World Health Organization. Diabetes. Available at: https://www.who.int/news-room/fact-sheets/detail/diabetes. Accessed April 8, 2019

Kannel WB, McGee DL (1979) Diabetes and cardiovascular disease. The Framingham study JAMA 241(19):2035–2038

CAS  PubMed  Google Scholar 

Shah AD, Langenberg C, Rapsomaniki E et al (2015)Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1.9 million people. Lancet Diabetes Endocrinol 3(2):105–113

Bertoni AG, Tsai A, Kasper EK, Brancati FL (2003) Diabetes and idiopathic cardiomyopathy: a nationwide case-control study. Diabetes Care 26(10):2791–2795

Article  Google Scholar 

Nichols GA, Hillier TA, Erbey JR, Brown JB (2001) Congestive heart failure in type 2 diabetes: prevalence, incidence, and risk factors. Diabetes Care 24(9):1614–1619

CAS  Article  Google Scholar 

Aronow WS, Ahn C (1999) Incidence of heart failure in 2,737 older persons with and without diabetes mellitus. Chest 115(3):867–868

CAS  Article  Google Scholar 

Thrainsdottir IS, Aspelund T, Hardarson T et al (2005) Glucose abnormalities and heart failure predict poor prognosis in the population-based Reykjavik Study. Eur J Cardiovasc Prev Rehabil 12:465–471

Article  Google Scholar 

Thrainsdottir IS, Aspelund T, Thorgeirsson G et al (2005) The association between glucose abnormalities and heart failure in the population based Reykjavik study. Diabetes Care 28:612–616

Article  Google Scholar 

Selvin E, Lazo M, Chen Y et al (2014) Diabetes mellitus, prediabetes, and incidence of subclinical myocardial damage. Circulation 130(16):1374–1382

CAS  Article  Google Scholar 

van de Weijer T, Schrauwen-Hinderling VB, Schrauwen P (2011) Lipotoxicity in type 2 diabetic cardiomyopathy. Cardiovasc Res 92(1):10–18

Article  Google Scholar 

Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC (2010) Myocardial fatty acid metabolism in health and disease. Physiol Rev 90(1):207–258

CAS  Article  Google Scholar 

Dennis VW, Brazy PC (1978) Phosphate and glucose transport in the proximal convoluted tubule: mutual dependency on sodium. Adv Exp Med Biol 103:79–80

CAS  Article  Google Scholar 

Hummel CS, Lu C, Loo DD, Hirayama BA, Voss AA, Wright EM (2011) Glucose transport by human renal Na+/D-glucose cotransporters SGLT1 and SGLT2. Am J Physiol Cell Physiol 300:C14–C21

CAS  Article  Google Scholar 

Rahmoune H, Thompson PW, Ward JM, Smith CD, Hong G, Brown J (2005) Glucose transporters in human renal proximal tubular cells isolated from the urine of patients with non-insulin-dependent diabetes. Diabetes 54:3427–3434

CAS  Article  Google Scholar 

Vallon V, Thomson SC (2017) Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia 60(2):215–225

CAS  Article  Google Scholar 

Merovci A, Solis-Herrera C, Daniele G et al (2014) Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J Clin Invest 124:509–514

CAS  Article  Google Scholar 

Ferrannini E, Muscelli E, Frascerra S et al (2014) Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 124:499–508

CAS  Article  Google Scholar 

Bolinder J, Ljunggren O, Kullberg J et al (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 97:1020–1031

CAS  Article  Google Scholar 

Takeuchi T, Dohi K, Omori T et al (2015) Diuretic effects of sodium-glucose cotransporter 2 inhibitor in patients with type 2 diabetes mellitus and heart failure. Int J Cardiol 201:1–3

Mazidi M, Rezaie P, Gao HK, Kengne AP (2017) 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

Chilton RJ, Gullestad L, Fitchett D, Inzucchi SE, Mattheus M, Woerle HJ et al (2016) Empagliflozin reduces markers of arterial stiffness, vascular resistance and cardiac workload in EMPA-REG OUTCOME. Circulation 134(25):A13520

