Sjöstrand M, Solomon SD, McMurray JJV; DAPA-HF Investigators and Committees. Effect of dapagliflozin in DAPA-HF according to background glucose-lowering therapy. Diabetes Care 2020;43:2878-2881.
    1. Shen L, Kristensen SL, Bengtsson O, Bohm M, de Boer RA, Docherty KF, Inzucchi SE, Katova T, Køber L, Kosiborod MN, Langkilde AM, Lindholm D, Martinez MFA, O'Meara E, Nicolau JC, Petrie MC, Ponikowski P, Sabatine MS, Schou M, Sjöstrand M, Solomon SD, Jhund PS, McMurray JJV. Dapagliflozin in HFrEF patients treated with mineralocorticoid receptor antagonists: an analysis of DAPA-HF. JACC Heart Fail 2021;9:254-264.
    1. Dapagliflozin 5 mg Summary of Product Characteristics. (2 January 2021).
    1. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Ofstad AP, Pfarr E, Jamal W, Packer M. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 2020;396:819-829.
    1. Boehringer I. Empagliflozin meets primary endpoint in reducing risk of cardiovascular death or hospitalization for heart failure in Phase III trial in adults with and without diabetes. (6 July 2021).
    1. Anker SD, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, Kimura K, Zeller C, George J, Brueckmann M, Zannad F, Packer M; EMPEROR-Preserved Trial Committees and Investigators. Evaluation of the effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality in patients with chronic heart failure and a preserved ejection fraction: rationale for and design of the EMPEROR-Preserved trial. Eur J Heart Fail 2019;21:1279-1287.
    1. Oshima M, Neuen BL, Jardine MJ, Bakris G, Edwards R, Levin A, Mahaffey KW, Neal B, Pollock C, Rosenthal N, Wada T, Wheeler DC, Perkovic V, Heerspink HJL. 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 2020;8:903-914.
    1. Woods TC, Satou R, Miyata K, Katsurada A, Dugas CM, Klingenberg NC, Fonseca VA, Navar LG. Canagliflozin prevents intrarenal angiotensinogen augmentation and mitigates kidney injury and hypertension in mouse model of type 2 diabetes mellitus. Am J Nephrol 2019;49:331-342.
    1. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018;61:2108-2117.
    1. Jensen J, Omar M, Kistorp C, Tuxen C, Gustafsson I, Kober L, Gustafsson F, Faber J, Malik ME, Fosbøl EL, Bruun NE, Forman JL, Jensen LT, Møller JE, Schou M. Effects of empagliflozin on estimated extracellular volume, estimated plasma volume, and measured glomerular filtration rate in patients with heart failure (Empire HF Renal): a prespecified substudy of a double-blind, randomised, placebo-controlled trial. Lancet Diabetes Endocrinol 2021;9:106-116.
    1. Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 2014;129:587-597.
    1. Ott C, Jumar A, Striepe K, Friedrich S, Karg MV, Bramlage P, Schmieder RE. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol 2017;16:26.
    1. Irace C, Casciaro F, Scavelli FB, Oliverio R, Cutruzzola A, Cortese C, Gnasso A. Empagliflozin influences blood viscosity and wall shear stress in subjects with type 2 diabetes mellitus compared with incretin-based therapy. Cardiovasc Diabetol 2018;17:52.
    1. Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, Woerle HJ, von Eynatten M, Broedl UC. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 2014;13:28.
    1. Mery PF, Brechler V, Pavoine C, Pecker F, Fischmeister R. Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature 1990;345:158-161.
    1. Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, Mari A, Pieber TR, Muscelli E. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 2016;65:1190-1195.
    1. Packer M, Anker SD, Butler J, Filippatos G, Zannad F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol 2017;2:1025-1029.
    1. Verma S, Mazer CD, Yan AT, Mason T, Garg V, Teoh H, Zuo F, Quan A, Farkouh ME, Fitchett DH, Goodman SG, Goldenberg RM, Al-Omran M, Gilbert RE, Bhatt DL, Leiter LA, Jüni P, Zinman B, Connelly KA. Effect of empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and coronary artery disease: the EMPA-HEART CardioLink-6 randomized clinical trial. Circulation 2019;140:1693-1702.
