Clinical pharmacology of imeglimin for the treatment of type 2 diabetes

ABSTRACT

Introduction

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.

Areas covered

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.

Expert opinion

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.

Abbreviations

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

KEYWORDS:

• Imeglimin
• tetrahydrotriazine
• oral antidiabetic (OAD)
• type 2 diabees (T2D)

Article highlights

• Imeglimin is an oral antidiabetic in development which seem to improve mitochondrial function in pancreatic beta cells leading to improved insulin secretion and lowering of plasma glucose level

• The intended future dosing (1,000-1,500 mg twice daily) leads to reduction in HbA1c of 6-11 mmol/mol (0.5-1.0%) as monotherapy and 7 mmol/mol (0.6%) as add-on therapy to metformin or sitagliptin in patients with T2D

• Adverse events are mostly gastrointestinal

Declaration of interest

FK Knop has served on scientific advisory panels and/or been part of speaker’s bureaus for, served as a consultant to and/or received research support from Amgen Inc, AstraZeneca, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly and Company, Gubra, Lupin, MedImmune, Merck Sharp and Dohme, Mundipharma, Norgine, Novo Nordisk, Sanofi and Zealand Pharma. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript has not been funded.