{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,19]],"date-time":"2026-01-19T15:58:40Z","timestamp":1768838320082,"version":"3.49.0"},"reference-count":39,"publisher":"The Endocrine Society","issue":"10","license":[{"start":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T00:00:00Z","timestamp":1623628800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100004325","name":"AstraZeneca","doi-asserted-by":"publisher","award":["EVS-20-01061"],"award-info":[{"award-number":["EVS-20-01061"]}],"id":[{"id":"10.13039\/100004325","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002923","name":"Brazilian National Research Council","doi-asserted-by":"publisher","award":["301465\/2017-7"],"award-info":[{"award-number":["301465\/2017-7"]}],"id":[{"id":"10.13039\/501100002923","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,9,27]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Sodium glucose co-transporter 2 inhibitors (SGLT2is) prevent hospitalization resulting from heart failure (HHF). However, patients with type 2 diabetes mellitus use multiple antihyperglycemic drugs to achieve glycosylated hemoglobin (HbA1c) targets. In these drug combinations, the risk of HHF is unpredictable and so is the parallel effect of glucose-lowering.<\/jats:p><\/jats:sec><jats:sec><jats:title>Purpose<\/jats:title><jats:p>To examine the impact of antihyperglycemic drugs and their association on HHF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Data Sources<\/jats:title><jats:p>Forty randomized controlled trials (RCTs) reporting HHF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Study Selection<\/jats:title><jats:p>Published RCTs were the data source.<\/jats:p><\/jats:sec><jats:sec><jats:title>Data Extraction<\/jats:title><jats:p>Incidence rates of HHF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Data Synthesis<\/jats:title><jats:p>Random additive-effects network meta-analysis showed that metformin (P\u2005=\u20050.55), sulfonylureas (P\u2005=\u20050.51), glucagon-like peptide-1 receptor-agonist (P\u2005=\u20050.16), and dipeptidyl peptidase 4 inhibitors (DPP4is; P\u2005=\u20050.54) were neutral on the risk of HHF. SGLT2is and SGLT2is\u2005+\u2005DPP4is reduced the risk of HHF with a hazard ratio (HR) of 0.68 (95% CI, 0.60-0.76; P\u2005&amp;lt;\u20050.0001) and 0.70 (95% CI, 0.60-0.81; P\u2005&amp;lt;\u20050.0001), respectively. Increased risk of HHF was associated with thiazolidinediones (TZDs) as monotherapy or in combination with DPP4is (HR: 1.45; 95% CI, 1.18-1.78; P\u2005=\u20050.0004) and 1.49 (95% CI, 1.18-1.88; P\u2005=\u20050.0008), respectively. Regardless of the therapy, a 1% reduction in HbA1c reduced the risk of HHF by 31.3% (95% CI, 9-48; P\u2005=\u20050.009).<\/jats:p><\/jats:sec><jats:sec><jats:title>Limitations<\/jats:title><jats:p>There are no data to verify drug combinations available for clinical use and to discriminate the effect of drugs within each of the therapeutic classes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The risk of HHF is reduced by SGLT2is as monotherapy or in combination with DPP4is and increased by TZDs as monotherapy or in combination. Glucose-lowering provides an additive effect of reducing HHF.<\/jats:p><\/jats:sec>","DOI":"10.1210\/clinem\/dgab428","type":"journal-article","created":{"date-parts":[[2021,6,14]],"date-time":"2021-06-14T15:59:35Z","timestamp":1623686375000},"page":"3060-3067","source":"Crossref","is-referenced-by-count":10,"title":["Glucose-lowering Drugs and Hospitalization for Heart Failure: A Systematic Review and Additive-effects Network Meta-analysis With More Than 500 000 Patient-years"],"prefix":"10.1210","volume":"106","author":[{"given":"Riobaldo M","family":"Cintra","sequence":"first","affiliation":[{"name":"Atherosclerosis and Vascular Biology Laboratory (Atherolab), Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ana Claudia","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Directory of Clinical Research and Innovation, Institute for Strategic Management in Healthcare (IGESDF), Bras\u00edlia, DF, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Isabella","family":"Bonilha","sequence":"additional","affiliation":[{"name":"Atherosclerosis and Vascular Biology Laboratory (Atherolab), Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz M","family":"Luchiari","sequence":"additional","affiliation":[{"name":"Atherosclerosis and Vascular Biology Laboratory (Atherolab), Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Otavio R","family":"Coelho-Filho","sequence":"additional","affiliation":[{"name":"Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Otavio R","family":"Coelho","sequence":"additional","affiliation":[{"name":"Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro","family":"Schwartzmann","sequence":"additional","affiliation":[{"name":"Atherosclerosis