Medical Research Council Epidemiology Unit, University of Cambridge, Cambridge, UK.
Institute of Public Health, University of Cambridge, Cambridge, UK.
Health Technol Assess. 2018 Apr;22(18):1-64. doi: 10.3310/hta22180.
BACKGROUND: The treatment of people with diabetes with metformin can reduce cardiovascular disease (CVD) and may reduce the risk of cancer. However, it is unknown whether or not metformin can reduce the risk of these outcomes in people with elevated blood glucose levels below the threshold for diabetes [i.e. non-diabetic hyperglycaemia (NDH)]. OBJECTIVE: To assess the feasibility of the Glucose Lowering In Non-diabetic hyperglycaemia Trial (GLINT) and to estimate the key parameters to inform the design of the full trial. These parameters include the recruitment strategy, randomisation, electronic data capture, postal drug distribution, retention, study medication adherence, safety monitoring and remote collection of outcome data. DESIGN: A multicentre, individually randomised, double-blind, parallel-group, pragmatic, primary prevention trial. Participants were individually randomised on a 1 : 1 basis, blocked within each site. SETTING: General practices and clinical research facilities in Cambridgeshire, Norfolk and Leicestershire. PARTICIPANTS: Males and females aged ≥ 40 years with NDH who had a high risk of CVD. INTERVENTIONS: Prolonged-release metformin (500 mg) (Glucophage SR, Merck KGaA, Bedfont Cross, Middlesex, UK) or the matched placebo, up to three tablets per day, distributed by post. MAIN OUTCOME MEASURES: Recruitment rates; adherence to study medication; laboratory results at baseline and 3 and 6 months; reliability and acceptability of study drug delivery; questionnaire return rates; and quality of life. RESULTS: We sent 5251 invitations, with 511 individuals consenting to participate. Of these, 249 were eligible and were randomised between March and November 2015 (125 to the metformin group and 124 to the placebo group). Participants were followed up for 0.99 years [standard deviation (SD) 0.30 years]. The use of electronic medical records to identify potentially eligible individuals in individual practices was resource intensive. Participants were generally elderly [mean age 70 years (SD 6.7 years)], overweight [mean body mass index 30.1 kg/m (SD 4.5 kg/m)] and male (88%), and the mean modelled 10-year CVD risk was 28.8% (SD 8.5%). Randomisation, postal delivery of the study drug and outcome assessment using registers/medical records were feasible and acceptable to participants. Most participants were able to take three tablets per day, but premature discontinuation of the study drug was common (≈30% of participants by 6 months), although there were no differences between the groups. All randomised participants returned questionnaires at baseline and 67% of participants returned questionnaires by the end of the study. There was no between-group difference in Short Form questionnaire-8 items or EuroQol-5 Dimensions scores. Compared with placebo, metformin was associated with small improvements in the mean glycated haemoglobin level [-0.82 mmol/mol, 95% confidence interval (CI) -1.39 to -0.24 mmol/mol], mean estimated glomerular filtration rate (2.31 ml/minute/1.73 m, 95% CI -0.2 to 4.81 ml/minute/1.73 m) and mean low-density lipoprotein cholesterol level (-0.11 mmol/l, 95% CI -0.25 to 0.02 mmol/l) and a reduction in mean plasma vitamin B level (-16.4 ng/l, 95% CI -32.9 to -0.01 ng/l). There were 35 serious adverse events (13 in the placebo group, 22 in the metformin group), with none deemed to be treatment related. LIMITATIONS: Changes to sponsorship reduced the study duration, the limited availability of information in medical records reduced recruitment efficiency and discontinuation of study medication exceeded forecasts. CONCLUSIONS: A large, pragmatic trial comparing the effects of prolonged-release metformin and placebo on the risk of CVD events is potentially feasible. However, changes to the study design and conduct are recommended to enable an efficient scaling up of the trial. Recommendations include changing the inclusion criteria to recruit people with pre-existing CVD to increase the recruitment and event rates, using large primary/secondary care databases to increase recruitment rates, conducting follow-up remotely to improve efficiency and including a run-in period prior to randomisation to optimise trial adherence. TRIAL REGISTRATION: Current Controlled Trials ISRCTN34875079. FUNDING: The project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 22, No. 18. See the NIHR Journals Library website for further project information. Merck KGaA provided metformin and matching placebo.
