---
title: "Safety comparison of imeglimin versus sitagliptin in Japanese patients with type 2 diabetes"
id: "plos-one-8-comparative-safety-of-imeglimin-versus-sitagliptin-in-japanese-patients-with"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-8-comparative-safety-of-imeglimin-versus-sitagliptin-in-japanese-patients-with"
content_type: "clinical_feed_article"
specialty: "Endocrinology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359960"
published_at: "2026-10-07T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Safety comparison of imeglimin versus sitagliptin in Japanese patients with type 2 diabetes
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-8-comparative-safety-of-imeglimin-versus-sitagliptin-in-japanese-patients-with
- **Specialty:** [Endocrinology](https://medichelpline.com/clinical-feed/endocrinology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0359960)
- **Published At:** 2026-10-07T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This pharmacy-based retrospective new-user cohort study compared safety outcomes among new users of **imeglimin** (n=1,140) and **sitagliptin** (n=990) in Japanese community practice using data pooled from 2022–2024. - Community pharmacists actively monitored and recorded adverse events during a 4-month observation window (September 1–December 31 each year) and coded events with MedDRA v27.0. - Primary outcomes included treatment-related adverse events, with specific attention to **gastrointestinal** events and **hypoglycemia**; events were analyzed using Cox proportional hazards models with multivariable adjustment. - Overall, 31% of imeglimin users and 22% of sitagliptin users reported at least one event (crude RR 1.39; 95% CI 1.20–1.60). - Imeglimin was associated with substantially higher adjusted risks of gastrointestinal events (aHR 5.44; 95% CI 3.44–8.61) and markedly elevated risks for specific symptoms: nausea (aHR 15.34; 95% CI 3.50–67.23), diarrhea (aHR 7.90; 95% CI 2.54–24.62), and abdominal discomfort (aHR 6.02; 95% CI 1.47–24.58). - No significant difference in hypoglycemia risk was observed (aHR 0.66; 95% CI 0.20–2.22), but the authors note limited event numbers warrant cautious interpretation. - Sensitivity analyses in monotherapy users (imeglimin n=114; sitagliptin n=561) confirmed increased gastrointestinal risk with imeglimin (aHR 5.36; 95% CI 2.63–10.91; absolute risk difference 13.4%). - Firth’s penalized likelihood Cox regression yielded similar hazard estimates, supporting robustness despite small-event counts for some outcomes. - The study emphasizes the value of pharmacist-led active surveillance in capturing events underreported in claims data and recommends clinicians monitor gastrointestinal symptoms early after initiating imeglimin, especially in older patients with complex regimens. - Data were provided under a usage agreement with the Japan Pharmaceutical Association; raw data are not publicly available.
## Clinical Analysis & Structured Key Points
Comparative safety of imeglimin versus sitagliptin in Japanese patients with type 2 diabetes: A pharmacy-based retrospective cohort study | PLOS One Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click here . Article Authors Metrics Comments Media Coverage Reader Comments Figures Figures Abstract 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 2022–2024 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]: 0.20–2.22). However, imeglimin was associated with substantially higher risks of gastrointestinal events than sitagliptin (aHR: 5.44; 95% CI: 3.44–8.61), particularly nausea (aHR: 15.34; 95% CI: 3.50–67.23), diarrhea (aHR: 7.90; 95% CI: 2.54–24.62), and abdominal discomfort (aHR: 6.02; 95% CI: 1.47–24.58). Sensitivity analyses in patients receiving monotherapy yielded increased risk (hazard ratio (HR): 5.36; 95% CI: 2.63–10.92). 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. Citation: Suzuki N, Ooba N, Nakajima R, Takabatake K, Saita M, Kawakami E, et al. (2026) Comparative safety of imeglimin versus sitagliptin in Japanese patients with type 2 diabetes: A pharmacy-based retrospective cohort study. PLoS One 21(10): e0359960. https://doi.org/10.1371/journal.pone.0359960 Editor: Amr Ahmed El-Arabey, Al-Azhar University / King Khalid University, EGYPT Received: May 26, 2026; Accepted: September 21, 2026; Published: October 7, 2026 Copyright: © 2026 Suzuki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The data analyzed in this study were provided by the Japan Pharmaceutical Association under a data usage agreement. To protect the privacy of the participants, these data are not publicly available. Restrictions apply to the availability of these data, and the authors do not have permission to share the raw data. Requests for data access should be directed to the Japan Pharmaceutical Association via email at di@nichiyaku.or.jp (Website: https://www.nichiyaku.or.jp/) . Funding: The full name of each funder: Japan Pharmaceutical Association (JPA) URL of each funder website: https://www.nichiyaku.or.jp/ This work was supported by the Japan Pharmaceutical Association (JPA) [URL: https://www.nichiyaku.or.jp/] . The funder provided support in the form of financial compensation to authors