Zepbound® and gallbladder problems

The numbers, regulator by regulator

Section 5.4 of the US label opens with a statement that covers Zepbound® and the GLP-1 receptor agonist class alike: treatment is associated with more acute gallbladder disease ^[1]. Its figures come from Study 1 and Study 2, better known as SURMOUNT-1 and SURMOUNT-2, in which 2,519 adults with obesity or overweight took Zepbound® for up to 72 weeks ^[1]. The gallbladder rows cover all doses together rather than dose by dose. Canada repeats the count with a third weight trial added. The European Medicines Agency has no Zepbound® document, because tirzepatide is authorised there only as Mounjaro®; its product information reports pooled weight-management, sleep apnoea and heart failure trials ^[3][4].

Stones were level; inflammation was not

Read across the rows and one pattern repeats. Gallstones alone were reported almost as often on placebo as on Zepbound®, both in the US pool and in Canada’s wider one ^[1][3]. The gap opens at the more serious end: inflamed gallbladders in 0.7% against 0.2% in the US pool and 0.6% against 0.2% in Canada’s, and every gallbladder removal in people taking the medicine ^[1][3].

Canada’s pool adds SURMOUNT-3, in which 287 people on Zepbound® had first completed an intensive lifestyle programme ^[1][3]. The EU reports acute gallbladder disease as one combined figure instead of separate rows for stones, inflammation and surgery, so its 2.0% is not directly comparable with the US rows ^[4].

Sleep apnea, heart failure and older adults

Zepbound® also carries a sleep apnea indication ^[1]. The US label prints no separate gallbladder table for its two sleep apnea trials, which enrolled 467 adults, but says gallstone rates there were similar to the weight trials ^[1]. The EU figures for its sleep apnoea trials, 0.9% on tirzepatide and 0.9% on placebo, point the same way ^[4].

The highest figure comes from SUMMIT, a placebo-controlled trial of tirzepatide in 731 adults with obesity and heart failure with preserved ejection fraction. Their average age was 65.2 years and they were followed for a median of 104 weeks ^[4]. Acute gallbladder disease was reported in 4.4% on tirzepatide and 2.7% on placebo ^[4]. Heart failure is not a US Zepbound® indication, and this was an older group followed for longer.

In the US weight pool, 226 people on Zepbound®, or 9%, were 65 or older, and the label reports no overall safety differences from younger adults ^[1]. A post hoc analysis led by Lilly-affiliated authors pooled SURMOUNT-1 to -5, the sleep apnea trials and SUMMIT; among adults aged 65 and over it found no clinically meaningful difference between tirzepatide and placebo in gallbladder and biliary events ^[6]. Post hoc analyses were not planned in advance and cannot settle a rare risk alone.

What studies after approval add

A 2025 systematic review pooled 13 randomised trials with 26,894 people who had obesity but not diabetes, the population closest to SURMOUNT-1 ^[5]. Stomach and bowel side effects were clearly more frequent with tirzepatide than with placebo, while its biliary risk did not reach statistical significance, and hepatic and pancreatic events did not rise either ^[5]. Because gallbladder events are rare, a non-significant result means an increase was not shown, not that it is ruled out.

SURMOUNT-1’s 176-week extension in people with prediabetes, the longest placebo-controlled follow-up, reported no new safety signals ^[7]. An analysis of the FDA Adverse Event Reporting System from 2022 to early 2025, covering 67,305 tirzepatide cases, placed cholelithiasis among the signals more often linked with serious outcomes ^[8]. Such spontaneous reports cannot give a frequency or prove cause.

Where weight loss fits: three levels of evidence

• Backed by the product information: the US and Canadian documents say acute gallbladder events were associated with weight reduction, and the EU information calls the association positive ^[1][3][4]. None of them names a threshold, a speed of loss or a time of highest risk.
• Plausible but not measured for Zepbound®: the weight change in these trials was large. After 72 weeks of SURMOUNT-1, 50.1% of people on 10 mg and 56.7% on 15 mg had lost at least 20% of their body weight, against 3.1% on placebo ^[1]. Whether those who lost the most, or lost it fastest, were the ones with gallbladder events is not reported in the documents we checked.
• General medical knowledge: the NIH explains that stones form when bile carries too much cholesterol or bilirubin, or too few bile salts, or when the gallbladder does not empty often or completely enough ^[10]. Rapid weight loss and long gaps without food push more cholesterol into bile and can leave the gallbladder emptying poorly ^[11].

Gallstones are common anyway

Not every gallstone found during treatment comes from it. The NIH estimates that gallstones affect 10 to 15 percent of people in the US ^[9]. It lists groups at higher risk regardless of medicine: women, especially with extra oestrogen from pregnancy, hormone therapy or birth control pills; older people; anyone with a family history; American Indians and Mexican Americans; and people with obesity, diabetes, metabolic syndrome, high triglycerides or cirrhosis ^[9]. Most stones never cause symptoms and, when silent, usually need no treatment ^[9][10].

Upper-belly pain has plenty of other sources on Zepbound®. In the label’s main table, stomach pain was reported by 9% to 10% of people on the medicine against 5% on placebo, and indigestion by 9% to 10% against 4% ^[1]. The NIH adds that gallstone symptoms can resemble appendicitis, an ulcer, pancreatitis or reflux disease ^[10].

What official and NIH sources describe

The Zepbound® documents give no self-care steps for the gallbladder; they ask for symptoms to be reported and, if inflammation is suspected, for tests and follow-up ^[1][2]. NIH gallstone guidance, written for anyone losing weight, adds the following.

• Eat more high-fibre foods such as fruit, vegetables, beans, peas and whole grains, and fewer refined carbohydrates and sugars ^[12].
• Prefer healthy fats such as fish oil and olive oil, which the NIH says help the gallbladder contract and empty regularly, and cut back on fats from fried foods and desserts ^[12].
• Steer clear of crash diets and long stretches without food, and aim to keep lost weight off, because repeated loss and regain is also linked to gallstones ^[11].
• Stay physically active; regular activity may lower the chance of gallstones ^[11].
• Talk with your health care professional before changing your eating plan ^[12].

If tests confirm a gallbladder problem

Section 5.4 tells clinicians that suspected cholecystitis calls for gallbladder diagnostic studies and suitable follow-up, and section 17 asks that patients be told about the risk ^[1]. The US label does not say Zepbound® must be stopped. Canada’s patient information, however, places sudden gallbladder problems, with severe belly pain, yellow skin or a high fever with chills, among the effects for which you stop the medicine and get immediate help ^[3].

According to the NIH, the usual treatment for gallstones that cause symptoms is surgery to remove the gallbladder, nearly always done laparoscopically. People live normally without one, and a small number notice softer, more frequent stools for a while afterwards ^[13].

If an operation is planned, tell the surgical and anaesthesia team that you use Zepbound®. Because it slows stomach emptying, the label describes rare reports of stomach contents being breathed into the lungs under general anaesthesia or deep sedation, and says the data are too limited to show whether changing fasting rules or pausing treatment would help ^[1][2].

Zepbound® and Mounjaro® are registered trademarks of Eli Lilly and Company. PepLabo is not affiliated with or endorsed by Eli Lilly and Company.