Efficacy of prophylactic ursodeoxycholic acid in preventing gallstone formation after metabolic bariatric surgery: an updated systematic review and meta-analysis of randomized controlled trials

Abstract

Background

Rapid weight loss following Metabolic bariatric surgery (MBS) is associated with an increased risk of developing de novo gallstone formation. We aimed to evaluate the efficacy of prophylactic ursodeoxycholic acid (UDCA) in preventing gallstone formation and reducing gallstone-related outcomes after MBS.

Methods

We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) following the PRISMA guidelines through PubMed/MEDLINE, Cochrane, Embase, Scopus, Google Scholar, and clinicaltrials.gov. The primary outcome was gallstone formation at 12–24 months, while symptomatic gallstones and cholecystectomy incidence were secondary outcomes. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using random-effects models. Subgroup analysis was conducted according to UDCA dose, duration of administration, and the type of operation. Meta-regression was performed to assess the effect of age and baseline BMI on gallstone formation. I² and Cochrane Q p-value were used to assess the heterogeneity of the studies.

Results

Ten RCTs, including 3,575 participants, were included. Prophylactic UDCA reduced the incidence of gallstone formation by 67% at 12–24 months, and 73% at 6 months, while symptomatic gallstones were reduced by 70%. No statistically significant difference was found in the cholecystectomy rates. Subgroup analysis showed that UDCA doses of 500–600 mg daily administered for 6–12 months were effective, with no significant differences in gallstone formation between surgical procedures. Meta-regression analysis showed a slight increase in gallstone risk with age and a slight decrease with higher BMI, although neither relationship reached statistical significance.

Conclusions

Prophylactic UDCA may be an effective preventive measure for gallstone formation in MBS patients, however additional studies are needed to assess its effect on cholecystectomy.

Trial registration

The systematic review was registered in PROSPERO under registration number CRD420251004594.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12893-026-03983-0.

Introduction

Obesity is a global health concern, accounting for more than one billion adults classified as obese, and approximately 43% overweight between 2022 and 2024, driving a rapid increase in metabolic bariatric surgery (MBS) worldwide [1, 2]. Subsequently, more than 500,000 bariatric procedures are performed annually, with sleeve gastrectomy (SG) accounting for 60–65% of primary operations and Roux-en-Y gastric bypass (RYGB) remaining the most common revision procedure [3, 4]. This burden is particularly pronounced in Kuwait, where over 40% of adults have a body mass index (BMI) ≥ 30 kg/m², placing the country among those with the highest obesity prevalence worldwide [5]. Accordingly, MBS is one of the most frequently performed surgical interventions nationally [6].

On the other hand, rapid and substantial weight loss following MBS leads to biliary cholesterol supersaturation and gallbladder hypomotility, which are strongly associated with de novo gallstone formation [7]. The reported incidence of gallstones varies by operation type, follow-up duration, and baseline gallstone prevalence; however, pooled estimates suggest that 10–50% of patients develop gallstones within the first postoperative year, with rates clustering at 30–40% in high-risk populations [8, 9]. These gallstones may result in clinically significant complications, including symptomatic cholelithiasis, readmission, and cholecystectomy, contributing to increased morbidity and healthcare utilization during the early postoperative period [10].

To prevent such outcomes, some surgeons perform concomitant prophylactic cholecystectomies during MBS, even in asymptomatic patients [11]. However, this strategy remains controversial, as routine cholecystectomy prolongs the operative time and increases surgical morbidity without consistent evidence of benefit for all patients [12]. Therefore, prophylactic cholecystectomy is not routinely advised for patients with asymptomatic gallstones undergoing sleeve gastrectomy or Roux-en-Y gastric bypass. An exception to this is biliopancreatic diversion with duodenal switch, where cholecystectomy is suggested regardless of the gallstone formation [12]. Additionally, cholecystectomy after metabolic bariatric surgery is very difficult due to changes in the intra-abdominal anatomy, or adhesions, which lead to visualization difficulties in the operation, increasing the operation risks [13].

As a less invasive alternative, ursodeoxycholic acid (UDCA) has been used to prevent gallstone formation during rapid weight loss. UDCA reduces biliary cholesterol supersaturation and enhances bile flow, inhibiting cholesterol crystal formation and gallstone development [14]. Randomized controlled trials (RCTs) have evaluated UDCA administration (300–900 mg/day) for durations of 3–12 months, with multiple meta-analyses demonstrating substantial reductions in radiologically detected gallstones, and in some analyses, lower cholecystectomy rates. However, heterogeneity in dosing regimens, treatment duration, surgical procedures, and outcome definition limits the generalizability of these results [15]. Moreover, the large multicenter UPGRADE trial (n = 477; UDCA 900 mg daily for 6 months) reported no significant reduction in symptomatic gallstone disease at 24 months, although a subgroup analysis showed potential benefits in patients without baseline gallstones, particularly after RYGB. This finding has renewed the debate regarding patient selection, endpoint choice, and prophylaxis policy [16]. Collectively, the conflicting results across trials, heterogeneity in treatment protocols, and uncertainty regarding clinically meaningful outcomes create a significant evidence gap in defining the role of UDCA prophylaxis after MBS. Therefore, we aimed to pool the previous randomized controlled trials to evaluate the efficacy of UDCA in preventing gallstone formation and its effect on reducing cholecystectomy rates, examine the dose-response and duration effects, and provide evidence-based recommendations for postoperative prophylaxis. We also aimed to assess the association between patients’ age or baseline BMI on the progress of gallstone formation.

Methods

Study design

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [17]. The methodology followed the standards outlined in the Cochrane Handbook for Systematic Reviews of Interventions [18]. The study was registered on PROSPERO and assigned the following code: CRD420251004594 before data extraction. The study did not receive any funding.

Eligibility criteria

The PICOS framework, as shown in Table 1, was used to guide study selection and ensure a focused clinical question. (i) Population: Adult patients (aged ≥ 18 years) who underwent laparoscopic SG, RYGB, or OAGB as a primary bariatric procedure, with no history of gallstones or biliary pathology documented by ultrasound examination preoperatively. (ii) Intervention: Postoperative administration of UDCA at any dose, formulation, or duration to prevent gallstone formation, including both fixed-dose and weight-adjusted regimens. (iii) Comparator: Placebo, standard postoperative care, or no prophylactic treatment. (iv) Other: The selected studies included only RCTs, while observational studies, case reports, reviews, editorials, and nonrandomized interventions were excluded. Studies published in English or with available English abstracts were considered eligible. Finally, studies including multiple surgical modalities were eligible only if they included both gastric sleeve and gastric bypass and reported gallstone rates for each procedure separately.

Table 1.

PICO framework

Domain	Inclusion criteria	Exclusion criteria
Population	Adults aged 18 years or older undergoing primary LSG, RYGB, or OAGB, with no preoperative gallstone disease on screening.	Pediatric patients, pregnant women, patients with preexisting gallstones, biliary sludge, or cholecystitis, and patients undergoing other bariatric procedures.
Intervention	Prophylactic postoperative administration of UDCA at any dose.	Other pharmacologic agents, such as UDCA, are started preoperatively, or UDCA is used for stone dissolution.
Comparator	Placebo, no treatment, or standard care.	Active drug comparators or prophylactic cholecystectomy.
Outcomes	Primary: incidence of radiologically confirmed gallstones or biliary sludge at 12–24 months. Secondary: symptomatic gallstones, cholecystectomy rates, gallstone formation at 6 months, and between 6 and 12 months. Change of BMI at 12 months and %EWL at 12 months	Studies reporting only biochemical endpoints without clinical or radiological gallstone data.
Study design	RCTs.	Observational studies, case reports, reviews, editorials, and non-randomized designs.
Other	Minimum follow-up of six months. Full text or only- abstract available in English.	Follow-up less than six months or unavailable full text or data.

Study outcomes

The Primary outcome was radiologically confirmed gallstone formation or biliary sludge following surgery at the last follow-up time (12–24 months). Secondary outcomes included the incidence of symptomatic gallstones, cholecystectomy rate, gallstone formation at 6-month follow-up time, and between 6 and 12 months of follow-up time. Finally, BMI change at 12 months and Percentage of excess weight loss (%EWL) at 12 months were assessed as an exploratory analysis. These two outcomes were not presented primarily in the protocol registered on PROSPERO; however, we aimed to further explore the impact of UDCA on patients undergoing bariatric surgery.

Information sources and search strategy

We conducted a comprehensive search for targeted RCTs and the following databases were searched: PubMed/MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), Embase via Ovid, Scopus, Clinicaltrials.gov, and Google Scholar. The reference lists of included trials and relevant reviews were manually screened for additional trials. A representative PubMed query combined UDCA terms with metabolic bariatric surgery and gallstone terms, and then filtered the results for RCTs. The terms included medical subject headings and text words such as (ursodeoxycholic acid OR ursodiol OR UDCA) AND (sleeve gastrectomy OR gastric sleeve OR Roux-en-Y, RYGB OR weight loss) AND (cholelithiasis OR gallstone OR biliary sludge) AND (randomized OR placebo OR clinical trial). No language restrictions were applied. During the search stage, only studies written in English or with English abstracts and sufficient extractable data were included in the final analysis. The complete and exact search strategy is provided in Supplementary Table S1.

Study selection

Study selection was performed independently using Covidence software [19]. The records were imported, and duplicates were removed in the software. Intra-rater reliability test was performed by randomly selecting 10% of the records (50 studies) for independent title and abstract screening by two reviewers. Cohen’s kappa showed a substantial agreement between the two reviewers ( K = 0.623). The analysis was made using an Excel sheet via the proper equation of the kappa agreement results. Detailed results are presented in supplementary materials Table S2. Titles and abstracts were screened using the eligibility criteria by two independent authors, and the results were entered into the full text screening. The full texts of potentially eligible reports were retrieved and assessed for inclusion. Any discrepancies between the two authors (A.A., F.A.) were resolved via discussion or consultation with a third author (A.F.K).

Data extraction and management

Two authors independently extracted the data using a standardized, pre-piloted data extraction form. The extracted information included study characteristics, such as the first author, year of publication, country, design features, and trial registration identifier. Participant characteristics were recorded, including sample size, age, sex, baseline BMI, type of MBS, and methods used for preoperative gallstone screening. Details of the intervention and comparator were collected, including UDCA formulation, daily dose, time of initiation, treatment duration, and description of the comparator.

Risk of bias assessment

Two authors independently appraised trial quality using the revised Cochrane risk-of-bias tool for randomized trials (RoB 2.0) for the primary outcome of the studies [20]. The tool assesses five domains: randomization process, deviations from intended interventions, missing outcome data, outcome measurements, and selective reporting. Each domain was judged as “low-risk,” “some concerns,” or “high-risk.” An overall risk-of-bias judgment was derived from the domain-level assessments. Disagreements were resolved by consensus. The results were presented graphically to summarize the evidence base.

Data synthesis

A random-effects meta-analysis was performed to account for anticipated clinical and methodological heterogeneity, including variation in UDCA dose, surgical procedure, and follow-up. Dichotomous outcomes were pooled as risk ratios (RRs) with 95% confidence intervals (CIs), while continuous data were pooled via mean difference (MD) with 95% CI. We also reported 95% predictive interval to estimate the potential effect size in future studies. Statistical heterogeneity was quantified using the I² statistic, as I² of.

≥ 50% indicates meaningful heterogeneity. Also, a Cochrane Q P-value < 0.1 was considered significant for homogeneity. Subgroup analyses were conducted for the primary outcome according to the surgery type, the dose of UDCA, and the duration of administration of UDCA. Also, a meta-regression model was conducted to assess the effect of age and baseline BMI on the primary outcome. Although these extra-analyses were not added in the protocol registered on PROSPERO, we decided to do them to further explore the baseline effect of UDCA. A p-value of < 0.05 was considered statistically significant. A sensitivity analysis using a leave-one-out test, Baujat plot, and influence analysis was conducted to assess the effect of each study on the heterogeneity of the results. Publication bias was assessed visually with funnel plots and a Doi plot. All analyses were conducted using R version 4.5.2 and RStudio using the following packages: “meta”, “dmetar”, and “metasens” [21–23].

Results

Study selection and literature search results

A systematic literature search identified a total of 535 records from PubMed/MEDLINE, Embase, Scopus, Google Scholar, Clinicaltrials.gov, and the Cochrane Central Register of Controlled Trials. After removing 119 duplicate records, 416 unique citations were screened according to the title and abstract. Of these, 376 records were excluded because they did not meet the predefined eligibility criteria. Forty full-text articles were retrieved, of which four could not be accessed. The remaining 36 full-text articles were then assessed for eligibility, 26 of which were excluded because of a non-randomized study design, lack of an appropriate comparator, or ineligible surgical procedures. The list of the excluded studies are provided in table S3 in the supplementary material. A total of 10 RCTs met all eligibility criteria and were included in the qualitative synthesis and quantitative meta-analysis [16, 24–32]. (Fig. 1).

Fig. 1.

PRISMA flow diagram showing study identification, screening, eligibility, and inclusion

Characteristics of the included RCTs

The characteristics of the 10 RCTs included in this review are summarized in Table 2. The trials collectively enrolled 3,575 participants. The studies were conducted across multiple regions, including North America, Europe, and the Middle East. The sample sizes ranged from 40 to 1432 participants, with most comprising predominantly female cohorts (mean age,42–46 years). The Mean baseline BMI ranged from 41 to 46 kg/m², and all studies excluded patients diagnosed with preoperative gallstones based on imaging findings. LSG was the most frequently studied procedure, included in seven studies either alone or within mixed bariatric cohorts. RYGB and OAGB were evaluated in four and three studies, respectively. Overall, the included studies comprised 1,751 patients who underwent laparoscopic sleeve gastrectomy (LSG), 1,162 patients who underwent Roux-en-Y gastric bypass (RYGB), and 469 patients who underwent one-anastomosis gastric bypass (OAGB). In the study by Sakran et al. [24], 45 patients underwent LSG, while 47 additional patients underwent either RYGB or OAGB; however, the authors did not separately report the number of patients in each bypass subgroup. Therefore, these 47 patients were not included in the procedure-specific pooled totals. In the study by Talha et al. [25], only data related to the relevant procedure were included, while other procedures were excluded from the analysis. The UDCA regimens varied across studies, daily doses ranged from 500 to 900 mg, and most regimens were initiated within the first 2 weeks postoperatively and continued for 6 months, although two trials evaluated a 12-month course [28, 30]. The comparator groups consisted of placebo, matched placebo, or no prophylactic treatment. Gallstone outcomes were primarily assessed using scheduled abdominal ultrasonography, with follow-up durations ranging from 6 months to 2 years. The baseline demographic and clinical characteristics between the intervention and control groups in the individual trials were comparable.

Table 2.

Characteristics of the included RCTs

Study ID	Design / center(s)	Country	Surgery type(s)	N (UDCA / Control)	UDCAdose, frequency, start	Duration of prophylaxis	Exclude of sludge	Preoperative screening model	US/follow-up schedule	Funding source
Sugerman 1995 [31]	RCT pilot study, single center	USA	RYGB	53/61/63/56	300 mg/ 600 mg or 1200 mg after the operation	6 months	Patients with sludge were excluded	gallbladder sonography (US)	Pre-op US, post-op US at 6 months	Ciba-Geigy Corporation. Summit. New Jersey.
Wudal 2002 [32]	RCT, single center	USA	RYGB	20/20	600 mg/day, after the recovery from the operation	6 months	Not reported	transabdominal ultrasound	Pre-op US, post-op US at 6 months	Clinical Nutrition Research Unit Award
Adams 2016 [27]	RCT, single center	USA	LSG	28 / 29	300 mg twice daily, startedimmediately postoperatively	6 months	Patients with sludge were excluded	serum testing of liver function and trans-abdominal ultrasounds	Pre-op US, post-op US at 6 and 12 months	no outside funding support
Nabil 2019 [26]	RCT, two centers	Egypt	LSG	106/111	250 mg twice daily, started post-op	6 months	Not reported	Abdominal ultrasonography	Post-op US at 3, 6, 9, 12 months	No funding
Abouzeid 2018 [28]	RCT, single center	Egyptand Saudi Arabia	LSG	44 / 45	500 mg/daystarted within 3 days post-op	12 months	Patients with sludge were excluded	transabdominal ultrasound	Post-op US at 3, 6, 9, 12 months	No funding
Pizza 2020 [29]	RCT, single center	Italy	OAGB	95 / 95	600 mg/day, started day 2 post-op	6 months	Not reported	Abdominal ultrasonography	Clinical exam + US at 3, 6, 12 months	No funding
Sakran 2020 [24]	RCT, multi- center, double- blinded	Israel	Mixed bariatric (LSG, RYGB, OAGB)	46 / 46	300 mg twice daily orally	6 months	Patients with sludge were excluded	transabdominal ultrasound 10 days preop	US at 6 months	the MIGAL-Galilee Research Institute LTD
Talha 2020 [25]	RCT, multi-center	Egypt	LSG, OAGB, GCP	1137/295	500 mg/day started post-op	6 months	Not reported	Abdominal ultrasonography	1, 3, 6, and 12 postoperativemonths and then annually	No funding
Haal 2021 [16]	RCT, multi- center, double- blinded	Netherlands	LSG, RYGB	477/490	900 mg, once daily, started postoperatively	6 months	Patients with sludge were excluded	Gallbladder ultrasonography	6 weeks and 16 weeks, and at 6, 12, and 24 months after surgery	The Netherlands Organization for Health Research and Development
Salman 2022 [30]	RCT	Egypt	LSG	130 / 128	500 mg, once daily, started post-op	12 months	Not excluded	Ultrasonography	US at 6 and 12 months	No funding

RCT Randomized Controlled Trial, LSG Laparoscopic sleeve gastrectomy, RYGB Roux-en-Y gastric bypass, OAGB One-anastomosis gastric bypass, GCP Greater curvature plication, US Ultrasound

The comparator groups were a placebo of no prophylaxis

Study outcomes

Our study revealed a significant reduction in gallstone formation at 12–24 months follow-up. UDCA was associated with 67% risk reduction of gallstone formation (RR: 0.33, 95% CI [0.23; 0.47], 95% PI: [0.127; 0.857], P value: <0.0001, I²: 57.3%, Cochrane Q p value: 0.02). UDCA was also associated with a significant 73% risk reduction in gallstone formation at 6 months (RR: 0.27, 95% CI [0.156; 0.48], 95% PI: [0.066; 1.148], P value: <0.001, I²: 49.9%, Cochrane Q p value: 0.062) and a significant 70% risk reduction of symptomatic gallstone formation (RR: 0.3085, 95% CI [0.1749; 0.5443], 95% PI: [0.0761; 1.2502], P value: < 0.0001, I²: 15.7%, Cochrane Q p value: 0.3134). See Fig. 2; Table 3.

