背景:胰岛素的发现已经过去了一百年,这是20世纪最相关的事件之一。这一时期在改善葡萄糖控制的新型分子的开发中取得了非凡的进展,简化胰岛素治疗方案,改善生活质量。2024年3月下旬,第一个每周一次的基础模拟Icodec被批准用于糖尿病,产生很高的期望。我们的目的是系统地回顾和荟萃分析Icodec与每日一次胰岛素类似物在1型(T1D)和2型糖尿病(T2D)中的疗效和安全性。
方法:PubMed/MEDLINE,科克伦图书馆,和ClinicalTrials.gov搜索随机临床试验(RCTs)。根据以下预先指定的纳入标准,纳入合成研究:不受控制的T1D或T2D,年龄≥18岁,胰岛素Icodecvs.主动比较器(DegludecU100、GlineU100、GlineU300和Detemir),第三阶段,多中心,双盲或开放标签RCT,研究持续时间≥24周。
结果:系统评价包括4347例T1D和T2D控制不足的患者(2172例随机分为Icodecvs.2175随机分配至每日一次的基础类似物)。Icodec,与每日一次的基础类似物相比,糖化血红蛋白(HbA1c)水平略有降低,估计治疗差异(ETD)为-0.14%[95CI-0.25;-0.03],p=0.01,I2为68%。与每天使用一次基础类似物的患者相比,随机接受Icodec的患者在随机分组后12周内达到HbA1c<7%而无临床相关或严重低血糖事件的可能性更大,估计风险比(ERR)为1.17,[95CI1.01,1.36],p=0.03,I2为66%。我们没有发现空腹血糖水平的差异,范围内的时间,和时间高于Icodec和比较器之间的范围。Icodec,与每日一次的基础类似物相比,导致体重略有增加,但具有统计学意义的0.62kg[95CI0.25;0.99],p=0.001,I2为25%。低血糖事件的频率(ERR1.16[95CI0.95;1.41]),不良事件(ERR1.04[95CI1.00;1.08]),注射部位反应(ERR1.08[95CI0.62;1.90]),两组之间停止治疗的情况相似。发现Icodec在HbA1c为-0.22%的ETD的基础推注方案中使用时比基础推注方案更好。实现+33%的葡萄糖控制的概率,在没有临床相关或严重低血糖的情况下实现血糖控制的概率为+28%,更多的时间花费在目标(+4.55%)和更少的时间花费在高血糖(-5.14%).当在基础类似物中加入背景格列奈类药物和磺酰脲类时,发生临床相关或严重低血糖事件的风险显著更高(ERR1.42[95CI1.05;1.93])。
结论:在T2D中,胰岛素Icodec基本上不劣于每日一次的胰岛素类似物,未经胰岛素治疗或胰岛素治疗。然而,当用于仅基础而不是基础推注方案时,Icodec的效果比竞争对手略好。体重增加和低血糖风险相当低,但不可忽视。病人的教育,适当的生活方式和药物干预,和适当的治疗调整是必不可少的,以尽量减少风险。本系统综述注册为PROSPEROCRD42024568680。
BACKGROUND: One hundred years have passed since the discovery of insulin, which is one of the most relevant events of the 20th century. This period resulted in extraordinary progress in the development of novel molecules to improve glucose control, simplify the insulin regimen, and ameliorate the quality of life. In late March 2024, the first once-weekly basal analog Icodec was approved for diabetes mellitus, generating high expectations. Our aim was to systematically review and meta-analyze the efficacy and safety of Icodec compared to once-daily insulin analogs in type 1 (T1D) and type 2 diabetes (T2D).
METHODS: PubMed/MEDLINE, Cochrane Library, and ClinicalTrials.gov were searched for randomized clinical trials (RCTs). Studies were included for the synthesis according to the following prespecified inclusion criteria: uncontrolled T1D or T2D, age ≥ 18 years, insulin Icodec vs. active comparators (Degludec U100, Glargine U100, Glargine U300, and Detemir), phase 3, multicenter, double-blind or open-label RCTs, and a study duration ≥ 24 weeks.
RESULTS: The systematic review included 4347 patients with T1D and T2D inadequately controlled (2172 randomized to Icodec vs. 2175 randomized to once-daily basal analogs). Icodec, compared to once-daily basal analogs, slightly reduced the levels of glycated hemoglobin (HbA1c) with an estimated treatment difference (ETD) of -0.14% [95%CI -0.25; -0.03], p = 0.01, and I2 68%. Patients randomized to Icodec compared to those on once-daily basal analogs had a greater probability to achieve HbA1c < 7% without clinically relevant or severe hypoglycemic events in 12 weeks from randomization with an estimated risk ratio (ERR) of 1.17, [95%CI 1.01, 1.36], p = 0.03, and I2 66%. We did not find a difference in fasting glucose levels, time in range, and time above range between Icodec and comparators. Icodec, compared to once-daily basal analogs, resulted in a slight but statistically significant weight gain of 0.62 kg [95%CI 0.25; 0.99], p = 0.001, and I2 25%. The frequency of hypoglycemic events (ERR 1.16 [95%CI 0.95; 1.41]), adverse events (ERR 1.04 [95%CI 1.00; 1.08]), injection-site reactions (ERR 1.08 [95%CI 0.62; 1.90]), and the discontinuation of treatments were similar between the two groups. Icodec was found to work better when used in a basal-only than basal-bolus regimen with an ETD in HbA1c of -0.22%, a probability of achieving glucose control of +33%, a probability of achieving glucose control without clinically relevant or severe hypoglycemia of +28%, more time spent in target (+4.55%) and less time spent in hyperglycemia (-5.14%). The risk of clinically relevant or severe hypoglycemic events was significantly higher when background glinides and sulfonylureas were added to basal analogs (ERR 1.42 [95%CI 1.05; 1.93]).
CONCLUSIONS: Insulin Icodec is substantially non-inferior to once-daily insulin analogs in T2D, either insulin-naïve or insulin-treated. However, Icodec works slightly better than competitors when used in a basal-only rather than basal-bolus regimen. Weight gain and hypoglycemic risk are substantially low but not negligible. Patients\' education, adequate lifestyle and pharmacological interventions, and appropriate therapy adjustments are essential to minimize risks. This systematic review is registered as PROSPERO CRD42024568680.