Cardiorenal protection with SGLT2: Lessons from the cardiovascular outcome trials
SGLT2的心肾保护作用:来自心血管结局试验的经验教训
José Silva-Cardoso
Department of Medicine, University of Porto, Porto, Portugal
Search for more papers by this authorOmar Sheikh
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorCorresponding Author
Mouhamed Nashawi
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Correspondence
Mouhamed Nashawi, Division of Cardiology, MC 7872 UT Health San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229.
Email: [email protected]
Search for more papers by this authorSon Pham
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorKelly M. Gallegos
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorLaith R. Dinkha
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorRobert J. Chilton
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorJosé Silva-Cardoso
Department of Medicine, University of Porto, Porto, Portugal
Search for more papers by this authorOmar Sheikh
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorCorresponding Author
Mouhamed Nashawi
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Correspondence
Mouhamed Nashawi, Division of Cardiology, MC 7872 UT Health San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78229.
Email: [email protected]
Search for more papers by this authorSon Pham
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorKelly M. Gallegos
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorLaith R. Dinkha
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorRobert J. Chilton
Department of Medicine, Division of Cardiology, UT Health San Antonio, San Antonio, Texas
Search for more papers by this authorAbstract
enSodium glucose cotransporter 2 (SGLT2) inhibitors are a class of drugs that were primarily developed for the treatment of type 2 diabetes mellitus. However, these agents have shown to provide additional beneficial effects. We will discuss three main topics regarding the use of SGLT2 inhibitors: noncardiovascular effects, cardiovascular benefits, and novel clinical indications. Multiple clinical trials and preliminary studies across varying disciplines have shown that these agents exhibit cardiorenal-protective benefits, retinoprotective benefits, and may aid in weight loss without causing marked hypoglycemia. Therefore, these agents represent an avenue in clinical practice to manage comorbid conditions in the hyperglycemic patient. Because of their multifaceted effects and robust action, SGLT2 inhibitors represent therapy options for providers that not only provide beneficial clinical results but also reduce total patient drug burden.
摘要
zh钠-葡萄糖协同转运蛋白-2(SGLT2)抑制剂是一类主要用于治疗2型糖尿病的药物。然而, 这些制剂已经显示额外的益处。我们将讨论有关SGLT2抑制剂使用的三个主要方向:非心血管效果、心血管益处和新的临床适应症。跨学科的多项临床试验和初步研究表明, 这些药物显示出保护心肾以及视网膜的好处, 并可能有助于减肥, 而且不会导致明显的低血糖。因此, 这些药物代表了临床实践中管理高血糖患者共存疾病的一条途径。由于SGLT2抑制剂的多方面效应和强大的作用, SGLT2抑制剂提供了新的治疗选项, 不仅有好的临床结果, 而且减少了患者的总药物负担。
CONFLICT OF INTEREST
None of the authors have any conflicts of interest related to this submission.
REFERENCES
- 1Gyberg V, De Bacquer D, De Backer G, et al; EUROASPIRE Investigators. Patients with coronary artery disease and diabetes need improved management: a report from the EUROASPIRE IV survey: a registry from the EuroObservational Research Programme of the European Society of Cardiology. Cardiovasc Diabetol. 2015; 14: 133.
- 2Dickinson JK, Guzman SJ, Maryniuk MD, et al. The use of language in diabetes care and education. Diabetes Care. 2017; 43: 551-564.
- 3Zinman B, Wanner C, Lachin JM, et al; for the EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015; 373: 2117-2128.
- 4Bilezikian JP, Watts NB, Usiskin K, et al. Evaluation of bone mineral density and bone biomarkers in patients with type 2 diabetes treated with canagliflozin. J Clin Endocrinol Metab. 2016; 101: 44-51.
- 5Inzucchi SE, Iliev H, Pfarr E, Zinman B. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME trial. Diabetes Care. 2018; 41: e4-e5.
- 6Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia. 2018; 61: 2079-2086.
- 7Tahrani AA, Barnett AH, Bailey CJ. SGLT inhibitors in management of diabetes. Lancet Diabetes Endocrinol. 2013; 1: 140-151.
