Emerging Advances in Obesity Treatment: Exploring Quintuple and Super Polyagonists for Better Weight Management

Recent developments in obesity pharmacotherapy have generated significant excitement within the medical community. A key focus is on new incretin-based drugs, including glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide, and dual GIP and GLP-1 receptor agonists like tirzepatide. These agents have shown promising results in promoting weight loss and improving metabolic health. Extensive research funding is driven by the goal of creating medications that deliver stronger effects with fewer side effects.

Beyond current mono- and dual-agonist drugs, innovation is advancing toward more complex molecules, notably a novel quintuple agonist. At the European Association for the Study of Diabetes Annual Meeting in Vienna, researchers highlighted this cutting-edge development. The quintuple agent combines GLP-1, GIP, and a third component called lamifibrnor, which activates three different PPAR receptors—alpha, delta, and gamma—that are central to energy regulation. This amalgamation results in a molecule with five distinct targets.

The aim is to amplify the metabolic benefits achieved through existing incretin and PPAR therapies. Dr. Daniela Liskiewicz from Helmholtz Zentrum München detailed preclinical efforts to develop a single, unimolecular compound that merges the weight-reducing and glucose-lowering effects of incretin co-agonists with the insulin-sensitizing and lipid-normalizing actions of PPAR activation.

PPARs—nuclear receptors—are critical regulators of metabolism, located in key tissues like liver, fat, muscle, and heart. PPAR-γ enhances insulin sensitivity and promotes adipose tissue differentiation. PPAR-α, highly expressed in liver, facilitates fatty acid oxidation and lowers triglyceride levels. PPAR-δ, found broadly in tissues, boosts fatty acid utilization and energy expenditure. Lanifibrnor, a pan-PPAR agonist, is being evaluated in Phase III trials for metabolic liver diseases such as MASLD (NAFLD), demonstrating a favorable safety profile.

The innovative design involves targeted delivery of the pan-PPAR agonist to cells expressing GIP and GLP-1 receptors, ensuring precise action while avoiding widespread distribution. After binding to these receptors, the complex enters cells and releases the PPAR agonist, which then travels to the nucleus to modulate gene expression.

In preclinical models, including diet-induced and genetic obesity models, the quintuple agonist has demonstrated potent effects—more than GLP-1 or GIP alone, or even semaglutide—by reducing body weight, decreasing food intake, and improving blood glucose levels. These effects are attributed to synergistic actions on the brain and adipose tissue, offering promising prospects for obesity and type 2 diabetes treatment.

Dr. Liskiewicz emphasized that this combined approach surpasses traditional therapies in efficacy, with safety profiles encouraging further development. Although initial results stem from animal studies, the research team plans to publish additional data and eventually progress to human trials, with a timeline yet to be determined.

This promising avenue in pharmacotherapy could revolutionize how metabolic diseases are managed, offering a multi-targeted strategy with unprecedented effectiveness.

source: https://medicalxpress.com/news/2025-09-future-obesity-quintuple-super-polyagonists.html