{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T02:18:04Z","timestamp":1787883484855,"version":"build-2784847793"},"reference-count":56,"publisher":"American Diabetes Association","issue":"5","content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2016,5,1]]},"abstract":"<jats:p>Although cardiovascular (CV) mortality is the principal cause of death in individuals with type 2 diabetes (T2DM), reduction of plasma glucose concentration has little effect on CV disease (CVD) risk. Thus, novel strategies to reduce CVD risk in T2DM patients are needed. The recently published BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) study demonstrated that in T2DM patients with high CVD risk empagliflozin reduced the primary major adverse cardiac event end point (CV death, nonfatal myocardial infarction, nonfatal stroke) by 14%. This beneficial effect was driven by a 38% reduction in CV mortality with no significant decrease in nonfatal myocardial infarction or stroke. Empagliflozin also caused a 35% reduction in hospitalization for heart failure without affecting hospitalization for unstable angina. Although sodium\u2013glucose cotransporter 2 inhibitors exert multiple metabolic benefits (decreases in HbA1c, body weight, and blood pressure and an increase in HDL cholesterol), all of which could reduce CVD risk, it is unlikely that the reduction in CV mortality can be explained by empagliflozin\u2019s metabolic effects. More likely, hemodynamic effects, specifically reduced blood pressure and decreased extracellular volume, are responsible for the reduction in CV mortality and heart failure hospitalization. In this Perspective, we will discuss possible mechanisms for these beneficial effects of empagliflozin and their implications for the care of T2DM patients.<\/jats:p>","DOI":"10.2337\/dc16-0041","type":"journal-article","created":{"date-parts":[[2016,4,21]],"date-time":"2016-04-21T19:26:14Z","timestamp":1461266774000},"page":"717-725","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":254,"title":["SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study"],"prefix":"10.2337","volume":"39","author":[{"given":"Muhammad","family":"Abdul-Ghani","sequence":"first","affiliation":[{"name":"Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX"},{"name":"Diabetes and Obesity Clinical Research Center, Department of Medicine, Hamad General Hospital, Doha, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Del Prato","sequence":"additional","affiliation":[{"name":"Department of Clinical and Experimental Medicine, University of Pisa School of Medicine, Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Chilton","sequence":"additional","affiliation":[{"name":"Division of Cardiology, University of Texas Health Science Center at San Antonio and South Texas Veterans Health Care System, San Antonio, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralph A.","family":"DeFronzo","sequence":"additional","affiliation":[{"name":"Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, TX"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2016,4,14]]},"reference":[{"key":"2022031221122516600_B1","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B2","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1001\/jama.2015.7008","article-title":"Association of cardiometabolic multimorbidity with mortality","volume":"314","author":"Di Angelantonio","year":"2015","journal-title":"JAMA"},{"key":"2022031221122516600_B3","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1016\/S0140-6736(98)07019-6","article-title":"Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33)","volume":"352","author":"UK Prospective Diabetes Study (UKPDS) Group","year":"1998","journal-title":"Lancet"},{"key":"2022031221122516600_B4","doi-asserted-by":"crossref","first-page":"2545","DOI":"10.1056\/NEJMoa0802743","article-title":"Effects of intensive glucose lowering in type 2 diabetes","volume":"358","author":"Gerstein","year":"2008","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B5","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.1056\/NEJMoa0802987","article-title":"Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes","volume":"358","author":"Patel","year":"2008","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B6","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1056\/NEJMoa0808431","article-title":"Glucose control and vascular complications in veterans with type 2 diabetes","volume":"360","author":"Duckworth","year":"2009","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B7","doi-asserted-by":"crossref","first-page":"1577","DOI":"10.1056\/NEJMoa0806470","article-title":"10-year follow-up of intensive glucose control in type 2 diabetes","volume":"359","author":"Holman","year":"2008","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B8","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1056\/NEJMoa1414266","article-title":"Follow-up of glycemic control and cardiovascular outcomes in type 2 