ADA Outstanding Scientific Achievements Award Lecture Speaking from the gut – From Gastrointestinal Hormones to Combinatorial Therapy. Matthias Tschop; ADA 2011.

Obesity represents one of societies' most urgent health threats. Thus the discovery that the stomach secreted Ghrelin opposes the effects of Leptin and induces adiposity offered a significant opportunity to intervene in the progress of the obesity epidemic.

However, Ghrelin is actually a food substrate/hormone polymer as shown in rat models that is in reality more involved in the control of lipid metabolism. Thus the search went on for therapy that works in treating obesity.

Research in the field turned to establishing the hormone profile that occurs in bariatric surgery, which has been shown to reduce obesity. Studies in patients with gastric bands (which induce less weight loss than bypass surgery) have demonstrated that the combination of gastric band plus GLP-1 therapy seemed to induce a similar weight loss as bypass surgery.

This observation led to the hypothesis that combining satiety control agents might offer synergistic effects. In rats, a combination of GLP-1 plus diet does not induce the same weight loss as combining GLP-1 with leptin, thus combined drug therapy seems to offer greater weight benefit. There was therefore good theoretical reason to think that combined stimulation of the glucagon and GLP-1 pathways might offer interesting therapeutic opportunities.

This led to the search for novel molecules which combine homology for the receptors for both native hormones. Bio-engineered glucagon-GLP-1 co-agonist resulted. In mice engineered to have no GLP-1 receptors it was shown that there was still weight loss thus establishing that the co-agonist works. The co-agonist was then tested in obese rats and resulted in significant weight loss. The theoretical benefit of co-agonist therapy is that leveraging the synergistic effect of dual stimulation is likely to overcome the side effects that occur if a single agent is used at sufficient dose to achieve the same efficacy as a synergistic co-agonist.

Early studies in humans suggest that glucagon-GLP-1 co-agonist does not result in altered gastric emptying, thus suggesting that the theory may work. However outcome data are needed.

The next step in the pharma R&D cycle was the development of GLP-1 pro-drugs which may induce a slower onset of GLP-1 receptor stimulation and possibly reduce side effects. These agents are now in early trials in animals.

Attention then turns to tri-agonists. The GIP-GLP-1 co-agonists, combined with glucagon agonists yielded significantly greater weight loss and this experimental observation has led to a recent tri-agonist peptide development. There is clearly much research still to be done, but the latest tri-agonist seems in early studies to induce weight loss at almost homeopathic doses thus there is much hope for a new class of obesity management agents.

Looking to the future there is growing interest in non-labile steroid-peptide hybrids, which combine GLP-1-estrogen in a non-labile stable hybrid. The importance of this approach is that there are neurons in the hypothalamus which control appetite and have both GLP-1 and estrogen receptors. Targeting agents that only release the estrogen when GLP-1 binding has occurred avoid the toxic side effects of estrogen. In early rat studies it appears that this approach achieves substantial weight loss without side effects in the trial animals.