Fullerton Birgit, Siebenhofer Andrea, Jeitler Klaus, Horvath Karl, Semlitsch Thomas, Berghold Andrea, Gerlach Ferdinand M
Institute of General Practice, Goethe University, Theodor-Stern-Kai 7, Frankfurt am Main, Hesse, Germany, 60590.
Cochrane Database Syst Rev. 2018 Dec 17;12(12):CD013228. doi: 10.1002/14651858.CD013228.
The use of short-acting insulin analogues (insulin lispro, insulin aspart, insulin glulisine) for adult, non-pregnant people with type 2 diabetes is still controversial, as reflected in many scientific debates.
To assess the effects of short-acting insulin analogues compared to regular human insulin in adult, non-pregnant people with type 2 diabetes mellitus.
For this update we searched CENTRAL, MEDLINE, Embase, the WHO ICTRP Search Portal, and ClinicalTrials.gov to 31 October 2018. We placed no restrictions on the language of publication.
We included all randomised controlled trials with an intervention duration of at least 24 weeks that compared short-acting insulin analogues to regular human insulin in the treatment of people with type 2 diabetes, who were not pregnant.
Two review authors independently extracted data and assessed the risk of bias. We assessed dichotomous outcomes by risk ratios (RR), and Peto odds ratios (POR), with 95% confidence intervals (CI). We assessed continuous outcomes by mean differences (MD) with 95% CI. We assessed trials for certainty of the evidence using the GRADE approach.
We identified 10 trials that fulfilled the inclusion criteria, randomising 2751 participants; 1388 participants were randomised to receive insulin analogues and 1363 participants to receive regular human insulin. The duration of the intervention ranged from 24 to 104 weeks, with a mean of about 41 weeks. The trial populations showed diversity in disease duration, and inclusion and exclusion criteria. None of the trials were blinded, so the risk of performance bias and detection bias, especially for subjective outcomes, such as hypoglycaemia, was high in nine of 10 trials from which we extracted data. Several trials showed inconsistencies in the reporting of methods and results.None of the included trials defined all-cause mortality as a primary outcome. Six trials provided Information on the number of participants who died during the trial, with five deaths out of 1272 participants (0.4%) in the insulin analogue groups and three deaths out of 1247 participants (0.2%) in the regular human insulin groups (Peto OR 1.66, 95% CI 0.41 to 6.64; P = 0.48; moderate-certainty evidence). Six trials, with 2509 participants, assessed severe hypoglycaemia differently, therefore, we could not summarise the results with a meta-analysis. Overall, the incidence of severe hypoglycaemic events was low, and none of the trials showed a clear difference between the two intervention arms (low-certainty evidence).The MD in glycosylated haemoglobin A1c (HbA1c) change was -0.03% (95% CI -0.16 to 0.09; P = 0.60; 9 trials, 2608 participants; low-certainty evidence). The 95% prediction ranged between -0.31% and 0.25%. The MD in the overall number of non-severe hypoglycaemic episodes per participant per month was 0.08 events (95% CI 0.00 to 0.16; P = 0.05; 7 trials, 2667 participants; very low-certainty evidence). The 95% prediction interval ranged between -0.03 and 0.19 events per participant per month. The results provided for nocturnal hypoglycaemic episodes were of questionable validity. Overall, there was no clear difference between the two short-acting insulin analogues and regular human insulin. Two trials assessed health-related quality of life and treatment satisfaction, but we considered the results for both outcomes to be unreliable (very low-certainty evidence).No trial was designed to investigate possible long term effects (all-cause mortality, microvascular or macrovascular complications of diabetes), especially in participants with diabetes-related complications. No trial reported on socioeconomic effects.
AUTHORS' CONCLUSIONS: Our analysis found no clear benefits of short-acting insulin analogues over regular human insulin in people with type 2 diabetes. Overall, the certainty of the evidence was poor and results on patient-relevant outcomes, like all-cause mortality, microvascular or macrovascular complications and severe hypoglycaemic episodes were sparse. Long-term efficacy and safety data are needed to draw conclusions about the effects of short-acting insulin analogues on patient-relevant outcomes.
短效胰岛素类似物（赖脯胰岛素、门冬胰岛素、谷赖胰岛素）在成年非妊娠2型糖尿病患者中的应用仍存在争议，这在许多科学辩论中都有所体现。
评估短效胰岛素类似物与常规人胰岛素相比，对成年非妊娠2型糖尿病患者的影响。
本次更新检索了截至2018年10月31日的Cochrane系统评价数据库（CENTRAL）、医学期刊数据库（MEDLINE）、荷兰医学文摘数据库（Embase）、世界卫生组织国际临床试验注册平台（WHO ICTRP Search Portal）和美国国立医学图书馆临床试验数据库（ClinicalTrials.gov）。我们对出版物的语言没有限制。
我们纳入了所有干预持续时间至少24周的随机对照试验，这些试验比较了短效胰岛素类似物与常规人胰岛素在非妊娠2型糖尿病患者治疗中的效果。
两位综述作者独立提取数据并评估偏倚风险。我们通过风险比（RR）和Peto比值比（POR）及95%置信区间（CI）评估二分法结局。我们通过均数差（MD）及95%CI评估连续型结局。我们使用GRADE方法评估试验证据的确定性。
我们确定了10项符合纳入标准的试验，共纳入2751名参与者；1388名参与者被随机分配接受胰岛素类似物治疗，1363名参与者接受常规人胰岛素治疗。干预持续时间为24至104周，平均约41周。试验人群在病程、纳入和排除标准方面存在差异。所有试验均未设盲，因此在我们提取数据的10项试验中有9项存在执行偏倚和检测偏倚的高风险，尤其是对于低血糖等主观结局。几项试验在方法和结果报告方面存在不一致。纳入的试验均未将全因死亡率定义为主要结局。六项试验提供了试验期间死亡参与者人数的信息，胰岛素类似物组1272名参与者中有5人死亡（0.4%），常规人胰岛素组1247名参与者中有3人死亡（0.2%）（Peto比值比1.66，95%CI 0.41至6.64；P = 0.48；中等确定性证据）。六项试验共2509名参与者对严重低血糖的评估方法不同，因此我们无法通过Meta分析总结结果。总体而言，严重低血糖事件的发生率较低，且没有试验显示两个干预组之间存在明显差异（低确定性证据）。糖化血红蛋白A1c（HbA1c）变化的均数差为-0.03%（95%CI -0.16至0.09；P = 0.60；9项试验，2608名参与者；低确定性证据）。95%预测区间在-0.31%至0.25%之间。每位参与者每月非严重低血糖发作总数的均数差为0.08次事件（95%CI 0.00至0.16；P = 0.05；7项试验，2667名参与者；极低确定性证据）。95%预测区间为每位参与者每月-0.03至0.19次事件。夜间低血糖发作的结果有效性存疑。总体而言，两种短效胰岛素类似物与常规人胰岛素之间没有明显差异。两项试验评估了健康相关生活质量和治疗满意度，但我们认为这两个结局的结果都不可靠（极低确定性证据）。没有试验旨在研究可能的长期影响（全因死亡率、糖尿病的微血管或大血管并发症），尤其是糖尿病相关并发症患者。没有试验报告社会经济影响。
我们的分析发现，短效胰岛素类似物在2型糖尿病患者中相对于常规人胰岛素没有明显益处。总体而言，证据的确定性较差，与患者相关结局（如全因死亡率、微血管或大血管并发症以及严重低血糖发作）的结果稀少。需要长期疗效和安全性数据来得出关于短效胰岛素类似物对患者相关结局影响的结论。
