Tilpotide, the strongest weight-loss drug, has a unique activity to stimulate insulin secretion
Tirzepatide is a diabetes treatment developed by Eli Lilly and Company. It is a dual agonist of glucose-dependent insulin-stimulating polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor. Activating the GLP-1 receptor reduces hunger and thus diet and caloric intake, while activating the GIP receptor reduces diet and caloric intake and increases energy expenditure. Tilpotide is being fast-tracked for approval as a new weight loss treatment and is expected to be available by the end of the year.
A previous Phase 3 clinical trial showed that participants in the 15mg dose group lost an average of up to 22.5% (24 kg) of body weight after a 72-week treatment with tilpotide. It is the first investigational drug to achieve an average weight loss of more than 20% in a Phase 3 clinical trial, and it is the best drug to date for weight loss.
On June 5, 2023, researchers from Duke University, the German Diabetes Research Center, and Eli Lilly collaborated to publish a paper in the journal Nature Metabolism entitled: The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets.
The study is the first to use human donor cells to demonstrate that tilpotide is indeed a dual GIP receptor and GLP-1 receptor agonist, and not just a so-called super GLP-1 receptor agonist. The study also demonstrated that Tipotide’s activation of the GIP receptor is integral to its stimulation of insulin secretion.
Corresponding author Jonathan Campbell, a professor at Duke University School of Medicine, said that understanding the multiple targeted mechanisms of action of tilpotide opens up a whole new world for the development of better drugs for weight loss and diabetes.
Targeting the glucagon-like peptide-1 (GLP-1) receptor to treat diabetes has a long history, and for people with type 2 diabetes, GLP-1-based drugs can restore insulin production and thus lower blood sugar. In addition, the drug can increase the feeling of fullness and reduce appetite, which can help with weight loss. This makes GLP-1-based drugs very attractive in the treatment of diabetes and obesity. One intuitive feeling is that Semaglutide, a GLP-1 receptor agonist developed by Novo Nordisk, will have sales of more than $10 billion in 2022.
Tirzepatide is a dual agonist of glucose-dependent insulin-stimulating polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor. It can increase satiety, reduce appetite, and increase energy consumption, resulting in better weight loss.
However, the GIP receptor has long been unpromising as a therapeutic target for metabolic diseases, and it has even been suggested to block the receptor rather than activate it. Some in the industry have speculated that telpotide’s activation of the GIP receptor may not be important, or that it may be acting as a “super” GLP-1 receptor agonist to exert a better therapeutic effect.
So is this really the case?
In this latest paper, the research team found that in mice, tilpotide does stimulate insulin secretion primarily by activating the GLP-1 receptor, but this is actually due to the low level of GIP receptor expression in mice.
In human islet cells, GIP receptors are essential for insulin secretion when stimulated with tilpotide. They also found that tilpotide stimulated the islets to secrete another hormone, glucagon. GIP stimulates glucagon secretion, while GLP-1 inhibits glucagon secretion. The discovery that tilpotide stimulates glucagon secretion provides further evidence that the drug has important activity on GIP receptors.
This study shows that tilpotide is a true dual receptor agonist and not just a super GLP-1 receptor agonist, which also validates the great potential of using single molecules with multiple receptor activity as drugs for the treatment of metabolic diseases.