In recent years, a new class of incretin drugs that includes glucagon-like-peptide-1 inhibitors (single agonists such as semaglutide) and also dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonists (dual agonists such as tirzepatide) has built much excitement. Millions are being invested in the research of anti-obesity medications. As the quest for medications that have a stronger effect but fewer side effects continues, new research discusses the possibility of a new quintuple agonist. Yes, it does not end with the existing mono- and dual-agonists.
A new research presented at this year’s Annual Meeting of the European Association for the Study of Diabetes in Vienna, Austria, researchers, including Dr Daniela Liskiewicz (Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany, and German Center for Diabetes research (DZD), Munich, Germany) presented their work on a new type of medication: the quintuple agonist. The quintuple and other super poly agonists could be the future of obesity management.
What makes it a quintuple agonist?The compound, which is being investigated, is named a ‘quintuple agonist’ because it targets five pathways at once. Alongside GLP-1R and GIPR agonists, it incorporates lanifibranor, a molecule that activates three types of peroxisome proliferator-activated receptors (PPARs): alpha, delta, and gamma. These receptors are considered master regulators of metabolism.
“Drugs to improve obesity-linked metabolic dysfunction are on the rise, with unimolecular GLP-1R:GIPR co-agonism emerging as the most effective approach for managing obesity and type 2 diabetes,” Dr Liskiewicz said in a release, about the ongoing development of GLP-1R/GIPR/Pan-PPAR quintuple agonists.
The researchers are looking forward to improving the metabolic benefits of GLP-1R:GIPR co-agonism. Dr Liskiewicz (from Timo Müller’s group) is reporting the design and preclinical evaluation of the novel unimolecular quintuple agonist. This new treatment combines weight loss and blood glucose-reducing effects of GLP-1R:GIPR co agonism with the insulin-sensitising and cholesterol-lowering properties of PPAR agonism.
“PPARs are master regulators of metabolism expressed in key metabolic tissues. PPAR-γ drives adipose tissue differentiation and lipid storage, and by doing so, it improves systemic insulin sensitivity. PPAR-α (alpha) is highly expressed in the liver, heart, and muscle, where it promotes fatty acid oxidation and reduces circulating triglycerides. PPAR-δ (delta) is broadly expressed across tissues. It enhances fatty acid utilisation and energy expenditure, thereby contributing to improved fat and glucose metabolism. In our design, we have chosen lanifibranor, a pan-PPAR agonist that activates all three PPAR isoforms. Lanifibranor is currently in Phase III clinical trials for metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD) and has demonstrated a favourable safety profile. The targeted delivery of the pan-PPAR agonist is restricted to cells expressing receptors for either GIP or GLP-1, ensuring precise action. The science is quite complex - PPARs are nuclear receptors. GLP-1R and GIPR are cell membrane receptors. Thanks to the fact that the treatment is a single molecule not a combination therapy the nuclear hormone ligand (lanifibranor) is not distributed all over the body but just to cells that express the cell surface receptors for GLP-1 and GIP. After binding to the GLP-1R / GIP receptors, the complex enters the cell and the PPAR agonist is released inside, where it can travel to the nucleus where it exerts its action,” she explains.
The researchers are currently testing on mouse models to understand how the new compound works. The quintuple agonist has shown potent effects on in both diet-induced obesity and genetically driven obesity and diabetes models.
Video
In animal studies, the GLP-1:GIP:PanPPAR quintuple agonist worked better than GLP-1:GIP or semaglutide alone. It reduced body weight and food intake, and also improved hyperglycaemia in mice with obesity and insulin resistance. “These enhanced effects stem from the synergistic actions of incretin and PPAR pathways in the brain and adipose tissue,” Dr Liskiewicz said.
“The GLP-1:GIP:PanPPAR agonist is significantly more effective than either GLP-1:GIP or pan-PPAR agonist alone, or when administered as a loose combination, in reducing body weight and improving glucose control. Building on these findings, this novel quintuple polyagonist holds unprecedented therapeutic value to treat obesity and type 2 diabetes. Lanifibranor appears to be relatively safe based on results from Phase II clinical trials,” she added.
