Interview Reversing Obesity with Multi-Receptor Drugs

The "weight loss injection." This term refers to active therapeutic drugs that enable considerable weight reduction – with current weight loss champion Tirzepatide even inducing an average weight loss of 22.5 percent! These types of drugs have recently received a lot of media attention, also because celebrities are using them to get their bodies into shape quickly.

With these new types of multi-receptor drugs, we have discovered over the last 15 years, highly effective and safe therapeutics for human obesity will become available for the first time in the history of medicine. These dual and triple agonists also offer direct superior benefits for type 2 diabetes, but their main impact there may be that through control of obesity, it may be possible to prevent most of type 2 diabetes in the future. Both obesity and type 2 diabetes are global pandemics and so far, there had been no medicine with the potential to stop or reverse them.

“New multi-receptor drugs like Tirzepatide are transformative medicines, allowing for the first time pharmacological control of body weight. They are also an opportunity to jumpstart a healthier lifestyle with healthy diet, exercise, reduced stress, and sufficient sleep.”
_{Prof. Matthias Tschöp}

Tirzepatide is a gut hormone like molecule that has been engineered to activate two different receptors: GIP (Glucose-dependent insulinotropic peptide)-receptors and GLP-1 (Glucagon-like Peptide-1)-receptors. While the ratio of GIP to GLP-1 is 5:1, both hormones have enormous synergistic potential and act together in the brain to promote weight loss. Specifically, appetite is reduced, while feelings of satiety prevail. Such dual agonist also changes brain settings that orchestrate metabolism in the body and improve insulin sensitivity. These actions work synergistically to maximize potential to overcome obesity and diabetes.

How did you come up with the idea of combining gut hormones and modifying them to work in the brain for the treatment of obesity?
 

We realized early that pharmacological targeting of just one pathway would not be sufficient to overcome the powerful drive to eat and store calories. There are simply too many signals at work in our bodies to ensure full calorie storage. At the same time, we observed that key hormones regulating body weight, like the satiety hormone leptin and the hunger hormone ghrelin, were acting in the brain to achieve their effects. It became clear that a combination of signals with target receptors in the brain was going to be necessary to overcome obesity.

Another important finding was that changing the metabolic balance in the brain and achieving a healthy body weight requires more than one factor, more than one signal. Our vision was to target multiple receptors with a single compound to avoid technical difficulties with combining several compounds into “cocktail syringes” with several chambers etc. After years of studies and many unsuccessful attempts, we ended up finding three gut hormones that fulfilled the necessary demands: Glucagon, GLP-1, and GIP are all secreted in relation to consumed food, and they activate specific neurons in the human brain that are responsible for hunger or satiety. In addition, the specific chemistry of the three hormones offered opportunities to engineer one of them into a dual and triple receptor activator.

“These new multi-receptor drugs are game changers in the fight against obesity and diabetes – effects of a weekly injection is starting to resemble the effects of gastric bypass surgery.”
_{Prof. Matthias Tschöp}

Tirzepatide is a very useful drug with very few side effects that helps to reduce body weight to a healthy level – and weight loss is maintained as long as the drug is being taken. As a matter of fact, the higher the body weight is, the better it works. It so far has only been approved in the USA and for diabetes. Still, approval for obesity is being expected to follow, as dual agonists offer unprecedented improvements for people suffering from obesity: Many key factors of their metabolism including blood sugar, insulin secretion, and blood pressure are all brought down to healthy levels. While all these effects are primarily a consequence of the therapy, patients always need to adjust their lifestyle, eat healthier, and stay active in parallel. Some cases of abuse by those who just want to get rid of the few final pounds to achieve a particularly lean body driven by vanity will be difficult to prevent. Still, these multi-receptor therapeutics will always have to be prescribed by a physician.

“Our researchers at Helmholtz Munich are driven to deliver breakthrough solutions for human health and a healthier society.”
_{Prof. Matthias Tschöp}

The success of multi receptor drugs is convincing – we are eagerly awaiting more clinical data from the first triple hormone drugs, another class of therapeutics we had discovered in 2015. In addition to GLP-1 and GIP, which are combined in Tirzepatide, this triple agonist also contains the gut hormone Glucagon. Based on our extensive pre-clinical studies, these triple agonists should outperform even dual agonists and may achieve body weight loss of up to 30 percent in obesity.

For one we are working hard on dissecting the molecular mechanisms behind all of these new drugs – there is a lot more we need to understand. For example the question: Which exact neurons are being activated or deactivated? But there are also other questions we need to solve – like if there might be a set of moderately active drugs that could help with maintaining a healthy weight and metabolism once weight loss has occurred. That could allow stopping treatment with the powerful multi-receptor drugs at some point, rather than forcing a life long treatment. In parallel, we are working on next generations of metabolic medicines which we are aiming to tailor toward the needs of specific subpopulations of patients. These next generation medicines should get us close to a personalized metabolic medicine of the future.

After three decades of hard work and numerous setbacks, these awards are a wonderfully inspiring recognition – for me personally, for the wonderful collaboration I had been fortunate to experience with the chemist Prof. Richard Dimarchi, for both our teams of researchers that supported and shared our vision. But most important is the medical progress it means for patients worldwide: The discovery of these multi-receptor drugs may mean we can for the first time overcome obesity and prevent the majority of new diabetes cases.

Latest update: January 2023.