Long term efficacy and safety of orlistat for type 1 hyperlipoproteinemia: a randomized, double-blind, placebo-controlled trial

摘要 I型高脂蛋白血症（T1 HLP，也称为家族性乳糜微粒血症综合征或FCS）是一种罕见的， 一种常染色体隐性遗传的代谢紊乱，特征是由于缺乏 脂蛋白脂肪酶或相关蛋白质。这些患者的治疗是具有挑战性的，因为传统的甘油三酯- 降低血糖的药物，如贝特类和鱼油，是无效的。然而，极低脂肪的饮食是有帮助的， 尽管有良好的饮食依从性，但一些患者仍有严重的高血糖和复发性高血糖。 胰腺炎可能危及生命。迫切需要开发新的治疗选择， 这些患者，因为目前，没有FDA批准的药物。我们最近的初步数据来自一个 奥利司他（一种肠脂肪酶抑制剂）的随机、开放标签、四阶段、两序列临床试验 （“奥利司他”和“停用奥利司他”3个月），交叉研究设计，在两名年轻男性（11岁和9岁）中， T1 HLP显示空腹血清甘油三酯降低超过50%，副作用极小。然而，在这方面， 奥利司他治疗儿童和成人T1 HLP的长期疗效和安全性仍然未知。 长期使用奥利司他的潜在并发症包括脂溶性维生素缺乏，脂肪酸， 高尿酸性肾结石和粪便微生物群的改变。 因此，我们希望研究奥利司他降低血清甘油三酯水平的长期疗效和安全性， T1 HLP患者我们计划入组28例T1 HLP（空腹血清甘油三酯≥ 1，000 mg/dL）患者， 随机、双盲、安慰剂对照、交叉试验，具有开放标签扩展。放映后 评估时，将建议受试者食用极低脂肪饮食（脂肪占总能量的≤15%）， 整个研究期间。在8周基线期后，他们将被随机分配到安慰剂组 或奥利司他持续24周（第1阶段）。1期后，所有患者将进入开放标签扩展期 （阶段2）并接受奥利司他24周，总持续时间为48周。月最后一周 基线期、I期和II期第24周时，患者将进入住院临床研究中心， 研究单位连续4天测量血清脂蛋白和化学面板连续3天，脂溶性 维生素水平，24小时尿草酸盐和结石风险概况，矿物质平衡，72小时粪便脂肪，粪便微生物群， 肝脏甘油三酯、肝脏和脾脏体积，并将完成胃肠道和生活质量问卷。 主要终点为空腹血清甘油三酯。次要终点变量为载脂蛋白 B-48水平，肝脏脂肪含量和体积。将通过测量脂溶性维生素水平、体内 体重、生活质量、胃肠道症状、草酸尿、粪便脂肪排泄和粪便微生物群。 广义线性混合模型将用于统计比较。我们的数据将决定长期的 奥利司他治疗T1 HLP患者的安全性和有效性，奥利司他可能成为一线治疗， 作为这些患者极低脂肪饮食的辅助。

Abstract Type I hyperlipoproteinemia (T1HLP, also known as familial chylomicronemia syndrome or FCS) is a rare, autosomal recessive metabolic disorder characterized by extreme hypertriglyceridemia due to a deficiency of lipoprotein lipase or related proteins. Treatment of these patients is challenging as conventional triglyceride- lowering medications, such as fibrates and fish oil, are ineffective. An extremely low fat diet is helpful, however, despite good dietary compliance, some patients continue to have severe hypertriglyceridemia and recurrent pancreatitis which can be life threatening. There is a pressing need for developing novel therapeutic options for these patients, as currently, there is no FDA approved medication. Our recent preliminary data from a randomized, open-label, clinical trial of orlistat (an inhibitor of intestinal lipase) with a four-period, two- sequence (“orlistat” and “off orlistat” for 3 months), crossover study design in two young males (11 and 9 years old) with T1HLP revealed more than 50% reduction in fasting serum triglycerides with only minimal side effects. However, the long-term efficacy and safety of orlistat therapy for children and adults with T1HLP remains unknown. Potential complications of long-term orlistat use include deficiencies in fat soluble vitamins, steatorrhea, hyperoxaluric nephrolithiasis, and alteration in fecal microbiota. Therefore, we wish to study the long-term efficacy and safety of orlistat for reducing serum triglyceride levels in patients with T1HLP. We plan to enroll 28 patients with T1HLP (fasting serum triglycerides ≥ 1,000 mg/dL) in a randomized, double-blind, placebo-controlled, cross-over trial with an open-label extension. After a screening evaluation, the subjects will be advised to consume an extremely low fat diet (≤15% of total energy from fat) for the entire duration of the study. After the baseline period of 8 weeks, they will be randomly assigned to placebo or orlistat for the duration of 24 weeks (Phase 1). After Phase 1, all patients will enter an open-label extension (Phase 2) and receive orlistat for a period of 24 weeks for a total duration of 48 weeks. During the last week of Baseline Period, Phase 1, and at 24 weeks of Phase 2, patients will be admitted to the in-patient Clinical Research Unit for 4 days to measure serum lipoproteins and chemistry panel for 3 consecutive days, fat-soluble vitamin levels, 24 hour urine oxalate and stone risk profile, mineral balance, 72 hour fecal fat, fecal microbiota, hepatic triglyceride, liver and spleen volume, and will complete gastrointestinal and quality of life questionnaires. The primary endpoint will be fasting serum triglycerides. The secondary endpoint variables will be apolipoprotein B-48 levels, liver fat content and volume. Safety will be assessed by measuring fat soluble vitamins levels, body weight, quality of life, gastrointestinal symptoms, oxalic aciduria, fecal fat excretion and fecal microbiota. Generalized linear mixed models will be used for statistical comparisons. Our data will determine long-term safety and efficacy of orlistat therapy for patients with T1HLP and orlistat may become the first line therapy as an adjunct to extremely low fat diet in these patients.