    1. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med 2017;104:298-310.
    1. Baartscheer A, Schumacher CA, Wust RC, Fiolet JW, Stienen GJ, Coronel R, Zuurbier CJ. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 2017;60:568-573.
    1. Packer M, Anker SD, Butler J, Filippatos G, Ferreira JP, Pocock SJ, Sattar N, Brueckmann M, Jamal W, Cotton D, Iwata T, Zannad F; EMPEROR-Reduced Trial Committees and Investigators. Empagliflozin in patients with heart failure, reduced ejection fraction, and volume overload: EMPEROR-Reduced trial. J Am Coll Cardiol 2021;77:1381-1392.
    1. Basu D, Huggins LA, Scerbo D, Obunike J, Mullick AE, Rothenberg PL, Di Prospero NA, Eckel RH, Goldberg IJ. Mechanism of increased LDL (low-density lipoprotein) and decreased triglycerides with SGLT2 (sodium-glucose cotransporter 2) inhibition. Arterioscler Thromb Vasc Biol 2018;38:2207-2216.
    1. 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. 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;393:31-39.
    1. Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 2018;41:356-363.
    1. Levey AS, Coresh J. Chronic kidney disease. Lancet 2012;379:165-180.
    1. House AA, Wanner C, Sarnak MJ, Pina IL, McIntyre CW, Komenda P, Kasiske BL, Deswal A, deFilippi CR, Cleland JGF, Anker SD, Herzog CA, Cheung M, Wheeler DC, Winkelmayer WC, McCullough PA; Conference Participants. Heart failure in chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 2019;95:1304-1317.
    1. Park M, Hsu CY, Li Y, Mishra RK, Keane M, Rosas SE, Dries D, Xie D, Chen J, He J, Anderson A, Go AS, Shlipak MG; Chronic Renal Insufficiency Cohort (CRIC) Study Group. Associations between kidney function and subclinical cardiac abnormalities in CKD. J Am Soc Nephrol 2012;23:1725-1734.
    1. Perkovic V, Agarwal R, Fioretto P, Hemmelgarn BR, Levin A, Thomas MC, Wanner C, Kasiske BL, Wheeler DC, Groop PH; Conference Participants. Management of patients with diabetes and CKD: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int 2016;90:1175-1183.
    1. Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease (CKD). (2 July 2021).
    1. Herrington W, Emberson J, Mihaylova B, Blackwell L, Reith C, Solbu MD, Mark PB, Fellström B, Jardine AG, Wanner C, Holdaas H, Fulcher J, Haynes R, Landray MJ, Keech A, Simes J, Collins R, Baigent C; Cholesterol Treatment Trialists' (CTT) Collaboration. How are the effects of reducing LDL cholesterol with a statin-based regime influenced by renal function? Meta-analysis of individual data from 28 randomised trials. Lancet Diabetes Endocrinol 2016;4:829-839.
    1. Wanner C, Inzucchi SE, Lachin JM, Fitchett D, von Eynatten M, Mattheus M, Johansen OE, Woerle HJ, Broedl UC, Zinman B; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016;375:323-334.
    1. Vallon V, Thomson SC. The tubular hypothesis of nephron filtration and diabetic kidney disease. Nat Rev Nephrol 2020;16:317-336.
    1. Neuen BL, Young T, Heerspink HJL, Neal B, Perkovic V, Billot L, Mahaffey KW, Charytan DM, Wheeler DC, Arnott C, Bompoint S, Levin A, Jardine MJ. SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol 2019;7:845-854.
    1. Fried LF, Emanuele N, Zhang JH, Brophy M, Conner TA, Duckworth W, Leehey DJ, McCullough PA, O'Connor T, Palevsky PM, Reilly RF, Seliger SL, Warren SR, Watnick S, Peduzzi P, Guarino P; VA NEPHRON-D Investigators. Combined angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med 2013;369:1892-1903.
    1. Kraus BJ, Weir MR, Bakris GL, Mattheus M, Cherney DZI, Sattar N, Heerspink HJL, Ritter I, von Eynatten M, Zinman B, Inzucchi SE, Wanner C, Koitka-Weber A. 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 2021;99:750-762.
