What’s Coming Next for GLP-1 and Metabolic Disease Treatment

What’s Coming Next for GLP-1 and Metabolic Disease Treatment

Moving from academia to industry led to advancing groundbreaking diabetes and obesity therapies.

Kieren Mather, MD, is vice president of medical incretin and diabetes breakthroughs in the early clinical research division at Eli Lilly, where he leads efforts to develop next-generation treatments for diabetes and metabolic disorders. He was previously a physician-scientist at Indiana University, where he practiced as an endocrinologist while conducting research focused on preventing heart disease and other diabetes complications. We caught up with Mather, who participated in the game changer session “The Risks and Rewards of GLP-1 Agonists Beyond Diabetes” at the 2025 American Physiology Summit in April. 

What are the biggest challenges in diabetes and obesity research today? How do they shape your approach?
Despite decades of research and medical advancements, significant challenges remain. While we have developed new treatments for type 2 diabetes and obesity, such as glucagon-like peptide-1 (GLP-1) receptor agonists, their efficacy and accessibility are still limited. At the same time, type 1 diabetes is experiencing an unexplained epidemic, with its prevalence steadily rising since the 2010s. 

Even with advances in knowledge and therapy, these diseases continue to present a massive unmet need. Hundreds of millions of people worldwide still need help. Moving forward means taking one step at a time—developing the next medicine, identifying what’s still missing and continuing the cycle of improvement. Every advance we make matters.

What appealed to you about transitioning to industry? 
I am an endocrinologist by training and spent 20 years researching diabetes and obesity at Indiana University while also seeing patients. I was working to answer physiology questions like how does diabetes affect the heart and how does diabetes affect muscle glucose uptake? 

When the opportunity arose in 2020 to join Lilly and work in the early-phase group that brings new molecules forward to be tested as potential treatments for obesity and diabetes, I decided to take it. Being a part of the stage of drug development where a molecule gets tested in people for the first time struck me as something I wanted to be a part of. It’s pretty exciting.

At Lilly, the goal is to bring transformative medicines to the field and the opportunity to work on potential game-changers is a unique one. These are medicines with the potential to significantly impact care delivery and effectiveness. The chance to work on such high-impact initiatives has been a key part of the opportunities I’ve had at Lilly, where real advances in therapy are within reach.

People often see corporate medical research as different from academic research and while the goal is slightly different—producing a medicine versus focusing on advancing knowledge—the science is driven by the same factors: opportunity, curiosity and leveraging what’s available. There are more similarities than differences between the work done in companies and academia, and both are equally valid in my mind.

How did your experience and skills translate to this new role? 
My time at Indiana University gave me insight into what patients truly need and how doctors make decisions—how choices about medications and treatment adjustments are made in real time. I was also fortunate to work on both large clinical trials and small studies involving precise physiological measurements. Many of the metabolic measurement methods I used there are just as valuable for the work I do now. Also, being involved in large-scale trials run by the National Institutes of Health and other major organizations taught me how these studies operate and how to contribute within large teams. 

What are you focusing on at Eli Lilly and what’s unique about these medications?
I work on taking emerging drugs into the first stages of clinical trial testing. For example, our group conducted the first testing on tirzepatide, which is a GIP/GLP-1 receptor agonist that is now on the market and has been a big success. 

Our team is also working on the next wave of medicines, including a non-incretin injection weight loss drug called eloralintide that is related to an old medicine called pramlintide. As we’ve made progress in understanding how weight loss drugs work, we’ve recognized that there is a complementary mechanism to those based on GLP-1 agonists. This mechanism, evident in pramlintide, involves amylin-based pathways. By combining these mechanisms in eloralintide, we aim to achieve an additive effect, enhancing the efficacy of weight loss treatments. This drug is currently in Phase 2 clinical trials. 

We’re also working on a new drug called orforglipron, which is a nonpeptide GLP-1 agonist that is taken orally instead of by injection, which is not only more convenient for patients but also easier to produce. There are very few options today for orally delivered GLP-1 drugs. Orforglipron is in Phase 3 clinical trials now. 

What’s next in the pipeline? 
We’re still chasing better ways to get to weight loss and glucose control. For example, an insulin that modifies its action based on current glucose levels would be a significant advance for everyone who uses insulin, not just those with type 1 diabetes. Work on this is very early and it’s not clear yet whether this is possible. 

We’re also pursuing some truly new mechanisms with the aim of achieving durable weight loss. Maintaining weight loss remains a challenge with GLP-1 drugs, as many patients experience weight regain once the treatment is discontinued or after prolonged use. While we don’t yet fully understand the biology behind this, we’re working to figure it out. We’re also exploring old and new mechanisms in type 2 diabetes and delving deeper into factors that can help improve glucose control. 

What have you learned from your work as a physician-researcher? 
One of the most profound things I’ve learned is that every time you think you know something, you find something else that you didn’t know—and many times even two other things that you didn’t know. So, having humility around what you think you know and don’t know is very helpful. 

My advice for young investigators is to be curious because curiosity drives advances. It’s also important to remain open to new ideas while critically evaluating them. Ask yourself whether there is enough underlying structure to support their validity. If so, build on them; if not, take a step back and reassess with a critical, analytical mindset.

Interview conducted by science writer Nancy D. Lamontagne.

This article was originally published in the May 2025 issue of The Physiologist Magazine. Copyright © 2025 by the American Physiological Society. Send questions or comments to tphysmag@physiology.org.