M.K., D.W., and H.H. for their participation in the study committee, and played a role in data collection. However, the funder did not have any additional role in the study design, data analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ‘author contributions’ section. Furthermore, although authors M.S. and E.K. are affiliated with the funder (Japan Pharmaceutical Association [JPA]), they did not receive any salary or financial compensation from JPA for this work. Competing interests: The authors have no conflict of interest to report. Introduction Diabetes is characterized by hyperglycemia and is diagnosed using HbA1c and plasma glucose levels [ 1 , 2 ]. Diabetes represents a major risk factor for microvascular and macrovascular complications [ 3 ], making effective glycemic management essential to reduce these risks [ 4 , 5 ]. In 2024, the global prevalence of diabetes was estimated at 589 million individuals, accounting for 11.1% of adults aged 20–79 years [ 6 ]. In Japan, approximately 10.8 million people are affected [ 6 ]. With 29.3% of the Japanese population aged 65 years and older [ 7 ] and diabetes incidence increasing with age, the number of affected individuals is expected to rise further [ 8 ]. Older patients often present with multiple comorbidities, including hypertension and dyslipidemia, which increase the risk of renal failure and cardiovascular disease [ 9 ]. International guidelines, such as the American Diabetes Association Standards of Care, recommend therapies, including metformin, sodium–glucose cotransporter-2 (SGLT2) inhibitors, and glucagon-like peptide-1 (GLP-1) receptor agonists, tailored to a patient’s pathophysiology [ 10 ]. In the United Kingdom, treatment guidelines advocate biguanides, particularly metformin, as first-line therapy for type 2 diabetes [ 11 ]. In contrast, dipeptidyl peptidase-4 (DPP-4) inhibitors remain the most frequently prescribed glucose-lowering agents in Japan, followed by biguanides and SGLT2 inhibitors [ 12 ]. This pattern likely reflects their efficacy in lowering HbA1c, low hypoglycemia risk, and high treatment persistence among Japan’s predominantly older population with diabetes [ 12 – 14 ]. DPP-4 inhibitors are generally not associated with increased gastrointestinal symptoms [ 15 , 16 ] or digestive system infections [ 17 ]. Previous trials, including meta-analyses, have reported a low risk of hypoglycemia with sitagliptin, a widely used DPP-4 inhibitor [ 14 , 16 ]. Imeglimin is a novel therapeutic agent that lowers blood glucose by enhancing insulin secretion and improving insulin sensitivity [ 18 ]. It was first approved for clinical use in Japan, with further development and regulatory approvals ongoing in other Asian countries. According to the Japanese Risk Management Plan, hypoglycemia and gastrointestinal symptoms are identified as notable potential risks [ 19 ]. In line with this, randomized controlled trials (RCTs) have demonstrated that while imeglimin effectively reduces HbA1c by approximately 0.46% [ 20 ], it is also associated with adverse effects such as diarrhea (5.4%), gastritis (2.7%), abdominal discomfort (2.7%), and hypoglycemia (2.7%) [ 21 ]. Despite its clinical approval, comparative real-world data on hypoglycemia and gastrointestinal events between imeglimin and widely used DPP-4 inhibitors, especially in older populations, remain limited. Therefore, in this study, we aimed to evaluate these outcomes among new users of imeglimin and sitagliptin using a retrospective cohort design based on primary community pharmacy data. To distinguish clinical from statistical significance, a 10% absolute difference in the incidence of gastrointestinal symptoms was prespecified as the minimum clinically relevant threshold. In the absence of a universally established standard for this outcome [ 22 ], this threshold was chosen as a pragmatic benchmark to guide potential changes in prescribing practices, informed by the known safety profiles of oral hypoglycemic agents. By conducting this analysis, we sought to characterize the comparative safety of these therapies in a real-world setting and provide clinically relevant evidence to support treatment selection. Materials and methods Study design and participants This retrospective cohort study employed a new-user design [ 23 ] to compare the incidence of events between users of imeglimin and sitagliptin. Sitagliptin was selected as the sole active comparator because DPP-4 inhibitors are the most frequently prescribed first-line oral antidiabetic agents in Japan [ 12 ]. Furthermore, sitagliptin has the highest prescription rate among the DPP-4 inhibitors in Japanese real-world clinical practice [ 24 ]. From February 2023 through February 2025, questionnaires were distributed by the Japan Pharmaceutical Association (JPA) to 50,710–53,350 affiliated pharmacies. In accordance with methodologies of previous studies [ 25 – 27 ], these questionnaires were used to identify new users of imeglimin and sitagliptin and record baseline characteristics and event data. Survey participation included 4,795 pharmacies in 2022, 4,545 in 2023, and 4,517 in 2024. Consistent with established protocols [ 25 – 27 ], community pharmacists identified new users