diabetes","volume":"372","author":"Hayward","year":"2015","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B9","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0300-2977(97)00012-0","article-title":"Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis","volume":"50","author":"DeFronzo","year":"1997","journal-title":"Neth J Med"},{"key":"2022031221122516600_B10","doi-asserted-by":"crossref","first-page":"1270","DOI":"10.1007\/s00125-010-1684-1","article-title":"Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009","volume":"53","author":"DeFronzo","year":"2010","journal-title":"Diabetologia"},{"key":"2022031221122516600_B11","doi-asserted-by":"crossref","first-page":"1169","DOI":"10.1016\/j.mcna.2007.06.003","article-title":"Cardiovascular morbidity and mortality of the metabolic syndrome","volume":"91","author":"Obunai","year":"2007","journal-title":"Med Clin North Am"},{"key":"2022031221122516600_B12","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1007\/s00125-012-2817-5","article-title":"Revisiting the links between glycaemia, diabetes and cardiovascular disease","volume":"56","author":"Sattar","year":"2013","journal-title":"Diabetologia"},{"key":"2022031221122516600_B13","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1056\/NEJMoa1203858","article-title":"Basal insulin and cardiovascular and other outcomes in dysglycemia","volume":"367","author":"Gerstein","year":"2012","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B14","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1056\/NEJMoa1307684","article-title":"Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus","volume":"369","author":"Scirica","year":"2013","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B15","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1056\/NEJMoa1305889","article-title":"Alogliptin after acute coronary syndrome in patients with type 2 diabetes","volume":"369","author":"White","year":"2013","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B16","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1056\/NEJMoa1501352","article-title":"Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes","volume":"373","author":"Green","year":"2015","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B17","doi-asserted-by":"crossref","first-page":"710","DOI":"10.2337\/diacare.24.4.710","article-title":"Improved glycemic control and enhanced insulin sensitivity in type 2 diabetic subjects treated with pioglitazone","volume":"24","author":"Miyazaki","year":"2001","journal-title":"Diabetes Care"},{"key":"2022031221122516600_B18","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.1016\/S0140-6736(05)67528-9","article-title":"Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial","volume":"366","author":"Dormandy","year":"2005","journal-title":"Lancet"},{"key":"2022031221122516600_B19","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1210\/er.2010-0029","article-title":"Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes","volume":"32","author":"Abdul-Ghani","year":"2011","journal-title":"Endocr Rev"},{"key":"2022031221122516600_B20","doi-asserted-by":"crossref","first-page":"1020","DOI":"10.1210\/jc.2011-2260","article-title":"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","volume":"97","author":"Bolinder","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"2022031221122516600_B21","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/dom.12127","article-title":"Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes","volume":"15","author":"Lambers Heerspink","year":"2013","journal-title":"Diabetes Obes Metab"},{"key":"2022031221122516600_B22","doi-asserted-by":"crossref","first-page":"F889","DOI":"10.1152\/ajprenal.00267.2015","article-title":"Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus","volume":"309","author":"Abdul-Ghani","year":"2015","journal-title":"Am J Physiol Renal Physiol"},{"key":"2022031221122516600_B23","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1186\/1472-6823-14-37","article-title":"Efficacy and safety of canagliflozin compared with placebo in older patients with type 2 diabetes mellitus: a pooled analysis of clinical studies","volume":"14","author":"Sinclair","year":"2014","journal-title":"BMC Endocr Disord"},{"key":"2022031221122516600_B24","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1172\/JCI70704","article-title":"Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production","volume":"124","author":"Merovci","year":"2014","journal-title":"J Clin Invest"},{"key":"2022031221122516600_B25","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1172\/JCI72227","article-title":"Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients","volume":"124","author":"Ferrannini","year":"2014","journal-title":"J Clin