The Wegovy prescribing information reports cholelithiasis, gallstones, in 1.6% of adults treated with the injection in randomized weight-reduction trials and in 0.7% given placebo. Cholecystitis, inflammation of the gallbladder, was reported in 0.6% of those adults on the injection and in 0.2% on placebo. The Ozempic prescribing information reports cholelithiasis in 1.5% of patients treated with 0.5 mg and in 0.4% treated with 1 mg, and states that cholelithiasis was not reported in placebo-treated patients.
The question is asked about peptides as a class. The counted risk is the risk on the approved GLP-1 labels, and the percentages above belong to semaglutide. Unapproved research peptides have no gallbladder-outcome trials.
The incidence of acute gallbladder disease was greater in Wegovy-treated patients than in placebo-treated patients, even after accounting for the degree of weight loss.
Rapid weight loss pushes more cholesterol into bile than the bile can hold
The stones in this literature are cholesterol stones. Bile has to hold cholesterol in solution, and a stone can form when the liver secretes more than the bile can keep dissolved. In a 2000 review of obesity, weight loss, and gallstones, Serge Erlinger writes that the increased prevalence is mostly due to supersaturation of bile with cholesterol, from increased synthesis in the liver and secretion into bile. Saturation rises further during weight loss. After weight stabilizes, saturation returns toward normal, and some stones dissolve. At the highest body mass index, the review puts the relative risk at 5 to 6. It summarizes new gallstones on low-calorie diets as reaching 10 to 12% after 8 to 16 weeks, and names a loss greater than 24% of initial weight, a rate greater than 1.5 kilograms a week, a very-low-calorie diet with no fat, a long overnight fast, and a high serum triglyceride level.
In an eight-week study published in 1989, Liddle, Goldstein, and Saxton followed 51 obese men and women whose first ultrasound was clear, on a diet of 2,100 kilojoules a day, and 26 people who were not dieting. Mean weight fell from 105.9 kilograms to 89.4 kilograms, a loss of 16.5 kilograms in eight weeks, just over 2 kilograms a week. At four weeks, four dieters had new stones and one had sludge. At eight weeks, 13 of the 51 (25.5%) had stones and three had sludge. None of the 26 controls developed an abnormality the scan could see. Three people came to surgery, one during the diet and two after ordinary eating resumed, and in each case the stones were cholesterol stones. Of 11 followed for six months after the diet stopped, three had undergone cholecystectomy, four still had stones on ultrasound, and in four the stones were no longer visible.
A 1988 trial sampled the bile while the weight was coming off. Sixty-eight obese subjects without gallstones entered a program of 520 kilocalories a day for up to 16 weeks, randomized to ursodeoxycholic acid (1,200 mg a day), aspirin (1,300 mg a day), or placebo. By the fourth week, in the placebo group, the bile saturation index had risen from 1.07 ± 0.26 to 1.29 ± 0.27, and glycoprotein in bile had risen 27.9 ± 14.5%. Gallstones formed in five people on placebo, and cholesterol crystals in six. On ursodeoxycholic acid the index fell from 1.11 ± 0.34 to 0.91 ± 0.24, and no stones or crystals formed. On aspirin, stones formed in two and crystals in one, and the saturation index did not change significantly.
The trial the Wegovy label calls Study 2 moved more slowly than that eight-week diet. In the 68-week trial published in 2021, mean loss was 15.3 kilograms with once-weekly semaglutide 2.4 mg and 2.6 kilograms with placebo, or 14.9% versus 2.4% of baseline weight, a difference of 12.4 percentage points (95% confidence interval, −13.4 to −11.5). Spread over 68 weeks, 15.3 kilograms is about 0.23 kilograms a week, under the 1.5 kilograms a week in Erlinger's list. The Wegovy label still states the older observation in its own words: substantial or rapid weight loss can increase the risk of cholelithiasis. The same warning continues: the incidence of acute gallbladder disease was greater in Wegovy-treated patients than in placebo-treated patients, even after accounting for the degree of weight loss. The label does not print the adjusted percentages. It also says gallbladder disease may occur in the absence of substantial or rapid weight loss, and that if cholelithiasis is suspected, gallbladder studies and appropriate clinical follow-up are indicated.