Zhou H, Wang S, Zhu P, Hu S, Chen Y, Ren J (2018) Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol 15:335-346

Ribola FA, Cancado FB, Schoueri JH et al (2017) Effects of SGLT2 inhibitors on weight loss in patients with type 2 diabetes mellitus. Eur Rev Med Pharmacol Sci 21:199–211

CAS  PubMed  Google Scholar 

Yagi S, Hirata Y, Ise T, Kusunose K, Yamada H, Fukuda D, Salim HM, Maimaituxun G, Nishio S, Takagawa Y, Hama S, Matsuura T, Yamaguchi K, Tobiume T, Soeki T, Wakatsuki T, Aihara KI, Akaike M, Shimabukuro M, Sata M (2017) Canagliflozin reduces epicardial fat in patients with type 2 diabetes mellitus. Diabetol Metab Syndr 9:78. https://doi.org/10.1186/s13098-017-0275-4. PMID: 29034006; PMCID: PMC5628447

Zhao Y, Xu L, Tian D et al (2017) Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: a meta-analysis of randomized controlled trials. Diabetes Obes Metab 20:458–462

Article  Google Scholar 

McMurray J (2016) EMPA-REG—the “diuretic hypothesis.” J Diabetes Complications 30(1):3–4

Rahman A, Hitomi H, Nishiyama A (2017) Cardioprotective effects of SGLT2 inhibitors are possibly associated with normalization of the circadian rhythm of blood pressure. Hypertens Res 40:535–540

Ferrannini E, Mark M, Mayoux E (2016) CV protection in the EMPA-REG OUTCOME trial: a ‘‘thrifty substrate’’ hypothesis. Diabetes Care 39:1108–14

Kimura T, Sanada J, Shimoda M et al (2017) Switching from low-dose thiazide diuretics to sodium-glucose cotransporter 2 inhibitor improves various metabolic parameters without affecting blood pressure in patients with type 2 diabetes and hypertension. J Diabetes Investig 9:875–881

Ojima A, Matsui T, Nishino Y et al (2015) Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis. Horm Metab Res 47:686–692

Matthews VB, Elliot RH, Rudnicka C, Hricova J, Herat L, Schlaich MP (2017) Role of the sympathetic nervous system in regulation of the sodium glucose cotransporter 2. J Hypertens 35(10):2059-2068

Bertero E, Prates Roma L, Ameri P et al (2018) Cardiac effects of SGLT2 inhibitors: the sodium hypothesis. Cardiovasc Res 114:12–18

CAS  Article  Google Scholar 

Bell RM, Yellon DM (2018) SGLT2 inhibitors: hypotheses on the mechanism of cardiovascular protection. Lancet Diabetes Endocrinol 6(6):435-437

Takeuchi T, Dohi K, Omori T, Moriwaki K, Sato Y, Nakamori S, Fujimoto N, Fujii E, Yamada N, Ito M (2015) Diuretic effects of sodium-glucose cotransporter 2 inhibitor in patients with type 2 diabetes mellitus and heart failure. Int J Cardiol 201:1-3

Zinman B, Inzucchi SE, Lachin JM, Wanner C, Ferrari R, Fitchett D, Bluhmki E, Hantel S, Kempthorne-Rawson J, Newman J, Johansen OE, Woerle HJ, Broedl UC (2014) Rationale, design, and baseline characteristics of a randomized, placebocontrolled cardiovascular outcome trial of empagliflozin (EMPA-REG OUTCOME). Cardiovasc Diabetol 13:102

Neal B, Perkovic V, Matthews DR, Mahaffey KW, Fulcher G, Meininger G, Erondu N, Desai M, Shaw W, Vercruysse F, Yee J, Deng H, de Zeeuw D (2017) CANVAS-R Trial Collaborative Group. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab 19:387-393

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR (2017) CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377:644-657

Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ (2016) Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation 134(10):752-72

Lee HC, Shiou YL, Jhuo SJ, Chang CY, Liu PL, Jhuang WJ, Dai ZK, Chen WY, Chen YF, Lee AS (2019) The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol 18(1):45