and Vascular Biology Laboratory (Atherolab), Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elza","family":"Muscellie","sequence":"additional","affiliation":[{"name":"Atherosclerosis and Vascular Biology Laboratory (Atherolab), Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wilson","family":"Nadruz","sequence":"additional","affiliation":[{"name":"Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luiz Sergio F","family":"Carvalho","sequence":"additional","affiliation":[{"name":"Atherosclerosis and Vascular Biology Laboratory (Atherolab), Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"},{"name":"Directory of Clinical Research and Innovation, Institute for Strategic Management in Healthcare (IGESDF), Bras\u00edlia, DF, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7127-2052","authenticated-orcid":false,"given":"Andrei C","family":"Sposito","sequence":"additional","affiliation":[{"name":"Atherosclerosis and Vascular Biology Laboratory (Atherolab), Cardiology Department, State University of Campinas (Unicamp), Campinas, SP, Brazil"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2021,6,14]]},"reference":[{"issue":"8","key":"2021110612090888800_CIT0001","doi-asserted-by":"crossref","first-page":"1342","DOI":"10.1002\/ejhf.1858","article-title":"Epidemiology of heart failure","volume":"22","author":"Groenewegen","year":"2020","journal-title":"Eur J Heart Fail."},{"issue":"3","key":"2021110612090888800_CIT0002","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s10741-018-9669-0","article-title":"Clinical impact of oral antidiabetic medications in heart failure patients","volume":"23","author":"Palazzuoli","year":"2018","journal-title":"Heart Fail Rev."},{"issue":"4","key":"2021110612090888800_CIT0003","doi-asserted-by":"crossref","first-page":"590","DOI":"10.1161\/CIRCHEARTFAILURE.113.001281","article-title":"Influence of previous heart failure hospitalization on cardiovascular events in patients with reduced and preserved ejection fraction","volume":"7","author":"Bello","year":"2014","journal-title":"Circ Heart Fail."},{"issue":"3","key":"2021110612090888800_CIT0004","doi-asserted-by":"crossref","first-page":"606","DOI":"10.1161\/HHF.0b013e318291329a","article-title":"Forecasting the impact of heart failure in the United States: a policy statement from the American Heart Association","volume":"6","author":"Heidenreich","year":"2013","journal-title":"Circ Heart Fail."},{"issue":"11","key":"2021110612090888800_CIT0005","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1007\/s00125-009-1470-0","article-title":"Intensive glucose control and macrovascular outcomes in type 2 diabetes","volume":"52","author":"Turnbull","year":"2009","journal-title":"Diabetologia."},{"key":"2021110612090888800_CIT0006","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/1471-2261-14-129","article-title":"The risk of heart failure associated with the use of noninsulin blood glucose-lowering drugs: systematic review and meta-analysis of published observational studies","volume":"14","author":"Varas-Lorenzo","year":"2014","journal-title":"BMC Cardiovasc Disord."},{"key":"2021110612090888800_CIT0007","doi-asserted-by":"crossref","first-page":"i610","DOI":"10.1136\/bmj.i610","article-title":"Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies","volume":"352","author":"Li","year":"2016","journal-title":"BMJ."},{"issue":"2","key":"2021110612090888800_CIT0008","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1002\/ejhf.1673","article-title":"European Society of Cardiology\/Heart Failure Association position paper on the role and safety of new glucose-lowering drugs in patients with heart failure","volume":"22","author":"Seferovi\u0107","year":"2020","journal-title":"Eur J Heart Fail."},{"issue":"7","key":"2021110612090888800_CIT0009","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1056\/NEJMoa1611925","article-title":"Canagliflozin and cardiovascular and renal events in type 2 diabetes","volume":"377","author":"Neal","year":"2017","journal-title":"N Engl J Med."},{"issue":"4","key":"2021110612090888800_CIT0010","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1056\/NEJMoa1812389","article-title":"Dapagliflozin and cardiovascular outcomes in type 2 diabetes","volume":"380","author":"Wiviott","year":"2019","journal-title":"N Engl J Med."},{"issue":"22","key":"2021110612090888800_CIT0011","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."},{"issue":"21","key":"2021110612090888800_CIT0012","doi-asserted-by":"crossref","first-page":"1995","DOI":"10.1056\/NEJMoa1911303","article-title":"Dapagliflozin in patients with heart failure and reduced ejection fraction","volume":"381","author":"McMurray","year":"2019","journal-title":"N Engl J Med."