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Introduction and Background

Glucagon-like peptide-1 receptor (GLP-1R) agonists have been receiving a tremendous amount of attention recently because of their ability to help individuals with obesity reduce their body weight substantially—up to 20 percent or more of total body weight in many cases (Campbell, 2023). First developed as a treatment for type 2 diabetes, GLP-1R agonists have been found to have promising effects in other disease areas besides obesity, such as ingestive disorders (e.g., binge eating disorder, bulimia, and anorexia nervosa), substance use disorders (e.g., alcohol, tobacco, opioids), and neurodegenerative diseases (e.g., Parkinson’s disease, multiple sclerosis, and Alzheimer’s disease) (Hölscher, 2022; Jerlhag, 2023; Jing et al., 2023; Kopp et al., 2022). In this rapidly evolving field, new and potentially effective applications are emerging frequently, making it challenging to stay up-to-date with the current state of knowledge.

To examine the promising yet understudied applications of GLP-1R agonists in neurological and psychiatric disorders, on September 10, 2024, the Forum on Neuroscience and Nervous System Disorders of the National Academies of Sciences, Engineering, and Medicine held a workshop, Examining Glucagon-Like Peptide-1 Receptor (GLP-1R) Agonists for Central Nervous System Disorders.¹ At the workshop, experts from a range of disciplines and perspectives reviewed the current knowledge and research gaps about the mechanisms of action of GLP-1R agonists and the evidence of their

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¹ To learn more about the workshop, see: https://www.nationalacademies.org/our-work/examining-glucagon-like-peptide-1-receptor-glp-1r-agonists-for-central-nervous-system-disorders-a-workshop (accessed October 22, 2024).

clinical efficacy for eating disorders, neurodegenerative diseases, substance use disorders, and pain. Workshop participants also discussed the regulatory challenges and opportunities that may arise with the repurposing of GLP-1R agonists for central nervous system (CNS) disorders. This Proceedings of a Workshop summarizes the presentations and discussions from that meeting.²

HISTORY OF GLP-1 RECEPTORS AND CURRENT THERAPEUTIC APPLICATIONS

Glucagon-like peptide-1 (GLP-1) is an incretin hormone that has quickly emerged as being multifaceted and contributing to inhibition of food intake, proliferation of beta cells, and decreasing inflammation and apoptosis (Müller et al., 2019). Because of GLP-1’s ability to decrease plasma glucose concentrations and revive insulin excretion, treatments that mimic this hormone, referred to as GLP-1R agonists, have been used primarily to treat type 2 diabetes and obesity (Collins and Costello, 2019; Hinnen, 2017).

Daniel Drucker, a professor of medicine in the Division of Endocrinology at the University of Toronto, began by sharing the history of GLP-1R agonists to treat various disorders. In the mid-1980s, he made one of the foundational discoveries, showing that GLP-1 directly stimulated insulin secretion and insulin gene expression but only when glucose was elevated (Drucker et al., 1987). At the same time, Drucker said, multiple studies showed the same effect in the rat pancreas, and soon after, clinical results showed that GLP-1 stimulated insulin secretion in humans. “We were very fortunate,” Drucker said, “to have proof of concept translationally very quickly.”

In 1996 three studies in rats and mice demonstrated that GLP-1 also inhibits food intake (Scrocchi et al., 1996; Tang-Christensen et al., 1996; Turton et al., 1996). Furthermore, if the GLP-1 receptor was blocked—with the GLP-1R receptor antagonist, exendin 9-39, or, in the case of the work in Drucker’s lab, by using GLP-1R-knockout mice—the effect disappeared (Scrocchi et al., 1996). “So this was not an off-target, nonspecific effect,” Drucker said. “This really was mediated through the GLP-1 receptor.”

After those preclinical studies in 1996, it was not until 2014 that the Food and Drug Administration (FDA) approved the first GLP-1R agonist, liraglutide, for use in treating obesity in humans. Another GLP-1R agonist, exenatide, had been approved for type 2 diabetes in 2005. “So it took quite a while to go from bench to clinical approval,” Drucker commented. But today, a decade after FDA approval of liraglutide to treat obesity, there are

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² The planning committee’s role was limited to planning the workshop, and the workshop summary has been prepared by the workshop rapporteurs as a factual summary of what occurred at the workshop. Statements, recommendations, and opinions expressed are those of individual presenters and participants and are not necessarily endorsed or verified by the National Academies, and they should not be construed as reflecting any group consensus.

many highly effective GLP-1R agonists available for clinical use, and dozens of these medicines are in clinical trials. “If you feel like you missed the last 30 years and you’re getting into this late, we’re really only just starting a new era of GLP-1 medicines in the clinic,” Drucker said, adding that there are still opportunities for additional investigation.

