A new drug concept for treating obesity and type 2 diabetes has advanced in preclinical trials by merging two metabolic mechanisms into one molecule. The design aims to improve effectiveness while reducing side effects.
How the hybrid drug works
The method, created by a group headed by Prof. Timo D. Müller at Helmholtz Munich, leverages the body’s natural GLP-1/GIP signaling pathway. These pathways control appetite and blood sugar. The new compound attaches lanifibranor, a pan-PPAR agonist, to the incretin component, enabling more precise cell entry.
Inside cells, the second drug activates PPAR receptors, which manage genes tied to fat and sugar processing. The effect resembles a “Trojan horse”: the incretin acts as the entry point, while the attached drug works only in specific cells. This targeted action allows lower doses of the second drug, cutting the risk of widespread side effects.
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Müller, who leads the Institute for Diabetes and Obesity, explained the problem his team addressed. “Our guiding question was: how can we enhance incretin activity without creating a second, systemically active source of side effects?” The solution relied on an existing pathway rather than flooding the body with additional compounds.
Results in mice and next steps
In tests, mice with diet-induced obesity consumed less food and lost more weight than those given a standard GLP-1/GIP co-agonist. Some achieved greater weight loss than mice treated with a GLP-1-only drug. Blood-glucose levels improved, and there were indications of better insulin action in the body. Insulin was better able to channel glucose from the blood into tissues, and the liver released less glucose into the bloodstream.
Side effects did not increase compared to current therapies. In the parameters examined, the researchers found no indications of two feared issues associated with the coupled component: fluid retention and anaemia.
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For now, findings are limited to animal models. The researchers report that mouse and human GIP receptors differ, meaning lab success may not guarantee clinical results.
The research, published in Nature, included contributions from Helmholtz Munich, Ludwig Maximilian University of Munich, and the German Center for Diabetes Research. The drug’s five-target mechanism—activating two cell-surface receptors (GLP-1R and GIPR) and three nuclear PPAR “switches”—acts specifically in GLP-1R/GIPR-expressing cells rather than throughout the body. Müller described the principle as a “Trojan horse”: the incretin part opens the door; the “cargo” acts only once inside the target cell. A key advantage is the dose: because the second component is not administered separately but “travels along” with the incretin part, it can be used at a much lower dose.
