imeglimin and Diabetes-Mellitus--Type-2

Imeglimin is a novel new oral compound recently approved for treating type 2 diabetes (T2D) in India. We conducted a systematic review and meta-analysis to evaluate the efficacy of imeglimin in people with T2D in the approved dose of 1000 mg twice daily (BID).. We systematically searched the database of PubMed until December 20, 2022, and retrieved all published double-blind, randomized, placebo-controlled trials (RCTs) conducted with imeglimin 1000 mg BID, using appropriate keywords and MeSH terms. A meta-analysis was conducted to study the HbA1c lowering effect of imeglimin 1000 mg BID in people with T2D using the Comprehensive meta-analysis (CMA) software Version 3, Biostat Inc. Englewood, NJ, USA.. Of the seven Phase 2 studies and three Phase 3 studies conducted so far, only three published double-blind RCTs have reported the efficacy and safety of imeglimin 1000 mg BID against the placebo. Our meta-analysis using the random-effects model from two monotherapy studies (n = 360) showed imeglimin 1000 mg BID reduce HbA1c significantly (Δ -0.9%, 95% Confidence Interval [CI], -1.1 to -0.74%; P < 0.0001) against the placebo, without any heterogeneity (I. This meta-analysis found a significant HbA1c lowering effect of imeglimin in people with T2D with an acceptable tolerability profile. Still, larger and longer studies are needed.

Topics: Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; India; Randomized Controlled Trials as Topic; Triazines

This meta-analysis aimed to evaluate the efficacy and safety/tolerability of imeglimin, a novel oral antihyperglycemic agent, administered as monotherapy and adjunctive therapy in patients with type 2 diabetes mellitus.. Parallel-group randomized controlled trials comparing imeglimin with placebo in adults with type 2 diabetes mellitus were included. Risk ratios or weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated using random effects models. The primary outcome for efficacy was the change in glycated hemoglobin (HbA1c). Secondary outcomes included other efficacy-related outcomes, specific adverse events, and changes in body weight and lipid parameters.. Nine randomized controlled trials (n = 1,655) were included. When analyzed by dose, there was a significant difference in glycated hemoglobin (%) between imeglimin monotherapy and placebo at doses >1,000 mg twice daily (1,000 mg: studies N = 3, patients n = 517, WMD = -0.714, P < 0.001; 1,500 mg: N = 5, n = 448, WMD = -0.531, P = 0.020; 2,000 mg: N = 1, n = 149, WMD = -0.450, P = 0.005). Imeglimin adjunctive therapy significantly improved glycated hemoglobin over placebo at doses of 1,000 mg (N = 1, n = 214, WMD = -0.600, P < 0.001) and 1,500 mg (N = 2, n = 324, WMD = -0.576, P < 0.001). Subgroup analysis of the primary outcome showed that imeglimin was effective regardless of chronic kidney disease category, with studies carried out in Japan and in patients with lower body mass index showing a trend toward improved imeglimin efficacy. There were no significant differences between imeglimin and placebo in the risk of all-cause discontinuation and the proportion of patients who presented with at least one adverse event.. Imeglimin is efficacious, safe, and well tolerated as monotherapy and adjunctive therapy.

Topics: Adult; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Randomized Controlled Trials as Topic

Imeglimin (PXL008, EMD-387008, Twymeeg

Topics: Biological Transport; Diabetes Mellitus, Type 2; Humans; Pharmacology, Clinical

Type 2 diabetes mellitus is a chronic disease most often characterized by increased glucose levels. When blood glucose levels are inadequately controlled or left untreated, the result is a variety of microvascular and macrovascular complications. To prevent these outcomes, many medications are available to manage type 2 diabetes mellitus and prevent disease progression. However, most of the medications available to date only target a few of the physiological defects caused by diabetes and may come with side effects that make adherence to the medication improbable. Imeglimin, a medication currently under investigation in the United States and approved in Japan, is a novel, first-in-its-class medication with a mechanism that is currently understood to target multiple pathways to provide glycemic control. This review aims to present and discuss the current clinical and scientific evidence pertaining to imeglimin.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Humans; Japan; Triazines; United States

Imeglimin hydrochloride (TWYMEEG

Topics: Clinical Trials, Phase III as Topic; Diabetes Mellitus, Type 2; Drug Approval; Humans; Hypoglycemic Agents; Japan; Triazines

Imeglimin is the first of the "glimins," a new class of drugs developed for the treatment of type 2 diabetes mellitus (T2DM). This review highlights its mechanism of action and its context in the field of T2DM treatment. Preclinical data in multiple rodent models have detailed significant effects on mitochondria, particularly improved mitochondrial bioenergetics. This includes changes favoring complex II and complex III metabolism, a mechanism potentially promoting increased fatty acid oxidation, leading to the decrease in hepatic lipid accumulation observed in these mice. Imeglimin was also shown to increase muscle glucose uptake and decrease hepatic glucose production, both in vitro and in vivo. Though studies have also shown imeglimin to significantly improve insulin secretion and decrease β-cell death, whether its physiologic effects are purely insulin dependent remains unclear. Early preclinical studies have shown evidence for improvements in cardiac and renal function in rats with metabolic syndrome, effects not conferred by most currently available T2DM drugs. Clinical studies of imeglimin in humans have shown increased insulin secretion, along with decreased fasting plasma glucose and glycated hemoglobin. Its observed efficacy was comparable to that of currently available agents metformin and sitagliptin and was increased when given in combination with either agent. When considered alongside its benign safety profile reported in patients with chronic kidney disease, imeglimin shows true promise to provide a novel mechanism for T2DM treatment, with potential application in a larger, more comprehensive patient population.

