Introduction

Glucagon-like-peptide 1 (commonly known as GLP-1) is a type of incretin, a group of natural hormones released in the gut in response to food intake.¹ They are responsible for several different metabolic actions throughout the body and play an important role in human health. Recently, synthetic versions of this hormone, known as GLP-1 agonists, have been produced to mimic the action of this hormone throughout the body. Most notably, the drugs have been discovered since the late 20th century and manufactured to be used in the treatment of type 2 diabetes since the early 2000s, as they have useful effects in reducing circulating blood glucose levels by increasing insulin secretion in the body.² They also have some useful effects on body habitus, resulting in rapid weight loss in those who use GLP-1 agonists. Recently, GLP-1s have been discussed in the media in great detail due to their action in aiding weight loss in both those suffering from diabetes and those without diabetes. Less commonly known, however, these drugs also have a major impact on other areas of human health, including metabolic and cardiovascular health.

GLP-1: roles in the body

Mechanism of action

GLP-1 is released from enteroendocrine cells, specialised cells that are present within the gastrointestinal (GI) tract, including the stomach and pancreas.³ From here, they bind to special receptors that are found in different organs within the body, causing activation of specific pathways and the release of certain molecules that have effects throughout the body. Once the hormone has been released, it is quickly metabolised in the body by the DPP4 enzyme (another site targeted by anti-diabetes medications), stopping any further action of the hormone.¹

Medical uses and examples

GLP-1 agonists are one of several classes of medications that can be used to treat type 2 diabetes and obesity. Most commonly used are the Semaglutide (Ozempic) and Tirzepatide (Mounjaro) medications, given via an injection into the upper arm, lower abdomen or upper thigh area.⁴ Due to their effects on lowering weight, in recent years, GLP-1s have become very popular outside of the diabetic community. This led to pharmacies having supply issues for these drugs. Subsequently, this has been an issue for those with type 2 diabetes who depend on these drug types to control their blood sugar levels and their overall health. People can be on both the private and NHS in the UK, but they must meet certain criteria before treatment can be offered. This includes having type 2 diabetes failing to be treated with first-line medications, having an associated heart or chronic kidney condition or having a BMI of greater than 35.⁵

Use as an anti-diabetes and weight loss medication

One of the most common roles of GLP-1 is the regulation of blood sugar in response to food intake. GLP-1 agonists can mimic this action of the hormone, causing increased insulin release when carbohydrates or lipids enter circulation. Insulin is then present in the body to manage the higher blood sugar levels that may occur after eating food. This keeps blood sugar levels relatively stable throughout the day in those with type 2 diabetes, in the same way that the GLP-1 hormone works in healthy individuals.⁶ It is often not used as a first-line treatment in diabetes; however, it is commonly trialled if people are intolerant to other drugs or have other medical conditions affecting the heart and kidneys alongside diabetes. 

Another role GLP-1s have in the body is in weight management. Using a range of different body mechanisms, these medications work to lower body weight by around 12%-18%, depending on the drug type.⁷ They work to reduce gastric emptying, ensuring that people stay fuller for longer and require less calorie intake. They also reduce the reward process in the brain that is felt when eating, further ensuring that people won’t have as strong desires to reach for food and eventually decreasing overall weight.⁶

Metabolic effects

GLP-1s act on many different metabolically active organs and tissues in the body. This includes the kidneys, brain, pancreas, muscle, bone, reproductive organs and the GI tract. In the liver, incretins can help to protect against hepatotoxicity in people suffering from acute liver failure and fatty liver disease. In the brain and the rest of the central nervous system (CNS), the hormone works in many different ways that are mainly associated with appetite regulation but also related to neuroplasticity and neurological conditions.⁸ It is thought that GLP-1s have some input in brain/neural adaptation and renewal of unhealthy brain tissue.¹ This is increasingly beneficial in people with type 2 diabetes who also may suffer from conditions like Parkinson’s disease and Alzheimer's disease that involve long-term damage and change to brain tissue. 

In people with higher levels of low-density lipids (LDLs), the bad type of fat that can be found in the body on blood tests, GLP-1 can be used to reduce these circulating levels of blood fat, ensuring that fat throughout the body is used and/or stored in a more cost-effective manner.⁹ This is useful both from a metabolic point of view and also a cardiovascular point, reducing the amounts of visceral fat around different organs of the body.

Cardiovascular effects

In a meta-analysis of clinical trials, it was found that the use of GLP-1 agonists causes a significant reduction in the incidence of major cardiovascular events in comparison to those not take the medication.¹ These cardiac events may include atherosclerosis, stroke and coronary heart disease. These drugs work in a few different ways to reduce the risk of developing cardiovascular disease. Most importantly, the drugs act on the kidneys to help reduce blood pressure as well as on blood vessels, working to dilate them, and reducing the amount of work needed from the heart to pump blood around the body. Additionally, vascular inflammation is reduced, which can help improve movement of the blood, reducing the risk of blood clots and stroke.¹⁰

Side effects

Even though GLP-1 agonists are used in healthcare to provide a range of health benefits for certain groups of people, there are still some side effects that must not be overlooked. The most common side effects typically reported in people using these medications are those related to the GI tract. Nausea and vomiting, diarrhoea and abdominal pain are often reported within the first 8-16 weeks of starting the medication, but are usually mild enough to tolerate further treatment.¹ More rare and severe side effects include pancreatitis and increased risk of gallstones in patients who have other risk factors for developing the disease; For example, having high cholesterol or a high alcohol intake.¹¹

Summary

GLP-1 agonists like Semaglutide and Tirzepatide can be very vital medications for some populations of people. They have a vast range of actions throughout the body, including the more well-known reduction in circulating glucose levels and body weight, as well as the lesser-known cardiovascular and metabolic benefits. If the body is unable to respond to different needs and produce its incretins in response to food intake and high blood fat levels as well as other metabolic changes, then the use of GLP-1 analogues can be very beneficial in promoting healthier bodies. 

Having become popular due to their ability to achieve rapid weight loss in those who are classed as overweight or obese, the supply of GLP-1s has taken quite a hit in recent times. It is important that those with serious medical conditions like type 2 diabetes and, in some cases, chronic kidney and heart conditions, are still able to get their medication as and when required, something that is becoming increasingly more difficult to achieve due to this demand.

As more and more data is being produced and released surrounding the use of these medications for a range of treatments, it will become more apparent what the true benefits and risks of their use are in a range of people. More research is required in regards to the side effect profile of these medications, ensuring that patient safety is at the forefront of scientists’ minds when doing so. Particularly focusing on the risk of developing pancreatitis from using this medication, as well as the long-term benefit vs risk, could be an area in which we can improve knowledge bases on GLP-1s for the future.

FAQ’s

What are the common benefits of taking GLP-1 agonists?

Aside from the reduction in weight over time and the maintenance of stable, healthy blood sugar levels, GLP-1 has many actions throughout the body. The hormone works on the brain, kidneys, heart and muscles, amongst other areas of the body. It can help decrease appetite and increase satiety and slow gastric emptying. It has strong links to cardiovascular health as well by lowering blood pressure and reducing the risk of blood clots forming in the body, reducing the risk of stroke and heart attacks.

Where is GLP-1 made in the body?

GLP-1 is made in response to the consumption of food and is released from enteroendocrine cells found in the stomach and pancreas. From here, they travel through the body and bind to receptors on different organs and tissues to cause different metabolic and cardiac actions on the body.