sitagliptin-phosphate and imeglimin

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

Imeglimin (IMEG) is the first in a novel class of oral glucose-lowering agents with a unique mechanism of action targeting mitochondrial bioenergetics. We assessed whether repeated co-administration of IMEG and either metformin (MET) or sitagliptin (SITA) would influence the pharmacokinetics of either MET or SITA in healthy Caucasian men.. Healthy Caucasian men received either MET 850 mg twice daily with placebo (n = 16) or SITA 100 mg once daily with placebo (n = 16) on days 1-6, followed by MET 850 mg twice daily with IMEG 1500 mg twice daily or SITA 100 mg once daily with IMEG 1500 mg twice daily on days 7-12. Pharmacokinetic parameters were determined from blood and urine; levels of all compounds were evaluated using liquid chromatography with tandem mass spectrometry.. Systemic exposure (AUC. Co-administration of IMEG with MET or SITA did not result in clinically relevant changes in systemic exposure to MET or SITA, although minor reductions in exposure (AUC. EudraCT2009-014520-40 (MET-IMEG DDI) and EudraCT2010-022926-34 (SITA-IMEG DDI).

Topics: Area Under Curve; Healthy Volunteers; Humans; Hypoglycemic Agents; Male; Metformin; Sitagliptin Phosphate; 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

Imeglimin is a new antidiabetic drug structurally related to metformin. Despite this structural similarity, only imeglimin augments glucose-stimulated insulin secretion (GSIS), with the mechanism underlying this effect remaining unclear. Given that glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) also enhance GSIS, we examined whether these incretin hormones might contribute to the pharmacological actions of imeglimin.. Blood glucose and plasma insulin, GIP, and GLP-1 concentrations were measured during an oral glucose tolerance test (OGTT) performed in C57BL/6JJcl (C57BL/6) or KK-Ay/TaJcl (KK-Ay) mice after administration of a single dose of imeglimin with or without the dipeptidyl peptidase-4 inhibitor sitagliptin or the GLP-1 receptor antagonist exendin-9. The effects of imeglimin, with or without GIP or GLP-1, on GSIS were examined in C57BL/6 mouse islets.. Imeglimin lowered blood glucose and increased plasma insulin levels during an OGTT in both C57BL/6 and KK-Ay mice, whereas it also increased the plasma levels of GIP and GLP-1 in KK-Ay mice and the GLP-1 levels in C57BL/6 mice. The combination of imeglimin and sitagliptin increased plasma insulin and GLP-1 levels during the OGTT in KK-Ay mice to a markedly greater extent than did either drug alone. Imeglimin enhanced GSIS in an additive manner with GLP-1, but not with GIP, in mouse islets. Exendin-9 had only a minor inhibitory effect on the glucose-lowering action of imeglimin during the OGTT in KK-Ay mice.. Our data suggest that the imeglimin-induced increase in plasma GLP-1 levels likely contributes at least in part to its stimulatory effect on insulin secretion.

Topics: Animals; Blood Glucose; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Glucose; Hypoglycemic Agents; Incretins; Insulin; Mice; Mice, Inbred C57BL; Sitagliptin Phosphate

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