Topics: Diabetes Mellitus, Type 2; Drug Development; Humans; Hypoglycemic Agents; Triazines

Imeglimin is an investigational first-in-class novel oral agent for the treatment of type 2 diabetes (T2D). Several pivotal phase III trials have been completed with evidence of statistically significant glucose lowering and a generally favourable safety and tolerability profile, including the lack of severe hypoglycaemia. Imeglimin's mechanism of action involves dual effects: (a) amplification of glucose-stimulated insulin secretion (GSIS) and preservation of β-cell mass; and (b) enhanced insulin action, including the potential for inhibition of hepatic glucose output and improvement in insulin signalling in both liver and skeletal muscle. At a cellular and molecular level, Imeglimin's underlying mechanism may involve correction of mitochondrial dysfunction, a common underlying element of T2D pathogenesis. It has been observed to rebalance respiratory chain activity (partial inhibition of Complex I and correction of deficient Complex III activity), resulting in reduced reactive oxygen species formation (decreasing oxidative stress) and prevention of mitochondrial permeability transition pore opening (implicated in preventing cell death). In islets derived from diseased rodents with T2D, Imeglimin also enhances glucose-stimulated ATP generation and induces the synthesis of nicotinamide adenine dinucleotide (NAD

Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Triazines

Diabetes mellitus is a serious metabolic disorder affecting millions of people worldwide. Phenformin and metformin are biguanide antidiabetic agents that are conveniently synthesized in a single-step chemical reaction. Phenformin was once used to lower blood glucose levels, but later withdrawn from the market in several countries because it was frequently associated with lactic acidosis. Metformin is still a widely prescribed medication for the treatment of type 2 diabetes despite the introduction of several newer antidiabetic agents. Metformin is administered orally and has desirable pharmacokinetics. Incidence of metformin-induced lactic acidosis is serious but very rare. Imeglimin, a novel molecule being investigated by Poxel and Sumitomo Dainippon Pharma in Japan, is currently in clinical trials for the treatment of type 2 diabetes. Unlike metformin, imeglimin is a cyclic molecule containing a triazine ring. However, like metformin, imeglimin is also a basic small molecule. Imeglimin is synthesized from metformin as a precursor via a single step chemical reaction. Recent mechanism of action studies suggests that imeglimin improves mitochondria function, when given in combination with metformin it helps achieve better glycemic control in patients with type 2 diabetes. We herein describe and compare the current status, synthesis, physicochemical properties, pharmacokinetic parameters, mechanism of action, and preclinical/clinical studies of metformin and imeglimin.

Topics: Acidosis, Lactic; Animals; Blood Glucose; Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Metformin; Phenformin; Triazines

With the rising prevalence of type 2 diabetes (T2D), there is a substantial interest in novel, glucose-lowering drugs that may complement existing treatment options. Imeglimin is an oral antidiabetic agent currently in clinical development.. This review is based on a literature search using PubMed and Embase including all published manuscripts and presentations concerning imeglimin. Supplementary information was retrieved from the manufacturer's official webpage. Preclinical and clinical data are summarized with a focus on mechanisms of action as well as clinical efficacy and safety in T2D.. Imeglimin's mode of action seems to be improved mitochondrial function in pancreatic beta cells leading to improved insulin secretion and lowering of plasma glucose levels. In clinical trials of up to 24 weeks, imeglimin in doses of 1,000-1,500 mg twice daily conferred modest reductions in glycates hemoglobin A1c of 6-11 mmol/mol (0.5-1.0%) (placebo-adjusted) as a monotherapy and 7 mmol/mol (0.6%) as an add-on therapy to metformin or sitagliptin in patients with T2D. Reported adverse effects were mainly gastrointestinal discomfort. The position of imeglimin among other pharmacotherapies in the treatment of T2D will be determined based on future studies more clearly outlining the safety and long-term cardiovascular effects.. AUC: area under the curve; BID: twice daily; DPP-4: dipeptidyl peptidase 4; GLP-1R: glucagon-like peptide-1 receptor; HbA1c: glycated hemoglobin A1c; HFHSD: high-fat high-sucrose diet; OAD: oral antidiabetic; OD: once daily; OGTT: oral glucose tolerance test; PPAR-γ: peroxisome proliferator-activated receptor gamma; PTP: permeability transition pore; SGLT-2: sodium-glucose transport protein 2; STZ: streptozotocin; T2D: type 2 diabetes.

Topics: Administration, Oral; Blood Glucose; Diabetes Mellitus, Type 2; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Triazines

Despite different classes of antidiabetic medications available for the management of patients with diabetes, efforts are underway to identify novel and safer antihyperglycemic agents with higher potency and increased tolerability. Imeglimin is a promising antidiabetic agent that has shown to have significant antihyperglycemic effects in studies, although it has not been approved yet. There is growing evidence that imeglimin improves glucose homeostasis in the diabetic milieu; however, the precise molecular mechanisms are still not elucidated. In this review, we discuss various molecular pathways by which imeglimin exerts its antihyperglycemic effects and improves glucose homeostasis in the diabetic milieu.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Homeostasis; Humans; Hypoglycemic Agents; Triazines

Imeglimin is a novel agent currently in development to treat type 2 diabetes. Laboratory studies have demonstrated that it has the potential to impact the three main pathophysiologic components of type 2 diabetes: impaired glucose uptake by muscle tissue, excess hepatic gluconeogenesis, and increased beta-cell apoptosis. Preliminary human studies that have been published within the last 2 years demonstrate that imeglimin improves hemoglobin A1c and fasting plasma glucose similarly when compared with metformin and with sitagliptin. There has also been a low incidence of adverse effects, especially hypoglycemia, reported in these early human studies. Currently, imeglimin is lacking long-term evidence to demonstrate any effects on its cardiovascular safety, and data on morbidity and mortality, though some studies are currently in progress. There is great potential for imeglimin, if FDA approved, to play a significant role in the type 2 diabetes management algorithm.

