{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:01:12Z","timestamp":1760148072553,"version":"build-2065373602"},"reference-count":42,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T00:00:00Z","timestamp":1680048000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009619","name":"Japan Agency for Medical Research and Development (AMED)","doi-asserted-by":"publisher","award":["JP16K1310001h0001","H30-Iryou-Ippan-013","JP18H04126","JP20H00623","JP18K17390"],"award-info":[{"award-number":["JP16K1310001h0001","H30-Iryou-Ippan-013","JP18H04126","JP20H00623","JP18K17390"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Health Science and Labor Research Grants (HSLRG)","award":["JP16K1310001h0001","H30-Iryou-Ippan-013","JP18H04126","JP20H00623","JP18K17390"],"award-info":[{"award-number":["JP16K1310001h0001","H30-Iryou-Ippan-013","JP18H04126","JP20H00623","JP18K17390"]}]},{"name":"Japan Society for the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research (KAKENHI)","award":["JP16K1310001h0001","H30-Iryou-Ippan-013","JP18H04126","JP20H00623","JP18K17390"],"award-info":[{"award-number":["JP16K1310001h0001","H30-Iryou-Ippan-013","JP18H04126","JP20H00623","JP18K17390"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Patient data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) are used to assess the effect of biguanide administration on rates of lactic acidosis (LA) in hospitalized diabetes mellitus (DM) patients. In this retrospective cohort study (from April 2013 to March 2016), we compare DM inpatients prescribed biguanides to DM inpatients who were not prescribed biguanides to quantify the association between biguanides and incidence of LA. In total, 8,111,848 DM patient records are retrieved from the NDB. Of the 528,768 inpatients prescribed biguanides, 782 develop LA. Of the 1,967,982 inpatients not prescribed biguanides, 1310 develop LA. The rate ratio of inpatients who develop LA and are administered biguanides to those who developed LA without receiving biguanides is 1.44 (95% CI, 1.32\u20131.58). Incidence rates and rate ratios for both sexes are elevated in the group prescribed biguanides for patients aged 70 years and older, markedly in those 80 years and older: 40.12 and 6.31 (95% CI, 4.75\u20138.39), respectively, for men and 34.96 and 5.40 (95% CI, 3.91\u20137.46), respectively, for women. Biguanides should be used conservatively in patients older than 70 years, particularly for those with comorbidities, and with caution in patients 80 years and older.<\/jats:p>","DOI":"10.3390\/ijerph20075300","type":"journal-article","created":{"date-parts":[[2023,3,29]],"date-time":"2023-03-29T02:03:53Z","timestamp":1680055433000},"page":"5300","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Risk of Lactic Acidosis in Hospitalized Diabetic Patients Prescribed Biguanides in Japan: A Retrospective Total-Population Cohort Study"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5211-4638","authenticated-orcid":false,"given":"Takako","family":"Mohri","sequence":"first","affiliation":[{"name":"Department of Diabetes and Endocrinology, Nara Medical University Hospital, Nara 634-8522, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7567-0290","authenticated-orcid":false,"given":"Sawako","family":"Okamoto","sequence":"additional","affiliation":[{"name":"Department of Public Health, Health Management and Policy, Nara Medical University, Nara 634-8521, Japan"},{"name":"Education Development Center, Nara Medical University, Nara 634-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1956-3925","authenticated-orcid":false,"given":"Yuichi","family":"Nishioka","sequence":"additional","affiliation":[{"name":"Department of Public Health, Health Management and Policy, Nara Medical University, Nara 634-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3820-6157","authenticated-orcid":false,"given":"Tomoya","family":"Myojin","sequence":"additional","affiliation":[{"name":"Department of Public Health, Health Management and Policy, Nara Medical University, Nara 634-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shinichiro","family":"Kubo","sequence":"additional","affiliation":[{"name":"Department of Public Health, Health Management and Policy, Nara Medical University, Nara 634-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsuneyuki","family":"Higashino","sequence":"additional","affiliation":[{"name":"Healthcare and Wellness Division, Mitsubishi Research Institute Inc., Tokyo 100-8141, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3097-8152","authenticated-orcid":false,"given":"Sadanori","family":"Okada","sequence":"additional","affiliation":[{"name":"Department of Diabetes and Endocrinology, Nara Medical University Hospital, Nara 634-8522, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0573-5762","authenticated-orcid":false,"given":"Yasuhiro","family":"Akai","sequence":"additional","affiliation":[{"name":"Department of Community-Based Medicine, Nara Medical University, Nara 634-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3652-7547","authenticated-orcid":false,"given":"Tatsuya","family":"Noda","sequence":"additional","affiliation":[{"name":"Department of Public Health, Health Management and Policy, Nara Medical University, Nara 634-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6214-0557","authenticated-orcid":false,"given":"Hitoshi","family":"Ishii","sequence":"additional","affiliation":[{"name":"Department of Doctor-Patient Relationships, Nara Medical University, Nara 634-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1981-9959","authenticated-orcid":false,"given":"Tomoaki","family":"Imamura","sequence":"additional","affiliation":[{"name":"Department of Public Health, Health Management and