Invest"},{"key":"2022031221122516600_B26","doi-asserted-by":"crossref","first-page":"1349","DOI":"10.1056\/NEJM199811053391902","article-title":"Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels","volume":"339","author":"The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group","year":"1998","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B27","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S0140-6736(07)61303-8","article-title":"Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial","volume":"370","author":"Patel","year":"2007","journal-title":"Lancet"},{"key":"2022031221122516600_B28","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/0026-0495(88)90110-2","article-title":"The theoretical bases of indirect calorimetry: a review","volume":"37","author":"Ferrannini","year":"1988","journal-title":"Metabolism"},{"key":"2022031221122516600_B29","doi-asserted-by":"crossref","first-page":"H1060","DOI":"10.1152\/ajpheart.00646.2012","article-title":"Ketone body metabolism and cardiovascular disease","volume":"304","author":"Cotter","year":"2013","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"2022031221122516600_B30","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1053\/j.ajkd.2014.04.024","article-title":"Uric acid levels, kidney function, and cardiovascular mortality in US adults: National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 1999-2002","volume":"64","author":"Odden","year":"2014","journal-title":"Am J Kidney Dis"},{"key":"2022031221122516600_B31","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1056\/NEJMra0800885","article-title":"Uric acid and cardiovascular risk","volume":"359","author":"Feig","year":"2008","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B32","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1038\/nm.3828","article-title":"Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion","volume":"21","author":"Bonner","year":"2015","journal-title":"Nat Med"},{"key":"2022031221122516600_B33","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.molmet.2014.11.005","article-title":"Cardiomyocyte glucagon receptor signaling modulates outcomes in mice with experimental myocardial infarction","volume":"4","author":"Ali","year":"2015","journal-title":"Mol Metab"},{"key":"2022031221122516600_B34","doi-asserted-by":"crossref","first-page":"71","DOI":"10.3109\/00365518809085396","article-title":"Low-dose intravenous glucagon has no effect on myocardial contractility in normal man. An echocardiographic study","volume":"48","author":"Thuesen","year":"1988","journal-title":"Scand J Clin Lab Invest"},{"key":"2022031221122516600_B35","doi-asserted-by":"crossref","first-page":"e0130605","DOI":"10.1371\/journal.pone.0130605","article-title":"Expression of SGLT1 in human hearts and impairment of cardiac glucose uptake by phlorizin during ischemia-reperfusion injury in mice","volume":"10","author":"Kashiwagi","year":"2015","journal-title":"PLoS One"},{"key":"2022031221122516600_B36","doi-asserted-by":"crossref","first-page":"44","DOI":"10.2337\/db15-0627","article-title":"Relationship between left ventricular structural and metabolic remodeling in type 2 diabetes","volume":"65","author":"Levelt","year":"2016","journal-title":"Diabetes"},{"key":"2022031221122516600_B37","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/S0140-6736(15)00805-3","article-title":"Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis","volume":"387","author":"Xie","year":"2016","journal-title":"Lancet"},{"key":"2022031221122516600_B38","doi-asserted-by":"crossref","first-page":"2085","DOI":"10.1161\/01.CIR.0000033824.02722.F7","article-title":"Aortic pulse-wave velocity and its relationship to mortality in diabetes and glucose intolerance: an integrated index of vascular function?","volume":"106","author":"Cruickshank","year":"2002","journal-title":"Circulation"},{"key":"2022031221122516600_B39","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1161\/HYPERTENSIONAHA.107.089078","article-title":"Central pressure more strongly relates to vascular disease and outcome than does brachial pressure: the Strong Heart Study","volume":"50","author":"Roman","year":"2007","journal-title":"Hypertension"},{"key":"2022031221122516600_B40","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1161\/CIRCULATIONAHA.105.595496","article-title":"Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study","volume":"113","author":"Williams","year":"2006","journal-title":"Circulation"},{"key":"2022031221122516600_B41","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/1475-2840-13-28","article-title":"The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus","volume":"13","author":"Cherney","year":"2014","journal-title":"Cardiovasc Diabetol"},{"key":"2022031221122516600_B42","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1007\/s13300-013-0030-2","article-title":"Safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple rising doses of empagliflozin in patients with type 2 diabetes mellitus","volume":"4","author":"Heise","year":"2013","journal-title":"Diabetes Ther"},{"key":"2022031221122516600_B43","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1056\/NEJM199909023411001","article-title":"The effect of spironolactone on morbidity and mortality in patients with severe heart failure","volume":"341","author":"Pitt","year":"1999","journal-title":"N