Semlitsch Thomas, Engler Jennifer, Siebenhofer Andrea, Jeitler Klaus, Berghold Andrea, Horvath Karl
Institute of General Practice and Evidence-Based Health Services Research, Medical University of Graz, Graz, Austria.
Institute for General Practice, Goethe University, Frankfurt am Main, Germany.
Cochrane Database Syst Rev. 2020 Nov 9;11(11):CD005613. doi: 10.1002/14651858.CD005613.pub4.
Evidence that antihyperglycaemic therapy is beneficial for people with type 2 diabetes mellitus is conflicting. While the United Kingdom Prospective Diabetes Study (UKPDS) found tighter glycaemic control to be positive, other studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, found the effects of an intensive therapy to lower blood glucose to near normal levels to be more harmful than beneficial. Study results also showed different effects for different antihyperglycaemic drugs, regardless of the achieved blood glucose levels. In consequence, firm conclusions on the effect of interventions on patient-relevant outcomes cannot be drawn from the effect of these interventions on blood glucose concentration alone. In theory, the use of newer insulin analogues may result in fewer macrovascular and microvascular events.
To compare the effects of long-term treatment with (ultra-)long-acting insulin analogues (insulin glargine U100 and U300, insulin detemir and insulin degludec) with NPH (neutral protamine Hagedorn) insulin (human isophane insulin) in adults with type 2 diabetes mellitus.
For this Cochrane Review update, we searched CENTRAL, MEDLINE, Embase, ICTRP Search Portal and ClinicalTrials.gov. The date of the last search was 5 November 2019, except Embase which was last searched 26 January 2017. We applied no language restrictions.
We included randomised controlled trials (RCTs) comparing the effects of treatment with (ultra-)long-acting insulin analogues to NPH in adults with type 2 diabetes mellitus.
Two review authors independently selected trials, assessed risk of bias, extracted data and evaluated the overall certainty of the evidence using GRADE. Trials were pooled using random-effects meta-analyses.
We identified 24 RCTs. Of these, 16 trials compared insulin glargine to NPH insulin and eight trials compared insulin detemir to NPH insulin. In these trials, 3419 people with type 2 diabetes mellitus were randomised to insulin glargine and 1321 people to insulin detemir. The duration of the included trials ranged from 24 weeks to five years. For studies, comparing insulin glargine to NPH insulin, target values ranged from 4.0 mmol/L to 7.8 mmol/L (72 mg/dL to 140 mg/dL) for fasting blood glucose (FBG), from 4.4 mmol/L to 6.6 mmol/L (80 mg/dL to 120 mg/dL) for nocturnal blood glucose and less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, when applicable. Blood glucose and glycosylated haemoglobin A1c (HbA1c) target values for studies comparing insulin detemir to NPH insulin ranged from 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for FBG, less than 6.7 mmol/L (120 mg/dL) to less than 10 mmol/L (180 mg/dL) for postprandial blood glucose, 4.0 mmol/L to 7.0 mmol/L (72 mg/dL to 126 mg/dL) for nocturnal blood glucose and 5.8% to less than 6.4% HbA1c, when applicable. All trials had an unclear or high risk of bias for several risk of bias domains. Overall, insulin glargine and insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH insulin. Changes in HbA1c were comparable for long-acting insulin analogues and NPH insulin. Insulin glargine compared to NPH insulin had a risk ratio (RR) for severe hypoglycaemia of 0.68 (95% confidence interval (CI) 0.46 to 1.01; P = 0.06; absolute risk reduction (ARR) -1.2%, 95% CI -2.0 to 0; 14 trials, 6164 participants; very low-certainty evidence). The RR for serious hypoglycaemia was 0.75 (95% CI 0.52 to 1.09; P = 0.13; ARR -0.7%, 95% CI -1.3 to 0.2; 10 trials, 4685 participants; low-certainty evidence). Treatment with insulin glargine reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Treatment with insulin detemir compared to NPH insulin found an RR for severe hypoglycaemia of 0.45 (95% CI 0.17 to 1.20; P = 0.11; ARR -0.9%, 95% CI -1.4 to 0.4; 5 trials, 1804 participants; very low-certainty evidence). The Peto odds ratio for serious hypoglycaemia was 0.16, 95% CI 0.04 to 0.61; P = 0.007; ARR -0.9%, 95% CI -1.1 to -0.4; 5 trials, 1777 participants; low-certainty evidence). Treatment with detemir also reduced the incidence of confirmed hypoglycaemia and confirmed nocturnal hypoglycaemia. Information on patient-relevant outcomes such as death from any cause, diabetes-related complications, health-related quality of life and socioeconomic effects was insufficient or lacking in almost all included trials. For those outcomes for which some data were available, there were no meaningful differences between treatment with glargine or detemir and treatment with NPH. There was no clear difference between insulin-analogues and NPH insulin in terms of weight gain. The incidence of adverse events was comparable for people treated with glargine or detemir, and people treated with NPH. We found no trials comparing ultra-long-acting insulin glargine U300 or insulin degludec with NPH insulin.
