GLP-1 Agonists

In recent years, the world of pharmaceuticals has witnessed significant advancements in the treatment of numerous health conditions, including obesity and mental health disorders. Among these advancements are a class of medications known as glucagon-like peptide-1 receptor agonists, or GLP-1 agonists.  GLP-1 agonists are primarily known for managing type 2 diabetes and, more recently, obesity; however, developmental research suggests that these medications may be repurposed to address certain aspects of mental health. In this blog post, we will delve into the basics of GLP-1 agonists, and examine their potential impact on the brain and mental health.

What are GLP-1 agonists?

Glucagon-like peptide-1 receptor agonists (GLP-1 agonists) are a category of medications that manage blood glucose levels for individuals with Type 2 diabetes.  Common GLP-1 agonists include semaglutide, dulaglutide, exenatide, liraglutide, lixisenatide, among others.¹ They may also be known by their brand names such as Ozempic, Wegovy, Trulicity, Byetta, Victoza, and Adlyxin.  These drugs were developed to mimic the effects of the naturally occuring GLP-1 hormones that are made in the small intestine. These hormones exert beneficial effects on the body, such as reducing inflammation, insulin resistance, glycemic control, lipid metabolism, and body weight.² In order to understand the function of GLP-1 agonists, it is important to understand how the GLP-1 hormone works.

GLP-1 hormone actually has several functions in the body, with the most impactful being its role in triggering the release of insulin from the body.  Insulin is a hormone that lowers the amount of glucose, or sugar, in your blood following a meal or rise in blood glucose levels.  If an individual does not have enough insulin, they will have high levels of sugar in the bloodstream, which can lead to diabetes.  Additionally, GLP-1 hormones also work to block the release of glucagon into the blood.  Glucagon is a hormone that raises blood sugar levels, so GLP-1 actually works to prevent more sugar from entering the bloodstream.  GLP-1 hormones also have roles in slowing digestion and increasing satiety following a meal by affecting areas of the brain that are associated with hunger and fullness.¹

GLP-1 agonists, subsequently, were developed to mimic this hormone.  They do this through attaching themselves to cell receptors and cause the same action that the naturally occurring GLP-1 hormone would.  The agonists bind to GLP receptors within the body and trigger these processes.  For individuals with Type 2 diabetes, GLP-1 agonists enable the pancreas to release more insulin as a way to keep blood glucose levels down.¹  Slowing digestion can also prevent sugar in the bloodstream from spiking as well.

 

GLP-1 Agonists treat obesity

Beyond their role in glycemic control, GLP-1 agonists have been popularized for their potential benefits in other areas, including weight management. One medication that has gained prominence in the treatment of obesity is Wegovy (semaglutide). Approved by the U.S. Food and Drug Administration (FDA) in 2021, the Wegovy injection has successfully helped generally obese and overweight individuals manage weight loss goals when used in addition to reduced calorie diets and increased physical activity.³  Similar to other GLP-1 agonists, Wegovy mimics the GLP-1 hormone and specifically targets brain areas that regulate food intake and appetite.  In the largest placebo-controlled trial, participants without diabetes received Wegovy while a control group received placebos. Individuals who were administered Wegovy lost an average of 12.4% of their initial body weight compared to the placebo group. Another trial that enrolled diabetic participants found that individuals who received Wegovy lost 6.2% of their initial body weight compared to the placebo group.³

 

GLP-1 Agonists and Multiple Sclerosis (MS)

In recent times, drug repurposing, or the process of identifying new indications for already existing drugs, has gained awareness within the medical community.  As a practice, it allows for more cost-effective and rapid production of developing newer treatments. As evidenced by its multi-functionality as a anti-diabetic and weight loss drug, GLP-1 agonists is an example of drug repurposing.  Consequently, researchers have delved deeper into other conditions that GLP-1 agonists could potentially treat; one of them being multiple sclerosis (MS).⁴  In relation to obesity, MS shares similar inflammatory components through the overproduction of pro-inflammatory adipokines and a reduction in the amount of anti-inflammatory adipokines.  Studies also show a close relationship between obesity and MS in that early childhood or adolescent cases of obesity increase the risk of MS and is also known to be a disease modifier for MS.  In a 2024 analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, researchers explored potential associations between MS and GLP-1 agonists based on data collected between 2003 and 2023.  Results showed that there is an inverse association between MS and GLP-1 agonists, including semaglutide, dulaglutide, liraglutide, empagliflozin, and metformin.⁴  The potential efficacy of GLP-1 agonists treating MS emphasizes its neuroprotective properties and application as a repurposed drug for a broader consumer population.

