Tokushima University, Medical Research, Nakashowa 1-61,Tokushima 770-0943, Japan; Japan Low Carbohydrate Diet Promotion Association (JLCDPA), Kyoto, JapanJapan
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Imeglimin (Twymeeg) is novel oral hypoglycemic agent (OHA) developed in the glimin category. It has dual action mechanisms of reducing insulin resistance and increasing insulin secretion. Trials of imeglimin for efficacy and safety 1 (TIMES 1), TIMES 2 and TIMES 3 were performed with significant clinical efficacy. Among them, HbA1c decrease for 52 weeks showed single imeglimin -0.46%, combined therapy of dipeptidyl peptidase-4i (DPP-4i)-0.92%, Glucagon-like peptide-1 receptor agonists (GLP-1RA)-0.12% and insulin -0.63%. From physiological and pharmacological points of view, the mechanism may include the enhancement action of glucose-stimulated insulin secretion (GSIS). For GSIS progress, transient receptor potential melastatin 2 (TRPM2) channel is activated.
Keywords: Imeglimin; Twymeeg; Trials of imeglimin for efficacy and safety 2 (TIMES 2); Glucose-stimulated insulin secretion (GSIS); Transient receptor potential melastatin 2 (TRPM2) channel; Imeglimin; Twymeeg; Trials of imeglimin for efficacy and safety 2 (TIMES 2)
Imeglimin (Twymeeg) is novel oral hypoglycemic agent (OHA) developed in the glimin category. It has dual action mechanisms of reducing insulin resistance and increasing insulin secretion. Trials of imeglimin for efficacy and safety 1 (TIMES 1), TIMES 2 and TIMES 3 were performed with significant clinical efficacy. Among them, HbA1c decrease for 52 weeks showed single imeglimin -0.46%, combined therapy of dipeptidyl peptidase-4i (DPP-4i)-0.92%, Glucagon-like peptide-1 receptor agonists (GLP-1RA)-0.12% and insulin -0.63%. From physiological and pharmacological points of view, the mechanism may include the enhancement action of glucose-stimulated insulin secretion (GSIS). For GSIS progress, transient receptor potential melastatin 2 (TRPM2) channel is activated.
Keywords Imeglimin; Twymeeg; Trials of imeglimin for efficacy and safety 2 (TIMES 2); Glucose-stimulated insulin secretion (GSIS); Transient receptor potential melastatin 2 (TRPM2) channel. or non-communicable disease (NCD), diabetes has been cru- On the other hand, oral hypoglycemic agents (OHAs) cial medical and social problem worldwide. Medical and health have played main role of treating diabetes for long. Metformin has F care for diabetes has been managed by International Diabetes Fed- been widely prescribed for first-line medicine with desirable phar- eration (IDF). IDF reported the increased prevalence of diabetes macokinetics. Similar to metformin, a novel OHA has been re- 1 7 and undiagnosed diabetes mellitus (UDM).1 Furthermore, latest cently developed, that is imeglimin associated with a triazine ring.7 standard guideline for diabetes was pronounced by American Dia- It is in the glimin category, which has tetrahydrotriazine-containing 2 8 betes Association (ADA) in Jan 2022.2 It presents recommendation agent.8 The characteristic function shows the dual action mecha- of medical care in diabetes.3 Recent topics include some types of nism of reducing insulin resistance for peripheral organs and also pharmacological treatment for diabetes. Among them, clinical ef- increasing insulin secretion from beta cell in the pancreas.9 Imegli- fect of glucagon-like peptide-1 receptor agonist (GLP-1RA) has min has been introduced to clinical application, and authors have been known.4 GLP-1RA has been recently prescribed more. Cases prescribed the adequate T2DM patients who had successful ef- of 932 type 2 diabetes mellitus (T2DM) were 63.8-years in average fects.10 In our report, T2DM case showed HbA1c decrease from 5 11 and used dulaglutide (65.7%) or liraglutide (29.1%).5 Hemoglobin 8.6% to 5.7% in 8-weeks.11 A1C (HbA1c) decreased for 6-months from 8.3% to 7.8%, and ratio of HbA1c<7.0% increased from 14.4% to 22.9%. Clinical ef- From clinical practice points of view, three series of in- ficacy of liraglutide and dulaglutide in real world was compared for vestigations were carried out. They are trials of imeglimin for effi- cacy and safety 1 (TIMES 1), TIMES 2 and TIMES 3. For TIMES 179 T2DM patients. HbA1c decreased 8.9% to 7.4% in liraglutide, and 8.7% to 7.5% in dulaglutide for 12-months. Both effects were 1, double-blind, randomized, parallel-group, placebo-controlled actually comparable. Thus, GLP-1RA would be in focus for inject- phase 3 trial was conducted in 30 sites in Japan.12 Protocol included able agent for diabetes in the medical practice.
