背景:来自一项为期2年的随机对照试验(CRAD001ADE12)的先前数据表明,依维莫司抑制哺乳动物雷帕霉素靶蛋白(mTOR)可减缓常染色体显性多囊肾病(ADPKD)患者的囊肿生长。在审判期间,我们注意到一些患者体重减轻,尤其是女性。我们假设依维莫司通过减少食物摄入和/或代谢变化导致体重减轻,会导致恶病质.
方法:在CRAD001ADE12试验的子分析中,研究了433例成人ADPKD患者的体重过程中的性别差异(依维莫司,n=215;安慰剂,n=218)。参加柏林临床试验中心的111名患者中有104名接受了依维莫司/安慰剂治疗(药物:依维莫司,n=48;安慰剂,n=56)和治疗后(停药:依维莫司,n=15;安慰剂,n=18)。通过有效的问卷评估饮食习惯和营养/热量摄入。通过使用量热法和脂肪/肌肉组织微透析评估了四名患者口服葡萄糖负荷(OGL)后的全身和局部代谢。
结果:在为期2年的CRAD001ADE12试验中,依维莫司组的女性患者与安慰剂组相比体重显著下降(P=0.0029).柏林队列的数据显示,依维莫司组的女性体重减轻比男性更大(P<0.01)。9个月后,男女体重减轻了2.6±3.8和0.8±1.5公斤(P<0.05),分别,21个月后,他们损失了4.1±6.6和1.0±3.3公斤(P<0.05),分别。在依维莫司上,女性热量摄入明显低于男性(1510±128vs.2264±216千卡/天,P<0.05),主要是由于女性和男性的脂肪和蛋白质摄入量较低。认知约束,抑制和饥饿保持不变。在一组患者中,静息代谢率不变,而OGL诱导的产热减少(7±2vs.11±2千卡,P<0.05)。与关闭依维莫司相比,空腹和OGL诱导的脂肪氧化增加(P<0.05)。在脂肪组织中,空腹脂解活动增加,但在OGL开启与关闭依维莫司后,脂解活性受到类似的抑制,分别。在骨骼肌中,服用依维莫司的患者餐后葡萄糖摄取和有氧糖酵解降低。
结论:依维莫司对mTOR的抑制可诱导体重减轻,特别是女性患者。这种作用可能是由中枢介导的食物(脂肪和蛋白质)摄入减少以及中枢/外周介导的脂肪氧化(全身)和动员(脂肪组织)增加引起的。骨骼肌中葡萄糖的摄取和氧化可能降低。这可能会导致恶病质,可能,肌肉萎缩.因此,我们的结果对接受免疫抑制性mTOR抑制治疗的患者具有重要意义.
Previous data from a 2-year randomized controlled trial (CRAD001ADE12) indicated that mammalian target of rapamycin (mTOR) inhibition by everolimus slowed cyst growth in patients with autosomal-dominant polycystic kidney disease (ADPKD). During the trial, we noted body weight loss in some patients, particularly in women. We hypothesized that everolimus causes body weight reduction by reduced food intake and/or metabolic changes, which could lead to cachexia.
Within a sub-analysis of the CRAD001ADE12 trial, body weight course was investigated regarding sex-specific differences in 433 adult ADPKD patients (everolimus, n = 215; placebo, n = 218). One hundred four out of 111 patients who participated in the clinical trial centre in Berlin were evaluated under everolimus/placebo therapy (on drug: everolimus, n = 48; placebo, n = 56) and after therapy (off drug: everolimus, n = 15; placebo, n = 18). Eating habits and nutrient/caloric intake were evaluated by validated questionnaires. Systemic and local metabolism was evaluated in four patients after an oral glucose load (OGL) by using calorimetry and adipose/muscle tissue microdialysis.
Within the 2-year CRAD001ADE12 trial, a significant body weight loss was observed in female patients on everolimus versus placebo (P = 0.0029). Data of the Berlin Cohort revealed that weight loss was greater in women on everolimus versus men (P < 0.01). After 9 months, women and men had lost 2.6 ± 3.8 and 0.8 ± 1.5 kg (P < 0.05) in body weight, respectively, and after 21 months, they had lost 4.1 ± 6.6 and 1.0 ± 3.3 kg (P < 0.05), respectively. On everolimus, caloric intake was significantly lower in women versus men (1510 ± 128 vs. 2264 ± 216 kcal/day, P < 0.05), caused mainly by a lower fat and protein intake in women versus men. Cognitive restraints, disinhibition and hunger remained unchanged. In a subgroup of patients resting metabolic rate was unchanged whereas OGL-induced thermogenesis was reduced (7 ± 2 vs. 11 ± 2 kcal, P < 0.05). Fasting and OGL-induced fat oxidation was increased (P < 0.05) on versus off everolimus. In adipose tissue, fasting lipolytic activity was increased, but lipolytic activity was inhibited similarly after the OGL on versus off everolimus, respectively. In skeletal muscle, postprandial glucose uptake and aerobic glycolysis was reduced in patients on everolimus.
mTOR inhibition by everolimus induces body weight reduction, specifically in female patients. This effect is possibly caused by a centrally mediated reduced food (fat and protein) intake and by centrally/peripherally mediated increased fat oxidation (systemic) and mobilization (adipose tissue). Glucose uptake and oxidation might be reduced in skeletal muscle. This could lead to cachexia and, possibly, muscle wasting. Therefore, our results have important implications for patients recieving immune-suppressive mTOR inhibition therapy.