Topics: Apoptosis; Blood Glucose; Diabetes Mellitus, Type 2; Gluconeogenesis; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Metformin; Sitagliptin Phosphate; Triazines

Substantial variability in demographic and clinical characteristics exists among patients with type 2 diabetes mellitus, which may impact treatment. This post-hoc analysis evaluated the efficacy and safety of imeglimin 1,000 mg twice daily (BID) monotherapy in type 2 diabetes mellitus patients according to demographic and clinical characteristics.. Data were pooled from two placebo-controlled, 24 week, randomized, double-blind studies in adults with type 2 diabetes mellitus. Outcomes (least squares mean [LSM] change in HbA1c from baseline to week 24, and safety) were analyzed according to subgroups based on demographics, clinical characteristics, and comorbidities.. The difference in LSM change in HbA1c from baseline to week 24 was statistically significant for imeglimin vs placebo in all patient subgroups analyzed (P < 0.05 each), including demographics (age, body mass index), clinical characteristics (duration of type 2 diabetes mellitus, chronic kidney disease [CKD] stage, and prior medication use) and comorbidities (hypertension, dyslipidemia, risk of hepatic fibrosis and liver function parameter status). A statistically significant separation from placebo in HbA1c was observed at week 4 and maintained through week 24. No new safety concerns were identified with imeglimin in any patient subpopulations.. The efficacy and safety of imeglimin was demonstrated across patient subgroups, irrespective of baseline demographic and clinical characteristics. Our findings confirm the efficacy and safety of imeglimin across a broad spectrum of patients with type 2 diabetes mellitus.

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; East Asian People; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Treatment Outcome

To evaluate the safety and efficacy of imeglimin for 52 weeks as monotherapy or combination therapy with existing antidiabetic agents in Japanese patients with type 2 diabetes.. TIMES 2 was a phase 3, pivotal, open-label trial including patients with type 2 diabetes inadequately controlled despite diet/exercise or despite treatment with a single agent from one of several available classes of antidiabetic drugs along with diet/exercise. All patients received imeglimin 1000 mg twice-daily orally for 52 weeks as monotherapy or combination therapy. The primary endpoint was safety (adverse events, laboratory results, ECG). The secondary endpoints were changes from baseline in HbA1c and fasting plasma glucose at week 52.. A total of 714 patients received the following treatments: imeglimin monotherapy (n = 134), combination with an α-glucosidase inhibitor (n = 64), biguanide (n = 64), dipeptidyl peptidase-4 inhibitor (DPP4-I; n = 63), glinide (n = 64), glucagon-like peptide-1 receptor agonist (GLP1-RA; n = 70), sodium-glucose co-transporter-2 inhibitor (n = 63), sulphonylurea (n = 127), or thiazolidinedione (n = 65). The percentage of patients experiencing at least one treatment emergent adverse event (TEAE) was 75.5%. Most of these events were mild or moderate in intensity. Serious TEAEs, none of them related to the study drug, occurred in 5.6% of all patients. No clinically significant changes in ECG, vital signs, physical examination, or laboratory tests were noted in any groups. At week 52, HbA1c decreased by 0.46% with imeglimin monotherapy, by 0.56%-0.92% with imeglimin as oral combination therapy, and by 0.12% with injectable GLP1-RA combination therapy. The greatest net HbA1c reduction (0.92%) occurred in patients receiving a DPP4-I in combination with imeglimin.. Imeglimin provides well-tolerated, long-term safety and efficacy in both monotherapy and oral combination therapy in Japanese patients with type 2 diabetes.

Topics: Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Humans; Hypoglycemic Agents; Japan; Treatment Outcome; Triazines

To evaluate the efficacy and safety of imeglimin for up to 52 weeks as combination therapy with insulin in Japanese patients with type 2 diabetes.. This double-blind, randomized, parallel-group phase 3 trial was performed at 35 sites in Japan. Eligible patients were individuals aged ≥20 years with type 2 diabetes and inadequate glycaemic control with insulin. Patients were randomly assigned (1:1) to either imeglimin (1000 mg twice daily) or matched placebo, in combination with insulin, for 16 weeks. In a subsequent 36-week, open-label extension period, all patients received imeglimin 1000 mg twice daily. The primary endpoint was change in mean glycated haemoglobin (HbA1c) from baseline to week 16.. In all, 108 and 107 patients were randomly assigned to treatment with imeglimin 1000 mg twice daily or placebo, respectively. Compared with placebo, the adjusted mean difference in change from baseline HbA1c at Week 16 was -0.60% (95% confidence interval [CI] -0.80 to -0.40; P < 0.0001). This decrease was sustained up to 52 weeks with a mean decrease of -0.64% (95% CI -0.82 to -0.46) versus baseline. The incidence of patients experiencing adverse events and serious adverse events was similar in the two treatment groups. The number of patients experiencing hypoglycaemia was similar in the two treatment groups. In patients receiving imeglimin, all hypoglycaemic events were mild in severity; no episodes required assistance.. Imeglimin significantly improved HbA1c in Japanese patients with insufficiently controlled type 2 diabetes by insulin and had a similar safety profile to placebo. The efficacy of imeglimin on top of insulin was sustained for 52 weeks. Imeglimin represents a potential new treatment option for this population as add-on to insulin therapy.