    1. Sridhar VS, Tuttle KR, Cherney DZI. We can finally stop worrying about SGLT2 inhibitors and acute kidney injury. Am J Kidney Dis 2020;76:454-456.
    1. Basile DP, Bonventre JV, Mehta R, Nangaku M, Unwin R, Rosner MH, Kellum JA, Ronco C; ADQI XIII Work Group. Progression after AKI: understanding maladaptive repair processes to predict and identify therapeutic treatments. J Am Soc Nephrol 2016;27:687-697.
    1. Weir MR, Slee A, Sun T, Balis D, Oh R, de Zeeuw D, Perkovic V. Effects of canagliflozin on serum potassium in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. Clin Kidney J 2021;14:1396-1402.
    1. Ferreira JP, Zannad F, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Jamal W, Steubl D, Schueler E, Packer M. Interplay of mineralocorticoid receptor antagonists and empagliflozin in heart failure: EMPEROR-Reduced. J Am Coll Cardiol 2021;77:1397-1407.
    1. Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 2014;124:499-508.
    1. Ferrannini E. Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell Metab 2017;26:27-38.
    1. Zaccardi F, Webb DR, Htike ZZ, Youssef D, Khunti K, Davies MJ. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes Obes Metab 2016;18:783-794.
    1. Bolinder J, Ljunggren O, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S. 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 2012;97:1020-1031.
    1. Horie I, Abiru N, Hongo R, Nakamura T, Ito A, Haraguchi A, Natsuda S, Sagara I, Ando T, Kawakami A. Increased sugar intake as a form of compensatory hyperphagia in patients with type 2 diabetes under dapagliflozin treatment. Diabetes Res Clin Pract 2018;135:178-184.
    1. Palmer BF, Clegg DJ. Electrolyte and acid-base disturbances in diabetes mellitus. N Engl J Med 2015;373:2482-2483.
    1. Liu J, Li L, Li S, Wang Y, Qin X, Deng K, Liu Y, Zou K, Sun X. Sodium-glucose co-transporter-2 inhibitors and the risk of diabetic ketoacidosis in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab 2020;22:1619-1627.
    1. Garg SK, Henry RR, Banks P, Buse JB, Davies MJ, Fulcher GR, Pozzilli P, Gesty-Palmer D, Lapuerta P, Simó R, Danne T, McGuire DK, Kushner JA, Peters A, Strumph P. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. N Engl J Med 2017;377:2337-2348.
    1. Rosenstock J, Marquard J, Laffel LM, Neubacher D, Kaspers S, Cherney DZ, Zinman B, Skyler JS, George J, Soleymanlou N, Perkins BA. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: the EASE trials. Diabetes Care 2018;41:2560-2569.
    1. Sotagliflozin Summary of Product Characteristics. (2 January 2021).
    1. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia 2017;60:215-225.
    1. Anker SD, Butler J, Filippatos G, Khan MS, Marx N, Lam CSP, Schnaidt S, Ofstad AP, Brueckmann M, Jamal W, Bocchi EA, Ponikowski P, Perrone SV, Januzzi JL, Verma S, Böhm M, Ferreira JP, Pocock SJ, Zannad F, Packer M. Effect of empagliflozin on cardiovascular and renal outcomes in patients with heart failure by baseline diabetes status: results from the EMPEROR-Reduced trial. Circulation 2021;143:337-349.
    1. Rosenstock J, Seman LJ, Jelaska A, Hantel S, Pinnetti S, Hach T, Woerle HJ. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab 2013;15:1154-1160.
    1. Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C, Chong WH. Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: a review of spontaneous postmarketing cases. Ann Intern Med 2019;170:764-769.
    1. Secker PF, Beneke S, Schlichenmaier N, Delp J, Gutbier S, Leist M, Dietrich DR. Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect. Cell Death Dis 2018;9:226.
    1. Perkovic V, de Zeeuw D, Mahaffey KW, Fulcher G, Erondu N, Shaw W, Barrett TD, Weidner-Wells M, Deng H, Matthews DR, Neal B. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018;6:691-704.
    1. Invokana (canagliflozin) tablets prescribing information. (6 Janaury 2021).
    1. US Food and Drug Administration. FDA News Release: FDA Approves Treatment for Chronic Kidney Disease. (3 May 2021).

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe