Ursodeoxycholic Acid Use After Bariatric Surgery: Effects on Metabolic and Inflammatory Blood Markers.

BACKGROUND: In addition to the reduction of symptomatic gallstone disease, ursodeoxycholic acid (UDCA) might also have beneficial metabolic effects after bariatric surgery. We examined the impact of UDCA on liver enzymes, hemoglobin A1c (HbA1c), lipids, and inflammation markers. METHODS: Patients in the UPGRADE trial (placebo-controlled, double-blind) were randomized between UDCA 900 mg daily or placebo pills for 6 months after bariatric surgery. Patients without blood measurements pre- or 6 months postoperatively were excluded. The change in liver enzymes, Hba1c, lipids, and inflammation markers after surgery were compared between the UDCA and placebo group, followed by a postoperative cross-sectional comparison. RESULTS: In total, 513 patients were included (age [mean ± SD] 45.6 ± 10.7 years; 79% female). Preoperative blood values did not differ between UDCA (n = 266) and placebo (n = 247) groups. Increase of alkaline phosphatase (ALP) was greater in the UDCA group (mean difference 3.81 U/l [95%CI 0.50 7.12]). Change in other liver enzymes, HbA1c, lipids, and CRP levels did not differ. Postoperative cross-sectional comparison in 316 adherent patients also revealed a higher total cholesterol (mean difference 0.25 mg/dl [95%CI 0.07-0.42]), lower aspartate aminotransferase (mean difference -3.12 U/l [-5.16 - -1.08]), and lower alanine aminotransferase level (mean difference -5.89 U/l [-9.41 - -2.37]) in the UDCA group. CONCLUSION: UDCA treatment leads to a higher, but clinically irrelevant increase in ALP level in patients 6 months after bariatric surgery. No other changes in metabolic or inflammatory markers were observed. Except for the reduction of gallstone formation, UDCA has no effects after bariatric surgery.

Cost-effectiveness of ursodeoxycholic acid in preventing new-onset symptomatic gallstone disease after Roux-en-Y gastric bypass surgery.

BACKGROUND: The aim was to evaluate the cost-effectiveness and cost-utility of ursodeoxycholic acid (UDCA) prophylaxis for the prevention of symptomatic gallstone disease after Roux-en-Y gastric bypass (RYGB) in patients without gallstones before surgery. METHODS: Data from a multicentre, double-blind, randomized placebo-controlled superiority trial were used. Patients scheduled for laparoscopic RYGB or sleeve gastrectomy were randomized to receive 900 mg UDCA or placebo for 6 months. Indicated by the clinical report, prophylactic prescription of UDCA was evaluated economically against placebo from a healthcare and societal perspective for the subgroup of patients without gallstones before surgery who underwent RYGB. Volumes and costs of in-hospital care, out-of-hospital care, out-of-pocket expenses, and productivity loss were assessed. Main outcomes were the costs per patient free from symptomatic gallstone disease and the costs per quality-adjusted life-year (QALY). RESULTS: Patients receiving UDCA prophylaxis were more likely to remain free from symptomatic gallstone disease (relative risk 1.06, 95 per cent c.i. 1.02 to 1.11; P = 0.002) compared with patients in the placebo group. The gain in QALYs, corrected for a baseline difference in health utility, was 0.047 (95 per cent bias-corrected and accelerated (Bca) c.i. 0.007 to 0.088) higher (P = 0.022). Differences in costs were -€356 (95 per cent Bca c.i. €-1573 to 761) from a healthcare perspective and -€1392 (-3807 to 917) from a societal perspective including out-of-pocket expenses and productivity loss, both statistically non-significant, in favour of UDCA prophylaxis. The probability of UDCA prophylaxis being cost-effective was at least 0.872. CONCLUSION: UDCA prophylaxis after RYGB in patients without gallstones before surgery was cost-effective.

Factors associated with adherence to ursodeoxycholic acid or placebo in patients after bariatric surgery.