imeglimin group (2000 mg/day, n=106) and placebo (n=107) for 24-weeks. As a result, HbA1c change from baseline was -0.87% at cc Copyright 2022 by Bando H. This is an open-access article distributed under Creative Commons Attribution 4.0 International License (CC BY 4.0), which allows to copy, redistribute, remix, transform, and reproduce in any medium or format, even commercially, provided the original work is properly cited. Diabetes Res Open J. 2022; 8(1): e1-e3. doi: 10.17140/DROJ-8-e017 24-weeks.
the first phase of insulin secretion. Another is the stimulation by GLP-1, exendin-4 and glucose-dependent insulinotropic polypep- Regarding TIMES 2, clinical efficacy of the combina- tide (GIP), that may activate cAMP production as the same route tion of imeglimin and other antidiabetic agents for 52-weeks was of glucose pathway.
investigated.13 It was a phase 3, pivotal, open-label trial including 714 T2DM patients. They were provided 1000 mg of imeglimin From these basic pharmacological mechanisms, imegli- twice a day for single therapy or combined therapy of other agents. min can contribute much for actual diabetic practice. As to chronic The primary endpoint was set for maintaining the safety such as kidney disease (CKD), pharmacokinetic (PK) characteristics were adverse events, laboratory results or electrocardiography (ECG). studied.19 Consequently, usual doses of 1000 mg of imeglimin twice The results showed the following: single imiglimin -0.46%, sulfo- daily can be given for case with estimated glomerular filtration rate nyl urea -0.56%, glinide -0.70%, biguanides -0.67%, α-GI -0.85%, (eGFR)>45 mL/min/1.73 m2, and 500 mg twice is recommended thiazolidine -0.88%, sodium/glucose cotransporter-2 inhibitors for case with eGFR 15-45 mL/min/1.73 m2. Study of imeglimin (SGLT2i) -0.57%, dipeptidyl peptidase-4i (DPP-4i) -0.92% as for patient with hepatic impairment was conducted by area under OHAs, and GLP-1RA -0.12% as injection.
the curve (AUC) and maximum observed plasma concentration (Cmax). The result showed 50% higher AUC and 30% higher Cmax, As TIMES 3, combined therapy of imeglimin and insulin indicating safe and well-tolerated administration of imeglimin for was performed for 35 multi-center study. The protocol was dou- hepatic impairment. Meta-analysis investigation was performed ble-blind, randomized, parallel-group phase 3 trial with 215 cases.14 for 1555 cases from 8 studies. As a result, Imeglimin group showed As a result, mean difference in HbA1c between study and control decreased HbA1c and no significant changes in homeostasis mod- group was -0.60 to -0.64% during 16-52-weeks. Thus, Imeglimin el assessment-estimated insulin resistance (HOMA-IR), triglycer- revealed a novel option for add-on therapy (AOT) to insulin ther- ide, and HDL-C. In summary, this article will be hopefully useful apy.
reference in the future diabetic research.
Among these, impressive comparison would be the com- FUNDING bined therapy of DPP-4i (-0.92%), GLP-1RA (-0.12%) and insulin (-0.63%).13 Common pathway of pharmacological mechanism ac- There was no funding received for this paper.
tion has been recognized in the DPP-4i and GLP-1RA. As a matter of fact, however, the clinical effect showed much difference. The