The Wegovy and Ozempic labels count different trials
The 1.6% and 0.7% are a pool of adult injection trials. In the same warning, cholelithiasis was reported by 2.5% of adults on the Wegovy tablet and by 1% on placebo tablet. Adult cholecystitis is stated for the injection, 0.6% versus 0.2%. Both cholelithiasis and cholecystitis were higher, the label says, in pediatric patients aged 12 years and older than in adults on the injection. In that pediatric trial, cholelithiasis was 3.8% on Wegovy and 0% on placebo, and cholecystitis was 0.8% and 0%. The label describes the trial as 201 patients. The adverse-reaction table lists 133 on Wegovy and 67 on placebo and prints cholelithiasis as 4% and 0%. The warning gives 3.8% for that same trial.
Ozempic's 1.5% and 0.4% come from placebo-controlled trials in type 2 diabetes, at 0.5 mg and 1 mg. The lower dose carries the higher percentage, and the label does not explain that pattern. The adverse-reaction section that carries the sentence describes its placebo-controlled pool as 260 patients on 0.5 mg and 261 on 1 mg, with a mean exposure of 32.9 weeks. Cholelithiasis was not reported in placebo-treated patients. The printed percentages are for 0.5 mg and 1 mg. Cholecystitis appears in postmarketing experience, listed with cholecystectomy, and the label attaches no percentage, because those reports come from a population of uncertain size. The same section states that adverse-reaction rates in the trials of one drug cannot be directly compared to rates in the trials of another, and may not reflect the rates observed in practice.
Study 2 on the Wegovy label is that 2021 trial, NCT03548935: 1,961 adults with overweight or obesity and without diabetes, 1,306 assigned to semaglutide 2.4 mg and 655 to placebo, for 68 weeks, with a reduced-calorie diet. Gallbladder-related disorders occurred in 34 participants on semaglutide (2.6%) and 8 on placebo (1.2%). Cholelithiasis occurred in 23 (1.8%), 24 events, 1.4 per 100 person-years, against 4 (0.6%), 4 events, 0.5 per 100 person-years. Those single-trial percentages sit beside the label's pooled adult injection figures of 1.6% and 0.7%, which draw on more than this one study. The authors write that the disorders, principally cholelithiasis, were more common with semaglutide, "a finding consistent with previous reports for GLP-1 receptor agonists and with the known effects of rapid weight loss." The Ozempic label locates the same event in the class, before giving 1.5% and 0.4%: acute events of gallbladder disease such as cholelithiasis or cholecystitis have been reported in GLP-1 receptor agonist trials and postmarketing.
Unapproved peptides have no gallbladder outcome to report
The percentages above are semaglutide, on two approved labels. Other approved GLP-1 receptor agonists have labels of their own. A research peptide outside that system has no gallbladder-outcome trial. There is no numerator, and no rate, on the page.
The Wegovy label describes a separate problem in another organ. Postmarketing reports of acute kidney injury, most of them after gastrointestinal reactions that led to dehydration, are taken up in Can peptides damage kidneys?. A stone is a biliary event, counted on a different line of the same prescribing information.
Substantial or rapid weight loss can increase the risk of cholelithiasis. Acute gallbladder disease was still greater on Wegovy after the degree of weight loss was accounted for. Gallbladder disease, the label says, may also occur in the absence of substantial or rapid weight loss. The Ozempic count is earlier, at diabetes doses, with a zero on placebo and no cholecystitis percentage. Under both figures is the older measurement: during rapid loss of weight, cholesterol in bile rises past what the bile can hold. The Wegovy label records an excess that remains after weight loss is taken into account, and it gives that excess no further mechanism.