of the study drugs. Patients prescribed either drug in September of each study year (2022–2024) were initially selected. “New users” were defined as individuals who had visited the pharmacy at least once prior to March of the same year but had no recorded use of the target drug during the 6-month washout period from March to August. Patients who were prescribed the drug in September but had no subsequent pharmacy visits were excluded. In addition, patients who switched from imeglimin to sitagliptin, or vice versa, during the observation period were excluded to ensure that any adverse events could be appropriately attributed to the specific medication. The final study population comprised pooled data from newly identified users across the 3-year study period. Data collection and follow-up The observation period for each year spanned 4 months, from September 1 to December 31. Community pharmacists played a critical role in clinical practice by explaining prescribed medications to patients and actively monitoring treatment adherence and the incidence of adverse drug reactions. The time scale for the survival analysis was days. The event dates were determined from pharmacy records. Pharmacists monitored and recorded the occurrence of adverse events through direct patient interviews conducted at each pharmacy visit upon presentation of a prescription, rather than at fixed monthly intervals. Pharmacists reviewed pharmacy records to identify relevant events within this timeframe. Baseline data (collected during the 6 months preceding therapy initiation) included the drug class, start date, daily dosage, smoking and alcohol status, use of over-the-counter (OTC) medications, comorbidities, concomitant therapies, and history of hospitalization. Information regarding hospitalization history was obtained from pharmacy records, including information collected through patient interviews and medication notebooks. All data were entered into a predesigned web-based reporting form. Specifically, the survey was conducted at each pharmacy over a one-month period in February of 2023, 2024, and 2025. Subsequently, the authors had access to the compiled, anonymized data for this research from March 1, 2023 to March 5, 2025. Definition of events Pharmacists identified events, including adverse drug reactions, from pharmacy records that were evaluated for a potential causal relationship with the medication [ 28 ]. Data regarding the discontinuation of the target drug or initiation of additional medications were collected to support event assessment. All reported events were coded using the Medical Dictionary for Regulatory Activities, version 27.0. First, low-level terms were assigned to each event and subsequently converted to preferred terms for analysis [ 29 ]. Statistical analysis Summary statistics were calculated for sex, age, comorbidities, concomitant medications, and hospitalization history. There were no missing data for the baseline characteristics, including smoking status, as these variables were routinely collected and verified by pharmacists through direct patient interviews during medication counseling. Baseline characteristics between the two groups were assessed using standardized mean differences (SMDs), with an SMD > 0.10 indicating a clinically meaningful imbalance. Variables showing notable differences were included as covariates in the multivariable analysis. Given the limited number of outcome events, covariates for the multivariable models were selected using a stepwise approach to reduce the risk of model overfitting while accounting for confounding. Established risk factors, including use of antidiabetic agents other than insulin and insulin use as indicators of diabetes severity, were retained in the final multivariable model regardless of significance. The incidence of events, including treatment discontinuation, was calculated for each group. Events reported in ≥5 cases, as well as all serious events, were analyzed in detail. As presented in the tables, incidence proportions, absolute risk differences, and corresponding 95% confidence intervals (CIs) were calculated for adverse events and add-on medications. Additionally, Kaplan-Meier curves were generated to estimate the cumulative incidence of the primary outcome over the follow-up period. HRs with 95% CIs were estimated using Cox proportional hazards models and presented as unadjusted, age- and sex-adjusted, and multivariable-adjusted. The observation period was defined from drug initiation to the earliest of the following: event occurrence, drug switch or discontinuation, addition of an alternative glucose-lowering agent, last patient visit, or December 31 of the respective year. Adjustment factors included age, sex, smoking status, alcohol consumption, hypertension, dyslipidemia, hyperuricemia, myocardial infarction, heart failure, cancer, hospitalization history, and concomitant medications (antihypertensives; glucose-lowering agents excluding insulin; insulin; lipid-lowering drugs; and hypouricemic agents). As part of sensitivity analyses, the risk of gastrointestinal symptoms was evaluated in a subpopulation of monotherapy users who were not receiving other glucose-lowering agents at