Many different organs contain GLP-1 receptors, he said, which is why GLP-1R agonists are being explored for a wide variety of disorders, including metabolic liver disease, peripheral artery disease, cardiovascular diseases, kidney diseases, and disorders of the central nervous system (Drucker, 2024). The FDA’s approval of liraglutide for the treatment of obesity has made it possible for researchers to collect useful data on cardiovascular and other outcomes in patients taking that GLP-1R agonist. And recently, clinical trials of such agonists have been carried out for a variety of conditions, such as heart failure with preserved ejection fraction, and renal impairment in people with kidney disease (Drucker and Holst, 2023). The result, Drucker said, is that a number of benefits of GLP-1R agonists have been well established for a number of different diseases or disorders. The most exciting to date have been the benefits for people with obesity, where tirzepatide has allowed many people to lose an unprecedented 20 percent or more of their body weight, he added, and understanding how all this works has tremendous potential for improving human health (Aronne et al., 2024; Garvey et al., 2016; Jastreboff et al., 2022; Wadden et al., 2023).

Another area where GLP-1R agonists have particular promise, Drucker said, is the central nervous system, which was the focus of the workshop. Some of the earliest work in that area came 20 years ago, when research using animal models showed that increasing expression of GLP-1 in the CNS was neuroprotective, while loss of function enhanced susceptibility to injury in the brain (During et al., 2003). Later, as large numbers of people took GLP-1 medicines for diabetes and then obesity, researchers observed that people taking these medicines had a certain amount of neuroprotection from other medical conditions such as stroke (Strain et al., 2022). Now, a number of ongoing and emerging clinical trials will test how well GLP-1R agonists can protect against Parkinson’s disease, alcohol and substance use disorders, and other central nervous system disorders. For example, the agonists are being studied for their potential to control inflammation through the central nervous system (Wong et al., 2024), Drucker said, “and I think this is particularly relevant to understanding how GLP-1 might work in the brain.” Other questions that Drucker mentioned need to be answered include: How many of these benefits in the brain and elsewhere are driven by reduction of inflammation? How many are driven by other mechanisms? How many are weight loss dependent? One recent cardiovascular outcome trial with the GLP-1R agonist semaglutide has indicated, for example, that at least some of the benefits may not be strictly dependent on weight loss (Lincoff et al., 2023; Ryan et al., 2024).

GLP-1 medicines do have some side effects, he said. Most of them are gastrointestinal, and, fortunately, these adverse effects tend to be reduced over time. On the other hand, the desired effects, such as enhancement of insulin secretion and reduction in appetite, do not disappear. Many of the effects are mediated through the central nervous system, Drucker continued, which is why the drugs are effective against maladies beyond diabetes and obesity (Drucker, 2022).

One exciting new front, Drucker said, is the new generation of GLP-1 medicines that activate multiple receptors, with tirzepatide being the first of what is expected to be a series of multiagonists. However, Drucker cautioned, every time something is added to GLP-1, it’s important to consider whether GLP-1’s effects are being preserved, enhanced, or offset. Those questions cannot be answered easily, he said, and answering them will require a great deal of work.

According to Drucker, “The future is unbelievably exciting. We’re going to have different molecules and different delivery systems and different ways of manipulating GLP-1-based pathways, and the future is wide open for understanding how these might advance the therapeutic opportunity.”

WORKSHOP OBJECTIVES

Matthew Hayes, Albert J. Stunkard Professor in Psychiatry and vice chair of basic and translational neuroscience at the University of Pennsylvania’s Perelman School of Medicine, explained the workshop’s four primary objectives (see Box 1-1). The first was to review the current state of knowledge regarding the mechanisms of action of GLP-1R agonists. The second was to discuss available scientific evidence on the clinical efficacy of GLP-1R agonists for treating various central nervous system disorders, specifically, eating disorders, neurodegenerative diseases, and alcohol and substance use disorders. The third was to examine the real-world evidence, accessibility, systemic challenges in health care access, and regulatory considerations surrounding the application of GLP-1R agonists as therapeutic treatments for central nervous system disorders. And, finally, Hayes asked presenters to highlight current research gaps and to consider opportunities to move the field forward.

Workshop co-chair Brian Fiske, the chief scientist at the Michael J. Fox Foundation for Parkinson’s Research, reminded attendees that while they would be delving deeply into the biology of the field as they discussed the various aspects of diseases being targeted by GLP-1R agonists, they should keep in mind that there are real people who live with these conditions and deal with the effects in their daily lives.

ORGANIZATION OF THE PROCEEDINGS

Chapter 2 provides an overview of GLP-1R agonists, the GLP-1 system in the central nervous system, and the mechanisms through which the

agonists interact with that system. Chapter 3 illustrates the human impact and significance of the work in this field with summaries highlighting the perspectives shared by individuals who have used GLP-1R medications. Chapters 4 through 6 examine the use of GLP-1R agonists in ingestive behavior disorders, substance use disorders, and neurodegenerative disorders and pain, respectively. Next, Chapter 7 tackles three topics pertaining to the widespread use of GLP-1R agonists: the use of real-world evidence such as electronic health records; the effects that rapidly increasing demand will have on the supply of GLP-1R agonists; and ways to encourage impartial and equal treatment of patients with GLP-1R agonists. Finally, Chapter 8 summarizes the key points and themes from the workshop as identified by workshop participants and potential opportunities moving forward. The references provided throughout the proceedings can be found in Appendix A, and the workshop agenda can be found in Appendix B.

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