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Japan; Treatment Outcome; Triazines; Young Adult

Imeglimin is a first-in-class novel oral antidiabetic marketed in Japan as TWYMEEG. To assess the pharmacokinetic and safety profile of imeglimin in Caucasian and Japanese healthy individuals.. Two randomized placebo-controlled phase 1 clinical studies were conducted in Caucasian subjects after single (250-8000 mg) and multiple (250-2000 mg twice daily) ascending doses and in Japanese subjects after single (500-6000 mg) and multiple (500-2000 mg twice daily) ascending doses. Imeglimin plasma and urine concentrations were measured.. All imeglimin doses achieved maximal concentration between 1 and 3.5 h in Caucasians, and 1.5 and 3 h in Japanese subjects. The elimination half-lives (t. Imeglimin was safe and well tolerated in these two phases 1 studies, with pharmacokinetics comparable between the two populations.. EudraCT 2005-001946-18 and 2014-004679-21.

Topics: Area Under Curve; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Healthy Volunteers; Humans; Japan; Triazines

The aim of the present study was to evaluate the effect of 18-week monotherapy with imeglimin on glucose tolerance and on insulin secretion/sensitivity in type 2 diabetic (T2D) patients.. The study was an 18-week, double-blind clinical trial in T2D subjects previously treated with stable metformin therapy and washed out for 4 weeks. Subjects were randomized 1:1 to receive a 1500 mg bid of imeglimin or placebo. The primary endpoint was the effect of imeglimin vs placebo on changes from baseline to week 18 in glucose tolerance (glucose area under the curve [AUC]) during a 3 h-glucose tolerance test [OGTT]). Secondary endpoints included glycaemic control and calculated indices of insulin secretion and sensitivity.. Results are consistent with a mode of action involving insulin secretion as well as improved insulin sensitivity and further support the potential for imeglimin to improve healthcare in T2D patients.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Double-Blind Method; Humans; Hypoglycemic Agents; Insulin Resistance; Insulin Secretion

Imeglimin is a novel anti-hyperglycemic drug that improves both insulin resistance and insulin secretion. The effects of imeglimin on glycemic control were confirmed in phase III clinical trials, but little is known about its effectiveness in daily clinical practice settings, especially compared with metformin. Therefore, we aim to clarify the efficacy of imeglimin in patients with type 2 diabetes (T2D) being treated with a dipeptidyl peptidase-4 (DPP-4) inhibitor plus low-dose metformin.. This is a multicenter, randomized, prospective, open-label, parallel-group trial. Seventy participants with T2D treated with a DPP-4 inhibitor plus metformin (500-1000 mg/day) for more than 12 weeks and a glycated hemoglobin (HbA1c) level of 52-85 mmol/mol (7.0%-9.9%) will be randomized to receive add-on imeglimin 1000 mg two times per day or metformin dose escalation for 24 weeks. Biochemical analyses and physical assessments will be performed at baseline and at the end of the study, and adverse events will be recorded. The primary endpoint is the change in HbA1c after 24 weeks. The secondary endpoints comprise the changes in blood pressure, pulse rate, body weight, abdominal circumference, and other laboratory parameters; the relationship between improvements of biological parameters including glycemic control and patient background characteristics; and side effects.. This study will reveal new insights into the incorporation of imeglimin into the diabetes treatment strategy.. This will be the first randomized controlled trial to compare the efficacy of adding imeglimin versus metformin dose escalation on glycemic control in patients with T2D.. jRCT1011220005.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; Drug Therapy, Combination; Glycated Hemoglobin; Glycemic Control; Humans; Hypoglycemic Agents; Metformin; Multicenter Studies as Topic; Prospective Studies; Randomized Controlled Trials as Topic; Treatment Outcome

Imeglimin is a novel oral antidiabetic drug used to treat type 2 diabetes, targeting the mitochondrial bioenergetics. Imeglimin is mainly excreted unchanged by the kidneys and is a substrate of organic cation transporters, which are expressed in the kidney and the liver.. The aim of this study was to assess the effect of hepatic impairment on the pharmacokinetics of imeglimin.. An open-label, single-dose, parallel-group study was carried out in seven subjects with normal hepatic function and seven subjects with moderate hepatic impairment who received a single dose of imeglimin 1000 mg. Blood and urine samples were collected up to 48 h after imeglimin administration. Pharmacokinetics were determined using non-compartmental methods.. Imeglimin was safe and well tolerated in all subjects.. EudraCT 2018-001950-83.