- 8Thewjitcharoen Y, Yenseung N, Malidaeng A, et al. Effectiveness of long-term treatment with SGLT2 inhibitors: real-world evidence from a specialized diabetes center. Diabetol Metab Syndr. 2017; 9: 96.
- 9List JF, Woo V, Morales E, Tang W, Fiedorek FT. Sodium-glucose cotransport inhibition with dapagliflozin in type 2 diabetes. Diabetes Care. 2009; 32: 650-657.
- 10Santer R, Calado J. Familial renal glucosuria and SGLT2: from a mendelian trait to a therapeutic target. Clin J Am Soc Nephrol. 2010; 5: 133-141.
- 11Monica Reddy RP, Inzucchi SE. SGLT2 inhibitors in the management of type 2 diabetes. Endocrine. 2016; 53: 364-372.
- 12Vallon V, Platt KA, Cunard R, et al. SGLT2 mediates glucose reabsorption in the early proximal tubule. J Am Soc Nephrol. 2011; 22: 104-112.
- 13Li L, Konishi Y, Morikawa T, et al. Effect of a SGLT2 inhibitor on the systemic and intrarenal renin-angiotensin system in subtotally nephrectomized rats. J Pharmacol Sci. 2018; 137: 220-223.
- 14Wang X, Li Y, Yang B, Li Z, Huang W, Qian H. C-aryl glucosides with substituents at the distal aryl ring as sodium-dependent glucose cotransporter inhibitors for the treatment of diabetes mellitus. Chem Biol Drug Des. 2015; 86: 246-253.
- 15Rao K, Kumar KPJH. Sodium glucose cotransporter-2 inhibitors in clinical practice: impact beyond glycemic control. Hypertension J. 2016; 2: 74-79. https://doi.org/10.5005/jp-journals-10043-0035
- 16Hjärne UJAMS. A study of orthoglycaemic glycosuria with particular reference to its hereditability. Acta Med Scand. 1927; 67: 495-571.
- 17Li H, Shin SE, Seo MS, et al. The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels. Life Sci. 2018; 197: 46-55.
- 18Ko EA, Park WS, Firth AL, Kim N, Yuan JX, Han J. Pathophysiology of voltage-gated K+ channels in vascular smooth muscle cells: modulation by protein kinases. Prog Biophys Mol Biol. 2010; 103: 95-101.
- 19Buja G, Miorelli M, Turrini P, Melacini P, Nava A. Comparison of QT dispersion in hypertrophic cardiomyopathy between patients with and without ventricular arrhythmias and sudden death. Am J Cardiol. 1993; 72: 973-976.
- 20Sato T, Miki T, Ohnishi H, et al. Effect of sodium-glucose co-transporter-2 inhibitors on impaired ventricular repolarization in people with type 2 diabetes. Diabet Med. 2017; 34: 1367-1371.
- 21Malik M, Batchvarov VN. Measurement, interpretation and clinical potential of QT dispersion. J Am Coll Cardiol. 2000; 36: 1749-1766.
- 22Tomiyama H, Doba N, Fu Y, et al. Left ventricular geometric patterns and QT dispersion in borderline and mild hypertension: their evolution and regression. Am J Hypertens. 1998; 11: 286-292.
- 23Verma S, Mazer CD, Bhatt DL, et al. Empagliflozin and cardiovascular outcomes in patients with type 2 diabetes and left ventricular hypertrophy: a subanalysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2019; 42: e42-e44.
- 24Tanriverdi H, Kaftan HA, Evrengul H, Dursunoglu D, Turgut G, Kilic M. QT dispersion and left ventricular hypertrophy in athletes: relationship with angiotensin-converting enzyme I/D polymorphism. Acta Cardiol. 2005; 60: 387-393.
- 25Neal B, Perkovic V, Mahaffey KW, et al; for the CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377: 644-657.
- 26Carbone S, Dixon DL. The CANVAS Program: implications of canagliflozin on reducing cardiovascular risk in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2019; 18: 64.
- 27Wiviott SD, Raz I, Bonaca MP, et al; for the DECLARE–TIMI 58 Investigators. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380: 347-357.
- 28 American Diabetes Association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2018. Diabetes Care. 2018; 41: S73.