AUTHORS' CONCLUSIONS: While the effects on HbA1c were comparable, treatment with insulin glargine and insulin detemir resulted in fewer participants experiencing hypoglycaemia when compared with NPH insulin. Treatment with insulin detemir also reduced the incidence of serious hypoglycaemia. However, serious hypoglycaemic events were rare and the absolute risk reducing effect was low. Approximately one in 100 people treated with insulin detemir instead of NPH insulin benefited. In the studies, low blood glucose and HbA1c targets, corresponding to near normal or even non-diabetic blood glucose levels, were set. Therefore, results from the studies are only applicable to people in whom such low blood glucose concentrations are targeted. However, current guidelines recommend less-intensive blood glucose lowering for most people with type 2 diabetes in daily practice (e.g. people with cardiovascular diseases, a long history of type 2 diabetes, who are susceptible to hypoglycaemia or older people). Additionally, low-certainty evidence and trial designs that did not conform with current clinical practice meant it remains unclear if the same effects will be observed in daily clinical practice. Most trials did not report patient-relevant outcomes.
关于降糖治疗对2型糖尿病患者有益的证据存在矛盾。英国前瞻性糖尿病研究（UKPDS）发现更严格的血糖控制具有积极作用，而其他研究，如糖尿病控制心血管风险行动（ACCORD）试验，发现强化治疗将血糖降至接近正常水平的效果弊大于利。研究结果还显示，无论血糖水平如何，不同的降糖药物有不同的效果。因此，仅从这些干预措施对血糖浓度的影响，无法得出关于干预措施对患者相关结局影响的确切结论。理论上，使用新型胰岛素类似物可能会减少大血管和微血管事件。
比较（超）长效胰岛素类似物（甘精胰岛素U100和U300、地特胰岛素和德谷胰岛素）与中性鱼精蛋白锌（NPH）胰岛素（人低精蛋白胰岛素）长期治疗对2型糖尿病成年患者的影响。
对于本Cochrane系统评价的更新，我们检索了Cochrane中心对照试验注册库（CENTRAL）、医学期刊数据库（MEDLINE）、荷兰医学文摘数据库（Embase）、国际临床试验注册平台（ICTRP）检索入口和美国国立医学图书馆临床试验注册库（ClinicalTrials.gov）。除Embase于2017年1月26日最后检索外，最后一次检索日期为2019年11月5日。我们未设语言限制。