Topics: Area Under Curve; Diabetes Mellitus, Type 2; Humans; Liver Diseases; Triazines

To assess the efficacy and safety of imeglimin monotherapy compared with placebo for 24 weeks in Japanese patients with type 2 diabetes (T2D).. In this 24-week, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging, phase 2b clinical trial, Japanese adults (age ≥ 20 years) with T2D either treatment-naïve or previously treated with one oral antidiabetes agent were eligible for participation. Patients were randomly assigned (1:1:1:1) to receive orally imeglimin 500, 1000 or 1500 mg, or placebo twice-daily over a 24-week period. The primary endpoint was the placebo-adjusted change at week 24 in HbA1c. Safety outcomes were assessed in all patients who received at least one dose of study drug.. A total of 299 patients were randomized to receive double-blind treatment with orally twice-daily placebo (n = 75), imeglimin 500 mg (n = 75), 1000 mg (n = 74) or 1500 mg (n = 75). At week 24, imeglimin significantly decreased HbA1c (difference vs. placebo: imeglimin 500 mg -0.52% [95% CI: -0.77%, -0.27%], imeglimin 1000 mg -0.94% [95% CI: -1.19%, -0.68%], imeglimin 1500 mg -1.00% [95% CI: -1.26%, -0.75%]; P < .0001 for all). Treatment-emergent adverse events were reported for 68.0%, 62.2%, 73.3% and 68.0% of patients receiving imeglimin 500, 1000 or 1500 mg and placebo, respectively. A small increase in gastrointestinal adverse effects (e.g. diarrhoea) occurred with the 1500 mg dose level. Hypoglycaemia was balanced among groups.. Imeglimin as monotherapy in Japanese patients with T2D was well tolerated and significantly improved glycaemic control with no significant increase in hypoglycaemic events versus placebo. Given the marginal increase in efficacy with the 1500 versus 1000 mg dose (along with the potential for gastrointestinal tolerability issues), a dose of 1000 mg twice-daily was selected for subsequent phase 3 studies.

Topics: Adult; Diabetes Mellitus, Type 2; Double-Blind Method; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Japan; Treatment Outcome; Triazines; Young Adult

Imeglimin is a novel oral antidiabetic drug for treatment of type 2 diabetes that targets mitochondrial bioenergetics. Its pharmacokinetics absorption characteristics, metabolism, distribution, and elimination were assessed through several in vitro and in vivo experiments in both animals and humans. Its potential to induce drug-drug interactions was also extensively assessed. Imeglimin is a small cationic compound with an intermediate intestinal permeability. Its absorption mechanism involves an active transport process in addition to passive paracellular absorption. Absorption was good (50%-80%) in vivo across several species but decreased with increasing dose, probably because of saturation of active transport. After absorption, imeglimin was rapidly and largely distributed to internal organs. Plasma protein binding was low, which can explain the rapid distribution to organs observed in all species. In animals and humans, imeglimin was largely excreted unchanged in urine, indicating a low extent of metabolism. Unchanged drug was the main circulating entity in plasma, and none of the identified metabolites were unique to human. Imeglimin renal clearance was higher than creatinine clearance, indicating that it was actively secreted into urine. There was no evidence that it had the potential to cause cytochrome P450 inhibition or induction. It was shown to be a substrate of organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 1, and MATE2-K and an inhibitor of OCT1, OCT2, and MATE1; as a consequence, corresponding clinical drug-drug interaction studies were performed and confirmed the absence of relevant interactions with substrates or inhibitors of these transporters. SIGNIFICANCE STATEMENT: Imeglimin is absorbed through a passive and active mechanism, which can be saturated. It is rapidly and largely distributed to internal organs and mainly excreted unchanged in urine. It is poorly metabolized and has no cytochrome P450 inhibition or induction potential. Imeglimin is a substrate of MATE2-K and also a substrate and an inhibitor of OCT1, OCT2, and MATE1 transporters; however, there are no clinically significant interactions when imeglimin is coadministered with either a substrate or an inhibitor of these transporters.

Topics: Administration, Intravenous; Administration, Oral; Adult; Animals; Caco-2 Cells; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Diabetes Mellitus, Type 2; Dogs; Drug Evaluation, Preclinical; Drug Interactions; Female; HEK293 Cells; Humans; Hypoglycemic Agents; Intestinal Absorption; Male; Middle Aged; Organic Cation Transport Proteins; Rats; Triazines

To assess the glucose-stimulated insulin secretion effect of imeglimin in patients with type 2 diabetes.. We conducted a double-blind, randomized, placebo-controlled study in 33 patients with type 2 diabetes [glycated haemoglobin 6.8 ± 0.1% (51 mmol/mol)], who were drug-naïve or withdrawn from their previous metformin monotherapy for 2 weeks and received imeglimin 1500 mg twice daily or placebo for 1 week. Glucose-stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response [incremental area under the curve (iAUC)0-45 min ] and insulin secretion rate (ISR) calculated from C-peptide deconvolution. β-cell glucose sensitivity at steady state (second phase: 25-45 min), hepatic insulin extraction and insulin clearance were also calculated.. Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0-45 , p = 0.035), first-phase ISR by +110% (p = 0.034) and second-phase ISR by +29% (p = 0.031). Imeglimin improved β-cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (-13%; p = 0.056). Imeglimin did not affect glucagon secretion.. In patients with type 2 diabetes, imeglimin improves β-cell function, which may contribute to the glucose-lowering effect observed with imeglimin in clinical trials.