- 29Piepoli MF, Hoes AW, Agewall S, et al; ESC Scientific Document Group. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). 2016; 37: 2315-2381.
- 30Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2018; 61: 2461-2498.
- 31Control CfD, Prevention %J Atlanta GUDoH, Human Services CfDC, Prevention. National chronic kidney disease fact sheet, 2014, 2017. US Department of Health and Human Services, Centers for Disease Control and Prevention, 2017. https://www.cdc.gov/diabeteS/pubs/pdf/kidney_factsheet.pdf
- 32Andersen AR, Christiansen JS, Andersen JK, Kreiner S, Deckert T. Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia. 1983; 25: 496-501.
- 33Afkarian M, Zelnick LR, Hall YN, et al. Clinical manifestations of kidney disease among US adults with diabetes, 1988–2014. JAMA. 2016; 316: 602-610.
- 34Wu B, Bell K, Stanford A, et al. Understanding CKD among patients with T2DM: prevalence, temporal trends, and treatment patterns—NHANES 2007-2012. BMJ Open Diabetes Res Care. 2016; 4:e000154.
- 35Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med. 2002; 346: 1145-1151.
- 36Ritz E, Orth SR. Nephropathy in patients with type 2 diabetes mellitus. N Engl J Med. 1999; 341: 1127-1133.
- 37Adler AI, Stevens RJ, Manley SE, Bilous RW, Cull CA, Holman RR. Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003; 63: 225-232.
- 38Mora-Fernández C, Domínguez-Pimentel V, Fuentes MM, Górriz JL, Martínez-Castelao A, Navarro-González JF. Diabetic kidney disease: from physiology to therapeutics. J Physiol. 2014; 592: 3997-4012.
- 39Gnudi L, Coward RJM, Long DA. Diabetic nephropathy: perspective on novel molecular mechanisms. Trends Endocrinol Metab. 2016; 27: 820-830.
- 40Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016; 134: 752-772.
- 41Wu JH, Foote C, Blomster J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2016; 4: 411-419.
- 42Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol. 2014; 306: F194-F204.
- 43Toth-Manikowski S, Atta MG. Diabetic kidney disease: pathophysiology and therapeutic targets. J Diabetes Res. 2015; 2015: 697010.
- 44Ha H, Hwang IA, Park JH, Lee HB. Role of reactive oxygen species in the pathogenesis of diabetic nephropathy. Diabetes Res Clin Pract. 2008; 82(Suppl 1): S42-S45.
- 45Chen S, Jim B, Ziyadeh FN. Diabetic nephropathy and transforming growth factor-beta: transforming our view of glomerulosclerosis and fibrosis build-up. Semin Nephrol. 2003; 23: 532-543.
- 46Salahudeen AK, Kanji V, Reckelhoff JF, Schmidt AM. Pathogenesis of diabetic nephropathy: a radical approach. Nephrol Dial Transplant. 1997; 12: 664-668.
- 47Wanner C, Inzucchi SE, Lachin JM, et al; for the EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016; 375: 323-334.
- 48Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018; 6: 691-704.
- 49Scheen AJ. Pharmacokinetics, pharmacodynamics and clinical use of SGLT2 inhibitors in patients with type 2 diabetes mellitus and chronic kidney disease. Clin Pharmacokinet. 2015; 54: 691-708.
- 50Kelly MS, Lewis J, Huntsberry AM, Dea L, Portillo I. Efficacy and renal outcomes of SGLT2 inhibitors in patients with type 2 diabetes and chronic kidney disease. Postgrad Med. 2019; 131: 31-42.
- 51Fioretto P, Del Prato S, Buse JB, et al; DERIVE Study Investigators. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): the DERIVE Study. Diabetes Obes Metab. 2018; 20: 2532-2540.
- 52Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013; 15: 463-473.
- 53Verma S, Bhatt DL. More CREDENCE for SGLT2 inhibition. Circulation. 2019; 140: 1-3.
- 54Jardine MJ, Mahaffey KW, Neal B, et al; CREDENCE study investigators. The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017; 46: 462-472.
- 55Perkovic V, Jardine MJ, Neal B, et al; for the CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019; 380: 2295-2306.