Loutradis C, Papadopoulou E, Theodorakopoulou M, Karagiannis A, Sarafidis P (2019) The effect of SGLT-2 inhibitors on blood pressure: a pleiotropic action favoring cardio- and nephroprotection. Future Med Chem 11(11):1285-1303

Neal B, Perkovic V, Matthews DR, Mahaffey KW, Fulcher G, Meininger G, Erondu N, Desai M, Shaw W, Vercruysse F, Yee J, Deng H, de Zeeuw D (2017) CANVAS-R Trial Collaborative Group. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab 19:387-393

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR (2017) CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377:644-657

Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Bansilal S, Bhatt DL, Leiter LA, McGuire DK, Wilding JP, Gause-Nilsson IA, Langkilde AM, Johansson PA, Sabatine MS (2018) The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J 200:83–89. https://doi.org/10.1016/j.ahj.2018.01.012 (Epub 2018 Feb 7 PMID: 29898853)

CAS  Article  PubMed  Google Scholar 

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 393:31-39

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 (2020) 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. https://doi.org/10.1161/CIRCULATIONAHA.120.050255. Epub ahead of print. PMID: 33026243

Packer M, Butler J, Filippatos GS, Jamal W, Salsali A, Schnee J, Kimura K, Zeller C, George J, Brueckmann M, Anker SD, Zannad F (2019) EMPEROR-reduced trial committees and investigators. Evaluation of the effect of sodium-glucose co-transporter 2 inhibition with empagliflozin on morbidity and mortality of patients with chronic heart failure and a reduced ejection fraction: rationale for and design of the EMPEROR-Reduced trial. Eur J Heart Fail 21(10):1270–1278

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 (2020) EMPEROR-reduced trial investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med. https://doi.org/10.1056/NEJMoa2022190. Epub ahead of print. (PMID:32865377)

Damman K, Beusekamp JC, Boorsma EM, Swart HP, Smilde TDJ, Elvan A, van Eck JWM, Heerspink HJL, Voors AA (2020) Randomized, double-blind, placebo-controlled, multicentre pilot study on the effects of empagliflozin on clinical outcomes in patients with acute decompensated heart failure (EMPA-RESPONSE-AHF). Eur J Heart Fail 22(4):713–722

CAS  Article  Google Scholar 

McMurray JJV, Solomon SD, Inzucchi SE, Køber 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 (2019) Held C1, 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 381(21):1995–2008

CAS  Article  Google Scholar 

Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Belohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukát A, Ge J, Howlett J, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O'Meara E, Vinh PN, Schou M, Tereshchenko S, Køber L, Kosiborod MN, Langkilde AM, Martinez FA, Ponikowski P, Sabatine MS, Sjöstrand M, Solomon SD, Johanson P, Greasley PJ, Boulton D, Bengtsson O, Jhund PS, McMurray JJV. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes. JAMA. 2020 Mar 27. https://doi.org/10.1001/jama.2020.1906. [Epub ahead of print]

McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN, Langkilde AM, Martinez FA, Bengtsson O, Ponikowski P, Sabatine MS, Sjöstrand M, Solomon SD (2019) DAPA-HF committees and investigators. The Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail 21(11):1402–1411

Solomon SD, Jhund PS, Claggett BL, Dewan P, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Inzucchi SE, Desai AS, Bengtsson O, Lindholm D, Sjostrand M, Langkilde AM, McMurray JJV (2020) Effect of dapagliflozin in patients with HFrEF treated with sacubitril/valsartan: the DAPA-HF Trial. JACC Heart Fail S2213–1779(20):30254–30257. https://doi.org/10.1016/j.jchf.2020.04.008

Article  Google Scholar 

Kosiborod MN, Jhund P, Docherty KF, Diez M, Petrie MC, Verma S, Nicolau JC, Merkely B, Kitakaze M, DeMets DL, Inzucchi SE, Køeber L, Martinez FA, Ponikowski P, Sabatine MS, Solomon SD, Bengtsson O, Lindholm D, Niklasson A, Sjöstrand M, Langkilde AM, McMurray JJV (2019) Effects of dapagliflozin on symptoms, function and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF trial. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.119.044138. [Epub ahead of print]