我们纳入了比较（超）长效胰岛素类似物与NPH胰岛素治疗对2型糖尿病成年患者影响的随机对照试验（RCT）。
两位综述作者独立选择试验、评估偏倚风险、提取数据并使用GRADE评估证据的总体确定性。试验采用随机效应荟萃分析进行合并。
我们识别出24项RCT。其中，16项试验比较了甘精胰岛素与NPH胰岛素，8项试验比较了地特胰岛素与NPH胰岛素。在这些试验中，3419例2型糖尿病患者被随机分配至甘精胰岛素组，1321例被分配至地特胰岛素组。纳入试验的持续时间为24周至5年。对于比较甘精胰岛素与NPH胰岛素的研究，空腹血糖（FBG）目标值范围为4.0 mmol/L至7.8 mmol/L（72 mg/dL至140 mg/dL），夜间血糖目标值为4.4 mmol/L至6.6 mmol/L（80 mg/dL至120 mg/dL），餐后血糖目标值在适用时小于10 mmol/L（＜180 mg/dL）。比较地特胰岛素与NPH胰岛素的研究中，FBG的血糖和糖化血红蛋白A1c（HbA1c）目标值范围为4.0 mmol/L至7.0 mmol/L（72 mg/dL至126 mg/dL），餐后血糖目标值小于6.7 mmol/L（＜120 mg/dL）至小于10 mmol/L（＜180 mg/dL），夜间血糖目标值为4.0 mmol/L至7.0 mmol/L（72 mg/dL至126 mg/dL），HbA1c目标值为5.8%至小于6.4%，在适用时。所有试验在多个偏倚风险领域的偏倚风险均不明确或较高。总体而言，与NPH胰岛素相比，甘精胰岛素和地特胰岛素导致发生低血糖的参与者较少。长效胰岛素类似物与NPH胰岛素的HbA1c变化相当。与NPH胰岛素相比，甘精胰岛素发生严重低血糖的风险比（RR）为0.68（95%置信区间（CI）0.46至1.01；P = 0.06；绝对风险降低率（ARR）-1.2%，95% CI-2.0至0；14项试验，6164名参与者；极低确定性证据）。严重低血糖的RR为0.75（95% CI 0.52至1.09；P = 0.13；ARR-0.7%，95% CI-1.3至0.2；10项试验，4685名参与者；低确定性证据）。甘精胰岛素治疗降低了确诊低血糖和确诊夜间低血糖的发生率。与NPH胰岛素相比，地特胰岛素治疗的严重低血糖RR为0.45（95% CI 0.17至1.20；P = 0.11；ARR-0.9%，95% CI-1.4至～0.4；5项试验，1804名参与者；极低确定性证据）。严重低血糖的Peto比值比为0.16，95% CI 0.04至0.61；P = 0.007；ARR-0.9%，95% CI-1.1至-0.4；5项试验，1777名参与者；低确定性证据）。地特胰岛素治疗也降低了确诊低血糖和确诊夜间低血糖发生率。几乎所有纳入试验中，关于患者相关结局的信息，如任何原因导致的死亡、糖尿病相关并发症、健康相关生活质量和社会经济影响等，均不足或缺乏。对于有一些数据的那些结局，甘精胰岛素或地特胰岛素治疗与NPH胰岛素治疗之间没有有意义的差异。胰岛素类似物与NPH胰岛素在体重增加方面没有明显差异。接受甘精胰岛素或地特胰岛素治疗的人与接受NPH胰岛素治疗的人不良事件发生率相当。我们未发现比较超长效甘精胰岛素U300或德谷胰岛素与NPH胰岛素的试验。
虽然对HbA1c的影响相当，但与NPH胰岛素相比，甘精胰岛素和地特胰岛素治疗导致发生低血糖的参与者较少。地特胰岛素治疗也降低了严重低血糖的发生率。然而，严重低血糖事件很少见，绝对风险降低效果较低。使用地特胰岛素而非NPH胰岛素治疗的人中，约每100人中有1人受益。在这些研究中，设定了低血糖和HbA1c目标，对应接近正常甚至非糖尿病的血糖水平。因此，研究结果仅适用于以这种低血糖浓度为目标的人群。然而，目前的指南建议在日常实践中，对大多数2型糖尿病患者采用强度较低的血糖控制（例如患有心血管疾病、2型糖尿病病史较长、易发生低血糖的患者或老年人）。此外，低确定性证据和不符合当前临床实践要求的试验设计意味着在日常临床实践中是否会观察到相同效果仍不清楚。大多数试验未报告患者相关结局。