},{"issue":"15","key":"2021110612090888800_CIT0013","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1056\/NEJMoa2022190","article-title":"Cardiovascular and renal outcomes with empagliflozin in heart failure","volume":"383","author":"Packer","year":"2020","journal-title":"N Engl J Med."},{"issue":"2","key":"2021110612090888800_CIT0014","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1093\/eurheartj\/ehz486","article-title":"2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD","volume":"41","author":"Cosentino","year":"2020","journal-title":"Eur Heart J."},{"issue":"15","key":"2021110612090888800_CIT0015","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1001\/jama.283.15.2008","article-title":"Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis of observational studies in epidemiology (MOOSE) group","volume":"283","author":"Stroup","year":"2000","journal-title":"Jama."},{"key":"2021110612090888800_CIT0016","article-title":"Glucose-lowering drugs and hospitalization for heart failure: a systematic review and additive-effects network meta-analysis","author":"Sposito"},{"issue":"3","key":"2021110612090888800_CIT0017","doi-asserted-by":"crossref","first-page":"808","DOI":"10.1002\/bimj.201800167","article-title":"Network meta-analysis of multicomponent interventions","volume":"62","author":"R\u00fccker","year":"2020","journal-title":"Biom J."},{"key":"2021110612090888800_CIT0018","doi-asserted-by":"crossref","first-page":"d5928","DOI":"10.1136\/bmj.d5928","article-title":"The Cochrane collaboration\u2019s tool for assessing risk of bias in randomised trials","volume":"343","author":"Higgins","year":"2011","journal-title":"BMJ."},{"issue":"12","key":"2021110612090888800_CIT0019","doi-asserted-by":"crossref","first-page":"1311","DOI":"10.1016\/j.jclinepi.2011.06.004","article-title":"GRADE guidelines: 9. Rating up the quality of evidence","volume":"64","author":"Guyatt","year":"2011","journal-title":"J Clin Epidemiol."},{"issue":"7258","key":"2021110612090888800_CIT0020","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1136\/bmj.321.7258.405","article-title":"Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study","volume":"321","author":"Stratton","year":"2000","journal-title":"BMJ."},{"issue":"3","key":"2021110612090888800_CIT0021","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1161\/CIRCHEARTFAILURE.114.001990","article-title":"Cardiac structure and function across the glycemic spectrum in elderly men and women free of prevalent heart disease: the atherosclerosis risk in the community study","volume":"8","author":"Skali","year":"2015","journal-title":"Circ Heart Fail."},{"issue":"11","key":"2021110612090888800_CIT0022","doi-asserted-by":"crossref","first-page":"2026","DOI":"10.1002\/ejhf.1958","article-title":"Association between glycated haemoglobin levels and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease: a secondary analysis of the TECOS randomized clinical trial","volume":"22","author":"McAlister","year":"2020","journal-title":"Eur J Heart Fail."},{"issue":"25","key":"2021110612090888800_CIT0023","doi-asserted-by":"crossref","first-page":"2393","DOI":"10.1093\/eurheartj\/ehaa344","article-title":"Are the benefits of SGLT2 inhibitors in heart failure and a reduced ejection fraction influenced by background therapy? Expectations and realities of a new standard of care","volume":"41","author":"Packer","year":"2020","journal-title":"Eur Heart J."},{"issue":"1","key":"2021110612090888800_CIT0024","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1186\/s12933-021-01264-z","article-title":"Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial","volume":"20","author":"Sposito","year":"2021","journal-title":"Cardiovasc Diabetol."},{"issue":"10166","key":"2021110612090888800_CIT0025","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0140-6736(18)32590-X","article-title":"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","volume":"393","author":"Zelniker","year":"2019","journal-title":"Lancet."},{"issue":"5","key":"2021110612090888800_CIT0026","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1016\/S2213-8587(20)30038-3","article-title":"Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials","volume":"8","author":"Ghosh-Swaby","year":"2020","journal-title":"Lancet Diabetes Endocrinol."},{"issue":"8","key":"2021110612090888800_CIT0027","doi-asserted-by":"crossref","first-page":"678","DOI":"10.1016\/j.jchf.2019.04.019","article-title":"Hemodynamic effects of weight loss in obesity: a systematic review and meta-analysis","volume":"7","author":"Reddy","year":"2019","journal-title":"JACC Heart Fail."},{"issue":"2","key":"2021110612090888800_CIT0028","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1136\/jim-52-02-18","article-title":"Insulin edema in the twenty-first century: review of the existing literature","volume":"52","author":"Chelliah","year":"2004","journal-title":"J Investig Med."