Policy, Nara Medical University, Nara 634-8521, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,3,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"140","DOI":"10.2337\/dc14-2441","article-title":"Management of hyperglycemia in type 2 diabetes, 2015: A patient-centered approach: Update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes","volume":"38","author":"Inzucchi","year":"2015","journal-title":"Diabetes Care"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2117","DOI":"10.1056\/NEJMoa1504720","article-title":"EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes","volume":"373","author":"Zinman","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1056\/NEJMoa1603827","article-title":"LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes","volume":"375","author":"Marso","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"657","DOI":"10.1016\/j.numecd.2017.04.009","article-title":"Metformin effects on the heart and the cardiovascular system: A review of experimental and clinical data","volume":"27","author":"Nesti","year":"2017","journal-title":"Nutr. Metab. Cardiovasc. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1007\/s13300-017-0296-x","article-title":"Costs and Treatment Pathways for Type 2 Diabetes in the UK: A Mastermind Cohort Study","volume":"8","author":"Eibich","year":"2017","journal-title":"Diabetes Ther."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"69","DOI":"10.2337\/dc17-1414","article-title":"Long-term Trends in Antidiabetes Drug Usage in the U.S.: Real-world Evidence in Patients Newly Diagnosed with Type 2 Diabetes","volume":"41","author":"Montvida","year":"2018","journal-title":"Diabetes Care"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e8257","DOI":"10.1097\/MD.0000000000008257","article-title":"The prescribing trend of oral antidiabetic agents for type 2 diabetes in Taiwan: An 8-year population-based study","volume":"96","author":"Chu","year":"2017","journal-title":"Medicine"},{"key":"ref_8","unstructured":"Nishioka, Y., Noda, T., Kubo, S., Myojin, T., and Imamura, T. (2021, May 02). Table 5.5-3. Utilization of the Receipt Information\/Specific Medical Examination Information Database (NDB): Overview of Diabetes Prescriptions in Japan. (In Japanese)."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1016\/j.metabol.2016.05.014","article-title":"Metformin-associated lactic acidosis: Current perspectives on causes and risk","volume":"65","author":"DeFronzo","year":"2016","journal-title":"Metabolism"},{"key":"ref_10","first-page":"795","article-title":"Beneficial Effects of Biguanides on Cardiovascular Events","volume":"41","author":"Nagai","year":"2021","journal-title":"Prog. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1502","DOI":"10.1111\/dom.12974","article-title":"Metformin-associated lactic acidosis (MALA): Moving towards a new paradigm","volume":"11","author":"Lalau","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1002\/pds.4030","article-title":"Epidemiology of lactic acidosis in type 2 diabetes patients with metformin in Japan","volume":"25","author":"Chang","year":"2016","journal-title":"Pharmacoepidemiol. Drug. Saf."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Aharaz, A., Potteg\u00e5rd, A., Henriksen, D.P., Hallas, J., Beck-Nielsen, H., and Lassen, A.T. (2018). Risk of lactic acidosis in type 2 diabetes patients using metformin: A case control study. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0196122"},{"key":"ref_14","first-page":"CD002967","article-title":"Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus","volume":"4","author":"Salpeter","year":"2010","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1499","DOI":"10.1111\/dom.12994","article-title":"Metformin-associated lactic acidosis: Moving towards a new paradigm?","volume":"11","author":"Bicsak","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2022","DOI":"10.1248\/bpb.b16-00517","article-title":"Investigation of Risk Factors Affecting Lactate Levels in Japanese Patients Treated with Metformin","volume":"39","author":"Yokoyama","year":"2016","journal-title":"Biol. Pharm. Bull."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1579","DOI":"10.1111\/dom.12978","article-title":"Acute kidney injury, plasma lactate concentrations and lactic acidosis in metformin users: AGoDartS study","volume":"11","author":"Connelly","year":"2017","journal-title":"Diabetes Obes. Metab."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1111\/j.1365-2265.2010.03891.x","article-title":"Diabetes, metformin and lactic acidosis","volume":"74","author":"Scale","year":"2011","journal-title":"Clin. Endocrinol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"660","DOI":"10.23876\/j.krcp.20.222","article-title":"Metformin use and cardiovascular outcomes in patients with diabetes and chronic kidney disease: A nationwide cohort study","volume":"40","author":"Kim","year":"2021","journal-title":"Kidney Res. Clin. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"107879","DOI":"10.1016\/j.diabres.2019.107879","article-title":"Metformin lactic acidosis: Should we still be afraid?","volume":"157","author":"Salvatore","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1111\/apt.15635","article-title":"The safety and pharmacokinetics of metformin in patients with chronic liver disease","volume":"51","author":"Smith","year":"2020","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.amjms.2022.01.026","article-title":"Relationship between metformin use and lactic acidosis in advanced chronic kidney disease: The REMIND-TMU study","volume":"364","author":"Chen","year":"2022","journal-title":"Am. J. Med. Sci."