Why Ozempic Causes Gallbladder Disease: The Biology Behind Semaglutide and Gallstones

What the Ozempic label says

The Ozempic label lists acute gallbladder disease under warnings and precautions, with one instruction: if cholelithiasis or cholecystitis are suspected, gallbladder studies are indicated [5]. Its postmarketing list includes cholecystitis and cholecystectomy, and the label notes that frequency cannot be estimated from voluntary reports [5]. Ozempic is approved for type 2 diabetes, not for weight loss [5].

What the semaglutide trials show

SELECT is where the gallbladder numbers are clearest. It enrolled 17,604 adults aged 45 or older with established cardiovascular disease and a body-mass index of 27 or higher, no diabetes, assigned to semaglutide 2.4 mg weekly or placebo [9]. Gallbladder-related disorders were reported in 2.8% of the semaglutide group versus 2.3% on placebo (p=0.04), driven mainly by cholelithiasis at 1.4% versus 1.1%; cholecystitis was 0.6% in both groups [4]. SELECT tested semaglutide 2.4 mg weekly [9], while Ozempic injection maintenance doses are 0.5, 1 or 2 mg weekly [5]; SELECT does not show whether gallbladder risk differs at those doses.

In the adolescent trial of 201 patients aged 12 to under 18 given semaglutide 2.4 mg or placebo for 68 weeks, cholelithiasis occurred in 4% versus 0% [10].

Pooled data across the class point the same way. A meta-analysis of 113 randomized trials of GLP-1 receptor agonists in type 2 diabetes found cholelithiasis more often than with placebo or another diabetes drug (odds ratio 1.30, 95% CI 1.01 to 1.68, P=0.041) [6]. A separate meta-analysis of nine randomized trials of once-weekly semaglutide in people with overweight or obesity, with 11,641 on semaglutide and 10,479 on placebo, reported an odds ratio of 2.06 for cholelithiasis (p=0.04) and 1.26 for gallbladder disorders (p=0.010) [7]. Across 21 trials and 99,599 patients, GLP-1 receptor agonists were associated with 26% more gallbladder disorders [11].

Reduced gallbladder emptying

Between meals the gallbladder stores bile and concentrates it, then contracts when cholecystokinin (CCK) signals that fat has arrived. The human evidence that a GLP-1 receptor agonist blunts that contraction comes from exenatide, not semaglutide.

In a randomized, double-blind, two-period crossover study, healthy fasting volunteers received a single 10 microgram subcutaneous dose of exenatide or placebo 60 minutes before a CCK infusion, and ultrasound measured gallbladder volume and ejection fraction [3]. Maximum ejection fraction was 28.79% on exenatide versus 46.13% on placebo, a difference of 17.34 percentage points (95% CI -30.54 to -4.13) [3]. Gallbladder volume before the infusion, and the minimum volume reached during it, were similar between treatments, and the pancreatic and bile ducts did not change to a clinically significant degree [3].

Reduced emptying is also part of what NIDDK describes during fast weight loss generally: fast weight loss can prevent the gallbladder from emptying properly [2].

Fast weight loss and cholesterol-loaded bile

NIDDK's account is direct. People with obesity may have higher cholesterol levels in their bile and large gallbladders that do not work well. When weight is lost quickly, the liver releases extra cholesterol into the bile, and diets or surgeries that cause fast weight loss may be more likely to lead to gallstone problems than slower ones [2].

Diet studies show both halves of that picture. In a randomized trial reported by Gebhard and colleagues, adults with obesity followed either a 520-kcal liquid diet with less than 2 g of fat a day, or a 900-kcal diet with 30 g of fat a day that included one 10-g fat meal [1]. Both diets produced comparable weight loss of 22%, and the bile cholesterol saturation index rose by 26% during both [1]. Gallstones developed in four of the six people on the low-fat diet and none of the seven on the diet that included the 10-g fat meal (P=0.021), and the trial was stopped early [1]. Maximal gallbladder emptying was 66% at baseline; the 520-kcal diet produced 35% emptying, while the 10-g fat meal produced maximal emptying [1].

Gallstone formation after rapid weight loss has also been followed after bariatric surgery. Shiffman and colleagues followed 81 patients who had a normal gallbladder ultrasound before gastric bypass. At six months, gallstones had developed in 36% and sludge in 13%, and the percentages were about the same at 12 and 18 months. Forty percent of the people who formed stones developed symptoms, and nine, or 28%, had an elective cholecystectomy [8]. The semaglutide studies above do not separate the effect of weight loss from any direct effect of the drug on the gallbladder.

Who starts with more gallbladder risk

Gallstones are common before any drug enters the picture. Up to 20% of adults develop them and more than 20% of those develop symptoms or complications [12]; prevalence among adults in Europe and the United States is estimated at 10% to 15% [13]. Listed risk factors include female sex, age, pregnancy, physical inactivity, obesity and overnutrition [12].

NIDDK adds that silent gallstones present before a rapid weight-loss diet or weight-loss surgery make later symptoms more likely, and that carrying a large amount of excess weight beforehand matters too [2].

What the stones are, and what they can do

Cholesterol gallstones are the predominant type. The other main group is pigment stones, with black pigment stones linked to chronic haemolysis and brown pigment stones forming in obstructed, infected bile ducts [12]. NIDDK's account is that higher cholesterol in bile can cause gallstones [2].

Gallstones can be asymptomatic, and more than 20% of people who develop them go on to have symptoms or complications [12]. Symptoms often precede the three common and potentially life-threatening complications: acute cholecystitis, acute cholangitis and biliary pancreatitis. Diagnosis rests mainly on symptoms, abdominal ultrasound and liver biochemistry [12].

How gallstones are prevented during rapid weight loss

NIDDK names one medicine: ursodiol can help prevent gallstones in people who lose weight rapidly through very-low-calorie diets or weight-loss surgery, and losing weight at a slower pace may make gallstones less likely [2]. In the feeding study above, keeping a small amount of fat in the diet maintained gallbladder emptying and was associated with fewer stones [1].