Glucagon-like peptide-1 (GLP-1) receptor agonists, including semaglutide and liraglutide, have transformed the management of type 2 diabetes and obesity. Whilst these medications offer substantial metabolic benefits, emerging evidence suggests a potential association between GLP-1 therapy and increased incidence of cholesterol gallstones. This article examines the link between GLP-1 agonists and gallstone formation, explores the underlying mechanisms—including rapid weight loss and altered gallbladder motility—and provides practical guidance on recognising symptoms, reducing risk, and knowing when to seek medical advice. Understanding this potential complication is essential for healthcare professionals and patients to optimise safe, effective use of GLP-1 medications.

What Are GLP-1 Medications and How Do They Work?

Glucagon-like peptide-1 (GLP-1) receptor agonists are a class of medications originally developed for managing type 2 diabetes mellitus, though some are now also licensed for weight management in individuals with obesity. These medications include semaglutide (marketed as Ozempic for diabetes and Wegovy for weight management), liraglutide (Victoza for diabetes and Saxenda for weight management), dulaglutide (Trulicity for diabetes), and tirzepatide (Mounjaro for diabetes), which combines GLP-1 action with glucose-dependent insulinotropic polypeptide (GIP) receptor agonism.

GLP-1 is a naturally occurring incretin hormone released by the intestine in response to food intake. GLP-1 receptor agonists work by mimicking this hormone's effects on multiple organ systems. Their primary mechanisms of action include:

• Enhancing insulin secretion from pancreatic beta cells in a glucose-dependent manner, which helps lower blood sugar levels with a low risk of hypoglycaemia when used alone (though risk increases when combined with insulin or sulfonylureas)

• Suppressing glucagon release from pancreatic alpha cells, reducing hepatic glucose production

• Slowing gastric emptying, which prolongs the feeling of fullness after meals

• Acting on appetite centres in the brain, particularly the hypothalamus, to reduce hunger and food intake

These combined effects result in improved glycaemic control for people with diabetes and significant weight loss. The magnitude of weight loss varies by product: semaglutide 2.4mg (Wegovy) can achieve approximately 15% reduction in body weight, while liraglutide 3mg (Saxenda) typically produces around 8% weight loss. Tirzepatide, as a dual GIP/GLP-1 receptor agonist, may achieve higher weight reductions (15-22%) but is currently licensed only for diabetes in the UK.

In the UK, the MHRA has approved specific GLP-1 agonists for different indications. For weight management, Wegovy (semaglutide) and Saxenda (liraglutide) are licensed for adults with a body mass index (BMI) of 30 kg/m² or greater, or 27 kg/m² or greater with weight-related comorbidities. Ozempic, Trulicity and Mounjaro are currently licensed only for type 2 diabetes. Whilst these medications offer substantial metabolic benefits, their use has raised questions about potential adverse effects, including impacts on gallbladder health.

The Link Between GLP-1 Agonists and Gallstone Formation

Emerging evidence suggests a potential association between GLP-1 receptor agonist therapy and an increased incidence of gallbladder-related complications, including cholesterol gallstone formation and acute cholecystitis. Several large-scale clinical trials and post-marketing surveillance studies have reported higher rates of cholelithiasis (gallstones) and cholecystitis (gallbladder inflammation) among patients treated with GLP-1 agonists compared to placebo or other glucose-lowering medications.

The STEP (Semaglutide Treatment Effect in People with obesity) trials, which evaluated semaglutide for weight management, documented gallbladder disorders in approximately 2.6% of participants receiving the medication versus 1.2% in the placebo group. Similarly, the SUSTAIN trials for diabetes management showed comparable trends. A 2022 systematic review and meta-analysis published in JAMA Internal Medicine found that GLP-1 receptor agonists were associated with increased risks of biliary disease compared to other diabetes medications, with higher risk observed at weight-loss doses and with longer duration of treatment.

It is important to note that whilst there appears to be an association, the precise causal relationship remains under investigation. The increased gallstone risk may be attributable to two mechanisms: the rapid and substantial weight loss these medications facilitate, and potentially direct effects of GLP-1 agonists on reducing gallbladder motility and emptying. Regulatory bodies including the MHRA and European Medicines Agency (EMA) continue to monitor safety data, and current product information for GLP-1 agonists includes cholelithiasis and cholecystitis as recognised adverse reactions.