},{"issue":"3","key":"2021110612090888800_CIT0029","doi-asserted-by":"crossref","first-page":"247","DOI":"10.3803\/EnM.2019.34.3.247","article-title":"A review of the effects of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors on lean body mass in humans","volume":"34","author":"Sargeant","year":"2019","journal-title":"Endocrinol Metab (Seoul)."},{"issue":"5","key":"2021110612090888800_CIT0030","doi-asserted-by":"crossref","first-page":"373","DOI":"10.14740\/jocmr2492w","article-title":"Factors influencing changes in hemoglobin A1c and body weight during treatment of type 2 diabetes with ipragliflozin: interim analysis of the ASSIGN-K study","volume":"8","author":"Iemitsu","year":"2016","journal-title":"J Clin Med Res."},{"issue":"4","key":"2021110612090888800_CIT0031","doi-asserted-by":"crossref","first-page":"740","DOI":"10.1016\/j.cmet.2018.03.001","article-title":"Mechanisms of action and therapeutic application of glucagon-like peptide-1","volume":"27","author":"Drucker","year":"2018","journal-title":"Cell Metab."},{"issue":"5","key":"2021110612090888800_CIT0032","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1016\/j.molmet.2014.04.009","article-title":"Inactivation of the cardiomyocyte glucagon-like peptide-1 receptor (GLP-1R) unmasks cardiomyocyte-independent GLP-1R-mediated cardioprotection","volume":"3","author":"Ussher","year":"2014","journal-title":"Mol Metab."},{"issue":"1","key":"2021110612090888800_CIT0033","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1161\/atv.0000615456.97862.30","article-title":"Endothelial GLP-1 (Glucagon-Like Peptide-1) receptor mediates cardiovascular protection by liraglutide in mice with experimental arterial hypertension","volume":"40","author":"Helmst\u00e4dter","year":"2020","journal-title":"Arterioscler Thromb Vasc Biol."},{"issue":"2","key":"2021110612090888800_CIT0034","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1111\/j.1365-2265.2009.03764.x","article-title":"The effect of DPP-4 inhibition with sitagliptin on incretin secretion and on fasting and postprandial glucose turnover in subjects with impaired fasting glucose","volume":"73","author":"Bock","year":"2010","journal-title":"Clin Endocrinol (Oxf)."},{"issue":"10157","key":"2021110612090888800_CIT0035","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1016\/S0140-6736(18)32261-X","article-title":"Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial","volume":"392","author":"Hernandez","year":"2018","journal-title":"Lancet."},{"issue":"9","key":"2021110612090888800_CIT0036","doi-asserted-by":"crossref","first-page":"e015716","DOI":"10.1161\/JAHA.119.015716","article-title":"Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and their combination on endothelial glycocalyx, arterial function, and myocardial work index in patients with type 2 diabetes mellitus after 12-month treatment","volume":"9","author":"Ikonomidis","year":"2020","journal-title":"J Am Heart Assoc."},{"issue":"1","key":"2021110612090888800_CIT0037","doi-asserted-by":"crossref","first-page":"256","DOI":"10.2337\/diacare.27.1.256","article-title":"Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association","volume":"27","author":"Nesto","year":"2004","journal-title":"Diabetes Care."},{"issue":"3","key":"2021110612090888800_CIT0038","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1161\/CIRCRESAHA.108.190918","article-title":"Activation of AMP-activated protein kinase by metformin improves left ventricular function and survival in heart failure","volume":"104","author":"Gundewar","year":"2009","journal-title":"Circ Res."},{"issue":"3","key":"2021110612090888800_CIT0039","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1161\/CIRCHEARTFAILURE.112.000162","article-title":"Comparative safety and effectiveness of metformin in patients with diabetes mellitus and heart failure: systematic review of observational studies involving 34,000 patients","volume":"6","author":"Eurich","year":"2013","journal-title":"Circ Heart Fail."}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgab428\/38866505\/dgab428.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/106\/10\/3060\/41098115\/dgab428.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/106\/10\/3060\/41098115\/dgab428.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,4]],"date-time":"2023-11-04T21:50:29Z","timestamp":1699134629000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/106\/10\/3060\/6298579"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,14]]},"references-count":39,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,6,14]]},"published-print":{"date-parts":[[2021,9,27]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgab428","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,10,1]]},"published":{"date-parts":[[2021,6,14]]}}}