Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands; Department of Internal Medicine, Spaarne Gasthuis, Hoofddorp, Netherlands.
Department of Internal and Vascular Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, Netherlands; Department of Internal Medicine, Spaarne Gasthuis, Hoofddorp, Netherlands.
Lancet Gastroenterol Hepatol. 2021 Dec;6(12):993-1001. doi: 10.1016/S2468-1253(21)00301-0. Epub 2021 Oct 27.
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.
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.
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.
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.
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.
快速减肥是胆固醇结石形成的一个主要危险因素。因此，接受减重手术的病态肥胖患者常发生有症状的胆囊结石病。本试验评估了熊去氧胆酸对比安慰剂用于预防减重手术后有症状的胆囊结石病。
这项多中心、双盲、随机、安慰剂对照的优效性试验纳入了荷兰三家医院接受腹腔镜 Roux-en-Y 胃旁路术（RYGB）或袖状胃切除术的完整胆囊的患者。患者通过基于网络的随机模块按 1:1 比例随机分配，每天接受 900mg 熊去氧胆酸治疗 6 个月或匹配的安慰剂。随机分组按基线时无症状胆囊结石的存在和手术类型分层。患者、临床医生和研究人员对治疗分配均设盲。主要终点是 24 个月内有症状的胆囊结石病，在改良意向治疗人群中评估（所有随机分组且有任何随机后测量的合格患者）。基于分层组进行了预先指定的亚组分析。在至少服用了一剂研究药物的所有患者中评估安全性。这项试验在荷兰试验注册中心注册，NL5954。
2017 年 1 月 11 日至 2018 年 10 月 22 日期间，纳入 985 例患者随机接受熊去氧胆酸（n=492）或安慰剂（n=493）治疗。967 例患者纳入改良意向治疗人群，其中 959 例有主要终点评估的数据。189 例（20%）患者基线时无症状胆囊结石，78 例（8%）接受了袖状胃切除术。熊去氧胆酸组 475 例患者中有 31 例（6.5%）发生有症状的胆囊结石病，安慰剂组 484 例患者中有 47 例（9.7%）发生（相对风险 0.67，95%CI 0.43-1.04，p=0.071）。逻辑回归显示熊去氧胆酸与基线时无症状胆囊结石的存在之间存在显著的交互作用（p=0.046），在无胆囊结石的患者中，熊去氧胆酸有作用（0.47，0.27-0.84，p=0.0081），而在基线时无症状胆囊结石的患者中无作用（1.22，0.61-2.47，p=0.57）。在无基线胆囊结石的 RYGB 患者中作用更强（0.37，0.20-0.71，p=0.0016），而接受袖状胃切除术的患者亚组太小，无法得出明确结论。不良事件罕见。熊去氧胆酸组 444 例患者中有 4 例（0.9%）发生腹泻，2 例（0.5%）发生皮疹；安慰剂组 453 例患者中有 2 例（0.4%）发生腹泻，2 例（0.4%）发生皮疹。试验组之间严重不良事件的总数无显著差异（熊去氧胆酸组 444 例患者中有 75 例[17%]，安慰剂组 453 例患者中有 102 例[23%]）。最常见的严重不良事件是腹痛和内疝。没有严重不良事件归因于研究药物。
熊去氧胆酸预防治疗并不能显著降低所有接受减重手术后患者有症状的胆囊结石病的发生。在 RYGB 手术前无胆囊结石的患者中，与安慰剂相比，熊去氧胆酸治疗可降低有症状的胆囊结石病的发生。需要进一步研究评估熊去氧胆酸在袖状胃切除术后的疗效。
荷兰健康研究与发展组织、赞邦荷兰 BV、斯劳特瓦特医院临床研究基金会、斯帕恩加斯图伊斯学术协会和阿姆斯特丹胃肠内分泌代谢学会。