BACKGROUND: Ursodeoxycholic acid (UDCA) reduces symptomatic gallstone disease after Roux-en-Y gastric bypass (RYGB). The beneficial effect of UDCA is reduced by poor adherence. OBJECTIVES: We aimed to identify factors associated with poor adherence to UDCA or placebo after bariatric surgery. SETTING: Outpatient clinic and department for bariatric surgery in three hospitals in the Netherlands. METHODS: Patients in the multicenter, double-blind, randomized, placebo-controlled UPGRADE trial were assessed for adherence to 900 mg UDCA or placebo for 6 months through a pill count, inquiries during follow-up, and a questionnaire. Poor adherence was defined as the usage of <300 of 364 pills within a maximum of 8 months postoperatively. Multivariable logistic regression analysis was used to identify factors contributing to poor adherence. RESULTS: In total, 967 patients were included (mean age [standard deviation (SD)]: 45.1 [11.1] years; female: 772 [80%]; RYGB: 889 [92%]; sleeve gastrectomy: 78 [8%]), of whom 357 (37%) were poor adherers. Factors associated with poor adherence were age (OR .97; 95% confidence interval [CI] .96-.98, a decrease in age increases the odds for poor adherence), foreign origin (odds ratio [OR] 2.07; 95%CI 1.50-2.84), unemployment (OR 1.73; 95%CI 1.28-2.34), and sleeve gastrectomy (OR 1.79; 95%CI 1.06-3.01). Furthermore, a difference in adherence status was also noted for the centers of surgery. CONCLUSIONS: The adherence rate to UDCA and placebo in the UPGRADE trial was suboptimal. Several factors were independently associated with poor adherence. Our findings can help to identify patients who may benefit from extra guidance to improve adherence.

Risk Factors for Symptomatic Gallstone Disease and Gallstone Formation After Bariatric Surgery.

PURPOSE: Patients who undergo bariatric surgery are at risk for developing cholesterol gallstones. We aimed to identify risk factors that are associated with symptomatic gallstone disease and gallstone formation after bariatric surgery. MATERIALS AND METHODS: We included participants of the UPGRADE trial, a multicenter randomized placebo-controlled trial on the prevention of symptomatic gallstone disease with ursodeoxycholic acid (UDCA) after bariatric surgery. The association between patient characteristics and symptomatic gallstone disease, and gallstone formation was evaluated using logistic regression analysis. RESULTS: Of 959 patients, 78 (8%) developed symptomatic gallstone disease within 24 months. Risk factors were the presence of a pain syndrome (OR 2.07; 95% CI 1.03 to 4.17) and asymptomatic gallstones before surgery (OR 3.15; 95% CI 1.87 to 5.33). Advanced age (OR 0.95; 95% CI 0.93 to 0.97) was protective, and UDCA prophylaxis did not reach statistical significance (OR 0.64; 95% CI 0.39 to 1.03). No risk factors were identified for gallstone formation, whereas advanced age (OR 0.98; 95% CI 0.96 to 1.00), statin use (OR 0.42; 95% CI 0.20 to 0.90), and UDCA prophylaxis (OR 0.47; 95% CI 0.30 to 0.73) all reduced the risk. CONCLUSION: Young patients with a preoperative pain syndrome and/or asymptomatic gallstones before bariatric surgery are at increased risk for symptomatic gallstone disease after surgery. Whether statins, either alone or in combination with UDCA prophylaxis, can further reduce the burden of gallstones after bariatric surgery should be investigated prospectively.

Pancreatic exocrine insufficiency after bariatric surgery.

