Clinical Overview: Ongoing Review of GLP-1 Receptor Agonists for Suicidal Ideations

The European Medicines Agency's Safety Committee will address the issue of suicidal thoughts and self-harm thoughts linked to type 2 diabetes medications or weight reduction therapies. Approximately 150 reports of such incidents have already been gathered and will undergo review to determine any potential connection with the use of glucagon-like peptide-1 (GLP-1) receptor agonists.¹

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GLP-1 receptor agonists are a class of medications primarily used in the management of type 2 diabetes and, more recently, in obesity treatment. These drugs mimic the action of the natural hormone GLP-1 and play a crucial role in regulating blood glucose levels and satiety. Understanding their mechanism of action is essential in appreciating their therapeutic benefits.

GLP-1 is a hormone produced in the intestines in response to food intake. Its primary function is to regulate blood sugar levels after a meal. It achieves this through several mechanisms:

• Insulin Release: GLP-1 stimulates the pancreas to release insulin in response to rising blood sugar levels. Insulin is essential for transporting glucose from the bloodstream into cells, where it can be used for energy or stored for later use.
• Glucagon Suppression: GLP-1 inhibits the release of glucagon, another hormone produced by the pancreas. Glucagon elevates blood glucose levels by stimulating the liver to break down glycogen. By suppressing glucagon, GLP-1 helps prevent excessive glucose release into the bloodstream.
• Slowing Gastric Emptying: GLP-1 slows down the emptying of the stomach, which reduces the rate at which glucose from food is absorbed into the bloodstream. This slower absorption helps prevent post-meal spikes in blood sugar.

GLP-1 receptor agonists are synthetic compounds designed to mimic the effects of naturally occurring GLP-1. GLP-1 receptor agonists bind to and activate GLP-1 receptors on various cells throughout the body, including pancreatic beta cells, which produce insulin, and alpha cells, which produce glucagon.

When GLP-1 receptor agonists activate GLP-1 receptors on beta cells, it stimulates the release of insulin. This insulin secretion is glucose-dependent, meaning it occurs in response to elevated blood sugar levels, helping to regulate blood glucose effectively. GLP-1 receptor agonists reduce the secretion of glucagon from pancreatic alpha cells, preventing excessive glucose production by the liver.

These drugs slow the emptying of the stomach, which helps control the rate at which glucose is absorbed from ingested food. GLP-1 receptor agonists act on the brain's satiety centers, leading to reduced appetite and a feeling of fullness, which can result in weight loss in some patients. By regulating insulin release, suppressing glucagon, and delaying gastric emptying, GLP-1 receptor agonists help stabilize blood sugar levels throughout the day, especially after meals.

GLP-1 receptor agonists offer a multifaceted approach to managing blood sugar levels in individuals with type 2 diabetes and obesity. By mimicking the actions of GLP-1, they enhance insulin secretion, suppress glucagon release, delay stomach emptying, and reduce appetite, all of which contribute to better glycemic control and, in some cases, weight loss. Their mechanism of action makes them valuable tools in the comprehensive management of these metabolic conditions.²

The EMA’s agency communication underscores the widespread use GLP-1 receptor antagonists.¹ However, it remains unclear whether the reported cases ofsuicidal ideations stem from the drug’s mechanisms of action or possibly result from concurrent medical conditions. Notably, thoughts or behaviors related to suicide or self-harm are currently not listed as known adverse effects (AEs) in the documentation for these medications.

Although GLP-1 receptor agonists have shown promise in promoting weight loss, they are prescription medications and should be used under the guidance of health care professionals. Close monitoring of patients' progress, potential AEs, and overall health is essential to ensure the best outcomes.

Obesity has been identified as a factor that elevates the risk of depression, with the most significant impact observed among Americans and in cases of clinically diagnosed depression. Furthermore, it has been established that depression can serve as a predictor for the development of obesity.

These findings underscore the prevalence of both depression and obesity, which are widespread issues carrying significant public health consequences.³ Nevertheless, within the United States, the prescribing information forliraglutide (Saxenda) and semaglutide (Wegovy) advises health care providers and patients to vigilantly watch for signs of depression and suicidal thoughts and to cease using the medication if such symptoms emerge.^4,5

It is recommended that both patients and health care professionals use GLP-1 receptor agonists in compliance with the approved product instructions. Additionally, individuals should promptly report any suspected AEs to the relevant authorities. Detailed instructions on how to report suspected AEs can be found in the package leaflets and on the websites of national medicine regulatory agencies.

References

1. European Medicine Agencies. EMA statement on ongoing review of GLP-1 receptor agonists. https://www.ema.europa.eu/en/news/ema-statement-ongoing-review-glp-1-receptor-agonists. Published on July 11, 2023. Accessed on September 1, 2023.
2. Luppino FS, de Wit LM, Bouvy PF, et al. Overweight, Obesity, and Depression: A Systematic Review and Meta-analysis of Longitudinal Studies. Arch Gen Psychiatry. 2010;67(3):220–229. doi:10.1001/archgenpsychiatry.2010.2
3. Bloemendaal L, Kulve JS, Fleur SE, Ijzerman RG, Diamant M. Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. Journal of Endocrinology. 2013;221(1):T1-T16. doi:https://doi.org/10.1530/joe-13-0414.
4. Saxenda (liraglutide) [prescribing information]. Plainsboro, NJ: Novo Nordisk; November 2018.
5. Wegovy (semaglutide) [prescribing information]. Plainsboro, NJ: Novo Nordisk; August 2022.