A new research presented at this year’s Annual Meeting of the European Association for the Study of Diabetes in Vienna, Austria, researchers, including Dr Daniela Liskiewicz (Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany, and German Center for Diabetes research (DZD), Munich, Germany) presented their work on a new type of medication: the quintuple agonist. The quintuple and other super poly agonists could be the future of obesity management.
What makes it a quintuple agonist?The compound, which is being investigated, is named a ‘quintuple agonist’ because it targets five pathways at once. Alongside GLP-1R and GIPR agonists, it incorporates lanifibranor, a molecule that activates three types of peroxisome proliferator-activated receptors (PPARs): alpha, delta, and gamma. These receptors are considered master regulators of metabolism.
“Drugs to improve obesity-linked metabolic dysfunction are on the rise, with unimolecular GLP-1R:GIPR co-agonism emerging as the most effective approach for managing obesity and type 2 diabetes,” Dr Liskiewicz said in a release, about the ongoing development of GLP-1R/GIPR/Pan-PPAR quintuple agonists.
The researchers are looking forward to improving the metabolic benefits of GLP-1R:GIPR co-agonism. Dr Liskiewicz (from Timo Müller’s group) is reporting the design and preclinical evaluation of the novel unimolecular quintuple agonist. This new treatment combines weight loss and blood glucose-reducing effects of GLP-1R:GIPR co agonism with the insulin-sensitising and cholesterol-lowering properties of PPAR agonism.
“PPARs are master regulators of metabolism expressed in key metabolic tissues. PPAR-γ drives adipose tissue differentiation and lipid storage, and by doing so, it improves systemic insulin sensitivity. PPAR-α (alpha) is highly expressed in the liver, heart, and muscle, where it promotes fatty acid oxidation and reduces circulating triglycerides. PPAR-δ (delta) is broadly expressed across tissues. It enhances fatty acid utilisation and energy expenditure, thereby contributing to improved fat and glucose metabolism. In our design, we have chosen lanifibranor, a pan-PPAR agonist that activates all three PPAR isoforms. Lanifibranor is currently in Phase III clinical trials for metabolic dysfunction–associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease (NAFLD) and has demonstrated a favourable safety profile. The targeted delivery of the pan-PPAR agonist is restricted to cells expressing receptors for either GIP or GLP-1, ensuring precise action. The science is quite complex - PPARs are nuclear receptors. GLP-1R and GIPR are cell membrane receptors. Thanks to the fact that the treatment is a single molecule not a combination therapy the nuclear hormone ligand (lanifibranor) is not distributed all over the body but just to cells that express the cell surface receptors for GLP-1 and GIP. After binding to the GLP-1R / GIP receptors, the complex enters the cell and the PPAR agonist is released inside, where it can travel to the nucleus where it exerts its action,” she explains.
The researchers are currently testing on mouse models to understand how the new compound works. The quintuple agonist has shown potent effects on in both diet-induced obesity and genetically driven obesity and diabetes models.
Video
In animal studies, the GLP-1:GIP:PanPPAR quintuple agonist worked better than GLP-1:GIP or semaglutide alone. It reduced body weight and food intake, and also improved hyperglycaemia in mice with obesity and insulin resistance. “These enhanced effects stem from the synergistic actions of incretin and PPAR pathways in the brain and adipose tissue,” Dr Liskiewicz said.
“The GLP-1:GIP:PanPPAR agonist is significantly more effective than either GLP-1:GIP or pan-PPAR agonist alone, or when administered as a loose combination, in reducing body weight and improving glucose control. Building on these findings, this novel quintuple polyagonist holds unprecedented therapeutic value to treat obesity and type 2 diabetes. Lanifibranor appears to be relatively safe based on results from Phase II clinical trials,” she added.
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