Witham Miles D, McDonald Claire, Wilson Nina, Rennie Katherine J, Bardgett Michelle, Bradley Penny, Clegg Andrew P, Connolly Stephen, Hancock Helen, Hiu Shaun, Nicholson Karen, Robertson Laura, Simms Laura, Steel Alison J, Steves Claire J, Storey Bryony, Wason James, von Zglinicki Thomas, Sayer Avan A
AGE Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK.
AGE Research Group, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Cumbria, Northumberland, Tyne and Wear NHS Foundation Trust and Newcastle University, Newcastle upon Tyne, UK; Queen Elizabeth Hospital, Gateshead Health NHS Trust, Gateshead, UK.
Lancet Healthy Longev. 2025 Mar;6(3):100695. doi: 10.1016/j.lanhl.2025.100695. Epub 2025 Mar 24.
Metformin has effects on multiple biological systems relevant to ageing and has been posited as a candidate therapy for sarcopenia and physical frailty. We aimed to test the efficacy and safety of metformin, a candidate geroprotector, to improve physical performance in older people with probable sarcopenia and physical prefrailty or frailty.
In this double-blind, randomised, parallel-group, placebo-controlled trial (MET-PREVENT), participants aged 65 years and older with a 4-m walk speed of less than 0·8 m/s and probable sarcopenia, characterised by low handgrip strength (<16 kg for women and <27 kg for men) or five times sit-to-stand time of longer than 15 s (or inability to complete five sit-to-stands) were recruited from primary care and hospital clinics in Gateshead and Newcastle, UK. Participants were randomly assigned (1:1), via a web-based system with minimisation to ensure balance by sex and baseline 4-m walk speed, to receive either 500 mg oral metformin or matching placebo three times a day for 4 months. The primary outcome was the adjusted between-group difference in 4-m walk speed at 4 months. The primary outcome was analysed in the intention-to-treat population (ie, all participants randomly assigned to treatment) who had complete data, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with the ISRCTN registry, ISRCTN29932357, and is now complete.
Between Aug 1, 2021, and Sept 30, 2022, 268 individuals were screened for inclusion in the trial, and 72 participants were randomly assigned to either metformin (n=36) or placebo (n=36; intention-to-treat population). Mean age was 80·4 years (SD 5·7), 42 (58%) of 72 participants were female, 30 (42%) were male, and 70 (97%) were White British. 70 (97%) of 72 participants had complete follow-up data (n=34 in the metformin group and n=36 in the placebo group). Mean 4-m walk speed at 4 months was 0·57 m/s (SD 0·19) in the metformin group and 0·58 m/s (0·24) in the placebo group (adjusted treatment effect 0·001 m/s [95% CI -0·06 to 0·06]; p=0·96). 108 adverse events occurred in 35 (100%) of 35 participants who received metformin and 77 adverse events occurred in 33 (92%) of 36 participants who received placebo, and 12 (34%) of 35 participants had hospital admissions in the metformin group versus three (8%) of 36 participants in the placebo group. One death occurred, in the metformin group (one [3%] of 35), and was judged to be unrelated to study treatment.
Metformin did not improve 4-m walk speed and was poorly tolerated in this population.
National Institute for Health and Care Research Newcastle Biomedical Research Centre.
二甲双胍对与衰老相关的多个生物系统有影响，被认为是治疗肌肉减少症和身体虚弱的候选疗法。我们旨在测试二甲双胍（一种潜在的老年保护剂）改善可能患有肌肉减少症、身体虚弱前期或虚弱的老年人身体机能的疗效和安全性。
在这项双盲、随机、平行组、安慰剂对照试验（MET - PREVENT）中，从英国盖茨黑德和纽卡斯尔的初级保健机构和医院诊所招募了年龄在65岁及以上、4米步行速度低于0.8米/秒且可能患有肌肉减少症（表现为握力低，女性<16千克，男性<27千克）或五次坐立时间超过15秒（或无法完成五次坐立）的参与者。参与者通过基于网络的系统以1:1随机分配（最小化以确保按性别和基线4米步行速度平衡），每天三次接受500毫克口服二甲双胍或匹配的安慰剂，共4个月。主要结局是4个月时4米步行速度的组间调整差异。在有完整数据的意向性分析人群（即所有随机分配接受治疗的参与者）中分析主要结局，并在所有接受至少一剂研究治疗的参与者中评估安全性。本研究已在国际标准随机对照试验编号注册中心注册，编号为ISRCTN29932357，现已完成。
在2021年8月1日至2022年9月30日期间，筛选了268人纳入试验，72名参与者被随机分配到二甲双胍组（n = 36）或安慰剂组（n = 36；意向性分析人群）。平均年龄为80.4岁（标准差5.7），72名参与者中42名（58%）为女性，30名（42%）为男性，70名（97%）为英国白人。72名参与者中的70名（97%）有完整的随访数据（二甲双胍组n = 34，安慰剂组n = 36）。4个月时，二甲双胍组的平均4米步行速度为0.57米/秒（标准差0.19），安慰剂组为0.58米/秒（0.24）（调整后的治疗效果为0.001米/秒[95%置信区间 -0.06至0.06]；p = 0.96）。接受二甲双胍的35名参与者中有35名（100%）发生了108起不良事件，接受安慰剂的36名参与者中有33名（92%）发生了77起不良事件，二甲双胍组35名参与者中有12名（34%）住院，而安慰剂组36名参与者中有3名（8%）住院。发生了1例死亡，在二甲双胍组（35名中的1名[3%]），被判定与研究治疗无关。
二甲双胍未能改善4米步行速度，且该人群对其耐受性较差。
英国国家健康与照护研究中心纽卡斯尔生物医学研究中心。