Engl J Med"},{"key":"2022031221122516600_B44","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1038\/nrcardio.2014.59","article-title":"Angiotensin-converting enzyme 2 and angiotensin 1-7: novel therapeutic targets","volume":"11","author":"Jiang","year":"2014","journal-title":"Nat Rev Cardiol"},{"key":"2022031221122516600_B45","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1016\/S2213-8587(15)00424-6","article-title":"Understanding EMPA-REG OUTCOME","volume":"3","author":"Muskiet","year":"2015","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2022031221122516600_B46","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1111\/dme.12232","article-title":"Sulphonylureas and risk of cardiovascular disease: systematic review and meta-analysis","volume":"30","author":"Phung","year":"2013","journal-title":"Diabet Med"},{"key":"2022031221122516600_B47","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1016\/j.jacc.2006.12.048","article-title":"The effect of pioglitazone on recurrent myocardial infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: results from the PROactive (PROactive 05) Study","volume":"49","author":"Erdmann","year":"2007","journal-title":"J Am Coll Cardiol"},{"key":"2022031221122516600_B48","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1161\/01.STR.0000257974.06317.49","article-title":"Effects of pioglitazone in patients with type 2 diabetes with or without previous stroke: results from PROactive (PROspective pioglitAzone Clinical Trial In macroVascular Events 04)","volume":"38","author":"Wilcox","year":"2007","journal-title":"Stroke"},{"key":"2022031221122516600_B49","first-page":"A298","article-title":"Improved left ventricular diastolic function (LVDF) following pioglitazone therapy is strongly related to increased myocardial insulin sensitivity [Abstract]","volume":"63","author":"Clarke","year":"2014","journal-title":"Diabetes"},{"key":"2022031221122516600_B50","doi-asserted-by":"crossref","first-page":"337","DOI":"10.2165\/00044011-200525050-00006","article-title":"Pioglitazone lowers blood pressure in hypertensive patients with type 2 diabetes mellitus : an open, multicentre, observational study","volume":"25","author":"Konrad","year":"2005","journal-title":"Clin Drug Investig"},{"key":"2022031221122516600_B51","doi-asserted-by":"crossref","first-page":"1561","DOI":"10.1001\/jama.299.13.1561","article-title":"Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial","volume":"299","author":"Nissen","year":"2008","journal-title":"JAMA"},{"key":"2022031221122516600_B52","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1161\/ATVBAHA.112.300346","article-title":"Pioglitazone slows progression of atherosclerosis in prediabetes independent of changes in cardiovascular risk factors","volume":"33","author":"Saremi","year":"2013","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"2022031221122516600_B53","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.atherosclerosis.2010.12.021","article-title":"Pioglitazone improves endothelial and adipose tissue dysfunction in pre-diabetic CAD subjects","volume":"215","author":"Rizza","year":"2011","journal-title":"Atherosclerosis"},{"key":"2022031221122516600_B54","doi-asserted-by":"crossref","DOI":"10.1056\/NEJMoa1506930","article-title":". Pioglitazone after ischemic stroke or transient ischemic attack","author":"Kernan","year":"2016","journal-title":"N Engl J Med. 17 February"},{"key":"2022031221122516600_B55","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1111\/dom.12261","article-title":"Modeling effects of SGLT-2 inhibitor dapagliflozin treatment versus standard diabetes therapy on cardiovascular and microvascular outcomes","volume":"16","author":"Dziuba","year":"2014","journal-title":"Diabetes Obes Metab"},{"key":"2022031221122516600_B56","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1016\/j.ahj.2013.05.007","article-title":"Rationale, design, and baseline characteristics of the Canagliflozin Cardiovascular Assessment Study (CANVAS)\u2014a randomized placebo-controlled trial","volume":"166","author":"Neal","year":"2013","journal-title":"Am Heart J"}],"container-title":["Diabetes Care"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/39\/5\/717\/625605\/dc160041.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/care\/article-pdf\/39\/5\/717\/625605\/dc160041.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,3,12]],"date-time":"2022-03-12T23:15:43Z","timestamp":1647126943000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/care\/article\/39\/5\/717\/30628\/SGLT2-Inhibitors-and-Cardiovascular-Risk-Lessons"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,14]]},"references-count":56,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2016,4,14]]},"published-print":{"date-parts":[[2016,5,1]]}},"URL":"https:\/\/doi.org\/10.2337\/dc16-0041","relation":{},"ISSN":["0149-5992","1935-5548"],"issn-type":[{"value":"0149-5992","type":"print"},{"value":"1935-5548","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,14]]}}}