- 56Ingelfinger JR, Rosen CJ. Clinical credence—SGLT2 inhibitors, diabetes, and chronic kidney disease. N Engl J Med. 2019; 380: 2371-2373.
- 57Jung CH, Jang JE, Park JY. A novel therapeutic agent for type 2 diabetes mellitus: SGLT2 inhibitor. Diabetes Metab J. 2014; 38: 261-273.
- 58 AstraZeneca. A Study to Evaluate the Effect of Dapagliflozin on Renal Outcomes and Cardiovascular Mortality in Patients with Chronic Kidney Disease (Dapa-CKD). Bethesda, MD: US National Library of Medicine; 2000.
- 59Pan CW, Wang S, Xu CL, Song E. Combined effect of glycemic and blood pressure control on diabetic retinopathy among Chinese with type-2 diabetes mellitus. Diabetol Metab Syndr. 2018; 10: 73.
- 60CDC. Watch out for diabetic retinopathy, 2014. https://www.cdc.gov/features/diabetic-retinopathy/index.html. Accessed October 10, 2018.
- 61Kohner EM, Patel V, Rassam SM. Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy. Diabetes. 1995; 44: 603-607.
- 62Crawford TN, Alfaro DV 3rd, Kerrison JB, Jablon EP. Diabetic retinopathy and angiogenesis. Curr Diabetes Rev. 2009; 5: 8-13.
- 63Nyengaard JR, Ido Y, Kilo C, Williamson JR. Interactions between hyperglycemia and hypoxia: implications for diabetic retinopathy. Diabetes. 2004; 53: 2931-2938.
- 64Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011; 118: 615-625.
- 65Gariano RF, Gardner TW. Retinal angiogenesis in development and disease. Nature. 2005; 438: 960-966.
- 66Mieno H, Yoneda K, Yamazaki M, Sakai R, Sotozono C, Fukui M. The efficacy of sodium-glucose cotransporter 2 (SGLT2) inhibitors for the treatment of chronic diabetic macular oedema in vitrectomised eyes: a retrospective study. BMJ Open Ophthalmol. 2018; 3:e000130.
- 67Kaul S. Response to comment on Kaul. 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;40:821–831. Diabetes Care. 2017; 40: e175-e176.
- 68Ott C, Jumar A, Striepe K, et al. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc Diabetol. 2017; 16: 26.
- 69Farkouh ME, Verma S. Prevention of heart failure with SGLT-2 inhibition: insights from CVD-REAL. J Am Coll Cardiol. 2018; 71: 2507-2510.
- 70McMurray JJ, Gerstein HC, Holman RR, Pfeffer MA. Heart failure: a cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol. 2014; 2: 843-851.
- 71Shah AD, Langenberg C, Rapsomaniki E, et al. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people. Lancet Diabetes Endocrinol. 2015; 3: 105-113.
- 72Seferovic PM, Petrie MC, Filippatos GS, et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of cardiology. Eur J Heart Fail. 2018; 20: 853-872.
- 73Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll Cardiol. 2014; 64: 1388-1400.
- 74Djousse L, Benkeser D, Arnold A, et al. Plasma free fatty acids and risk of heart failure: the Cardiovascular Health Study. Circ Heart Fail. 2013; 6: 964-969.
- 75Opie LH, Knuuti J. The adrenergic-fatty acid load in heart failure. J Am Coll Cardiol. 2009; 54: 1637-1646.
- 76Fragasso G, Palloshi A, Perseghin G. Letter by Fragasso et al regarding article by Tuunanen et al, "Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure". Circulation. 2007; 115:e546; author reply e7.
- 77Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322: 1561-1566.
- 78Katz SD, Hryniewicz K, Hriljac I, et al. Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure. Circulation. 2005; 111: 310-314.
- 79De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte PM. Endothelial dysfunction in diabetes. Br J Pharmacol. 2000; 130: 963-974.
- 80Seferovic PM, Paulus WJ. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur Heart J. 2015; 36: 1718-1727, 1727a-1727c.
- 81Loncarevic B, Trifunovic D, Soldatovic I, Vujisic-Tesic B. Silent diabetic cardiomyopathy in everyday practice: a clinical and echocardiographic study. BMC Cardiovasc Disord. 2016; 16: 242.