 

What does research say about GLP-1 and mental health?

Depression

Though naturally occuring GLP-1 hormones are typically found within the L cells of the small intestine, they can also originate from other organ systems, such as the central nervous system (CNS).²  They can develop in areas of the brain such as the hindbrain, hypothalamus, and amygdala, and even have the ability to cross the blood-brain barrier and directly impact physiological functions carried out by the brain.²  Due to their presence in these various brain regions, GLP-1 agonists can modulate neurotransmitter activity and neuronal function, which also impacts cognitive function. Research has found that GLP-1 hormones reduce inflammation, promote mitochondrial biogenesis, provide neurotrophic effects, and stimulate neurogenesis.²

In a 2024 meta-analysis, researchers looked at 6 studies to review the effects of GLP-1 agonists on depressive symptoms as they are reported on a depression rating system.  The data concluded that the change in depression rating scale scores decreased significantly when patients received GLP-1 agonists compared to control patients, suggesting that GLP-1 agonists exert antidepressant effects on patients.  In addition, the meta-analysis found that Type 2 diabetic patients experienced positive effects on depressive symptoms as a result of taking GLP-1 agonists.²  Though the exact mechanism by which this effect takes place is not confirmed, researchers posit that the neuroprotective and neurotrophic properties of GLP-1 agonists may be relevant in influencing synaptic plasticity, which can play a role in mental health, cognitive decline, and reducing nonfatal stroke.²

Parkinson’s Disease

Recent research trials have shown the potential of GLP-1 being able to provide support for other conditions that affect the brain, such as Parkinson’s disease (PD).⁵  Parkinson’s disease is a progressive disorder that specifically affects the CNS and the various parts of the body that are controlled by nerves.  The disease progresses quite slowly, and individuals may begin to notice visible symptoms such as tremors, slowed movements, rigid muscles, and a loss of automatic movements as it progresses. PD is caused by the breakdown and death of neurons within the brain.  Specifically, the neurons within the brain slowly lose the ability to produce dopamine, which can cause an irregularity of brain function as its levels decrease.

A common risk factor for developing PD is diabetes, and research shows that treating diabetes with GLP-1 agonists is associated with a 50% reduction in the risk of new-onset PD.⁶ Researchers believe that this may be due to the reduction in inflammation that is associated with GLP-1 agonists.  In an April 2024 New England Journal of Medicine publication, researchers reported on a recent trial of the GLP-1 agonist known as lixisenatide.⁶ In the trial, participants were individuals who had early stage clinical PD and were separated into a control group and a group that would receive- lixisenatide.  After 12 months, participants rated their changes in motor disability according to the Movement Disorder Society-Unified Parkinson’s Disease Rating Scale (MDS-UPDRS).  Results showed that the group who took the GLP-1 agonist did not have any changes on their scores, while the control group experienced a worsening of PD symptoms. Although these results suggest the role of lixisenatide being able to completely minimize the worsening of PD symptoms, there are adverse side effects that may make it an unappealing option for PD patients.  For example, 36% of trial participants who tried receiving lixisenatide at its highest dose had unacceptable symptoms, and even when the dose was lowered, 46% of participants experienced nausea and 13% experienced vomiting.⁶

 

What to consider

While the primary role of GLP-1 agonists have been in glycemic control and weight management, emerging evidence suggests that these medications may exert beneficial effects on various brain and mental health disorders. As the medical community continues to deepen its understanding of the interplay between these drugs and mental health, GLP-1 agonists hold promise as a therapeutic option for improving overall health and well-being. With that being said, however, it is important to remember that this is still a relatively new field of research.  GLP-1 agonists still need long-term research trials to determine what the potential risks and benefits are.  In addition, the individuals who take GLP-1 agonists have such extensive medical histories and combination of conditions that may affect research results. Lifestyle habits, medications, age, and so many other health factors influence why certain results come out the way they do.  As research in this field progresses, we can anticipate more developments on the impacts that GLP-1 agonists will have on the field of medicine and mental health