{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:59:10Z","timestamp":1791395950707,"version":"4.3.3"},"reference-count":38,"publisher":"Public Library of Science (PLoS)","issue":"10","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Japan Pharmaceutical Association","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Clinical evidence supports the safety and efficacy of imeglimin, a new oral antidiabetic medication that increases insulin secretion and reduces insulin resistance. However, comparative real-world safety data with dipeptidyl peptidase-4 inhibitors, widely used in Japan, remain limited. This retrospective, pharmacy-based cohort study compared the incidence of adverse events (gastrointestinal events and hypoglycemia) among patients newly prescribed imeglimin or sitagliptin in real-world settings. Using a new-user design, we analyzed the 2022\u20132024 community pharmacy data across Japan, including 1,140 and 990 new imeglimin and sitagliptin users, respectively. Primary outcome (incidence of treatment-related events classified using Medical Dictionary for Regulatory Activities terminology) was evaluated using Cox proportional hazards models. Unadjusted and multivariable-adjusted hazard ratios (aHRs) for events during a 4-month follow-up were estimated. At least one adverse event was reported among 31% of imeglimin users versus 22% of sitagliptin users. Hypoglycemia risk differed non-significantly between groups (aHR: 0.66; 95% confidence interval [CI]: 0.20\u20132.22). However, imeglimin was associated with substantially higher risks of gastrointestinal events than sitagliptin (aHR: 5.44; 95% CI: 3.44\u20138.61), particularly nausea (aHR: 15.34; 95% CI: 3.50\u201367.23), diarrhea (aHR: 7.90; 95% CI: 2.54\u201324.62), and abdominal discomfort (aHR: 6.02; 95% CI: 1.47\u201324.58). Sensitivity analyses in patients receiving monotherapy yielded increased risk (hazard ratio (HR): 5.36; 95% CI: 2.63\u201310.92). Imeglimin use was associated with a higher incidence of gastrointestinal events than sitagliptin in Japanese clinical practice, closely approaching our prespecified threshold for clinical significance. Conversely, no significant difference was observed in hypoglycemia risk, although this finding should be interpreted with caution owing to the limited number of events. Involving community pharmacists allowed for active monitoring and identification of events that are often underreported in large-scale claims databases. Clinicians should prioritize gastrointestinal monitoring during initial stages of imeglimin therapy, particularly in older patients with complex treatment regimens.<\/jats:p>","DOI":"10.1371\/journal.pone.0359960","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T17:27:12Z","timestamp":1791394032000},"page":"e0359960","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Comparative safety of imeglimin versus sitagliptin in Japanese patients with type 2 diabetes: A pharmacy-based retrospective cohort study"],"prefix":"10.1371","volume":"21","author":[{"given":"Nao","family":"Suzuki","sequence":"first","affiliation":[{"name":"Nihon University School of Pharmacy","place":["Funabashi, Chiba, Japan"],"department":["Department of Pharmacoepidemiology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0579-3946","authenticated-orcid":true,"given":"Nobuhiro","family":"Ooba","sequence":"additional","affiliation":[{"name":"Nihon University School of Pharmacy","place":["Funabashi, Chiba, Japan"],"department":["Department of Pharmacoepidemiology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rie","family":"Nakajima","sequence":"additional","affiliation":[{"name":"Nihon University School of Pharmacy","place":["Funabashi, Chiba, Japan"],"department":["Department of Pharmacy Practice in Primary Care"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasumi","family":"Takabatake","sequence":"additional","affiliation":[{"name":"Nihon University School of Pharmacy","place":["Funabashi, Chiba, Japan"],"department":["Department of Pharmacoepidemiology"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masahiro","family":"Saita","sequence":"additional","affiliation":[{"name":"Japan Pharmaceutical Association","place":["Shinjuku-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eiji","family":"Kawakami","sequence":"additional","affiliation":[{"name":"Japan Pharmaceutical Association","place":["Shinjuku-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michiyo","family":"Kawana","sequence":"additional","affiliation":[{"name":"Japan Pharmaceutical Association","place":["Shinjuku-ku, Tokyo, Japan"]},{"name":"Teikyo University School of Pharmacy","place":["Itabashi-ku, Tokyo, Japan"],"department":["Department of Pharmaceutical Sciences"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daiki","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Japan Pharmaceutical Association","place":["Shinjuku-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hajime","family":"Hashiba","sequence":"additional","affiliation":[{"name":"Japan Pharmaceutical Association","place":["Shinjuku-ku, Tokyo, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"pone.0359960.ref001","article-title":"2. diagnosis and classification of diabetes: Standards of care in diabetes-2025","volume":"48","author":"American Diabetes Association Professional Practice Committee","year":"2025","journal-title":"Diabetes Care"},{"issue":"10","key":"pone.0359960.ref002","doi-asserted-by":"crossref","DOI":"10.2337\/dci23-0048","article-title":"Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus","volume":"46","author":"DB Sacks","year":"2023","journal-title":"Diabetes Care"},{"key":"pone.0359960.ref003","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1016\/j.ahj.2021.10.181","article-title":"Incidence rates and predictors of microvascular and macrovascular complications in patients with type 2 diabetes: Results from the longitudinal global discover study","volume":"243","author":"SV Arnold","year":"2022","journal-title":"Am Heart J"},{"key":"pone.0359960.ref004","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"},{"issue":"23","key":"pone.0359960.ref005","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":"RA Hayward","year":"2015","journal-title":"N Engl J Med"},{"key":"pone.0359960.ref006","unstructured":"International Diabetes Federation IDF. 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