Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial
Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial
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DOI：
10.1016/s2213-8587(17)30398-4
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发表时间：
2018-03-01
影响因子：
44.5
通讯作者：
Lenzi, Andrea
中科院分区：
文献类型：
--
作者：
Isidori, Andrea M.;Venneri, Mary Anna;Lenzi, Andrea
背景：肾上腺功能不全患者的常规治疗包括每天多次使用糖皮质激素，这与体重增加和代谢障碍有关。由于缺乏随机试验的证据，对这些患者的最佳糖皮质激素替代疗法存在高度争议。我们的目的是确定糖皮质激素替代治疗的时间和药代动力学是否影响肾上腺功能不全患者的代谢和免疫系统。方法在意大利两所参考大学医院进行单盲随机对照试验。符合条件的肾上腺功能不全患者（年龄18-80岁）接受常规糖皮质激素治疗，入组前病情稳定至少3个月。根据肾上腺功能不全的类型和BMI指数按计算机生成的随机顺序随机分配患者（1:1），继续常规糖皮质激素治疗（标准治疗组）或转换为等量的每日一次、缓释口服氢化可的松（转换治疗组）。结果评估者不受治疗分配的影响。主要结局是体重从基线到24周的变化。次要结局包括免疫细胞谱、感染易感性和生活质量。疗效分析包括所有接受至少一剂研究药物的患者。该试验已在ClinicalTrials.gov注册，注册号为NCT02277587。在2014年3月1日至2016年6月30日期间，89例肾上腺功能不全患者被随机分配继续接受标准糖皮质激素治疗（n=43）或转换为每日一次的改型释放氢化可的松治疗（n=46）。24周时，每日一次氢化可的松组患者的体重减轻优于标准治疗组（-2.1 kg [95% CI -4.0至-0.3]vs . 1.9 kg[-0.1至3.9]；治疗差异-4.0 kg, 95% CI -6.9至-1.1;p=0.008）。此外，与标准糖皮质激素治疗组相比，每天一次的氢化可的松组患者有更正常的免疫细胞谱，对感染的易感性降低，生活质量提高。我们观察到两个干预组之间不良事件的频率和严重程度没有差异，尽管每日一次氢化可的松治疗的上呼吸道感染复发累积次数低于标准治疗（17 vs 38; p=0.016）。大多数不良事件是轻微的；两组均发生3例严重不良事件，其中转换治疗组1例不良事件（关节炎）可认为与药物相关。解释肾上腺功能不全患者每天多次接受常规糖皮质激素替代治疗，表现出促炎状态和免疫防御减弱。通过转换为每日一次的改良释放方案，恢复更生理的昼夜糖皮质激素节律，可减轻体重，使免疫细胞谱正常化，减少复发性感染，并改善肾上腺功能不全患者的生活质量。
Background Conventional treatment of patients with adrenal insufficiency involves administration of glucocorticoids multiple times a day and has been associated with weight gain and metabolic impairment. The optimal glucocorticoid replacement therapy for these patients is highly debated because of the scarcity of evidence from randomised trials. We aimed to establish whether the timing and pharmacokinetics of glucocorticoid replacement therapy affect the metabolism and immune system of patients with adrenal insufficiency.Methods We did a single-blind randomised controlled trial at two reference university hospitals in Italy. Eligible patients (aged 18-80 years) with adrenal insufficiency were on conventional glucocorticoid therapy and had been stable for at least 3 months before enrolment. Patients were randomly assigned (1: 1) with a computer-generated random sequence stratified by type of adrenal insufficiency and BMI to continue conventional glucocorticoid therapy (standard treatment group) or to switch to an equivalent dose of once-daily, modified-release oral hydrocortisone (switch treatment group). Outcome assessors were masked to treatment allocation. The primary outcome was bodyweight change from baseline to 24 weeks. Secondary outcomes included immune cell profiles, susceptibility to infections, and quality of life. Efficacy analyses included all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, NCT02277587.Findings Between March 1, 2014, and June 30, 2016, 89 patients with adrenal insufficiency were randomly assigned to continue standard glucocorticoid therapy (n=43) or to switch to once-daily, modified-release hydrocortisone (n=46). At 24 weeks, bodyweight reduction was superior in patients in the once-daily hydrocortisone group compared with those in the standard treatment group (-2.1 kg [95% CI -4.0 to -0.3] vs 1.9 kg [-0.1 to 3.9]; treatment difference -4.0 kg, 95% CI -6.9 to -1.1; p=0.008). Additionally, patients in the once-daily hydrocortisone group had more normal immune cell profiles, reduced susceptibility to infections, and improved quality of life compared with the standard glucocorticoid therapy group. We observed no difference in frequency or severity of adverse events between the two intervention groups, although a lower cumulative number of recurrent upper respiratory tract infections was observed with once-daily hydrocortisone than with standard treatment (17 vs 38; p=0.016). Most adverse events were mild; three serious adverse events occurred in each group, of which one adverse advent (arthritis) in the switch treatment group could be considered drug related.Interpretation Patients with adrenal insufficiency on conventional glucocorticoid replacement therapy multiple times a day exhibit a pro-inflammatory state and weakened immune defence. Restoration of a more physiological circadian glucocorticoid rhythm by switching to a once-daily, modified-release regimen reduces bodyweight, normalises the immune cell profile, reduces recurrent infections, and improves the quality of life of patients with adrenal insufficiency.