Healthcare professionals prescribing these medications should be aware of this potential risk and counsel patients accordingly, particularly those with pre-existing gallbladder disease or other risk factors for gallstone formation.

Why Rapid Weight Loss May Increase Gallstone Risk

The relationship between weight loss and gallstone formation is well established in medical literature, predating the widespread use of GLP-1 receptor agonists. Very rapid weight loss is a recognised risk factor for developing cholesterol gallstones, regardless of the method used to achieve weight reduction. UK guidance typically recommends a more gradual weight loss of 0.5-1 kg per week where feasible.

Under normal circumstances, the gallbladder stores and concentrates bile produced by the liver. Bile contains cholesterol, bile salts, and bilirubin in a delicate balance. When this balance is disrupted, cholesterol can precipitate out of solution and form crystals, which may aggregate into gallstones. Several physiological mechanisms explain why rapid weight loss promotes gallstone formation:

• Altered bile composition: During significant caloric restriction and rapid fat mobilisation, the liver secretes increased amounts of cholesterol into bile whilst bile salt secretion remains relatively constant, creating cholesterol-supersaturated bile

• Reduced gallbladder motility: Decreased food intake, particularly reduced dietary fat, means less frequent gallbladder contraction and emptying, allowing bile to stagnate and cholesterol crystals to form

• Increased cholesterol mobilisation: As adipose tissue is broken down, cholesterol is released into the circulation and subsequently excreted via bile

Studies of patients undergoing bariatric surgery—another intervention causing rapid weight loss—have demonstrated gallstone formation rates of 30–50% within the first year post-operatively when prophylactic measures are not employed, though many of these stones remain asymptomatic. The weight loss achieved with GLP-1 agonists, whilst generally less dramatic than bariatric surgery, still occurs at a pace that may exceed the body's ability to maintain optimal bile composition and gallbladder function.

Additionally, GLP-1 receptor agonists may directly reduce gallbladder emptying and motility, potentially contributing to bile stasis and gallstone formation independently of weight loss effects. This dual mechanism—rapid weight loss combined with potential direct effects on gallbladder function—may explain the observed association between GLP-1 therapy and gallstone risk.

Recognising Symptoms of Gallstones During GLP-1 Treatment

Many individuals with gallstones remain asymptomatic, with stones discovered incidentally during imaging for unrelated conditions. However, when gallstones cause symptoms—a condition termed symptomatic cholelithiasis or biliary colic—the presentation can range from mild discomfort to severe pain requiring urgent medical attention. Patients commencing GLP-1 receptor agonist therapy should be educated about the characteristic symptoms of gallbladder disease.

The hallmark symptom of gallstones is biliary colic, typically presenting as:

• Sudden-onset pain in the right upper quadrant or epigastrium (upper central abdomen), often described as severe, constant, or cramping

• Pain radiating to the right shoulder or between the shoulder blades

• Episodes lasting 30 minutes to several hours, often triggered by fatty meals

• Associated nausea and vomiting

• Pain that may wake the patient from sleep

When a gallstone obstructs the cystic duct or common bile duct, or when the gallbladder becomes inflamed, more serious complications can develop. Warning signs of acute cholecystitis or biliary obstruction include:

• Persistent pain lasting more than six hours

• Fever and rigors (shaking chills)

• Jaundice (yellowing of skin and eyes)

• Dark urine or pale stools

• Severe tenderness when pressing on the right upper abdomen

• Charcot's triad (fever, right upper quadrant pain, and jaundice), which suggests cholangitis requiring urgent medical care

It is worth noting that some gastrointestinal symptoms commonly associated with GLP-1 therapy—such as nausea, abdominal discomfort, and reduced appetite—may overlap with early gallbladder symptoms. Patients should be encouraged to report any new or worsening abdominal pain, particularly if it differs in character from their usual medication-related side effects. Healthcare professionals should maintain a low threshold for investigating potential biliary pathology in patients on GLP-1 agonists who present with compatible symptoms.

