GLP-1 and gallbladder: what to know about gallstones on semaglutide

GLP-1 receptor agonists (GLP-1 RAs) such as semaglutide are commonly prescribed for type 2 diabetes and weight management. Clinical trials and systematic reviews have reported an increased rate of gallbladder‑related events and cholecystectomy with GLP-1 RAs, though the absolute risk for most people remains small. Understanding mechanisms, risk factors, warning signs, and monitoring options helps patients and clinicians weigh benefits and risks.

How GLP-1 drugs may affect the gallbladder

GLP-1 receptor agonists influence digestive physiology in ways that can raise gallstone risk. Two mechanisms are most commonly discussed in the literature:

• Rapid weight loss: losing large amounts of weight in a short period increases bile cholesterol supersaturation and promotes gallstone formation.

• Altered motility: GLP-1 RAs slow gastric emptying and may reduce gallbladder contractility, which can increase bile stasis and stone formation.

These mechanisms are additive: the drug’s effects on motility plus rapid weight loss during treatment likely explain much of the observed increase in gallbladder events.

Evidence summary

Randomized trials and pooled analyses of GLP-1 RAs, including semaglutide, have shown higher rates of gallbladder events (symptomatic gallstones, cholecystitis, or cholecystectomy) compared with placebo or other comparators. The increase is generally modest in relative terms; individual absolute risk varies by baseline factors such as age, sex, BMI, and history of biliary disease.

Recognizing risk factors

Certain features raise the likelihood of developing gallstones while taking GLP-1 therapy:

• Rapid or very large weight loss (most important modifiable factor)

• Female sex and older age

• Obesity at baseline

• Prior history of gallstones or biliary colic

• Certain metabolic conditions (e.g., hyperlipidemia)

• Prolonged fasting or extreme calorie restriction

Practical steps to reduce risk include pursuing gradual weight loss when possible and avoiding extreme dietary restriction.

Warning signs and when to seek urgent care

Mild biliary colic can present as intermittent upper‑abdominal discomfort, but some presentations require immediate medical attention. Seek urgent care if you develop:

• Severe right‑upper‑quadrant (RUQ) or epigastric pain that is persistent or worsening

• Fever with RUQ pain or chills (possible cholecystitis or cholangitis)

• Jaundice (yellowing of skin or eyes) or dark urine

• Persistent vomiting or inability to keep fluids down

These signs may indicate complications such as acute cholecystitis, ascending cholangitis, or gallstone‑related pancreatitis that require prompt evaluation.

Monitoring and biomarkers: ALT, Bilirubin, Lipase

Laboratory testing can help evaluate suspected gallbladder or related complications:

• ALT (alanine aminotransferase): may be elevated with hepatocellular injury or biliary obstruction.

• Bilirubin: elevated direct bilirubin suggests obstruction of bile flow (common bile duct stones).

• Lipase: elevations suggest pancreatitis, which can be caused by gallstones.

Clinicians often check these biomarkers if symptoms arise. A baseline liver panel before starting therapy may be reasonable in some patients, with targeted testing based on symptoms or clinical concern.

Imaging and diagnostic steps

If symptoms or abnormal labs suggest biliary disease, common next steps include:

• Right‑upper‑quadrant ultrasound to look for gallstones and gallbladder inflammation

• If ultrasound is inconclusive and suspicion remains, cross‑sectional imaging or MRCP (magnetic resonance cholangiopancreatography) can assess the biliary tree

• Endoscopic retrograde cholangiopancreatography (ERCP) may be required to remove common bile duct stones if present

Asymptomatic gallstones discovered incidentally often do not require immediate surgery; management is individualized.

Dosing and usage considerations for semaglutide and other GLP-1s

Dosing strategies and gradual titration can reduce gastrointestinal side effects, which may influence tolerability and the pace of weight loss:

• GLP-1 RAs are typically started at low doses and increased over weeks per prescribing information to reduce GI adverse effects.

• Higher or more rapidly escalated doses used for weight management commonly achieve greater and faster weight loss than lower doses used for glycemic control.

• Faster weight loss may raise gallstone risk, so clinicians may consider the patient’s baseline risk when choosing dose and escalation speed.

Always follow product-specific dosing schedules and discuss titration pace with your prescriber.

Who should avoid GLP-1 therapy or use with caution

GLP-1 RAs are appropriate for many patients but require caution or avoidance in some situations:

• Known personal or strong family history of medullary thyroid carcinoma or MEN2 (contraindication for some agents)

• Pregnancy and breastfeeding: GLP-1 RAs are generally not recommended

• History of pancreatitis: use with caution and close monitoring; discuss risks with your clinician

• Active gallbladder disease: consult a specialist before starting therapy

• Those unable to tolerate GI side effects or at particularly high risk for rapid, large weight loss without close follow‑up

Decisions should be individualized and involve shared decision‑making between patient and clinician.

Prevention strategies to lower gallstone risk while on GLP-1 therapy

Practical measures that may reduce the chance of gallstones include:

• Aim for steady, moderate weight loss rather than very rapid reduction

• Stay well hydrated and avoid prolonged fasting

• Use standard titration schedules to reduce abrupt GI changes

• Report biliary-type symptoms early for prompt evaluation

• Consider baseline biliary history and discuss ultrasound screening if there is prior gallstone disease

These strategies do not eliminate risk but can help mitigate it.

Management of gallstones during GLP-1 treatment

If symptomatic gallstones occur, management options depend on severity:

• Mild, intermittent biliary colic: conservative management and outpatient evaluation

• Acute cholecystitis, cholangitis, or gallstone pancreatitis: typically requires urgent hospital evaluation and possible surgical or endoscopic intervention

• Elective cholecystectomy is considered for recurrent or complicated symptomatic stones

Decisions about stopping or continuing GLP-1 therapy should be individualized based on symptom severity, benefit from the drug, and specialist input.

Takeaways

• GLP-1 and gallbladder issues are linked: GLP-1 RAs, including semaglutide, have been associated with a modestly higher rate of gallbladder events, likely driven in part by rapid weight loss and altered biliary motility.

• Watch for warning signs: severe RUQ pain, fever, jaundice, or persistent vomiting require urgent evaluation.

• Monitor appropriately: clinical assessment, ALT, bilirubin, and lipase help evaluate complications; ultrasound is the first‑line imaging test for suspected gallstones.

• Risk reduction: gradual weight loss, adequate hydration, standard dose titration, and early symptom reporting can reduce the chance of complications.

• Individualized care: discuss personal risk factors and the pace of treatment with your clinician before starting or adjusting therapy.

Conclusion

GLP-1 receptor agonists are effective tools for diabetes and weight management but come with a recognized, generally modest increase in gallbladder‑related events. Awareness of risk factors, early symptom recognition, appropriate use of biomarkers (ALT, bilirubin, lipase), and shared decision‑making with your healthcare team can help manage and mitigate that risk. If you experience severe abdominal pain, fever, jaundice, or persistent vomiting while taking a GLP-1 drug, seek urgent medical care.

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