BACKGROUND: Chronic abdominal complaints after bariatric surgery may be explained by pancreatic exocrine insufficiency (PEI). OBJECTIVES: We aimed to evaluate the clinical value of the Pancreatic Exocrine Insufficiency Questionnaire (PEI-Q) as a screening tool to identify patients with a high probability of having PEI. SETTING: Outpatient clinic for bariatric surgery. METHODS: Patients scheduled for a screening or follow-up appointment were asked to complete the PEI-Q and the Gastrointestinal Quality of Life Index questionnaire (GIQLI). Postoperative patients with a high PEI-Q score (0,6) were offered a fecalelastase (FE) test (abnormal if <200 µg/g). RESULTS: Between June 2020 and February 2021, a total of 1600 of 1629 PEI-Qs were completed, 1073 (67%) of which after surgery. The postoperative group consisted mostly of females (81.9%), aged 49.0 ± 10.6 years, with a total weight loss of 30.3% ± 8.8%. Among them, 63.4% had abnormal PEI-Q scores compared with 34.9% before surgery (P < .01). In contrast, the median GIQLI score increased (119 [interquartile range (IQR), 107-129.25] versus 110 [IQR, 95-121.75]) before surgery (P < .01). Additionally, 310 FE tests were performed, of which only 11.9% was suggestive of PEI. No correlation was found between the PEI-Q scores and FE levels (c-index .55). CONCLUSION: The PEI-Q in its current version is not able to distinguish complaints of PEI and bariatric surgery itself and therefore cannot be used as a screening tool for PEI. The specificity of the FE test seems to be reduced after surgery. Future research should include a more direct pancreatic function test, which may provide more insight into PEI after bariatric surgery.

Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery (UPGRADE): a multicentre, double-blind, randomised, placebo-controlled superiority trial.

BACKGROUND: Rapid weight loss is a major risk factor for the formation of cholesterol gallstones. Consequently, patients with morbid obesity undergoing bariatric surgery frequently develop symptomatic gallstone disease. This trial assessed the efficacy of ursodeoxycholic acid versus placebo for the prevention of symptomatic gallstone disease after bariatric surgery. METHODS: This multicentre, double-blind, randomised, placebo-controlled superiority trial enrolled patients with an intact gallbladder scheduled for laparoscopic Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy in three hospitals in the Netherlands. Patients were randomly assigned (1:1) by a web-based randomisation module to receive 900 mg ursodeoxycholic acid daily for 6 months or matched placebo. Randomisation was stratified by the presence of asymptomatic gallstones at baseline and type of surgery. Patients, clinicians, and study staff were masked to treatment allocation. The primary endpoint was symptomatic gallstone disease within 24 months, assessed in the modified intention-to-treat population (all randomly assigned eligible patients with any post-randomisation measurement). Prespecified subgroup analyses were done based on the stratification groups. Safety was assessed in all patients who took at least one dose of the study drug. This trial is registered with the Netherlands Trial Register, NL5954. FINDINGS: Between Jan 11, 2017, and Oct 22, 2018, 985 patients were randomly assigned to receive either ursodeoxycholic acid (n=492) or placebo (n=493). 967 patients were included in the modified intention-to-treat population, of whom 959 had data available for primary endpoint assessment. 189 (20%) patients had asymptomatic gallstones at baseline and 78 (8%) received a sleeve gastrectomy. Symptomatic gallstone disease occurred in 31 (6·5%) of 475 patients in the ursodeoxycholic acid group and in 47 (9·7%) of 484 patients in the placebo group (relative risk 0·67, 95% CI 0·43-1·04, p=0·071). Logistic regression showed a significant interaction between ursodeoxycholic acid and the presence of asymptomatic gallstones at baseline (p=0·046), with an effect of ursodeoxycholic acid in patients without (0·47, 0·27-0·84, p=0·0081), and no effect in patients with asymptomatic gallstones at baseline (1·22, 0·61-2·47, p=0·57). The effect was stronger in patients without gallstones at baseline undergoing RYGB (0·37, 0·20-0·71, p=0·0016), whereas the subgroup of patients undergoing sleeve gastrectomy was too small to draw clear conclusions. Adverse events were rare. In the ursodeoxycholic acid group, diarrhoea occurred in four (0·9%) of 444 patients and skin rash in two (0·5%) patients. In the placebo group, diarrhoea occurred in two (0·4%) of 453 patients and skin rash in two (0·4%) patients. The total number of serious adverse events did not significantly differ between the trial groups (75 [17%] in 444 patients in the ursodeoxycholic acid group and 102 [23%] in 453 patients in the placebo group). The most common serious adverse events were abdominal pain and internal hernia. No serious adverse event was attributed to the study drug. INTERPRETATION: Ursodeoxycholic acid prophylaxis did not significantly reduce the occurrence of symptomatic gallstone disease in all patients after bariatric surgery. In patients without gallstones before RYGB surgery, ursodeoxycholic acid treatment reduced the occurrence of symptomatic gallstone disease compared with placebo. Further research is needed to assess the efficacy of ursodeoxycholic acid after sleeve gastrectomy. FUNDING: The Netherlands Organization for Health Research and Development, Zambon Netherlands BV, Foundation for Clinical Research of the Slotervaart Hospital, the Spaarne Gasthuis Academy, and Amsterdam Gastroenterology Endocrinology Metabolism.

