Imeglimin as a Replacement Therapy for Metformin in Patients With Type 2 Diabetes Mellitus Experiencing Metformin Intolerance: A Retrospective Observational Study.

Background Type 2 diabetes mellitus (T2DM) is a major global health burden. Despite being the preferred first-line therapy, metformin use is sometimes limited by gastrointestinal intolerance, creating a need for alternative management strategies. A promising oral antidiabetic substitute, imeglimin, a first-in-class tetrahydrotriazine, has a distinct mitochondrial mechanism of action. However, its real-world efficacy and tolerability as a direct replacement for metformin in GI-intolerant patients remain uncharacterized. Methods This retrospective observational study was conducted on 100 adult patients with T2DM who had documented metformin intolerance and were initiated on imeglimin monotherapy or combination therapy for three months. Primary outcomes included variations in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), and postprandial plasma glucose (PPG). Body weight, lipid profile, and renal function were the secondary outcomes. Normality was assessed using the Shapiro-Wilk test; paired t-tests and Wilcoxon signed-rank tests were applied as appropriate. Multivariate linear regression was performed with change in HbA1c as the dependent variable and key covariates (baseline HbA1c, age, sex, T2DM duration, body weight, imeglimin dose, and number of concomitant oral anti-diabetic drugs) as independent variables. A two-tailed p<0.05 was considered statistically significant. Results The study comprised 100 patients (55% female; mean age: 57.69 ± 9.24 years; mean T2DM duration: 10.38 ± 5.69 years). HbA1c decreased significantly from 7.96 ± 1.56% to 7.35 ± 1.02% (mean change: -0.62 ± 1.05%; p<0.001; n=77) after three months of imeglimin therapy. FPG decreased from 156.63 ± 48.48 mg/dL to 124.45 ± 20.46 mg/dL (-32.18 ± 47.02 mg/dL; p<0.001), and PPG decreased from 217.85 ± 84.08 mg/dL to 173.22 ± 39.71 mg/dL (-44.63 ± 68.44 mg/dL; p<0.001). Body weight decreased significantly (-0.81 kg; p<0.001). Low-density lipoprotein cholesterol and triglyceride levels also showed significant reductions (p<0.001). The estimated glomerular filtration rate remained stable (p=0.135), and gastrointestinal side effects were reported in only 2% of the patients. Conclusion Imeglimin demonstrated meaningful improvements in glycemic control, with a favorable safety and tolerability profile in metformin-intolerant patients with T2DM. These findings support the use of imeglimin as an effective and well-tolerated alternative option for metformin in patients with T2DM.