Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
Institute of Cardiovascular Science, University College London, London, UK.
Lancet Diabetes Endocrinol. 2017 Aug;5(8):597-609. doi: 10.1016/S2213-8587(17)30194-8. Epub 2017 Jun 11.
Metformin might reduce insulin requirement and improve glycaemia in patients with type 1 diabetes, but whether it has cardiovascular benefits is unknown. We aimed to investigate whether metformin treatment (added to titrated insulin therapy) reduced atherosclerosis, as measured by progression of common carotid artery intima-media thickness (cIMT), in adults with type 1 diabetes at increased risk for cardiovascular disease.
REMOVAL was a double-blind, placebo-controlled trial undertaken at 23 hospital diabetes clinics in five countries (Australia, Canada, Denmark, the Netherlands, and the UK). Adults aged 40 years and older with type 1 diabetes of at least 5 years' duration and at least three of ten specific cardiovascular risk factors were randomly assigned (via an interactive voice response system) to oral metformin 1000 mg twice daily or placebo. Participants and site staff were masked to treatment allocation. The primary outcome was averaged mean far-wall cIMT, quantified annually for 3 years, analysed in a modified intention-to-treat population (all randomly assigned participants with post-randomisation data available for the outcome of interest at any given timepoint, irrespective of subsequent adherence or study participation), using repeated measures regression. Secondary outcomes were HbA, LDL cholesterol, estimated glomerular filtration rate (eGFR), incident microalbuminuria (not reported), incident retinopathy, bodyweight, insulin dose, and endothelial function, also analysed in all participants with post-randomisation data available for the outcome of interest at any given timepoint. This trial is registered with ClinicalTrials.gov, number NCT01483560.
Between Dec 14, 2011, and June 24, 2014, 493 participants entered a 3 month run-in to optimise risk factor and glycaemic control (single-blind placebo in the final month). Of 428 randomly assigned patients, 219 were allocated to metformin and 209 to placebo. Progression of mean cIMT was not significantly reduced with metformin (-0·005 mm per year, 95% CI -0·012 to 0·002; p=0·1664), although maximal cIMT (a prespecified tertiary outcome) was significantly reduced (-0·013 mm per year, -0·024 to -0·003; p=0·0093). HbA (mean 8·1% [SD 0·9] for metformin and 8·0% [0·8] for placebo at baseline) was reduced on average over 3 years by metformin (-0·13%, 95% CI -0·22 to -0·037; p=0·0060), but this was accounted for by a reduction at the 3-month timepoint (-0·24%, -0·34 to -0·13; p<0·0001) that was not sustained thereafter (p=0·0163 for visit-by-treatment interaction). Bodyweight (-1·17 kg, 95% CI -1·66 to -0·69; p<0·0001) and LDL cholesterol (-0·13 mmol/L, -0·24 to -0·03; p=0·0117) were reduced with metformin over 3 years of treatment, and eGFR was increased (4·0 mL/min per 1·73m, 2·19 to 5·82; p<0·0001). Insulin requirement was not reduced on average over 3 years (-0·005 units per kg, 95% CI -0·022 to 0·012; p=0·545), but there was a significant visit-by-treatment interaction (p=0·0018). There was no effect on endothelial function as measured by reactive hyperaemia index, or on retinopathy. Discontinuation of treatment in 59 (27%) participants on metformin versus 26 (12%) on placebo (p=0·0002) was mainly due to an excess of gastrointestinal adverse effects, and there was no increase in hypoglycaemia with metformin. Five deaths occurred among patients allocated to metformin and two occurred among those allocated to placebo; none were judged by site principal investigators to be related to study medication.
These data do not support use of metformin to improve glycaemic control in adults with long-standing type 1 diabetes as suggested by current guidelines, but suggest that it might have a wider role in cardiovascular risk management.
JDRF.
二甲双胍可能会降低 1 型糖尿病患者的胰岛素需求并改善血糖水平，但它是否具有心血管益处尚不清楚。我们旨在研究二甲双胍治疗（添加到滴定胰岛素治疗中）是否可以减少动脉粥样硬化，动脉粥样硬化通过颈总动脉内膜中层厚度（cIMT）的进展来衡量，对于患有心血管疾病风险增加的 1 型糖尿病成年人。
REMOVAL 是一项在五个国家（澳大利亚、加拿大、丹麦、荷兰和英国）的 23 家医院糖尿病诊所进行的双盲、安慰剂对照试验。至少患有 5 年 1 型糖尿病且至少有 10 个特定心血管危险因素中的 3 个的成年患者被随机分配（通过交互式语音响应系统）接受二甲双胍 1000mg 每日两次或安慰剂。参与者和现场工作人员对治疗分配情况不知情。主要结局是平均远壁 cIMT，每年量化一次，在改良的意向治疗人群中进行分析（所有接受随机分组且在任何给定时间点均有后续随访数据的参与者，无论随后的依从性或研究参与情况如何），使用重复测量回归。次要结局是 HbA、LDL 胆固醇、估算肾小球滤过率（eGFR）、新发微量白蛋白尿（未报告）、新发视网膜病变、体重、胰岛素剂量和内皮功能，也在所有接受随机分组且在任何给定时间点均有后续随访数据的参与者中进行分析。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01483560。
2011 年 12 月 14 日至 2014 年 6 月 24 日期间，493 名患者进入了为期 3 个月的优化风险因素和血糖控制的洗脱期（最后一个月为单盲安慰剂）。在 428 名随机分配的患者中，219 名患者分配至二甲双胍组，209 名患者分配至安慰剂组。二甲双胍治疗并未显著降低平均 cIMT 的进展（每年减少 0.005 毫米，95%CI 为 0.012 至 0.002；p=0.1664），尽管最大 cIMT（一个预先指定的三级结局）显著降低（每年减少 0.013 毫米，95%CI 为 0.024 至 0.003；p=0.0093）。基线时，二甲双胍组的 HbA（平均 8.1%[0.9]）和安慰剂组的 HbA（8.0%[0.8]）在 3 年内平均降低了 0.13%（95%CI 为-0.22 至-0.037；p=0.0060），但这归因于 3 个月时的降低（-0.24%，-0.34 至-0.13；p<0.0001），此后并未持续（治疗与随访时间点的交互作用 p=0.0163）。体重（-1.17 公斤，95%CI 为-1.66 至-0.69；p<0.0001）和 LDL 胆固醇（-0.13mmol/L，95%CI 为-0.24 至-0.03；p=0.0117）在 3 年的治疗期间都有所降低，eGFR 则有所增加（4.0mL/min/1.73m，2.19 至 5.82；p<0.0001）。胰岛素需求在 3 年内平均没有降低（每公斤体重减少 0.005 单位，95%CI 为-0.022 至 0.012；p=0.545），但存在治疗与随访时间点的交互作用（p=0.0018）。反应性充血指数测量的内皮功能或视网膜病变没有受到影响。由于胃肠道不良反应过多，59 名（27%）接受二甲双胍治疗的患者和 26 名（12%）接受安慰剂治疗的患者（p=0.0002）停止了治疗，而二甲双胍治疗并未增加低血糖的发生。在接受二甲双胍治疗的患者中发生了 5 例死亡，在接受安慰剂治疗的患者中发生了 2 例死亡；没有一个被现场主要研究者认为与研究药物有关。
这些数据不支持目前指南建议的在患有长期 1 型糖尿病的成年人中使用二甲双胍来改善血糖控制，但表明它可能在心血管风险管理方面有更广泛的作用。
JDRF。