背景:在患有糖尿病的人群中使用二甲双胍治疗可以降低心血管疾病(CVD)的风险,并且可能降低癌症的风险。然而,尚不清楚二甲双胍是否可以降低血糖水平高于糖尿病阈值(即非糖尿病性高血糖症(NDH))的人群发生这些结局的风险。
目的:评估葡萄糖降低在非糖尿病性高血糖症试验(GLINT)的可行性,并估计告知完整试验设计的关键参数。这些参数包括招募策略、随机化、电子数据采集、邮寄药物分发、保留率、研究药物依从性、安全性监测和远程采集结局数据。
设计:一项多中心、个体随机、双盲、平行组、实用、初级预防试验。参与者按照 1:1 的比例进行个体随机分组,按每个站点进行分组。
地点:剑桥郡、诺福克郡和莱斯特郡的普通诊所和临床研究设施。
参与者:患有高 CVD 风险的年龄≥40 岁的男性和女性,伴有 NDH。
干预措施:延长释放二甲双胍(500mg)(Glucophage SR,Merck KGaA,Bedfont Cross,Middlesex,UK)或匹配的安慰剂,每天最多服用三片,通过邮寄分发。
主要结局测量:招募率;研究药物的依从性;基线和 3 个月及 6 个月时的实验室结果;研究药物递送的可靠性和可接受性;问卷回复率;和生活质量。
结果:我们发出了 5251 份邀请,有 511 人同意参加。其中,249 人符合条件并于 2015 年 3 月至 11 月之间进行了随机分组(125 人分到二甲双胍组,124 人分到安慰剂组)。参与者随访了 0.99 年[标准差(SD)为 0.30 年]。使用电子病历在个体实践中识别潜在的合格个体需要大量资源。参与者通常年龄较大[平均年龄 70 岁(SD 6.7 岁)]、超重[平均体重指数 30.1kg/m(SD 4.5kg/m)]和男性(88%),平均建模的 10 年 CVD 风险为 28.8%(SD 8.5%)。随机化、邮寄研究药物和使用登记册/病历进行结局评估是可行的,参与者也能够接受。大多数参与者能够每天服用三片,但研究药物的提前停药很常见(约 30%的参与者在 6 个月时停药),但两组之间没有差异。所有随机分组的参与者在基线时都返回了问卷,67%的参与者在研究结束时返回了问卷。短表-8 项和 EuroQol-5 维度评分在两组之间没有差异。与安慰剂相比,二甲双胍与糖化血红蛋白水平的平均降低相关[-0.82mmol/mol,95%置信区间(CI)-1.39 至-0.24mmol/mol]、平均估计肾小球滤过率(2.31ml/minute/1.73m,95%CI-0.2 至 4.81ml/minute/1.73m)和平均低密度脂蛋白胆固醇水平(-0.11mmol/l,95%CI-0.25 至 0.02mmol/l),并降低了平均血浆维生素 B 水平(-16.4ng/l,95%CI-32.9 至-0.01ng/l)。发生了 35 例严重不良事件(安慰剂组 13 例,二甲双胍组 22 例),没有一例被认为与治疗有关。
局限性:赞助的变化缩短了研究时间,医疗记录中信息的有限可用性降低了招募效率,研究药物的停药率超过了预测。
结论:比较长期释放二甲双胍和安慰剂对 CVD 事件风险的影响的大型实用试验是可行的。然而,建议改变研究设计和实施,以提高试验的效率。建议包括改变纳入标准,招募有预先存在的 CVD 的人群以增加招募和事件率,使用大型初级/二级保健数据库增加招募率,远程进行随访以提高效率,并在随机分组前进行纳入期,以优化试验依从性。
试验注册:当前对照试验 ISRCTN34875079。
资金:该项目由英国国家卫生研究所(NIHR)卫生技术评估计划资助,将在 ; Vol. 22,No. 18 中全文发表。请访问 NIHR 期刊库网站以获取更多项目信息。Merck KGaA 提供二甲双胍和匹配的安慰剂。
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