Docherty KF, Jhund PS, Inzucchi SE, Køber 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 (2020) Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur Heart J pii: ehaa183. https://doi.org/10.1093/eurheartj/ehaa183. [Epub ahead of print]

Serenelli M, Böhm M, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Solomon SD, DeMets DL, Bengtsson O, Sjöstrand M, Langkilde AM, Anand IS, Chiang CE, Chopra VK, de Boer RA, Diez M, Dukát A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Verma S, Docherty KF, Jhund PS, McMurray JJV (2020) Effect of dapagliflozin according to baseline systolic blood pressure in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial (DAPA-HF). Eur Heart J ehaa496

Jackson AM, Dewan P, Anand IS, Bělohlávek J, Bengtsson O, de Boer RA, Böhm M, Boulton DW, Chopra VK, Demets DL, Docherty KF, Dukát A, Greasley PJ, Howlett JG, Inzucchi SE, Katova T, Køber L, Kosiborod MN, Langkilde AM, Lindholm D, Ljungman CEA, Martinez FA, O’Meara E, Sabatine MS, Sjöstrand M, Solomon SD, Tereshchenko S, Verma S, Jhund PS, McMurray JJV (2020) Dapagliflozin and diuretic usein patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation. https://doi.org/10.1161/CIRCULATIONAHA.120.047077

Article  PubMed  PubMed Central  Google Scholar 

Nassif ME, Windsor SL, Tang F, Khariton Y, Husain M, Inzucchi SE, Mc-Guire DK, Pitt B, Scirica BM, Austin B, Drazner MH, Fong MW, Givertz MM, Gordon RA, Jermyn R, Katz SD, Lamba S, Lanfear DE, LaRue SJ, Lindenfeld J, Malone M, Margulies K, Mentz RJ, Mutharasan RK, Pursley M, Umpierrez G, Kosiborod M (2019) Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: the DEFINE-HF trial. Circulation 140(18):1463–1476

CAS  Article  Google Scholar 

Zannad F et al (2020) SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 396(10254):819–829

Article  Google Scholar 

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 Jun 13;380(24):2295–2306

Ryan PB, Buse JB, Schuemie MJ, DeFalco F, Yuan Z, Stang PE, Berlin JA, Rosenthal N (2018) Comparative effectiveness of canagliflozin, SGLT2 inhibitors and non-SGLT2 inhibitors on the risk of hospitalization for heart failure and amputation in patients with type 2 diabetes mellitus: a real-world meta-analysis of 4 observational databases (OBSERVE-4D). Diabetes Obes Metab 20(11):2585–2597

CAS  Article  Google Scholar 

Cannon CP et al (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 (Epub 2018 Sep 5)

CAS  Article  PubMed  Google Scholar 

Heerspink HJL, Stefansson BV, Chertow GM, Correa-Rotter R, Greene T, Hou FF, Lindberg M, McMurray J, Rossing P, Toto R, Langkilde AM, Wheeler DC, Investigators D-C (2020) Rationale and protocol of the Dapagliflozin And Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial. Nephrol Dial Transplant 35(2):274–282

Article  Google Scholar 

Jenifer M Brown, Brendan M Everett (2019) Cardioprotective diabetes drugs: what cardiologists need to know. Cardiovasc Endocrinol Metab 8(4):96–105

Sun H Kim, Tara I Chang, Kenneth W Mahaffey (2020) A call for a new paradigm for diabetes care in the era of sodium-glucose cotransporter 2 inhibitors (SGLT2i). Cardiol Ther.

Davies MJ, D’Alessio DA, Fradkin J et al (2018) 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 41:2669–701

Arnold SV, Inzucchi SE, Tang F et al (2017) Real-world use and modeled impact of glucose-lowering therapies evaluated in recent cardio-vascular outcomes trials: an NCDR research to practice project. Eur J Prev Cardiol 24:1637–1645

Article  Google Scholar