Larsen Julie R, Vedtofte Louise, Jakobsen Mathilde S L, Jespersen Hans R, Jakobsen Michelle I, Svensson Camilla K, Koyuncu Kamuran, Schjerning Ole, Oturai Peter S, Kjaer Andreas, Nielsen Jimmi, Holst Jens J, Ekstrøm Claus T, Correll Christoph U, Vilsbøll Tina, Fink-Jensen Anders
Psychiatric Centre, University of Copenhagen, Copenhagen, Denmark2currently with Novo Nordisk A/S, Bagsværd, Denmark.
Center for Diabetes Research, Gentofte Hospital, University of Copenhagen, Copenhagen, Denmark.
JAMA Psychiatry. 2017 Jul 1;74(7):719-728. doi: 10.1001/jamapsychiatry.2017.1220.
Compared with the general population, patients with schizophrenia have a 2- to 3-fold higher mortality rate primarily caused by cardiovascular disease. Previous interventions designed to counteract antipsychotic-induced weight gain and cardiometabolic disturbances reported limited effects.
To determine the effects of the glucagon-like peptide-1 receptor agonist liraglutide added to clozapine or olanzapine treatment of schizophrenia spectrum disorders.
DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical double-blind trial enrolled participants at 2 clinical sites in Denmark. Of 214 eligible participants with a schizophrenia spectrum disorder, 103 were randomized to liraglutide or placebo. Participants received stable treatment with clozapine or olanzapine, were overweight or obese, and had prediabetes. Data were collected from May 1, 2013, through February 25, 2016.
Treatment for 16 weeks with once-daily subcutaneous injection of liraglutide or placebo. Trial drug therapy was titrated during the first 2 weeks of the study.
The primary end point was change in glucose tolerance estimated by a 75-g oral glucose tolerance test result. Secondary end points included change in body weight and cardiometabolic parameters.
Of the 103 patients undergoing randomization (60 men [58.3%] and 43 women [41.7%]), 97 were included in the efficacy analysis, with a mean (SD) age of 42.5 (10.5) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 33.8 (5.9). The liraglutide and placebo groups had comparable characteristics (mean [SD] age, 42.1 [10.7] vs 43.0 [10.5] years; 30 men in each group; mean [SD] body mass index, 33.7 [5.1] vs 33.9 [6.6]). A total of 96 randomized participants (93.2%) completed the trial. Glucose tolerance improved in the liraglutide group compared with the placebo group (P < .001). Altogether, 30 liraglutide-treated participants (63.8%) developed normal glucose tolerance compared with 8 placebo-treated participants (16.0%) (P < .001; number needed to treat, 2). Body weight decreased with liraglutide compared with placebo (-5.3 kg; 95% CI, -7.0 to -3.7 kg). Reductions in waist circumference (-4.1 cm; 95% CI, -6.0 to -2.3 cm), systolic blood pressure (-4.9 mm Hg; 95% CI, -9.5 to -0.3 mm Hg), visceral fat (-250.19 g; 95% CI, -459.9 to -40.5 g), and low-density lipoprotein levels (-15.4 mg/dL; 95% CI, -23.2 to -7.7 mg/dL) occurred with liraglutide compared with placebo. Adverse events with liraglutide affected mainly the gastrointestinal tract.
Liraglutide significantly improved glucose tolerance, body weight, and cardiometabolic disturbances in patients with schizophrenia spectrum disorders treated with clozapine or olanzapine.
clinicaltrials.gov Identifier: NCT01845259.
与普通人群相比，精神分裂症患者的死亡率高出2至3倍，主要原因是心血管疾病。以往旨在对抗抗精神病药物引起的体重增加和心脏代谢紊乱的干预措施效果有限。
确定在氯氮平或奥氮平治疗精神分裂症谱系障碍的基础上加用胰高血糖素样肽-1受体激动剂利拉鲁肽的效果。
设计、地点和参与者：这项随机临床双盲试验在丹麦的2个临床地点招募参与者。在214名符合条件的精神分裂症谱系障碍参与者中，103人被随机分配接受利拉鲁肽或安慰剂治疗。参与者接受氯氮平或奥氮平的稳定治疗，超重或肥胖，且患有糖尿病前期。数据收集时间为2013年5月1日至2016年2月25日。
每日一次皮下注射利拉鲁肽或安慰剂，治疗16周。在研究的前2周对试验药物治疗进行滴定。
主要终点是通过75克口服葡萄糖耐量试验结果估计的葡萄糖耐量变化。次要终点包括体重和心脏代谢参数的变化。
在103名接受随机分组的患者中（60名男性[58.3%]和43名女性[41.7%]），97名被纳入疗效分析，平均（标准差）年龄为42.5（10.5）岁，平均（标准差）体重指数（按千克体重除以身高米的平方计算）为33.8（5.9）。利拉鲁肽组和安慰剂组具有可比的特征（平均[标准差]年龄，42.1[10.7]岁对43.0[10.5]岁；每组30名男性；平均[标准差]体重指数，33.7[5.1]对33.9[6.6]）。共有96名随机分组的参与者（93.2%）完成了试验。与安慰剂组相比，利拉鲁肽组的葡萄糖耐量有所改善（P < .001）。总共有30名接受利拉鲁肽治疗的参与者（63.8%）出现了正常的葡萄糖耐量，而接受安慰剂治疗的参与者中有8名（16.0%）（P < .001；治疗所需人数为2）。与安慰剂相比，利拉鲁肽使体重下降（-5.3千克；95%置信区间，-7.0至-3.7千克）。与安慰剂相比，利拉鲁肽使腰围减少（- 4.1厘米；95%置信区间，-6.0至-2.3厘米）、收缩压降低（-4.9毫米汞柱；95%置信区间，-9.5至-0.3毫米汞柱）、内脏脂肪减少（-250.19克；95%置信区间，-459.9至-40.5克）以及低密度脂蛋白水平降低（-15.4毫克/分升；95%置信区间，-23.2至-7.7毫克/分升）。利拉鲁肽的不良事件主要影响胃肠道。
利拉鲁肽显著改善了接受氯氮平或奥氮平治疗的精神分裂症谱系障碍患者的葡萄糖耐量、体重和心脏代谢紊乱。
clinicaltrials.gov标识符：NCT01845259。