Fig. 2.

Forest plots of A gallstone formation at 12–24 m, B gallstone formation at 6 m, and C symptomatic gallstone formation

Table 3.

Study outcomes

Outcome	Number of studies	Effect estimate*	95% CI	95% PI	P value	I2	Cochrane Q P value
Gall bladder stone formation at the last follow-up time	8	0.3301	[0.2331; 0.4675]	[0.1271; 0.8570]	< 0.0001	57.3%	0.02
Symptomatic GB stones	4	0.3085	[0.1749; 0.5443]	[0.0761; 1.2502]	< 0.0001	15.7%	0.3134
cholecystectomy rate	3	0.5904	[0.2296; 1.5187]	[0.0235; 14.8616]	0.2744	45.50%	0.1596
Gall bladder stone formation at 6 months	6	0.2743	[0.1560; 0.4823]	[0.0655; 1.1481]	< 0.0001	49.9%	0.0624
Gall bladder stone formation between 6 and 12 months	4	0.4596	[0.1953; 1.0815]	[0.1145; 1.8443]	0.075	0.00%	0.7298
%EWL	6	-1.396	[-2.4053; -0.3867]	[-3.1867; 0.3947]	0.0067	0.00%	0.5949
BMI	4	0.4353	[-0.3504; 1.2209]	[-0.8404; 1.7109]	0.2775	0.00%	0.7788
Subgroup analysis of Gall bladder stone formation according to the operation type
Sleeve Gastrectomy	4	0.2522	[0.1693; 0.3757]	[0.1321; 0.4817]	< 0.0001	0.00%	0.44
Gastric bypass	2	0.3668	[0.0861; 1.5621]		0.1	81.8%
Both used	2	0.3889	[0.2223; 0.6804]	[0.0011; 138.6690]	< 0.0001	81.20%
Subgroup analysis of Gall bladder stone formation according to the dose
600 mg	3	0.3616	[0.1509; 0.8663]	[0.0135; 9.6813]	0.02	66%	0.02
500 mg	4	0.2761	[0.2148; 0.3549]	[0.1836; 0.4151]	< 0.0001	0.00%
900 mg	1	0.5229	[0.3592; 0.7613]		< 0.0001
Subgroup analysis of Gall bladder stone formation according to the duration of the drug
6 months	6	0.3358	[0.2115; 0.5330]	[0.0888; 1.2692]	< 0.0001	67.9%	0.65
12 months	2	0.2859	[0.1710; 0.4781]	[0.0102; 8.0145]	< 0.0001	0.00%

EWL Excess weight loss

*The effect estimate used was: Relative risk for dichotomous data and mean difference for continuous data

On the other hand, no difference was observed in gallstone formation in the period of 6–12 months follow-up (RR: 0.4596, 95% CI [0.1953; 1.0815], 95% PI: [0.1145; 1.8443], P value: 0.075, I²: 0%, Cochrane Q p value: 0.7298) and cholecystectomy rate (RR: 0.5904, 95% CI [0.2296; 1.5187], P value: 0.2744, I²: 45.5%, Cochrane Q p value: 0.1596). Additionally, no difference was observed in the reduction of BMI (MD: 0.4353, 95% CI [-0.3504; 1.2209], 95% PI: [-0.8404; 1.7109], P value: 0.2775, I²: 0%, Cochrane Q p value: 0.7788), but a significant reduction in the postoperative %EWL was observed (MD: -1.396, 95% CI [-2.4053; -0.3867], 95% PI: [-3.1867; 0.3947], P value: 0.0067, I²: 0%, Cochrane Q p value: 0.5949). See Table 3 and Figures: S1: S4 in the supplementary materials.

Subgroup analysis of the gallstone formation at the last follow-up time based on the operation type showed that studies that used LSG were associated with a significant 75% risk reduction of gallstone formation, while studies that included both operations were associated with a significant 61% risk reduction. See Table 2. Another subgroup analysis based on the dose of UDCA showed that studies that used a 600 mg dose had a 76.8% risk reduction, while those that used a 500 mg dose had 64% risk reduction, and those that used a 900 mg dose had only a 47% risk reduction. Finally, a subgroup analysis based on the duration of administration of UDCA showed that administering the drug for 6 months had a 66% risk reduction, while administering it for 12 months had a 71% risk reduction. See Fig. 3 and S5, S6 in the supplementary materials.

Fig. 3.