Reducing Your Risk of Gallstones on GLP-1 Therapy

Whilst the increased risk of gallstone formation associated with GLP-1 receptor agonist therapy cannot be entirely eliminated, several strategies may help reduce this risk. These approaches focus on moderating the rate of weight loss and maintaining gallbladder function, though it should be noted that there is no official link established that these interventions definitively prevent gallstones in patients taking GLP-1 medications.

Gradual dose escalation and monitored weight loss form the cornerstone of risk reduction. GLP-1 agonists are typically initiated at low doses and gradually increased according to manufacturer guidelines, which helps minimise gastrointestinal side effects and may moderate the pace of weight reduction. Patients should work closely with their healthcare team to ensure weight loss occurs at a sustainable rate, ideally around 0.5-1 kg per week where possible.

Dietary considerations may play a supportive role, although these are not proven to prevent gallstones in GLP-1 users:

• Maintain regular meal patterns rather than severely restricting calories, which helps stimulate regular gallbladder contraction

• Include moderate amounts of healthy fats in the diet (such as olive oil, nuts, and oily fish) to promote gallbladder emptying

• Ensure adequate hydration to support bile flow

• Avoid very low-calorie diets unless under specialist supervision

For individuals at particularly high risk—such as those with a history of gallstones, rapid weight loss, or multiple risk factors—some specialists may consider ursodeoxycholic acid (UDCA) prophylaxis. This bile acid medication can help prevent gallstone formation during rapid weight loss, as evidenced by studies in bariatric surgery patients. However, it is important to note that UDCA use for gallstone prevention in patients taking GLP-1 agonists would be off-label, and there is limited evidence for this specific population. There is currently no official NICE guidance recommending routine UDCA prophylaxis for patients commencing GLP-1 therapy, and such decisions should be made only following specialist consultation.

Patients with pre-existing gallstones discovered incidentally before starting GLP-1 therapy should discuss the risks and benefits with their healthcare provider, as the presence of asymptomatic gallstones is not necessarily a contraindication to treatment.

When to Seek Medical Advice About Gallbladder Problems

Patients taking GLP-1 receptor agonists should be aware of when gallbladder-related symptoms warrant medical evaluation. Early recognition and appropriate management of biliary complications can prevent serious outcomes such as acute cholecystitis, biliary obstruction, or pancreatitis.

Contact your GP or healthcare provider within 24 hours if you experience:

• New or persistent abdominal pain in the right upper quadrant or epigastrium lasting more than a few hours

• Recurrent episodes of abdominal pain, particularly after meals

• Unexplained nausea and vomiting that differs from your usual GLP-1-related side effects

• Any yellowing of the skin or whites of the eyes

• Dark urine or pale-coloured stools

Seek immediate medical attention (attend A&E or call 999) if you develop:

• Severe, unrelenting abdominal pain

• High fever (temperature above 38°C) with abdominal pain

• Jaundice accompanied by confusion or drowsiness

• Signs of sepsis, including rapid heartbeat, rapid breathing, or feeling extremely unwell

When gallbladder disease is suspected, initial investigations typically include blood tests (full blood count, urea and electrolytes, liver function tests, C-reactive protein, bilirubin, and serum lipase or amylase) and abdominal ultrasonography, which is the first-line imaging modality for detecting gallstones and assessing the gallbladder. According to NICE guidance (CG188), patients with suspected acute cholecystitis should be referred for urgent hospital assessment, with ultrasound within 24 hours, and early laparoscopic cholecystectomy (within one week of diagnosis) should be offered if appropriate.

If symptomatic gallstones are confirmed, treatment options range from conservative management to laparoscopic cholecystectomy (surgical removal of the gallbladder), depending on symptom severity and frequency. The decision to continue or discontinue GLP-1 therapy should be made collaboratively between the patient and their healthcare team, weighing the metabolic benefits against the risk of recurrent biliary symptoms. In many cases, definitive treatment of gallbladder disease allows patients to safely continue their GLP-1 medication if clinically indicated.

If you suspect you have experienced an adverse reaction to a GLP-1 receptor agonist, including gallbladder problems, you can report this through the MHRA Yellow Card scheme (yellowcard.mhra.gov.uk or via the Yellow Card app).

Frequently Asked Questions