},{"key":"ref_23","unstructured":"The Japan Diabetes Society (2021, May 02). Committee on the Proper Use of Biguanides: Recommendation on the Proper Use of Biguanide Drugs. Available online: http:\/\/www.jds.or.jp\/modules\/important\/index.php?content_id=20."},{"key":"ref_24","first-page":"42","article-title":"Proper use of biguanide","volume":"40","author":"Kadowaki","year":"2012","journal-title":"Diabetes J."},{"key":"ref_25","first-page":"43","article-title":"Is metformin safe enough for ageing type 2 diabetic patients?","volume":"22","author":"Gregorio","year":"1996","journal-title":"Diabetes Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1016\/S1726-4901(10)70135-0","article-title":"Fasting plasma lactate concentrations in ambulatory elderly patients with type 2 diabetes receiving metformin therapy: A retrospective cross-sectional study","volume":"73","author":"Lin","year":"2010","journal-title":"J. Chin. Med. Assoc."},{"key":"ref_27","unstructured":"Kubo, S., Noda, T., Myojin, T., Nishioka, Y., Higashino, T., Matsui, H., Kato, G., and Imamura, T. (2018). National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB): Outline and Patient-Matching Technique. bioRxiv."},{"key":"ref_28","first-page":"7","article-title":"Improvement and verification of the patient matching method in National Database of Health Insurance Claims and Specific Health Checkups of Japan","volume":"64","author":"Noda","year":"2017","journal-title":"J. Health Welf. Stat."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1111\/jdi.13153","article-title":"Absolute risk of acute coronary syndrome after severe hypoglycemia: A population-based 2-year cohort study using the National Database in Japan","volume":"11","author":"Nishioka","year":"2020","journal-title":"J. Diabetes Investig."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"203","DOI":"10.14326\/abe.11.203","article-title":"Development of a New Method to Trace Patient Data Using the National Database in Japan","volume":"11","author":"Myojin","year":"2022","journal-title":"Adv. Biomed. Eng."},{"key":"ref_31","first-page":"64","article-title":"How to calculate and use the person-year method","volume":"26","author":"Aoki","year":"1991","journal-title":"J. Jpn. Assoc. Cereb. Cardiovasc. Dis. Control."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1001\/jamainternmed.2018.0292","article-title":"Association of Metformin Use with Risk of Lactic Acidosis Across the Range of Kidney Function: A Community-Based Cohort Study","volume":"178","author":"Lazarus","year":"2018","journal-title":"JAMA Intern. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"367","DOI":"10.5527\/wjn.v5.i4.367","article-title":"Metformin associated lactic acidosis in Auckland City Hospital 2005 to 2009","volume":"5","author":"Haloob","year":"2016","journal-title":"World J. Nephrol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1159\/000471917","article-title":"Metformin-Associated Lactic Acidosis Undergoing Renal Replacement Therapy in Intensive Care Units: A Five-Million Population-Based Study in the North-West of Italy","volume":"44","author":"Mariano","year":"2017","journal-title":"Blood Purif."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1462","DOI":"10.2337\/dc19-2391","article-title":"Hospitalization for Lactic Acidosis Among Patients with Reduced Kidney Function Treated with Metformin or Sulfonylureas","volume":"43","author":"Chu","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2008","DOI":"10.1002\/hep.27199","article-title":"Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes","volume":"60","author":"Zhang","year":"2014","journal-title":"Hepatology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1016\/j.cmet.2020.08.013","article-title":"Metformin Is Associated with Higher Incidence of Acidosis, but Not Mortality, in Individuals with COVID-19 and Pre-existing Type 2 Diabetes","volume":"32","author":"Cheng","year":"2020","journal-title":"Cell Metab."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"154","DOI":"10.2337\/cd15-0045","article-title":"Metformin use in Practice: Compliance with guidelines for patients with diabetes and preserved renal function","volume":"35","author":"Salber","year":"2017","journal-title":"Clin. Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Di Mauro, S., Filippello, A., Scamporrino, A., Purrello, F., Piro, S., and Malaguarnera, R. (2022). Metformin: When Should We Fear Lactic Acidosis?. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23158320"},{"key":"ref_40","first-page":"385","article-title":"Chronic kidney disease in the elderly","volume":"51","author":"Imai","year":"2014","journal-title":"Jpn. J. Geriatr."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1286","DOI":"10.1007\/s11096-020-01069-2","article-title":"Identifying patients with metformin associated lactic acidosis in the emergency department","volume":"42","author":"Gedik","year":"2020","journal-title":"Int. J. Clin. Pharm."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"(2012). Diabetes Prevention Program Research Group, Long-term safety, tolerability, and weight loss associated with metformin in the Diabetes Prevention Program Outcomes Study. Diabetes Care, 35, 731\u2013737.","DOI":"10.2337\/dc11-1299"}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/20\/7\/5300\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:05:32Z","timestamp":1760123132000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/20\/7\/5300"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,29]]},"references-count":42,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,4]]}},"alternative-id":["ijerph20075300"],"URL":"https:\/\/doi.org\/10.3390\/ijerph20075300","relation":{},"ISSN":["1660-4601"],"issn-type":[{"type":"electronic","value":"1660-4601"}],"subject":[],"published":{"date-parts":[[2023,3,29]]}}}