Subgroup analysis of the gallstone formation at 12–24 m based on the UDCA dose

Meta regression

Meta regression model for the gallstone formation showed that increasing patients’ age was associated with a higher incidence of gallstone formation without statistical significant difference (SE: 0.026, 95% CI [-0.002, 0.1], P value: 0.06, I²: 33.68%, R²: 52.42%, Cochran Q P value: 0.17), while BMI was associated with decrease rate of gallstone formation but without statistical significant difference also. (SE: 0.0491, 95% CI [-0.1549, 0.0377], P value: 0.233, I²: 35.35%, R²: 18.53%, Cochran Q P value: 0.1972). See Fig. 4 and Figure S7, and Table S4 in the supplementary material.

Fig. 4.

Bubble plot of the effect of age on the gallstone formation at 12–24 m follow-up

Sensitivity analysis

Sensitivity analysis via leave-one-out test, Baujat plot, and influence analysis were performed to assess the source of heterogeneity of the outcomes. Our results showed that omitting the Salman 2022 study of cholecystectomy outcomes resulted in a significant 40% risk reduction in the cholecystectomy rate. The same finding was observed in gallstone formation at 6–12 months when omitting Adams 2016, resulting in a significant reduction of gallstone formation at 6–12 months. (supplementary materials S8-S28)

Quality assessment

Quality assessment using the Rob2 sheet revealed that only Haal [16] was assigned low risk, while the rest of the studies were assigned some concerns or high risk. Adams [27] showed a high risk due to a significant loss of follow-up time, and Nabil [26] showed a high risk due to the absence of allocation information. Abouzeid [28] raised some concerns due to loss of follow-up and the absence of a predefined study protocol. Pizza [29] and Talha [25] raised some concerns due to the open-blind method. Finally, Sakran [24] showed some concerns due to open blinding and the awareness of investigators about the drugs patients were administered. Salman [30] showed some concerns in all domains except domain 4. Finally, Wudal 2002 [32] was assigned a high risk because of missing outcome data. (Fig. 5)

Fig. 5.

Summary of risk of bias of the included studies

Publication bias

A funnel plot was generated for the primary outcome, while the Doi plot was generated for each outcome that included ≥ 5 studies. Their results showed a symmetrical funnel plot and a DOI plot, suggesting no publication bias in the gallstone formation at 12–24 m (LFK index: -0.65) and a significant asymmetry for %EWL outcome (LFK index: -3.15), while a little asymmetry was observed in the gallstone at 6 m outcome (LFK index: -1.95). See Figures S29:S32 supplementary materials.

Discussion

Rapid weight loss following metabolic bariatric surgery is associated with an increased risk of postoperative gallstone formation. UDCA has been investigated in several studies as a prophylactic therapy to prevent gallstone formation in patients without preoperative gallstones undergoing MBS, including LSG and RYGB. Our study aimed to pool the previous RCTs to better evaluate the effectiveness of UDCA in preventing gallstone formation, determine the most effective dosage, and assess its impact on cholecystectomy rates. Our analysis showed that UDCA significantly reduced gallstone formation after MBS. The incidence of gallstones at 12–24 months was approximately 7.3% in the UDCA group compared with 24.5% in the control group, representing a 70% risk reduction. The pathophysiology of gallstone formation following MBS is multifactorial. Rapid weight loss leads to increased cholesterol mobilization and bile supersaturation [33]. In addition, reduced oral intake results in less gallbladder contraction and, consequently, bile stasis, further promoting stone formation [33]. In RYGB, reduced intestinal cholesterol absorption results in decreased formation of low-density lipoprotein. Consequently, hepatic cholesterol synthesis increases as a compensatory mechanism, increasing biliary cholesterol concentration [34]. This process, combined with increased mucin secretion, facilitates cholesterol aggregation and gallstone formation [33–37]. UDCA acts by decreasing cholesterol synthesis and reducing bile acid toxicity, ultimately lowering cholesterol saturation in bile and reducing gallstone formation [37]. Our findings support this proposed mechanism.

We also found that the UDCA demonstrated a significant protective effect as early as 6 months postoperatively, with an estimated 73% risk reduction in gallstone risk. This effect was similar to that observed at the 12-24-month follow-up. However, the 6–12 month interval did not demonstrate a statistically significant reduction of gallstone formation, indicating that the effect of UDCA occurs early in the postoperative period, when rapid weight loss and metabolic changes are most pronounced, and remains constant during longer follow-up. Another important note is that most studies used UDCA for only 6 months, and the current study found that the reduction of gallstone formation was achieved mostly in the first 6 months (period of taking UDCA), which indicates that the interruption of taking UDCA may lead to an increase in the gallstone incidence. However, due to the small number of studies with the small sample size, this could be only an association, not a definitive conclusion, and must be further explored with further studies. Despite these findings, the Haal 2021 trial used a 900 mg daily dose of UDCA for 6 months, and their results showed a statistically significant reduction in gallstone formation at 24 months. Also, because the number of population in the Haal 2021 [16] was large alongside their methodological rigor, their findings are more representative than our exploratory results, so again several studies should be conducted to further assess the effect of UDCA for preventing gallstone formation between 6 and 12 months.

