{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:48:14Z","timestamp":1787014094458,"version":"build-2736575974"},"reference-count":54,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2018,10,11]],"date-time":"2018-10-11T00:00:00Z","timestamp":1539216000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology, Taiwan","doi-asserted-by":"publisher","award":["MOST 104\u20102320\u2010B\u2010006\u2010008\u2010MY3"],"award-info":[{"award-number":["MOST 104\u20102320\u2010B\u2010006\u2010008\u2010MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["dom-pubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Diabetes Obesity Metabolism"],"published-print":{"date-parts":[[2019,2]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>To compare the effects of initiating insulin as a fourth\u2010line antidiabetic therapy with the effects of enhancing oral antidiabetic drug (OAD) therapy in patients with type 2 diabetes mellitus (T2DM) with triple OAD therapy failure.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Materials and methods<\/jats:title>\n                    <jats:p>We conducted a nationwide population\u2010based, retrospective cohort study involving 1022 (without prevalent diabetes\u2010related complications [PDRCs]) and 2077 (with\/without PDRCs) propensity score\u2010matched pairs of fourth\u2010line insulin therapy users and enhanced OAD therapy users identified in the period 2004 to 2010. Clinical outcomes including a composite cardiovascular outcome (myocardial infarction, stroke, heart failure or ischaemic heart disease), peripheral vascular disease (PVD), hypoglycaemia and all\u2010cause mortality were assessed up to 2013. Hypoglycaemia was adjusted in Cox models to consider its potential effect on study outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In a T2DM cohort without PDRCs, fourth\u2010line insulin therapy was not associated with greater risks of clinical outcomes, except hypoglycaemia (hazard ratio [HR] 1.45, 95% confidence interval [CI] 1.02\u20102.07), compared with enhanced OAD therapy. Among patients with T2DM with\/without PDRCs, fourth\u2010line insulin therapy was associated with greater risks of the composite cardiovascular outcome (HR 1.23, 95% CI 1.03\u20101.46), heart failure (HR 1.59, 95% CI 1.12\u20102.25), ischaemic heart disease (HR 1.37, 95% CI 1.09\u20101.73), PVD (HR 1.17, 95% CI 1.00\u20101.36), hypoglycaemia (HR 1.49, 95% CI 1.20\u20101.85) and all\u2010cause mortality (HR 1.48, 95% CI 1.01\u20102.17), but adjustment for hypoglycaemia significantly attenuated the risk of heart failure (HR 1.34, 95% CI 0.92\u20101.94), PVD (HR 1.15, 95% CI 0.98\u20101.34) and all\u2010cause mortality (HR 1.30, 95% CI 0.84\u20101.99).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Initiation of fourth\u2010line insulin therapy can be considered for patients with T2DM with triple OAD therapy failure, and the importance of awareness and prevention of hypoglycaemia among insulin\u2010treated patients with T2DM cannot be overstated.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/dom.13525","type":"journal-article","created":{"date-parts":[[2018,9,5]],"date-time":"2018-09-05T22:49:20Z","timestamp":1536187760000},"page":"312-320","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Effects on clinical outcomes of intensifying triple oral antidiabetic drug (OAD) therapy by initiating insulin versus enhancing OAD therapy in patients with type 2 diabetes: A nationwide population\u2010based, propensity\u2010score\u2010matched cohort study"],"prefix":"10.1111","volume":"21","author":[{"given":"Shihchen","family":"Kuo","sequence":"first","affiliation":[{"name":"Division of Metabolism, Endocrinology and Diabetes, Department of Internal Medicine University of Michigan  Ann Arbor Michigan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun\u2010Ting","family":"Yang","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin\u2010Shang","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Family Medicine National Cheng Kung University Hospital  Tainan Taiwan"},{"name":"Department of Family Medicine, College of Medicine National Cheng Kung University  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5475-7848","authenticated-orcid":false,"given":"Huang\u2010Tz","family":"Ou","sequence":"additional","affiliation":[{"name":"Institute of Clinical Pharmacy and Pharmaceutical Sciences, College of Medicine National Cheng Kung University  Tainan Taiwan"},{"name":"Department of Pharmacy, College of Medicine National Cheng Kung University  Tainan Taiwan"},{"name":"Department of Pharmacy National Cheng Kung University Hospital  Tainan Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2018,10,11]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.2310\/6650.2007.06036"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc11-2170"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60762-X"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc13-0331"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pcd.2014.05.005"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1751-9918(10)60004-6"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc09-1184"},{"key":"e_1_2_7_9_1","first-page":"194","article-title":"The barriers to initiating insulin therapy among people with type 2 diabetes in Taiwan \u2010 A qualitative study","volume":"3","author":"Chen KW","year":"2012","journal-title":"J Diabetes Metab."