Introduction

Glucagon-like peptide 1 (GLP-1) is an important regulatory hormone secreted by the cells of the small intestine. The hormone binds to the GLP-1 receptor, which is present in many tissues of the body, such as the pancreas and lungs. As its release is triggered by the consumption of food, GLP-1 oversees critical functions related to weight management, metabolism, and cardiovascular function. 

GLP-1 agonists, on the other hand, are drugs that mimic the action of the GLP-1 hormone by binding to the GLP-1 receptor. They are a class of anorectic drugs that work to regulate hunger pangs by reducing blood sugar levels. Currently, GLP-1 agonists are widely recommended as treatment options for obesity and type 2 diabetes. Some common brands of GLP-1 medications include Ozempic, Wegovy, and Mounjaro. 

Mechanism of action

GLP-1 is a metabolic hormone that works in close association with two other major endocrine hormones - insulin and glucagon. They are released by the Islet cells of the pancreas and have important counterbalancing effects. The main function of insulin is to prevent blood glucose levels from getting too high, whereas that of glucagon is to prevent these levels from getting too low. This generates a feedback loop that is critical to glucose homeostasis and metabolic health.

GLP-1, however, is secreted by the gut - more specifically, the enteroendocrine cells of the small intestine. The GLP-1 cycle begins during the fasting state, when it is released at slow basal rates.¹ These levels, however, dramatically rise once food is consumed. GLP-1 works to regulate glucose-dependent insulin release, thereby decreasing glucagon levels and consequently, hyperglycaemia.^1,2 It is also well-known for its ability to slow down gastric emptying, which is achieved when GLP-1 reduces the motility of the stomach and intestinal cells.² By doing so, it reduces appetite and food intake. Furthermore, GLP-1 is linked to reduced inflammation, a consequence of the production of growth factors.¹ GLP-1 also acts as an inflammation sensor, leading to an increase in its circulating levels following injury and sepsis.¹

Therapeutic applications of Glp-1 agonists

Diabetes and obesity

As stated, GLP-1 receptor agonists have significant positive impacts on body weight and blood sugar control. Long-acting GLP-1 drugs were more effective in lowering blood glucose levels than the short-acting drugs.² Both classes of drugs, however, exhibited similar efficiency in reducing body weight, with no clinically reported significant differences.² This sustained weight loss was achieved within 3-6 months of treatment and was also associated with improved insulin sensitivity.^1,2

Drugs like liraglutide and exenatide have been used as add-ons to insulin treatment in individuals with type 1 diabetes^.1,2 While liraglutide and exenatide were successful in reducing body weight, liraglutide was reported to increase hypoglycaemia.² Exenatide was also reported to decrease body weight and improve insulin sensitivity when administered for 6 months in individuals suffering from long-term type 1 diabetes. Preclinical studies have also highlighted the positive impact of Glp-1 agonists on pancreatic beta cell health and cell mass; however, more clinical research into this aspect is warranted.^1,3

Inflammation

GLP-1 treatment has been closely linked to reductions in local and systemic inflammation.^1,2,4 Following treatment with liraglutide for eight weeks, a notable decrease in proinflammatory cytokine levels was observed in people with obesity and type 2 diabetes.⁴ Similar results were obtained upon treatment with exendin-4. Additionally,  GLP-1 drugs have demonstrated superior efficiency in lowering inflammation when compared to other conventional antidiabetics (sitagliptin). Inflammation levels were higher in individuals treated with sitagliptin than in those undergoing liraglutide treatment.⁴

Cardiovascular and renal outputs

Cardiovascular disease is typically comorbid with diabetes, hypertension, and obesity. GLP-1 medications have been noted to have positive effects on cardiovascular function by virtue of their impact on blood glucose levels, insulin resistance, and weight loss. Mortality rates among patients with type 2 diabetes are higher in those who also suffer from cardiovascular anomalies.⁵ A study showed that the daily administration of liraglutide in individuals with type 2 diabetes and cardiovascular disease reduced the incidence of heart attacks and other cardiac-associated deaths.¹ In addition to liraglutide, classes of Glp-1 agonists like semaglutide and albiglutide have contributed to lowering the incidence of adverse cardiovascular effects.⁵ 

Furthermore, the positive effects of GLP-1 agonists can be extended to renal function. Diabetic kidney disease is another, often fatal symptom of diabetes, which commonly refers to the physiological alterations that are observed in the kidneys of individuals with diabetes. GLP-1 medication was found to lower the decline in glomerular filtration rates and prevent macroalbuminuria.⁶ These drugs were also shown to promote natriuresis and lesser oxidative stress and inflammation.²

Neurodegeneration

Neurodegenerative diseases are one of the leading causes of disability, with the main symptom being neurodegeneration. Neurodegeneration is defined by the gradual decline in structural and cognitive function and is typically accompanied by neuronal death. While its incidence is usually linked to factors such as ageing, stress, and cellular dysfunction, type 2 diabetes is also known to contribute to the onset of neurodegenerative diseases like Alzheimer’s.^2,7

While a good majority of studies on the protective effects of GLP-1 on neurodegeneration have been conducted in animals, these drugs hold great promise in managing the progression of Alzheimer’s and Parkinson’s disease.^2,7 Treatment with exenatide on a weekly basis improved motor symptoms in patients with Parkinson’s disease.² GLP-1 and GLP-1 analogues are reported to have similar impacts on synapse preservation and cell density; however, more research in the clinical setting must be conducted for the clear delineation of these benefits. 

Why are Glp-1 medications so popular lately?

The prominent effects of GLP-1 medications on weight loss and type 2 diabetes have rendered a dramatic increase in the popularity of these drugs among the general public. Prescriptions for GLP-1 drugs like Wegovy and Ozempic were reported to have increased by 300% over the last 3-4 years.⁸ The extensive promotion of these drugs has also been driven by celebrity endorsements and social media outlets.⁹ Trends from social media applications like Reddit and TikTok were analysed, and it was found that the most common search words included ‘Ozempic’, ‘Wegovy’, and ‘Semaglutide’.⁹ These applications also displayed over at least 12,000 comments about this topic.⁹ The immediate striking effects of these drugs on weight loss have pushed users to share their experiences. It is important to note, however, that in the majority of these cases, weight loss was pursued as the primary goal.  

Challenges: misuse and side effects

While the positive association between GLP-1 use and weight loss cannot be ignored, we must bear in mind that this increase in popularity has brought forth major public health concerns. As an example, people are now using Ozempic and other GLP-1 drugs to address cosmetic concerns, thereby creating a shortage of these drugs for those truly in need.¹⁰ More importantly, most of the GLP-1 agonists have not been FDA-approved - semaglutide and liraglutide are the only agonists that have received authorisation for medical use.¹⁰ They are marketed under the names Ozempic and Wegovy, of which only Wegovy has been approved for weight loss.¹⁰

The exponential rise in GLP-1 misuse has also resulted in “ozempic face”, a term referring to the harmful cosmetic side effects of Ozempic usage.⁸ These side effects are typically characterised by a shrunken face, development of wrinkles, and hollow eyes. Users have also reported symptoms of severe depression, suicidal ideation, and sleep-related troubles.⁹ Other physiological symptoms of nausea and vomiting have also been documented. 

Although initially approved for medical use, the increase in demand has led to the misuse of GLP-1 medications. The negative side effects can outweigh the true benefits, making the regulation of GLP-1 prescriptions of the utmost importance. This can, in addition, lead to efficient clinical health and research outcomes, better access to public health care, and lowered costs and insurance restrictions.