Nordsjællands University Hospital-Hillerød, Hillerød, Denmark; University of Copenhagen, Copenhagen, Denmark.
Nordsjællands University Hospital-Hillerød, Hillerød, Denmark; Steno Diabetes Center, Gentofte, Denmark.
Lancet Diabetes Endocrinol. 2014 Jul;2(7):553-61. doi: 10.1016/S2213-8587(14)70073-7. Epub 2014 May 2.
Insulin analogues have been developed to reduce the risk of hypoglycaemia in patients with diabetes who require insulin-based treatment, but their effect on this endpoint in patients with type 1 diabetes complicated by recurrent severe hypoglycaemia is unknown. We compared the occurrence of severe hypoglycaemic episodes in such patients during treatment with insulin analogues or human insulin.
In this investigator-initiated, prospective, randomised, open-label, blinded-endpoint crossover trial at seven medical centres in Denmark, we recruited patients (aged ≥18 years) with type 1 diabetes (diagnosed for >5 years) who had reported two or more episodes of severe hypoglycaemia in the preceding year. Patients were randomly assigned (1:1) using computer-generated site-specific randomisation lists in blocks of four to treatment with basal-bolus therapy with either analogue insulin (detemir and aspart) or human insulin (human neutral protamine Hagedorn and human regular) in a balanced crossover design. A 1-year plus 1-year treatment period was specified, consisting of two 3-month run-in periods, each followed by a 9-month maintenance period. The primary endpoint was the number of validated episodes of severe hypoglycaemia (defined by need for treatment assistance from others) reported during the maintenance periods, analysed by intention to treat. The study is registered with ClinicalTrials.gov, number NCT00346996.
Between May 9, 2007, and Oct 30, 2009, 159 patients were randomly assigned. 18 patients discontinued during the first run-in period, leaving 141 patients in the intention-to-treat population. 136 severe hypoglycaemic episodes were reported during treatment with human insulin and 105 episodes were reported during treatment with insulin analogues, resulting in an absolute rate reduction of 0.51 episodes (95% CI 0.19-0.84) per patient-year with insulin analogues. This result corresponds to a relative rate reduction of 29% (95% CI 11-48; p=0.010).
Treatment with insulin detemir and aspart in patients with type 1 diabetes and recurrent severe hypoglycaemia resulted in a clinically significant reduced rate of severe hypoglycaemia compared with human insulin. Patients with the greatest chance of benefitting from improved insulin therapy should be offered treatment with insulin analogues and be included in future trials of new insulins.
Novo Nordisk A/S.
胰岛素类似物的研发旨在降低需要胰岛素治疗的糖尿病患者发生低血糖的风险，但它们在伴有反复严重低血糖的 1 型糖尿病患者中的这一终点事件中的效果尚不清楚。我们比较了此类患者在接受胰岛素类似物或人胰岛素治疗时严重低血糖发作的发生情况。
在丹麦的七家医学中心开展的这项由研究者发起的、前瞻性、随机、开放标签、盲终点交叉试验中，我们招募了年龄≥18 岁、患有 1 型糖尿病（确诊>5 年）且在过去一年中报告过两次或两次以上严重低血糖发作的患者。使用基于站点的计算机生成随机分组列表，按 4 个为一组，将患者（1:1）随机分配接受基础-餐时胰岛素治疗，方案为使用胰岛素类似物（地特胰岛素和门冬胰岛素）或人胰岛素（人中性鱼精蛋白锌胰岛素和人普通胰岛素），采用平衡交叉设计。指定了为期 1 年加 1 年的治疗期，包括两个 3 个月的导入期，每个导入期后接着是 9 个月的维持期。主要终点是维持期内报告的经证实的严重低血糖发作次数（定义为需要他人协助治疗），采用意向治疗分析。该研究在 ClinicalTrials.gov 注册，编号为 NCT00346996。
2007 年 5 月 9 日至 2009 年 10 月 30 日期间，共纳入 159 名患者。18 名患者在第一个导入期内停药，意向治疗人群中剩余 141 名患者。人胰岛素治疗期间报告了 136 次严重低血糖发作，胰岛素类似物治疗期间报告了 105 次，导致胰岛素类似物治疗时患者每年严重低血糖发作的绝对发生率降低 0.51 次（95%CI 0.19-0.84）。这一结果相当于相对发生率降低了 29%（95%CI 11-48；p=0.010）。
在伴有反复严重低血糖的 1 型糖尿病患者中，使用地特胰岛素和门冬胰岛素治疗可显著降低严重低血糖的发生率。获益于改善胰岛素治疗可能性最大的患者应接受胰岛素类似物治疗，并纳入新胰岛素的未来试验中。
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