baseline, aside from the study drugs. Furthermore, because several outcomes had a very low number of events per variable, sensitivity analyses were performed using Firth’s penalized likelihood Cox regression for both adverse events and add-on medications. This approach was employed to address potential small-sample bias and improve the stability of the HR estimates. The results of these sensitivity analyses are presented in S1 and S2 Tables . Formal sample size calculations were not performed because all new users of imeglimin or sitagliptin during the observation period were included, minimizing selection bias. Nevertheless, the estimated sample size was 1,811, assuming a 2.5% event incidence in the control group, an α = 0.05, power = 0.8, and HR = 2.0. Statistical significance was defined as p 0.1, were observed for age, dyslipidemia, concomitant use of other antidiabetics or insulin, lipid-lowering drugs, and hospitalization history ( Table 1 ). Download: PNG larger image TIFF original image Table 1. Baseline characteristics. https://doi.org/10.1371/journal.pone.0359960.t001 Events The incidence of at least one reported event was 31% (351 cases) for imeglimin and 22% (220 cases) for sitagliptin (crude RR: 1.39; 95% CI: 1.20–1.60). Among imeglimin users, the most frequently reported adverse events were gastrointestinal symptoms (12.8%), decreased therapeutic response (6.1%), and nausea (3.6%; Table 2 ). Notably, imeglimin use was associated with a significantly higher risk of nausea (adjusted HR [aHR]: 15.34; 95% CI: 3.50–67.23), diarrhea (aHR: 7.90; 95% CI: 2.54–24.62), elevated blood glucose (aHR: 4.57; 95% CI: 1.20–17.34), and abdominal discomfort (aHR: 6.02; 95% CI: 1.47–24.58). This association may reflect confounding by indication or temporary worsening of glycemic control during treatment discontinuation or medication switching rather than a direct pharmacological effect of imeglimin. Additionally, events such as vomiting (1.4%), soft stools (1.1%), and dyspepsia (0.4%) were reported exclusively in the imeglimin group. The Kaplan-Meier curves illustrating the cumulative incidence of gastrointestinal events during follow-up are presented in Fig 1 . Download: PNG larger image TIFF original image Table 2. Incidence of common events among imeglimin and sitagliptin users. https://doi.org/10.1371/journal.pone.0359960.t002 Download: PNG larger image TIFF original image Fig 1. Kaplan-Meier curves for the cumulative incidence of gastrointestinal events. The curves show the cumulative incidence of gastrointestinal symptoms in patients newly prescribed imeglimin (dashed gray line) compared with that in patients prescribed sitagliptin (solid black line) during the follow-up period. The hazard ratio, 95% confidence interval, and p-value displayed in the figure were derived from the multivariable Cox proportional hazards model. https://doi.org/10.1371/journal.pone.0359960.g001 Among sitagliptin users, the most common events were decreased therapeutic response (4.3%), improvement in pre-existing conditions (1.8%), and inadequate control of diabetes mellitus (1.4%). The rate of improvement of pre-existing conditions was higher in the sitagliptin group than in the imeglimin group (aHR: 0.25; 95% CI: 0.09–0.70; Table 2 ). To minimize potential confounding effects of concomitant antidiabetic medications, we performed sensitivity analyses restricted to patients receiving monotherapy (imeglimin, n = 114; sitagliptin, n = 561). In this monotherapy subpopulation, 19 gastrointestinal events occurred in the imeglimin group and 15 among sitagliptin users. The sensitivity analyses showed an elevated risk of gastrointestinal events among imeglimin users (aHR: 5.36; 95% CI: 2.63–10.91), with an absolute risk difference of 13.4% (95% CI: 7.6%–21.2%). Similarly, the aHR (5.20; 95% CI: 2.55–10.61) estimated using Firth’s penalized likelihood approach for Cox regression was comparable to the primary analysis. The results of
## Related Clinical Research

- [Lifestyle Changes May Help Prevent Multimorbidity In Prediabetes](https://medichelpline.com/clinical-feed/medical-news-today-23-diet-weight-loss-and-150-minutes-of-exercise-may-protect-against-chronic.md)
- [Cardiovascular safety of oral orforglipron versus insulin glargine in T2D at increased CV risk (AC](https://medichelpline.com/clinical-feed/pubmed-42815506.md) (DOI: 10.1016/S0140-6736(26)01865-9)
- [Safiglipron vs dapagliflozin in type 2 diabetes: phase 3 randomized double-blind OUTSTAND-2 results](https://medichelpline.com/clinical-feed/nature-0-oral-small-molecule-glp-1ra-safiglipron-versus-dapagliflozin-in-type-2-diabetes.md)
- [SGLT2 inhibitors vs GLP-1 RAs and osteoarthritis risk in type 2 diabetes: a multi-institutional co](https://medichelpline.com/clinical-feed/plos-one-16-comparative-effects-of-sglt2-inhibitors-and-glp-1-receptor-agonists-on.md)
- [Beyond the Scale: What Else Glucagon-like Peptide-1 Receptor Agonists Can Do](https://medichelpline.com/clinical-feed/endocrine-news-34-beyond-the-scale-what-else-glucagon-like-peptide-1-receptor-agonists-can-do.md)

## Navigation
- [← Back to Endocrinology Feed](https://medichelpline.com/clinical-feed/endocrinology.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.