Adler Amanda I, Coleman Ruth L, Leal Jose, Whiteley William N, Clarke Philip, Holman Rury R
Diabetes Trials Unit, Radcliffe Department of Medicine, University of Oxford, Oxford, UK; NIHR Oxford Biomedical Research Centre, Oxford, UK.
NIHR Oxford Biomedical Research Centre, Oxford, UK; Health Economics Research Centre, University of Oxford, Oxford, UK.
Lancet. 2024 Jul 13;404(10448):145-155. doi: 10.1016/S0140-6736(24)00537-3. Epub 2024 May 18.
The 20-year UK Prospective Diabetes Study showed major clinical benefits for people with newly diagnosed type 2 diabetes randomly allocated to intensive glycaemic control with sulfonylurea or insulin therapy or metformin therapy, compared with conventional glycaemic control. 10-year post-trial follow-up identified enduring and emerging glycaemic and metformin legacy treatment effects. We aimed to determine whether these effects would wane by extending follow-up for another 14 years.
5102 patients enrolled between 1977 and 1991, of whom 4209 (82·5%) participants were originally randomly allocated to receive either intensive glycaemic control (sulfonylurea or insulin, or if overweight, metformin) or conventional glycaemic control (primarily diet). At the end of the 20-year interventional trial, 3277 surviving participants entered a 10-year post-trial monitoring period, which ran until Sept 30, 2007. Eligible participants for this study were all surviving participants at the end of the 10-year post-trial monitoring period. An extended follow-up of these participants was done by linking them to their routinely collected National Health Service (NHS) data for another 14 years. Clinical outcomes were derived from records of deaths, hospital admissions, outpatient visits, and accident and emergency unit attendances. We examined seven prespecified aggregate clinical outcomes (ie, any diabetes-related endpoint, diabetes-related death, death from any cause, myocardial infarction, stroke, peripheral vascular disease, and microvascular disease) by the randomised glycaemic control strategy on an intention-to-treat basis using Kaplan-Meier time-to-event and log-rank analyses. This study is registered with the ISRCTN registry, number ISRCTN75451837.
Between Oct 1, 2007, and Sept 30, 2021, 1489 (97·6%) of 1525 participants could be linked to routinely collected NHS administrative data. Their mean age at baseline was 50·2 years (SD 8·0), and 41·3% were female. The mean age of those still alive as of Sept 30, 2021, was 79·9 years (SD 8·0). Individual follow-up from baseline ranged from 0 to 42 years, median 17·5 years (IQR 12·3-26·8). Overall follow-up increased by 21%, from 66 972 to 80 724 person-years. For up to 24 years after trial end, the glycaemic and metformin legacy effects showed no sign of waning. Early intensive glycaemic control with sulfonylurea or insulin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 10% (95% CI 2-17; p=0·015) for death from any cause, 17% (6-26; p=0·002) for myocardial infarction, and 26% (14-36; p<0·0001) for microvascular disease. Corresponding absolute risk reductions were 2·7%, 3·3%, and 3·5%, respectively. Early intensive glycaemic control with metformin therapy, compared with conventional glycaemic control, showed overall relative risk reductions of 20% (95% CI 5-32; p=0·010) for death from any cause and 31% (12-46; p=0·003) for myocardial infarction. Corresponding absolute risk reductions were 4·9% and 6·2%, respectively. No significant risk reductions during or after the trial for stroke or peripheral vascular disease were observed for both intensive glycaemic control groups, and no significant risk reduction for microvascular disease was observed for metformin therapy.
Early intensive glycaemic control with sulfonylurea or insulin, or with metformin, compared with conventional glycaemic control, appears to confer a near-lifelong reduced risk of death and myocardial infarction. Achieving near normoglycaemia immediately following diagnosis might be essential to minimise the lifetime risk of diabetes-related complications to the greatest extent possible.
University of Oxford Nuffield Department of Population Health Pump Priming.
英国20年前瞻性糖尿病研究表明，与传统血糖控制相比，新诊断的2型糖尿病患者随机分配接受磺脲类或胰岛素强化血糖控制或二甲双胍治疗具有重大临床益处。试验后10年的随访确定了持久和新出现的血糖及二甲双胍遗留治疗效果。我们旨在通过再延长14年的随访来确定这些效果是否会减弱。
1977年至1991年招募了5102名患者，其中4209名（82.5%）参与者最初被随机分配接受强化血糖控制（磺脲类或胰岛素，或超重者接受二甲双胍）或传统血糖控制（主要是饮食控制）。在20年干预试验结束时，3277名存活参与者进入了为期10年的试验后监测期，该监测期持续到2007年9月30日。本研究的合格参与者是试验后10年监测期结束时所有存活的参与者。通过将他们与常规收集的国民健康服务（NHS）数据相链接，对这些参与者进行了另外14年的延长随访。临床结局来自死亡、住院、门诊就诊以及急诊就诊记录。我们使用Kaplan-Meier事件发生时间和对数秩分析，在意向性治疗基础上，按随机血糖控制策略检查了七个预先指定的总体临床结局（即任何糖尿病相关终点、糖尿病相关死亡、任何原因导致的死亡、心肌梗死、中风、外周血管疾病和微血管疾病）。本研究已在ISRCTN注册中心注册，注册号为ISRCTN75451837。
在2007年10月1日至2021年9月30日期间，1525名参与者中的1489名（97.6%）可与常规收集的NHS行政数据相链接。他们的基线平均年龄为50.2岁（标准差8.0），41.3%为女性。截至2021年9月30日仍存活者的平均年龄为79.9岁（标准差8.0）。从基线开始的个体随访时间从0到42年不等，中位数为17.5年（四分位间距12.3 - 26.8）。总体随访增加了21%，从66972人年增加到80724人年。在试验结束后的长达24年里，可以看到血糖及二甲双胍遗留效应没有减弱的迹象。与传统血糖控制相比，早期使用磺脲类或胰岛素强化血糖控制，任何原因导致的死亡总体相对风险降低10%（95%置信区间2 - 17；p = 0.015），心肌梗死降低17%（6 - 26；p = 0.002），微血管疾病降低26%（14 - 36；p < 0.0001）。相应的绝对风险降低分别为2.7%、3.3%和3.5%。与传统血糖控制相比，早期使用二甲双胍强化血糖控制，任何原因导致的死亡总体相对风险降低20%（95%置信区间5 - 32；p = 0.010），心肌梗死降低31%（12 - 46；p = 0.003）。相应的绝对风险降低分别为4.9%和6.2%。两个强化血糖控制组在试验期间或试验后均未观察到中风或外周血管疾病有显著风险降低，二甲双胍治疗也未观察到微血管疾病有显著风险降低。
与传统血糖控制相比，早期使用磺脲类或胰岛素或二甲双胍强化血糖控制似乎能带来近乎终身的死亡和心肌梗死风险降低。在诊断后立即实现接近正常血糖水平对于最大程度降低糖尿病相关并发症的终身风险可能至关重要。
牛津大学纳菲尔德人口健康系启动资金。