Our findings are consistent with previous literature. Ying et al., in a meta-analysis including both cohorts and RCTs, reported that UDCA was associated with 80% risk reduction in gallstones [38]. Similarly, Sharma et al. demonstrated a 73% risk reduction, with trial sequential analysis confirming the robustness of these findings [39]. Mulliri et al. reported comparable results, showing a 74% reduction in gallstone incidence [40]. Beyond prevention, UDCA can also dissolve pre-existing gallstones. Buyuker et al., in a retrospective cohort study, found that UDCA dissolved gallstones in about 43.1% of patients at 6 months and 56.8% at 12 months, compared with 0% and 0.3%, respectively, in the control group [41]. Furthermore, Lee et al. in an RCT involving patients undergoing gastrectomy for gastric cancer showed that UDCA reduced gallstone formation by 73% at a dose of 300 mg and by 80% at a dose of 600 mg daily compared with placebo [42]. Collectively, these findings support the efficacy of UDCA in both preventing and treating gallstone formation.

Vagal nerve injury may also contribute to gallstone development due to impaired gallbladder motility. Little et al. reported a 28% increase in gallstone incidence three years after abdominal surgery [43]. Moreover, studies in gastric cancer surgery demonstrated that procedures disrupting the vagus nerve increased the incidence of gallstones, whereas preservation of its hepatic branch reduced this risk [43–46]. With regards to MBS, Silva-Chavez et al. reported in a systematic review of observational studies comparing LSG and RYGB, that LSG was associated a lower risk of gallstone formation, with a 32% relative risk reduction and approximately 41% lower incidence within the first two postoperative years [47].

To further evaluate the impact of surgical technique, we performed a subgroup analysis based on the type of MBS. UDCA reduced gallstone formation by about 75% in patients undergoing LSG and by 83.3% in those undergoing gastric bypass, either RYGB or OAGB. Studies including both procedures showed 61.1% risk reduction. Despite the reduction being higher in gastric bypass surgeries, the results must be interpreted with caution, as only one study included patients with RYGB, and another study included OABG, while several studies reported them with gastric sleeve without differentiation between their results. Overall, these findings should be further explored in another primary studies to further assess the difference. Our results were consistent with Sharma et al. and Magouliotis et al., who found no difference in gallstone formation based on the type of bariatric procedure [13, 39].

The dose and duration of UDCA remain crucial considerations in clinical practice. Our subgroup analysis showed that doses of 500 mg and 600 mg daily were associated with substantial risk reductions (72.39% and 76.76%, respectively). In contrast, the 900 mg daily dose showed only about 48% risk reduction; however, this finding likely reflects this dose being evaluated in only one study Haal. Previous studies have reported that lower doses, such as 300 mg daily, are not effective, whereas doses of 500–600 mg or even more than 1000 mg daily provide optimal benefit, which aligns with our findings [38]. However, doses exceeding 1000 mg daily have been associated with poor compliance and higher discontinuation rates [31, 38, 48]. Moreover, Magouliotis et al. reported no difference between 500 mg once daily and 250 mg twice daily [13], while another study suggested that a dose of 500 mg once daily is effective following LSG and 600 mg once daily after RYGB [7]. Overall, current evidence supports a daily dose of approximately 500–600 mg as an effective and well-tolerated regimen [16].

With regards to treatment duration, our results showed that 6 months of UDCA therapy reduced gallstone formation by 66.22%, whereas extending treatment to 12 months increased the risk reduction to 76%. Hence, prolonging therapy to one year may further reduce gallstone incidence. But if patient compliance is of concern, a 6-month course is still beneficial.

Patient characteristics may also influence the effectiveness of UDCA. Our regression analysis showed that increasing age was associated with increasing gallstone formation, while baseline BMI was associated with a reduction of the UDCA efficacy in reducing gallstone formation at 12–24 months. Despite this, their results did not reach statistical significant effect. The association with age may be related to confounding factors such as decreased intestinal drug absorption or comorbidities such as hyperlipidaemia. Further studies are essential to clarify this relationship. The non-significant difference observed in the effect of baseline BMI is clinically useful, as it suggests that UDCA dosing does not need to be adjusted based on patient weight. We also should interpret these results with caution because the regression model included only 7–8 studies, which is lower than the recommended number by the Cochrane handout, so this may be interpreted as an exploratory analysis only, and further studies are needed to further assess this effect. Another important note is that the previous studies suggested that the rapid loss of weight was associated with an increase in gallstone formation [44]. In our results, a significant reduction in the EWL change was observed in the UDCA group, so because the rapid reduction in the weight loss was associated with increase the gallstone formation in the previous studies, our study suggested that the UDCA effectively prevent the formation of gallstone despite the rapid reduction in the weight. Despite that, our publication bias found a significant deviation in the EWL results so the results should be further investigated in future results.