Topics: Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Double-Blind Method; Female; Glucagon; Glucose Clamp Technique; Hepatobiliary Elimination; Humans; Insulin; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells; Male; Middle Aged; Triazines

This 12-week study assessed the efficacy and tolerability of imeglimin as add-on therapy to the dipeptidyl peptidase-4 inhibitor sitagliptin in patients with type 2 diabetes inadequately controlled with sitagliptin monotherapy.. In a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, imeglimin (1,500 mg b.i.d.) or placebo was added to sitagliptin (100 mg q.d.) over 12 weeks in 170 patients with type 2 diabetes (mean age 56.8 years; BMI 32.2 kg/m(2)) that was inadequately controlled with sitagliptin alone (A1C ≥7.5%) during a 12-week run-in period. The primary efficacy end point was the change in A1C from baseline versus placebo; secondary end points included corresponding changes in fasting plasma glucose (FPG) levels, stratification by baseline A1C, and percentage of A1C responders.. Imeglimin reduced A1C levels (least-squares mean difference) from baseline (8.5%) by 0.60% compared with an increase of 0.12% with placebo (between-group difference 0.72%, P < 0.001). The corresponding changes in FPG were -0.93 mmol/L with imeglimin vs. -0.11 mmol/L with placebo (P = 0.014). With imeglimin, the A1C level decreased by ≥0.5% in 54.3% of subjects vs. 21.6% with placebo (P < 0.001), and 19.8% of subjects receiving imeglimin achieved a decrease in A1C level of ≤7% compared with subjects receiving placebo (1.1%) (P = 0.004). Imeglimin was generally well tolerated, with a safety profile comparable to placebo and no related treatment-emergent adverse events.. Imeglimin demonstrated incremental efficacy benefits as add-on therapy to sitagliptin, with comparable tolerability to placebo, highlighting the potential for imeglimin to complement other oral antihyperglycemic therapies.

Topics: Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Humans; Hypoglycemic Agents; Male; Middle Aged; Pyrazines; Sitagliptin Phosphate; Treatment Outcome; Triazines; Triazoles

A 12-week study assessed the efficacy and safety of a new oral antidiabetic agent, imeglimin, as add-on therapy in type 2 diabetes patients inadequately controlled with metformin alone.. A total of 156 patients were randomized 1:1 to receive imeglimin (1,500 mg twice a day) or placebo added to a stable dose of metformin (1,500-2,000 mg/day). Change in A1C from baseline was the primary efficacy outcome; secondary outcomes included fasting plasma glucose (FPG) and proinsulin/insulin ratio.. After 12 weeks, the placebo-subtracted decrease in A1C with metformin-imeglimin was -0.44% (P < 0.001). Metformin-imeglimin also significantly improved FPG and the proinsulin/insulin ratio from baseline (-0.91 mg/dL and -7.5, respectively) compared with metformin-placebo (0.36 mg/dL and 11.81). Metformin-imeglimin therapy was generally well-tolerated with a comparable safety profile to metformin-placebo.. Addition of imeglimin to metformin improved glycemic control and offers potential as a new treatment for type 2 diabetes.

Topics: Adolescent; Adult; Aged; Diabetes Mellitus, Type 2; Female; Humans; Hypoglycemic Agents; Male; Metformin; Middle Aged; Treatment Outcome; Triazines; Young Adult

Imeglimin is the first in a new tetrahydrotriazine-containing class of oral antidiabetic agents, the glimins. It has been shown to act on the liver, muscle and pancreatic β-cells to uniquely target the key defects of type 2 diabetes. Two studies were performed to compare the safety and efficacy of imeglimin with metformin and placebo on glycaemic control in type 2 diabetes patients.. In a 4-week phase IIa, three-arm parallel group study, patients were randomized to imeglimin 2000 mg once daily (od), imeglimin 1000 mg twice daily (bid) or metformin 850 mg bid and responses to an oral glucose tolerance test (OGTT) were measured. In an 8-week phase IIa, four-arm controlled multi-centre study, patients were randomized to imeglimin 500 mg bid, imeglimin 1500 mg bid, metformin 850 mg bid or placebo. Glycaemic assessments included area under the curve (AUC) up to 6 h (AUC(0-6h)) for glucose during a prolonged meal, fasting plasma glucose (FPG) and HbA1c. Safety and tolerability were assessed in both studies through adverse event recording and laboratory parameters, vital signs and electrocardiogram.. Imeglimin was found to be as effective as metformin at reducing the AUC(PG) and AUC(0-6h) , FPG and HbA1c. Imeglimin exhibited a favourable tolerability profile in comparison to metformin.. The results from both studies confirm that imeglimin displays a superior benefit : risk profile compared with metformin in type 2 diabetes patients. The encouraging tolerability profile of imeglimin could make it suitable for combination with other classes of antidiabetic agents and may increase availability to a wider patient population.

Topics: Administration, Oral; Adolescent; Adult; Aged; Area Under Curve; Blood Glucose; Diabetes Mellitus, Type 2; Dose-Response Relationship, Drug; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Insulin; Male; Metformin; Middle Aged; Treatment Outcome; Triazines; Young Adult

Imeglimin hydrochloride (imeglimin) is an orally drug for type 2 diabetes mellitus, which was approved in Japan for the first in the world, with dual mode of actions: pancreatic action means amplifying glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and extrapancreatic action means improving insulin sensitivity by which gluconeogenesis suppresses in hepatocytes and glucose uptake increases in skeletal muscles. Although the molecular target of imeglimin is still unknown, imeglimin exerts some of its actions through modulation of the mitochondrial function. In pancreatic islets, imeglimin enhanced adenosine triphosphate and Ca

Topics: Diabetes Mellitus, Type 2; Glucose; Humans; Hypoglycemic Agents; NAD; Treatment Outcome

