Optimization of metabolic control by combining GLP-1 with second-generation insulin sensitizers

On June 5, 2024, at the annual meeting of the European Association for the Study of Hepatology (EASL) held in Milan, Italy, private clinical stage biopharmaceutical company Cirius Therapeutics presented new data showcasing the unique potential of its second-generation insulin sensitizer Azegliflok (MSDC-0602K) in combination with GLP-1 receptor agonists (GLP-1s).

The combination of GLP-1 drug and MSDC-0602K is beneficial for weight loss and muscle maintenance, expanding the indications of GLP-1 drug

GLP-1 is a highly effective weight loss drug that does not directly affect potential insulin resistance, typically has limited duration of use, and can lead to loss of fat and lean meat quality, which may limit its use in certain patient populations. Azeglitazone (MSDC-0602K) acts through newly discovered mitochondrial targets, adding cardiac metabolic benefits to GLP-1 receptor agonists, including muscle maintenance, which can expand the use of the new GLP-1 weight loss drug. In summary, this latest study suggests that this new combination can optimize metabolic control and achieve healthier weight loss and maintenance.

Cirius Therapeutics and Dr. Kyle McCommis from the University of St. Louis have released a latest report on how second-generation insulin sensitizers Azegliflozinone address the body composition issues caused by GLP-1. The report shows the posterior analysis of 23 patients with MASH, type 2 diabetes and having taken a stable dose of GLP-1 confirmed by biopsy in the 52 week Phase 2B EMMINENCE trial, as well as the data of preclinical study on diabetes db/db mice using GLP-1 liraglutide.

These data indicate that adding any dose of azeglitazone to patients receiving GLP-1 treatment can improve all circulatory parameters, especially HbA1c and liver histology. In the accompanying preclinical study of diabetes db/db mice, the combination of azeglitazone and GLP-1 liraglutide, and the new body composition measurement showed that in the case of combined use of azeglitazone, lean weight (or muscle) was significantly maintained.

Other synergistic effects of GLP-1 drug with MSDC-0602K

This combination also resulted in a synergistic improvement in glucose tolerance, which was accompanied by a decrease in circulating insulin elevation and an increase in pancreatic insulin content. Azeglitazone alone or in combination with liraglutide can increase the amount of brown adipose tissue (BAT). BAT is renowned for its ability to burn calories and store energy.

The safety of MSDC-0602K has been significantly improved, demonstrating its potential in cell type metabolism

Dr. Jerry Colca, Chief Scientific Officer of Cirius Therapeutics, stated, "This second-generation insulin sensitizer aims to utilize the newly discovered mitochondrial target of thiazolidinedione (TZD) drugs, namely the mitochondrial pyruvate carrier (MPC). Azeglitazone avoids direct activation of PPAR - γ, and its safety is significantly improved compared to the first generation insulin sensitizer. We realize that this newly discovered TZD mechanism of action can provide a differentiated solution to the limitations of GLP-1 receptor agonists. Based on these new preclinical results, Azeglitazone can help patients reduce fat without muscle loss." Adding all the additional advantages of other parameters may make azeglitazone the best partner for GLP-1 drugs

Dr. Kyle McCommis, Assistant Professor of Biochemistry and Molecular Biology at the University of St. Louis, said, "Our laboratory has always been interested in the significance of this newly discovered MPC target, which is at a crossroads in regulating metabolism of multiple cell types. We have only recently recognized its positive effects on skeletal muscle and body composition, and we look forward to conducting more detailed research on the potential mechanism of action of this new discovery."