Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial
Improved mobility with metformin in patients with myotonic dystrophy type 1: a randomized controlled trial
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DOI：
10.1093/brain/awy231
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发表时间：
2018-10-01
期刊：
影响因子：
14.5
通讯作者：
Peschanski, Marc
中科院分区：
文献类型：
--
作者：
Bassez, Guillaume;Audureau, Etienne;Peschanski, Marc
众所周知的抗糖尿病药物二甲双胍最近已被证明可改善1型肌强直性营养不良DMSXL小鼠模型的握力测试性能。该药物可能通过几种分子机制对肌肉功能产生积极影响，如RNA剪接、自噬、胰岛素敏感性或糖原合成。强直性肌营养不良仍然是一个基本上未满足的医疗需求。由于二甲双胍具有良好的毒性特征，因此我们研究了其改善患者活动能力的潜力。在Henri-Mondor医院的神经肌肉参考中心连续招募了40名门诊成人患者。参与者和研究者在试验结束前均对治疗保持盲态。口服二甲双胍或安慰剂，每日三次，剂量递增期为4周，最高剂量为3 g/天，随后为48周最大剂量。主要结局是6分钟步行试验期间步行距离从基线到研究结束的变化。研究了肌肉力量的伴随变化以及对肌强直、步态变量、生物学参数和生活质量的影响。随机分为两组的患者最终在所有物理测量和基线平均6分钟步行试验中显示出相似的结果。对于完全完成1年研究的23/40例患者，组间差异具有统计学意义，治疗组（n = 9）增加了32.9 +/-32.7 m的距离，而安慰剂组（n = 14）增加了3.7 +/- 32.4 m（P < 0.05）。活动性的改善与总机械功率的增加相关（P = 0.01），这是由于颅侧和前后方向的伴随增加，表明治疗对步态的影响。亚组分析显示，二甲双胍治疗对第一次中期评价（治疗16周后）的6分钟步行试验有积极影响，在数量上与1年时记录的结果相似。相比之下，除了二甲双胍治疗相关的预期有限体重减轻外，其他任何次要终点（包括肌强直和肌肉力量）均无变化。治疗组患者的轻度至中度不良反应发生率较高，主要是需要对症治疗的胃肠道功能障碍。尽管结果仅在符合方案的患者人群中具有统计学显著性，而在意向治疗分析中不具有统计学显著性，但最大耐受剂量的二甲双胍对肌强直患者的活动性和步态能力具有良好的影响。这些令人鼓舞的结果，在一个小规模的单中心II期研究呼吁复制在一个良好的动力多中心III期试验。
Metformin, the well-known anti-diabetic drug, has been shown recently to improve the grip test performance of the DMSXL mouse model of myotonic dystrophy type 1. The drug may have positively affected muscle function via several molecular mechanisms, on RNA splicing, autophagia, insulin sensitivity or glycogen synthesis. Myotonic dystrophy remains essentially an unmet medical need. Since metformin benefits from a good toxicity profile, we investigated its potential for improving mobility in patients. Forty ambulatory adult patients were recruited consecutively at the neuromuscular reference centre of Henri-Mondor Hospital. Participants and investigators were all blinded to treatment until the end of the trial. Oral metformin or placebo was provided three times daily, with a dose escalation period over 4 weeks up to 3 g/day, followed by 48 weeks at maximum dose. The primary outcome was the change in the distance walked during the 6-minute walk test, from baseline to the end of the study. Concomitant changes in muscle strength and effect on myotonia, gait variables, biological parameters and quality of life were explored. Patients randomized into two arms eventually revealed similar results in all physical measures and in the mean 6-minute walk test at baseline. For the 23/40 patients who fully completed the 1-year study, differences between the groups were statistically significant, with the treated group (n = 9) gaining a distance of 32.9 +/- 32.7m, while the placebo group (n = 14) gained 3.7 +/- 32.4 m (P < 0.05). This improvement in mobility was associated with an increase in total mechanical power (P = 0.01), due to a concomitant increase in the cranial and antero-posterior directions suggesting an effect of the treatment on gait. Subanalysis revealed positive effects of metformin treatment on the 6-minute walk test at the first intermediate evaluation (after 16 weeks of treatment), quantitatively similar to those recorded at 1 year. In contrast, except for the expected limited weight loss associated to metformin treatment, there was no change in any of the other secondary endpoints, including myotonia and muscle strength. Patients in the treated group had a higher incidence of mild-to-moderate adverse effects, mostly gastrointestinal dysfunctions that required symptomatic treatment. Although results were statistically significant only for the per protocol population of patients and not in the intent-to-treat analysis, metformin at the maximal tolerated dose provided a promising effect on the mobility and gait abilities of myotonic patients. These encouraging results obtained in a small-scale monocentric phase II study call for replication in a well-powered multicentre phase III trial.