GLP-1 Pioneers Propose Radical Shift: Drop GLP-1 Entirely for Weight Loss

Key Takeaways:

• Scientists who helped create current GLP-1 drugs propose dropping GLP-1 as a target entirely
• New experimental drug targets only GIP and glucagon receptors, potentially matching GLP-1 weight loss
• Approach could eliminate common GLP-1 side effects like nausea and vomiting
• Research is still in animal testing phase and needs human trials before becoming available

The scientists whose groundbreaking work led to today's blockbuster obesity medications like Zepbound and Wegovy are now proposing a radical shift: perhaps targeting the GLP-1 hormone isn't actually necessary for effective weight loss.

A group of researchers led by Richard DiMarchi and Matthias Tschöp has created an experimental drug that activates receptors of the GIP and glucagon hormones. They propose — based on rodent and monkey studies — that this kind of molecule, when administered at high enough doses, may result in weight loss comparable to the weight loss seen with drugs that include GLP-1 as a target, and without the tolerability issues like nausea and vomiting that often come with the approved treatments, according to research published this week in the journal Molecular Metabolism.

The Science Behind the Shift

DiMarchi, an Indiana University chemistry professor, and Tschöp, CEO at Helmholtz Munich, are no strangers to obesity drug development. Their discovery of gut hormone dual and triple co-agonist drug classes has led to a series of new therapeutics in clinical development. The first co-agonist at the receptors for GLP-1 and GIP has recently been approved by the FDA for the treatment of type 2 diabetes — that's tirzepatide, marketed as Mounjaro and Zepbound.

Now they're suggesting an even more radical approach. The research, funded by a biotech called BlueWater Biosciences, would still need to be confirmed in humans; oftentimes results seen in animals don't translate in the clinic. But the proposed approach, outlined in the journal Molecular Metabolism by some of the most well-known scientists in the field, is likely to stir controversy.

The experimental molecule targets only two hormone receptors instead of three. GLP-1 and GIP predominantly contribute to improved insulin release and a reduction of blood glucose levels. The third hormone, glucagon, primarily increases the long-term rate at which calories are burned and improves liver function. By removing GLP-1 from the equation, researchers believe they can maintain weight loss benefits while potentially reducing side effects.

Why This Matters for Side Effects

Anyone who's tried a GLP-1 medication knows the drill: nausea, vomiting, and digestive issues are incredibly common, especially when starting treatment or increasing doses. These side effects stem largely from GLP-1's action on slowing stomach emptying and affecting gut function.

The new approach may result in weight loss comparable to drugs that include GLP-1 as a target, and without the tolerability issues like nausea and vomiting that often come with the approved treatments. If confirmed in human trials, this could transform options for people who want the benefits of weight loss medications but can't tolerate current options.

The GIP and glucagon combination works differently than GLP-1-based drugs. While GLP-1 primarily works by slowing digestion and reducing appetite, GIP is involved in enhancing insulin action and reducing blood glucose in the body, while glucagon is involved in improving liver function and increasing the long-term rate at which calories are burned.

Challenging the Foundation of Modern Obesity Medicine

This research challenges a fundamental assumption in obesity medicine. For over a decade, the field has been built around the idea that targeting GLP-1 receptors is essential for effective weight loss medications. Current approved drugs like semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) all include GLP-1 as a core component.

But DiMarchi and Tschöp's work suggests this may not be necessary. The collaborative research demonstrated that glucagon had been narrowly mischaracterized as a counter-regulatory hormone, serving only to oppose insulin's glucose-lowering action. According to the researchers, it is much more than previously appreciated. It is a regulatory hormone as much as insulin, with unique biological actions that provide chronic health benefits to the liver, kidney and potentially other organs.

This understanding opens up new possibilities for targeting metabolic pathways that could deliver weight loss benefits through different mechanisms than current medications.

The Long Road to Human Testing

While these findings are intriguing, there's still a long road ahead. The research would still need to be confirmed in humans; oftentimes results seen in animals don't translate in the clinic.

The track record for translating animal obesity research to humans is mixed. Many promising approaches in mice have failed to show meaningful benefits in people. However, DiMarchi and Tschöp have a strong history of successful translation — their previous work led directly to tirzepatide, which delivers up to 22% weight loss in clinical trials.

Even if human trials begin soon, it would likely take 5-10 years before any new medication based on this approach could reach the market. The drug would need to progress through Phase I safety studies, Phase II efficacy trials, and Phase III large-scale studies before FDA approval.

Currently, people seeking GLP-1 treatment have limited options when it comes to avoiding side effects. Some find success by starting with very low doses and increasing slowly, while others switch between different medications to find what works best. If you're struggling with side effects from your current treatment, you can compare costs for different options or find a clinic near you to discuss alternatives with healthcare providers who understand these medications.

What This Means for You

If you're currently on a GLP-1 medication and tolerating it well, there's no reason to change anything based on this early research. These findings won't affect your current treatment options for years to come, as any new drug would need to complete extensive clinical trials before reaching the market.

However, this research offers hope for people who've been unable to tolerate current GLP-1 medications due to side effects. The possibility of achieving similar weight loss benefits without the nausea and digestive issues could open treatment to millions more people.

For now, your best option is to work with healthcare providers to find the right approach within current treatment options. If you're experiencing challenging side effects, compare telehealth providers who can offer personalized guidance on managing symptoms or finding the right medication and dose for your situation.

The research also highlights how quickly this field is evolving. What seemed like settled science around GLP-1's central role in weight loss may be shifting, potentially leading to better options in the future.