Gallstone Formation Follows a Different Trajectory in Bariatric Patients Compared to Nonbariatric Patients.

Since obese patients form cholesterol gallstones very rapidly after bariatric surgery, in patients who did not form gallstones during preceding years, we hypothesized that gallstone formation follows a different trajectory in bariatric patients compared to nonbariatric patients. We therefore analyzed the lipid composition of gallbladder bile derived from 18 bariatric gallstone patients and 17 nonbariatric gallstone patients (median (IQR) age, 46.0 (28.0-54.0) years; 33 (94%) female) during laparoscopic cholecystectomy using an enzymatic and lipidomics approach. We observed a higher concentration of total lipids (9.9 vs. 5.8 g/dL), bile acids (157.7 vs. 81.5 mM), cholesterol (10.6 vs. 5.4 mM), and phospholipids (30.4 vs. 21.8 mM) in bariatric gallstone patients compared to nonbariatric gallstone patients. The cholesterol saturation index did not significantly differ between the two groups. Lipidomics analysis revealed an interesting pattern. Enhanced amounts of a number of lipid species were found in the gallbladder bile of nonbariatric gallstone patients. Most striking was a fivefold higher amount of triglyceride. A concomitant ninefold increase of apolipoprotein B was found, suggesting secretion of triglyceride-rich lipoproteins (TRLs) at the canalicular pole of the hepatocyte in livers from nonbariatric gallstone patients. These findings suggest that gallstone formation follows a different trajectory in bariatric patients compared to nonbariatric patients. Impaired gallbladder emptying might explain the rapid gallstone formation after bariatric surgery, while biliary TRL secretion might contribute to gallstone formation in nonbariatric patients.

Ursodeoxycholic acid for the prevention of symptomatic gallstone disease after bariatric surgery: statistical analysis plan for a randomised controlled trial (UPGRADE trial).

BACKGROUND: Approximately 8-15% of patients undergoing bariatric surgery develop symptomatic gallstone disease within 24 months after surgery. Ursodeoxycholic acid (UDCA) seems to effectively prevent the formation of gallstones detectable by ultrasound after bariatric surgery. The aim of the UPGRADE trial is to provide evidence on the prophylactic use of UDCA in preventing symptomatic gallstone disease postoperatively. METHODS: The UPGRADE trial is designed as a randomised, placebo-controlled, double-blind multicentre trial in patients with morbid obesity undergoing Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG). Patients are randomly assigned to either UDCA 900 mg daily for 6 months or placebo treatment. This paper details the statistical analysis plan (SAP) of this trial and was submitted before outcome data were available. RESULTS: The primary endpoint of this trial is symptomatic gallstone disease within 24 months after bariatric surgery, defined as admission or hospital visit for symptomatic gallstone disease. Secondary outcomes consist of the development of gallstones/sludge on ultrasound at 24 months in the gallstone-negative group at baseline, presence of gallstones/sludge on ultrasound at 24 months, number of cholecystectomies, side effects of UDCA, therapy compliance, quality of life, costs and revenues. Analyses will be completed according to this pre-specified SAP. The main analysis will be performed as a standard ITT analysis using the chi-squared test. DISCUSSION: The UPGRADE trial will show if prophylactic use of UDCA reduces the incidence of symptomatic gallstone disease after bariatric surgery. Unforeseen deviations from the SAP at the time of analysis will be motivated and discussed. TRIAL REGISTRATION: The Netherlands Trial Register NL5954 . Registered on 21 November 2016.