(Press-News.org) Much excitement has built in recent years on the new class of incretin drugs that include glucagon-like-peptide-1 inhibitor (single agonists such as semaglutide) and also dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonists (dual agonists such tirzepatide). Billions of dollars is now being poured into research to develop new anti-obesity medications that exhibit stronger effects while minimising side-effect profiles.
But the excitement is not just limited to existing mono- and dual-agonists. In a session 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) discuss the development of a new quintuple agonist.
The compound being investigated is termed a quintuple agonist because, together with GLP-1R and GIPR agonists, there is a molecule called lamifibrnor which activates 3 different peroxisome proliferator-activated receptors PPARs – all involved in energy regulation – the alpha, delta and gamma variants (isoforms). Thus, there are 5 agonists in total.
In the presentation, Dr Liskiewicz explains the ongoing development of GLP-1R/GIPR/Pan-PPAR quintuple agonists. “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,” she says.
Their mission is to further enhance the metabolic benefits of GLP-1R:GIPR co-agonism, and Dr Liskiewicz (from Timo Müller’s group) is reporting the design and preclinical evaluation of the novel unimolecular quintuple agonist. This innovative therapeutic combines the body weight-lowering and blood glucose-reducing effects of GLP-1R:GIPR co agonism with the insulin-sensitising and anti-dislipidemic (blood fat normalising) properties of PPAR agonism.
She explains: “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.
This early work is being carried out in mouse models, to test the signalling properties of the new compound. The quintuple agonist shows potent effects in both a diet-induced obesity model as well as a genetically-induced model of obesity and diabetes.
In vivo, the GLP-1:GIP:PanPPAR quintuple agonist exhibits superior efficacy compared to GLP-1:GIP or semaglutide in reducing body weight, decreasing food intake, and improving 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,” explains Dr Liskiewicz.
She concludes: “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.”
The team will publish further data on the molecule soon. A date on trials beginning in humans is yet to be decided.
Dr Daniela Liskiewicz, Institute for Diabetes and Obesity, Helmholtz Zentrum München, Neuherberg, Germany, and German Center for Diabetes research (DZD), Munich, Germany. E) daniela.liskiewicz@helmholtz-munich.de
Alternative contact: Tony Kirby in The EASD Media Centre. T) +44 7834 385827 E) tony.kirby@tonykirby.com
The author declares no conflicts of interest.
For full abstract click here
For slide presentation click here
Note - This work was funded by the European Union within the scope of the European Research Council ERC-CoG Trusted #101044445, awarded to T.D.M.
Dr Liskiewicz presents her work in EASD session S46: How might anti-obesity medication look like in the future?
END
The future of obesity management – quintuple and other super polyagonists for weight loss and maintenance?
2025-09-19
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