Background Imeglimin, a novel oral antidiabetic agent, has demonstrated mitochondrial and anti-inflammatory benefits. This study evaluated the efficacy of Imeglimin-based therapies on glycemic control, mitochondrial stress (circulating cell-free mitochondrial DNA (ccf-mtDNA), and inflammation in type 2 diabetes mellitus (T2DM). Methods A total of 104 T2DM patients were enrolled and assigned to one of four groups out of which 96 patients completed follow-up and data was analyzed: Imeglimin monotherapy (n=23), Imeglimin + Metformin (n=24), Imeglimin + other Oral Hypoglycemic Agents (OHAs) (n=24), and Metformin + other OHAs (n=25). Assessments at baseline and 6 months included HbA1c, lipid profile, ccf-mtDNA, NOD-like receptor family, pyrin domain containing 3 (NLRP3), Interleukins-6, 1β and 18 (IL-6, IL-1β, and IL-18). Within-group changes were assessed using paired t-tests. Repeated measures ANCOVA models analyzed group-time interactions. Correlation analysis explored associations between Δ biomarkers and metabolic parameters. Results Combination therapies, particularly Imeglimin + other OHAs, significantly reduced HbA1c (Δ=–0.5%, p=0.001), ccf-mtDNA (Δ=–18.5 copies/μL, p=0.02), and IL-6 (p 0.001). Repeated measures ANCOVA revealed significant reductions in HbA1c (p=0.001), circulating cell-free mtDNA (p=0.004), and serum NLRP3 levels (p=0.037) across imeglimin-based therapy groups. Post hoc comparisons showed the greatest improvements in the Imeglimin + Other OHAs group versus control. Significant time × group effects for IL-6 and IL-1β. No changes were noted in IL-18. Conclusion Imeglimin, especially in combination with non-Metformin OHAs, improves glycemic control and reduces mitochondrial and inflammatory stress in T2DM patients. These findings support its use as an adjunctive therapy with broader metabolic benefits. Clinical Trial Registration https://ctri.nic.in/Clinicaltrials/advancesearchmain.php , identifier CTRI/2023/12/060844.
Satheesan et al. (2025) studied this question.