Overview

GLP-1s

Glucagon-Like-Peptide 1 (GLP-1) Receptor Agonists, more commonly shortened to GLP-1 RAs, are gaining popularity right now with both the NHS and privately. They are supplied under brand names including but not limited to Ozempic, Mounjaro and Trulicity, which contain active ingredients such as semaglutide, tirzepatide or dulaglutide. 

An agonist is like a copycat. Its purpose is to mimic the action of something by tricking the body into thinking it is that thing. It does this by sitting in the same place that the original thing usually sits, also known as the receptor. To demonstrate, imagine a throne where the King usually sits; this is like glucagon (a hormone) sitting on the receptor. If someone wearing the King's cloak sits on the throne to trick the public into thinking they are the king, this is similar to a GLP-1 RA sitting on the receptor to trick the body into acting like glucagon.

Therefore, before knowing what the GLP-1 RA does (i.e, the copycat), it is important to know what GLP-1s are (i.e the original).

GLP-1s are hormones synthesised in the small intestine, with 4 important roles in regulating blood sugar levels:¹ 

• Triggering insulin to be released from the pancreas in response to higher levels of glucose from digesting food
• Prevention of glucagon passing into the blood, resulting in less glucose being released into the blood
• Reducing the speed at which food is digested
• Keep the patient feeling fuller for longer through affecting mechanisms in the brain
  

GLP-1 RAs are increasingly being prescribed for the management of blood sugar levels in patients with diabetes, either in conjunction with other medications or in some cases in place of existing treatment where other medications have failed to reach optimum control. There has also been an increase in private clinics offering GLP-1 RAs for weight loss in patients both with and without a previous diagnosis of diabetes. Their preferences and high popularity stem from research which shows not only better control in blood sugar levels, but also a weight reduction (average 2.9 kg compared to placebo) and better control of blood pressure and total cholesterol, leading to an overall healthier outcome for the patient. Moreover, as most of the preparations are formulated as injections, the direct entry of the medication under the skin results in the GLP-1 RA being quickly absorbed into the blood, where it can travel to the correct site and begin to work.² 

Gallbladder

The gallbladder is a small organ located under the liver. Its sole purpose is to store bile, a fluid that is released to digest fat from the food we eat. The bile is transported around the digestive system through channels called the biliary tract.³

As you begin to eat fatty foods, signals are sent to the gallbladder to contract, releasing the bile it stores. The bile then travels to the first part of the small intestine, where it mixes with food that needs digesting.³ 

Gallbladder disease is the broad name for any issue affecting the health of the gallbladder. Common issues include:⁴

• Gallstones: Stones are composed of bile material that develops in the gallbladder or pipes called bile ducts. Most of the time, they aren’t dangerous but can cause symptoms such as pain, nausea or swelling, known as cholecystitis
• Cholecystitis: Inflammation of the gallbladder, caused by gallstones blocking the ducts. This means bile can no longer exit the gallbladder, leading to symptoms such as fever and pain, and may require treatment by operating
• Gallbladder cancer: This is rare but can be felt as a pain where the gallbladder is located, in the upper right of the abdomen
• Gallbladder dyskinesia: The gallbladder cannot contract properly, so bile does not move in the right direction down the bile ducts, towards the small intestine⁵

Certain groups of people are more likely to have gallbladder issues. Risk factors include patients with diabetes, being assigned female at birth, age (especially over the age of 40 years), obesity (BMI >30), prolonged fasting/ weight-loss, and use of medication including GLP-1 RAs.⁶

This report will explore the connection between GLP-1 RAs and gallbladder-related complications.

GLP-1 RAs And Gallbladder Issues

Studies investigating whether there are any links between GLP-1 RAs and gallbladder issues have recognised that there is a positive correlation; however, this becomes more evident at higher doses and with prolonged duration of treatment. The indication for prescribing also played a role in whether a link was seen, with those using it for weight-loss being at greater risk than those using it for other indications, such as diabetes. However, whilst there was a clear correlation compared to placebo, the numbers were not seen to be statistically significant.⁷

How GLP-1 RAs Affect the Gallbladder 

Studies have concluded that the increased risk of gallbladder disease may be directly linked to the mechanism of GLP-1 RAs. This is due to the suppression of gallbladder motility, i.e., lack of contraction and thereby delayed emptying of the gallbladder, leading to the buildup of bile. Moreover, sudden decreases in the patient's weight over a short duration, such as that caused by GLP-1 RAs, are also associated with an increased risk of gallbladder diseases. The weight loss triggered by the GLP-1 RA leads to an increase in the amount of cholesterol (a component of bile) in the gallbladder. Furthermore, fasting keeps the gallbladder inactive, leading to a buildup of thick bile, which eventually leads to the formation of gallstones. This effect on bile could be the reason why GLP-1 RAs are leading to gallbladder disease.⁸

Effect of Dose and Type of GLP-1 RA

When blood sugar is not appropriately controlled with lower-dose GLP1 RAs, the strength of the prescribed medication may be increased; however, prescribers and patients should be aware that increasing the dose may prompt gallbladder disease, and therefore, it is only logical that gallbladder function is monitored. ⁷ Similarly, higher doses are often prescribed in weight loss, which may account for why gallbladder disease is more likely to be diagnosed in these patients. 

The weight loss triggered by the GLP-1 RA leads to an increase in the amount of cholesterol (a component of bile) in the gallbladder. Furthermore, fasting keeps the gallbladder inactive, leading to a buildup of thick bile, which eventually leads to the formation of gallstones.⁸ This effect on bile could be the reason why GLP-1 RAs are leading to gallbladder disease. 

It is also worth noting that individual GLP-1 RAs may have different effects on the gallbladder, with some being more likely than others to cause gallbladder disease. For example, studies focusing on liraglutide have identified that it does affect the gallbladder, whereas semaglutide has not yet been observed to have such an effect.⁸ Furthermore, even though they are the same class of medicine and the mechanism of how they work is the same, some GLP-1 RAs are longer acting than others. As the name suggests, this means that not only do they sit on the receptor for longer, but they also stay in the body for longer, leading to a greater probability of affecting the gallbladder.⁹

Summary

• GLP-1 RAs are effective at controlling blood glucose and reducing weight, so their link to gallbladder issues should not be a reason to suddenly stop them
• If you are worried, it is important to have a conversation with your prescriber to discuss the best next steps for you
• Current research has identified the connection between gallbladder issues and GLP-1 RAs, but it is an area where further research and attention should be given
• This will help certify that there is a connection and identify which GLP-1 RAs are more likely to have the risk