- 82Kasznicki J, Drzewoski J. Heart failure in the diabetic population – pathophysiology, diagnosis and management. Arch Med Sci. 2014; 10: 546-556.
- 83van Melle JP, Bot M, de Jonge P, de Boer RA, van Veldhuisen DJ, Whooley MA. Diabetes, glycemic control, and new-onset heart failure in patients with stable coronary artery disease: data from the heart and soul study. Diabetes Care. 2010; 33: 2084-2089.
- 84Burrows NR, Li Y, Gregg EW, LS G. Declining rates of hospitalization for selected cardiovascular disease conditions among adults aged ≥35 years with diagnosed diabetes, U.S., 1998–2014. Diabetes Care. 2018; 41: 293-302.
- 85Bertoni AG, Hundley WG, Massing MW, Bonds DE, Burke GL, Goff DC Jr. Heart failure prevalence, incidence, and mortality in the elderly with diabetes. Diabetes Care. 2004; 27: 699-703.
- 86Mahaffey KW, Neal B, Perkovic V, et al; CANVAS Program Collaborative Group. Canagliflozin for primary and secondary prevention of cardiovascular events: results from the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation. 2018; 137: 323-334.
- 87Furtado RHM, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes mellitus and previous myocardial infarction. Circulation. 2019; 139: 2516-2527.
- 88Furtado RH, Bonaca MP, Raz I, et al. Dapagliflozin and cardiovascular outcomes in patients with type 2 diabetes and prior myocardial infarction: a sub-analysis from DECLARE TIMI-58 Trial. Circulation. 2019; 139:2516-2527.
- 89Kosiborod M, Lam CSP, Kohsaka S, et al; CVD-REAL Investigators and Study Group. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 Study. J Am Coll Cardiol. 2018; 71: 2628-2639.
- 90Packer 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.
- 91Wan N, Rahman A, Hitomi H, Nishiyama A. The effects of sodium-glucose cotransporter 2 inhibitors on sympathetic nervous activity. Front Endocrinol (Lausanne). 2018; 9: 421.
- 92Pham SV, Chilton RJ. EMPA-REG OUTCOME: the Cardiologist's point of view. Am J Cardiol. 2017; 120: S53-s8.
- 93Staels B. Cardiovascular protection by sodium glucose cotransporter 2 inhibitors: potential mechanisms. Am J Cardiol. 2017; 120: S28-s36.
- 94Food U, DAJA S. FDA Drug Safety Communication: FDA Revises Labels of SGLT2 Inhibitors for Diabetes to Include Warnings about too much Acid in the Blood and Serious Urinary Tract infections. Silver Spring, Maryland: Food and Drug Administration; 2016: 6.
- 95Dave CV, Schneeweiss S, Kim D, Fralick M, Tong A, Patorno E. Sodium-glucose cotransporter-2 inhibitors and the risk for severe urinary tract infections: a population-based cohort study. Ann Intern Med. 2019; 171(4):248-256.
- 96Canadian Diabetes Association Clinical Practice Guidelines Expert Committee,Harper W, Clement M, et al; Steering Committee for Canadian Diabetes Association 2013 Clinical Practice Guidelines for Prevention and Management of Diabetes in Canada.Policies, guidelines and consensus statements: pharmacologic management of type 2 diabetes-2015 interim update. Can J Diabetes. 2015; 39: 250-252.
- 97Marahrens L, Rock D, Ziemssen T, Kern R, Ziemssen F, Fritsche A. Implementation of the National Guidelines for the treatment of diabetes mellitus type 2 in secondary diabetes centers. Dtsch Med Wochenschr. 2017; 142: e131-e139.
- 98 Diabetes Association Of The Republic Of China Taiwan. Executive summary of the DAROC clinical practice guidelines for diabetes care- 2018. J Formos Med Assoc. 2019. https://doi.org/10.1016/j.jfma.2019.02.016
- 99Bailey CJ. Renal glucose reabsorption inhibitors to treat diabetes. Trends Pharmacol Sci. 2011; 32: 63-71.