{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T18:37:52Z","timestamp":1792780672888,"version":"4.5.0"},"reference-count":32,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T00:00:00Z","timestamp":1792713600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Objectives<\/jats:title>\n                    <jats:p>In recent years, with the considerable changes in the therapeutic armamentarium for diabetes, the incidence of hypoglycemia events, especially severe hypoglycemia events, associated with drug treatment in people with diabetes has markedly decreased. We were prompted to evaluate the threshold for each intervention target, especially glycemic control, associated with a minimized risk of the macrovascular complications of diabetes in this setting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In the Japan Diabetes Optimal Integrated Treatment study for 3 major risk factors of cardiovascular diseases (J-DOIT3) conducted by us previously, we recruited 2542 participants and assigned them to a conventional therapy group (n\u2009=\u20091271) and an intensive therapy group (n\u2009=\u20091271; two ineligible participants were removed from all analyses afterwards), and the incidence of severe hypoglycemia events was low in both groups (7 in the intensive therapy group and 4 in the conventional therapy group during a median 8.5 years\u2019 follow-up). Towards the objective of this study, we undertook a landmark analysis with a landmark time-point of 1 year after the baseline of the J-DOIT3 study. Then, using the updated mean values of the glycated hemoglobin (HbA1c), systolic blood pressure, and LDL-cholesterol and HDL-cholesterol levels, we determined the optimal levels of each of these variables associated with the lowest hazard ratios for outcomes, including the primary and cardiovascular outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>For glycemic control, our results revealed no clear lower threshold of the glycated hemoglobin associated with the lowest risk of myocardial infarction or all-cause mortality; for other risk factors, it might be an important treatment target to maintain the LDL-cholesterol levels at below 80 mg\/dL to minimize the risk of stroke.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The present analysis suggested that the treatment target for HbA1c to minimize the risk of all-cause mortality in participants with diabetes with a low incidence of severe hypoglycemia episodes could be\u2009&lt;\u20096.5% (ClinicalTrials.gov, number NCT00300976).<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0360295","type":"journal-article","created":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T17:41:50Z","timestamp":1792777310000},"page":"e0360295","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Search for the glycated hemoglobin target minimizing mortality among people with type 2 diabetes with rare incidence of treatment-related severe hypoglycemia \u2013 Epidemiologic analysis of J-DOIT3 randomized controlled trial"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0413-4631","authenticated-orcid":true,"given":"Mitsuhiko","family":"Noda","sequence":"first","affiliation":[{"name":"International University of Health and Welfare","place":["Chiba, Japan"],"department":["Department of Diabetes, Metabolism and Endocrinology, Ichikawa Medical Center"]},{"name":"Saitama Medical University","place":["Saitama, Japan"],"department":["Department of Endocrinology and Diabetes"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohjiro","family":"Ueki","sequence":"additional","affiliation":[{"name":"Japan Institute for Health Security","place":["Tokyo, Japan"],"department":["Diabetes Research Center"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7644-309X","authenticated-orcid":true,"given":"Takayoshi","family":"Sasako","sequence":"additional","affiliation":[{"name":"International University of Health and Welfare","place":["Chiba, Japan"],"department":["Department of Diabetes, Metabolism and Endocrinology, Ichikawa Medical Center"]},{"name":"The University of Tokyo","place":["Tokyo, Japan"],"department":["Department of Diabetes and Metabolic Diseases, Graduate School of Medicine"]},{"name":"Okachimachi Ohisama Clinic","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Ishizuka","sequence":"additional","affiliation":[{"name":"Kyoto University School of Medicine","place":["Kyoto, Japan"],"department":["Center for Digital Transformation for Health"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kana","family":"Miyake","sequence":"additional","affiliation":[{"name":"The University of Tokyo","place":["Tokyo, Japan"],"department":["Department of Diabetes and Metabolic Diseases, Graduate School of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kengo","family":"Miyoshi","sequence":"additional","affiliation":[{"name":"The University of Tokyo","place":["Tokyo, Japan"],"department":["Department of Diabetes and Metabolic Diseases, Graduate School of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohisa","family":"Aoyama","sequence":"additional","affiliation":[{"name":"The University of Tokyo","place":["Tokyo, Japan"],"department":["Department of Diabetes and Metabolic Diseases, Graduate School of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukiko","family":"Okazaki","sequence":"additional","affiliation":[{"name":"Juntendo University Graduate School of Medicine","place":["Tokyo, Japan"],"department":["Department of Metabolism and Endocrinology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuo","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Chuo University","place":["Tokyo, Japan"],"department":["Department of Integrated Science and Engineering for Sustainable Society"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshimasa","family":"Yamauchi","sequence":"additional","affiliation":[{"name":"The University of Tokyo","place":["Tokyo, Japan"],"department":["Department of Diabetes and Metabolic Diseases, Graduate School of Medicine"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kadowaki","sequence":"additional","affiliation":[{"name":"The University of Tokyo","place":["Tokyo, Japan"],"department":["Department of Diabetes and Metabolic Diseases, Graduate School of Medicine"]},{"name":"Toranomon Hospital","place":["Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"The J-DOIT3 Study 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