Evaluation and comparison of efficacy and safety of mitochondrial modulator (Imeglimin) and DPP-4 inhibitors in patients with type 2 diabetes mellitus: A Bayesian network meta-analysis.

Purpose: Imeglimin (Imeg), a novel oral antidiabetic drug that acts as a mitochondrial modulator and targets multiple metabolic pathways, offers a novel therapeutic option for type 2 diabetes mellitus (T2DM). Although both Imeg and dipeptidyl peptidase-4 inhibitors (DPP-4i) enhance glucose-stimulated insulin secretion (GSIS), their comparative clinical benefits remain uncertain. Therefore, we comprehensively evaluated and compared the efficacy and safety of Imeg and DPP-4i in the treatment of T2DM using Bayesian network meta-analysis (BNMA).

Methods: PubMed, Web of Science, EMBASE, Cochrane Library, and ClinicalTrials.gov were systematically searched from inception to 1 October, 2024. Randomized clinical trials (RCTs) comparing the efficacy and safety of Imeg or DPP-4i with placebo or other antidiabetic drugs in treating T2DM were included. The primary efficacy outcomes included changes in glycated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and 2-hours postprandial plasma glucose (2h PPG), as well as the proportion of participants with HbA1c < 7%. The secondary efficacy outcomes included changes in body weight (BW), total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides, homeostasis model assessment of β-cell function (HOMA-β), and homeostatic model assessment for insulin resistance (HOMA-IR). The safety outcomes included the proportion of participants with adverse events, infection, and gastrointestinal adverse events (GIAEs).

Results: 145 studies with 71,476 participants were included in the BNMA. Imeg 500 mg,1000 mg, 1500 mg and 2000 mg BID all exhibited significant efficacy in reducing HbA1c compared to placebo (mean difference (MD) [95% confidence interval (CI)], -0.29 [-0.51, -0.06] %, -0.67 [-0.83, -0.51] %, -0.73 [-0.90, -0.56] %, and - 0.63 [-0.95, -0.30] %, respectively). Compared to placebo, the majority of DPP-4i (except for Gosogliptin (Goso) 2 mg QD (MD [95% CI], -0.32 [-0.73, 0.09] %), Omarigliptin 0.25 mg QW (-0.26 [-0.54, 0.01] %), and Sitagliptin (Sita) 5 mg BID (-0.24 [-0.50, 0.01] %)) demonstrated significant efficacy in reducing HbA1c. Compared to the FDA-approved DPP-4i, i.e., Sita 100 mg QD, Saxagliptin 5 mg QD, Linagliptin 5 mg QD, and Alogliptin (Alog) 25 mg QD, Imeg showed no significant differences in glycemic control. Compared to placebo, Alog 50 mg QD (MD [95% CI], -11.15 [-19.99, -2.48] mg/dL), Alog 25 mg QD (-6.11 [-10.33, -2.07] mg/dL), and Alog 12.5 mg QD (-5.53 [-9.72, -1.49] mg/dL) exhibited notable total cholesterol-lowering effects. Compared to placebo, only Alog 50 mg QD (OR [95% CI], 1.91 [1.02, 3.28]) and Goso 30 mg QD (2.14 [1.07, 3.86]) exhibited a higher incidence of adverse events. Compared to placebo, only Imeg 500 mg BID was associated with a significantly increased risk of infection (OR [95% CI], 2.30 [1.01, 4.61]). Compared to placebo, Imeg 1500 mg BID (OR [95% CI], 2.74 [1.09, 5.78]), Sita 100 mg QD (OR [95% CI], 1.36 [1.02, 1.75]) and Vildagliptin 50 mg BID (1.50 [1.06, 2.06]) were associated with a significantly increased risk of GIAEs. According to the surface under the cumulative ranking curve (SUCRA) value, among the included DPP-4i, 20 mg QD and 40 mg QD of Teneligliptin (Tene) demonstrated significant efficacy in lowering HbA1c (73.08% and 84.8%, respectively) and 2h PPG (68.05% and 79.24%, respectively). Alog 25 mg QD was identified as the most effective DPP-4i for increasing the proportion of participants with HbA1c < 7% (91.07%).

Conclusion: Imeg and DPP-4i demonstrated favorable antidiabetic effects and good safety. Imeg exhibited comparable glycemic control to that of DPP-4i. Overall, Alog was the most suitable option among the included DPP-4i for T2DM patients with hyperlipidemia. Tene demonstrated significant efficacy in glycemic control, and can be a first-line choice among the included DPP-4i.