Most gallstones formed following MBS remain asymptomatic. Previous studies showed that symptomatic gallstones occur in about 3 to 22.9% of patients who did not receive prophylactic therapy [49–52]. In our study, we found that UDCA significantly reduced the risk of symptomatic gallstone formation by approximately 70%, which is consistent with previous meta-analysis reporting reductions ranging from 69 to 76% [38, 53]. Nevertheless, continued follow-up remains crucial to avoid serious complications that may arise from asymptomatic gallstones, including cholecystitis, obstructive jaundice, or pancreatitis [10].

Finally, UDCA was also associated with a 41% risk reduction in the cholecystectomy rate; however, the results did not reach a statistically significant difference. Historically, prophylactic cholecystectomy was performed in all patients undergoing MBS using open surgery, regardless of the gallstone status [54]. However, with the advances in surgical procedures, this concept has changed. Current practices vary across regions, with some centres in China advocating routine cholecystectomy during MBS, whereas many European guidelines discourage prophylactic cholecystectomy in asymptomatic patients [55]. Our findings support a selective strategy in which cholecystectomy is reserved for symptomatic patients due to the technical challenge associated with performing cholecystectomy after bariatric procedures. Again, this result is consistent with previous studies, which showed a reduction ranging from 66 to 76% [38].

Strengths and limitations of the study

This systematic review has several strengths. First, only RCTs were included to minimize confounding factors and strengthen the internal validity of the pooled estimates. This review also incorporates contemporary evidence, including large multicenter trials, thereby enhancing the statistical power and relevance to current bariatric practice. Further, compared to previous meta-analyses of UDCA prophylaxis after metabolic bariatric surgery, this review provides a more comprehensive and methodologically robust synthesis of the available evidence. Contrastingly, the present review incorporated contemporary randomized data, including the large multicenter UPGRADE trial, and separately evaluated radiological outcomes and clinically relevant endpoints such as symptomatic gallstones and cholecystectomy. Methodological rigor was ensured through protocol registration, PRISMA-compliant reporting, application of the Cochrane Risk of Bias 2.0 tool, use of random-effects models, and formal assessment of publication bias, which further strengthens the transparency and reliability of our findings.

Some limitations exist and must be identified. First, the relatively small number of studies included and the small sample size of the patients in the studies. Also, most studies were assigned some concerns and high risk in the quality assessment, which reduces the strength of the study. In terms of the rate of gallstone formation, most of the included studies assessed it after LSG, while few studies assessed it after gastric bypass, which made it underpowered to compare the two procedures effectively. Finally, female patients were predominant in the included studies, which again limits the generalizability of the results.

Conclusion

Our findings indicate that prophylactic UDCA effectively prevents gallstone formation after metabolic bariatric surgery. It reduces the incidence of gallstone formation and symptomatic gallstones; however, no statistically significant difference was observed in the cholecystectomy rate. A dose of 500–600 mg daily administered for 6–12 months represents an effective option. Increasing age and baseline BMI appear not to affect the gallstone formation rates. Routine UDCA prophylaxis may be effective in preventing gallstone formation; however, further studies are needed to assess its effect on cholecystectomy rate. Future studies should aim to establish standardized dosing regimens, durations, and patient selection criteria to optimize UDCA benefits for gallstone prevention after metabolic bariatric surgery.

Abbreviations

BMI

Body mass index

CI

Confidence interval

UDCA

Ursodeoxycholic acid

I²

Inconsistency index

LSG

Laparoscopic sleeve gastrectomy

RYGB

Roux-en-Y gastric bypass

OAGB

One Anastomosis Gastric Bypass

PRISMA

Preferred Reporting Items for Systematic Reviews and Meta-Analyses

RCT

Randomized controlled trial

RR

Risk ratio

RoB 2

Revised Cochrane Risk of Bias tool

PROSPERO

Prospective Register of Systematic Reviews

Authors' contributions

A.A. and F.A. contributed to study conception, data analysis, study supervision, and manuscript drafting. A.A., F.A., and A.F.A. conducted the literature review and investigation. A.A., F.A., A.F.A., S.A., and N.A. contributed to study design, data collection, data validation, data interpretation, and critical revision of the manuscript for important intellectual content. All authors read and approved the final version of the manuscript.

Funding

Not applicable.

Data availability

All data are available within the manuscript and its supplemental files.

Declarations

Ethics approval and consent to participate

Not required, as this research was a systematic review and meta-analysis.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.