Imeglimin and metformin act in metabolic organs, including β-cells, via different mechanisms. In the present study, we investigated the impacts of imeglimin, metformin, or their combination (Imeg + Met) on β-cells, the liver, and adipose tissues in db/db mice. Imeglimin, metformin, or Imeg + Met treatment had no significant effects on glucose tolerance, insulin sensitivity, respiratory exchange ratio, or locomotor activity in db/db mice. The responsiveness of insulin secretion to glucose was recovered by Imeg + Met treatment. Furthermore, Imeg + Met treatment increased β-cell mass by enhancing β-cell proliferation and ameliorating β-cell apoptosis in db/db mice. Hepatic steatosis, the morphology of adipocytes, adiposity assessed by computed tomography, and the expression of genes related to glucose or lipid metabolism and inflammation in the liver and fat tissues showed no notable differences in db/db mice. Global gene expression analysis of isolated islets indicated that the genes related to regulation of cell population proliferation and negative regulation of cell death were enriched by Imeg + Met treatment in db/db islets. In vitro culture experiments confirmed the protective effects of Imeg + Met against β-cell apoptosis. The expression of Snai1, Tnfrsf18, Pdcd1, Mmp9, Ccr7, Egr3, and Cxcl12, some of which have been linked to apoptosis, in db/db islets was attenuated by Imeg + Met. Treatment of a β-cell line with Imeg + Met prevented apoptosis induced by hydrogen peroxide or palmitate. Thus, the combination of imeglimin and metformin is beneficial for the maintenance of β-cell mass in db/db mice, probably through direct action on β-cells, suggesting a potential strategy for protecting β-cells in the treatment of type 2 diabetes.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Type 2; Glucose; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Metformin; Mice; Mice, Inbred Strains

Topics: Animals; Diabetes Mellitus, Type 2; Insulin-Secreting Cells; Male; Metformin; Mice; Triazines

Mitochondrial dysfunction causes maternally inherited deafness and diabetes (MIDD). Herein, we report improved glycemic control in a 47-year-old Japanese woman with MIDD using imeglimin without major adverse effects. Biochemical tests and metabolome analysis were performed before and after imeglimin administration. Blood glucose level fluctuations were determined. Sulfonylureas, dipeptidyl peptidase-4 inhibitors (DPP4is), and sodium glucose transporter-2 inhibitors (SGLT2i) were administered to evaluate the efficacy of their combination with imeglimin. Imeglimin decreased the HbA1c and ammonia levels and increased the time-in-range, C-peptide reactivity, and glucagon level. Elevated citrulline and histamine levels were decreased by imeglimin. The hypoglycemic effect was not enhanced by imeglimin when combined with sulfonylurea or DPP4i, but the blood glucose level was improved when combined with SGLT2i. Imeglimin improved glucose concentration-dependent insulin secretion and maximized the insulin secretory capacity by improving mitochondrial function and glutamine metabolism and urea circuit abnormalities by promoting glucagon secretion. Imeglimin could improve glycemic control in MIDD.

Topics: Blood Glucose; Deafness; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Female; Glucagon; Glycemic Control; Humans; Hypoglycemic Agents; Maternal Inheritance; Middle Aged; Sodium-Glucose Transporter 2 Inhibitors

Topics: Acidosis, Lactic; Animals; Diabetes Mellitus, Type 2; Dogs; Humans; Hypoglycemic Agents; Lactic Acid; Metformin; Mice; Rats; Renal Insufficiency; Triazines

Imeglimin (IMEG) is the first drug of the "glimin" group. Glimin is a new group of hypoglycaemic drugs for the treatment of patients with type 2 diabetes mellitus (T2DM). The chemical structure and action mechanism of the drug are presented in the paper. Imeglimin is unique and different in action compared to other hypoglycaemic drugs. Imeglimin has been shown to have a beneficial effect on 3 key pathogenetic elements of T2DM, i.e., 1. increased gluconeogenesis, 2. inadequate glucose-induced insulin secretion by beta cells, and 3. peripheral insulin resistance. The peak effect on fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c) levels of IMEG is reached after 16 weeks of treatment. Subjects receiving IMEG at 1000- and 1500-mg doses twice daily also achieved significantly greater reductions in fasting plasma glucose (FPG) levels at week 24 compared to the placebo group (IMEG in humans causes increased insulin secretion as well as reductions in fasting plasma glucose and glycated haemoglobin). This paper also presents the pharmacokinetics of IMEG action, clinical evidence for its efficacy, results of phase II and III clinical trials, and drug tolerability. Our paper seems to show that IMEG, with its novel mechanism of action, has a chance to improve treatment results in a larger population of T2DM patients.

Topics: Blood Glucose; Diabetes Mellitus, Type 2; Glycated Hemoglobin; Humans; Hypoglycemic Agents; Triazines

Imeglimin is the first drug in a new class of tetrahydrotriazine-containing oral hypoglycemic agents called «glimines». Its mechanism of action is aimed at achieving a double effect, firstly, to improve the function of beta cells of the pancreas, and secondly, to enhance the action of insulin in key tissues, including the liver and skeletal muscles. At the cellular level, imeglimin modulates mitochondrial function, which leads to an improvement in cellular energy metabolism, as well as to the protection of cells from death in conditions of excessive accumulation of reactive oxygen species. It is important to note that the mechanism of action of imeglimin differs from existing drugs used for the treatment of type 2 diabetes mellitus. Like glucagon-like peptide-1 receptor agonists, imeglimin enhances insulin secretion in an exclusively glucose-dependent manner, but their mechanism of action at the cellular level diverges. Sulfonylureas and glinides function by closing ATP-sensitive potassium channels to release insulin, which is also different from imeglimin. Compared with metformin, the effect of imeglimine is also significantly different. Other major classes of oral antihypertensive agents, such as sodium-glucose transporter-2 inhibitors, thiazolidinediones and α glucosidase inhibitors mediate their action through mechanisms that do not overlap with imeglimine. Given such differences in the mechanisms of action, imeglimin can be used as part of combination therapy, for example with sitagliptin and metformin. The imeglimine molecule is well absorbed (Tmax-4), and the half-life is 5-6 hours, is largely excreted through the kidneys, and also has no clinically significant interactions with either metformin or sitagliptin.