},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-S011"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0806470"},{"issue":"367","key":"e_1_2_7_12_1","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1056\/NEJMoa1203858","article-title":"Basal insulin and cardiovascular and other outcomes in dysglycemia","volume":"2012","author":"Origin Trial Investigators","year":"2012","journal-title":"N Engl J Med"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.109.913111"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00125-011-2084-x"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2016.09.002"},{"key":"e_1_2_7_16_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2016.9400"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12116"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-3042"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2014.4312"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2016.12.004"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12704"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000003995"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1136\/heartjnl-2015-309164"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1177\/1479164116687102"},{"key":"e_1_2_7_25_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.i3477"},{"key":"e_1_2_7_26_1","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.f4533"},{"key":"e_1_2_7_27_1","doi-asserted-by":"publisher","DOI":"10.4093\/dmj.2016.40.3.202"},{"key":"e_1_2_7_28_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1003795"},{"key":"e_1_2_7_29_1","doi-asserted-by":"publisher","DOI":"10.1377\/hlthaff.22.3.61"},{"issue":"3","key":"e_1_2_7_30_1","first-page":"157","article-title":"Accuracy of diabetes diagnosis in health insurance claims data in Taiwan","volume":"104","author":"Lin CC","year":"2005","journal-title":"J Formos Med Assoc"},{"key":"e_1_2_7_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.2087"},{"key":"e_1_2_7_32_1","doi-asserted-by":"publisher","DOI":"10.2188\/jea.JE20140076"},{"key":"e_1_2_7_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2013.11.036"},{"key":"e_1_2_7_34_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.117.006406"},{"key":"e_1_2_7_35_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0112257"},{"key":"e_1_2_7_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2016.04.069"},{"key":"e_1_2_7_37_1","doi-asserted-by":"publisher","DOI":"10.1186\/1472-6823-8-4"},{"issue":"11","key":"e_1_2_7_38_1","first-page":"721","article-title":"Validating the adapted Diabetes Complications Severity Index in claims data","volume":"18","author":"Chang HY","year":"2012","journal-title":"Am J Manag Care"},{"key":"e_1_2_7_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2015.07.075"},{"key":"e_1_2_7_40_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.13241"},{"key":"e_1_2_7_41_1","doi-asserted-by":"publisher","DOI":"10.1162\/003465302317331982"},{"key":"e_1_2_7_42_1","first-page":"214","volume-title":"Proceedings of the 26th Annual SAS Users Group International Conference","author":"Parsons LS","year":"2001"},{"key":"e_1_2_7_43_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11606-007-0310-5"},{"key":"e_1_2_7_44_1","volume-title":"Statistical Power Analysis for the Behavioral Sciences","author":"Cohen J","year":"1988"},{"key":"e_1_2_7_45_1","doi-asserted-by":"publisher","DOI":"10.1080\/03610910902859574"},{"key":"e_1_2_7_46_1","unstructured":"YangD DaltonJE. A unified approach to measuring the effect size between two groups using SAS. SAS Global Forum 2012: Statistics and Data Analysis; Paper 335\u20132012."},{"key":"e_1_2_7_47_1","doi-asserted-by":"publisher","DOI":"10.1093\/biomet\/80.3.557"},{"key":"e_1_2_7_48_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-1669"},{"key":"e_1_2_7_49_1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.115.002875"},{"key":"e_1_2_7_50_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-1778"},{"key":"e_1_2_7_51_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/eht332"},{"key":"e_1_2_7_52_1","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-2677"},{"key":"e_1_2_7_53_1","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12598"},{"key":"e_1_2_7_54_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.diabres.2008.04.007"},{"key":"e_1_2_7_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/14651858.CD005613.pub3"}],"container-title":["Diabetes, Obesity and Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fdom.13525","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/pdf\/10.1111\/dom.13525","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,31]],"date-time":"2025-10-31T05:23:32Z","timestamp":1761888212000},"score":1,"resource":{"primary":{"URL":"https:\/\/dom-pubs.pericles-prod.literatumonline.com\/doi\/10.1111\/dom.13525"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,10,11]]},"references-count":54,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2019,2]]}},"alternative-id":["10.1111\/dom.13525"],"URL":"https:\/\/doi.org\/10.1111\/dom.13525","archive":["Portico"],"relation":{},"ISSN":["1462-8902","1463-1326"],"issn-type":[{"value":"1462-8902","type":"print"},{"value":"1463-1326","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,10,11]]},"assertion":[{"value":"2018-05-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-09-01","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2018-10-11","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}