Topics: Diabetes Mellitus, Type 2; Humans; Hypoglycemic Agents; Insulin; Metformin; Sitagliptin Phosphate; Triazines

Imeglimin is a new anti-diabetic drug commercialized in Japan (Twymeeg®) and has been drawing much attention in diabetes research area as well as in clinical practice. In this study, we evaluated the effect of imeglimin on pancreatic β-cells. First, single-dose administration of imeglimin enhanced insulin secretion from β-cells and decreased blood glucose levels in type 2 diabetic db/db mice. In addition, single-dose administration of imeglimin significantly augmented insulin secretion in response to glucose from islets isolated from non-diabetic db/m mice. Second, during an oral glucose tolerance test 4-week chronic treatment with imeglimin enhanced insulin secretion and ameliorated glycemic control in diabetic db/db mice. Furthermore, the examination with electron microscope image showed that imeglimin exerted favorable effects on morphology in β-cell mitochondria and substantially increased the number of insulin granules in type 2 diabetic db/db and KK-Ay mice. Finally, imeglimin reduced the percentage of apoptotic β-cell death which was accompanied by reduced expression levels of various genes related to apoptosis and inflammation in β-cells. Taken together, imeglimin directly enhances insulin secretion in response to glucose from β-cells, increases the number of insulin granules, exerts favorable effects on morphology in β-cell mitochondria, and reduces apoptotic β-cell death in type 2 diabetic mice, which finally leads to amelioration of glycemic control.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Glucose; Insulin; Insulin-Secreting Cells; Mice; Mitochondria; Triazines

Pancreatic islet β-cell dysfunction is characterized by defective glucose-stimulated insulin secretion (GSIS) and is a predominant component of the pathophysiology of diabetes. Imeglimin, a novel first-in-class small molecule tetrahydrotriazine drug candidate, improves glycemia and GSIS in preclinical models and clinical trials in patients with Type 2 diabetes; however, the mechanism by which it restores β-cell function is unknown. Here, we show that imeglimin acutely and directly amplifies GSIS in islets isolated from rodents with Type 2 diabetes via a mode of action that is distinct from other known therapeutic approaches. The underlying mechanism involves increases in the cellular nicotinamide adenine dinucleotide (NAD+) pool-potentially via the salvage pathway and induction of nicotinamide phosphoribosyltransferase (NAMPT) along with augmentation of glucose-induced ATP levels. Further, additional results suggest that NAD+ conversion to a second messenger, cyclic ADP ribose (cADPR), via ADP ribosyl cyclase/cADPR hydrolase (CD38) is required for imeglimin's effects in islets, thus representing a potential link between increased NAD+ and enhanced glucose-induced Ca2+ mobilization which-in turn-is known to drive insulin granule exocytosis. Collectively, these findings implicate a novel mode of action for imeglimin that explains its ability to effectively restore-β-cell function and provides for a new approach to treat patients suffering from Type 2 diabetes.

Topics: Adenosine Triphosphate; Animals; Calcium; Cyclic ADP-Ribose; Cytokines; Diabetes Mellitus, Type 2; Glucose; Insulin Secretion; Islets of Langerhans; Male; Models, Biological; NAD; Niacinamide; Nicotinamide Phosphoribosyltransferase; Rats, Wistar; Ryanodine Receptor Calcium Release Channel; Sulfonylurea Compounds; Triazines

Type 2 diabetes (T2D) is driven by progressive dysfunction and loss of pancreatic β-cell mass. Imeglimin is a first-in-class novel drug candidate that improves glycaemia and glucose-stimulated insulin secretion in preclinical models and patients. Given evidence that imeglimin can attenuate β-cell dysfunction and protect β cells. Zucker diabetic fatty (ZDF) male rats were treated by oral gavage with imeglimin at a standard dose of 150 mg/kg or vehicle, twice daily for five weeks. At treatment completion, oral glucose tolerance tests were performed in fasted animals before a thorough histomorphometry and immunohistochemical analysis was conducted on pancreas tissue slices to assess cellular composition and disease status.. Imeglimin treatment significantly improved glucose-stimulated insulin secretion (augmentation of the insulinogenic index) and improved glycaemia. Both basal insulinaemia and pancreatic insulin content were also increased by imeglimin. In ZDF control rats, islet structure was disordered with few β-cells; after imeglimin treatment, islets appeared healthier with more normal morphology in association with a significant increase in insulin-positive β-cells. The increase in β-cell mass was associated with a greater degree of β-cell proliferation in the presence of reduced apoptosis. Unexpectedly, a decrease in as a α-cell mass was also documented due to an apparent antiproliferative effect of imeglimin on this cell type.. In male ZDF rats, chronic imeglimin treatment corrects a paramount component of type 2 diabetes progression: progressive loss of functional β-cell mass. In addition, imeglimin may also moderate a-cell turnover to further ameliorate hyperglycaemia. Cumulatively, these cellular effects suggest that imeglimin may provide for disease modifying effects to preserve functional β-cell mass.

Topics: Animals; Apoptosis; Cell Proliferation; Cells, Cultured; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose Intolerance; Hyperglycemia; Insulin; Insulin Secretion; Insulin-Secreting Cells; Male; Rats, Zucker; Triazines