Diabetes Research Institute, IRCCS San Raffaele Hospital and San Raffaele Vita Salute University, Milan, Italy.
Department of Internal Medicine, King's College Hospital, Diabetes Research Group, Weston Education Center, London, UK.
Lancet Diabetes Endocrinol. 2019 Jun;7(6):462-472. doi: 10.1016/S2213-8587(19)30150-0. Epub 2019 Apr 29.
Hypoglycaemia unawareness and severe hypoglycaemia can increase fear of hypoglycaemia and the risk of subsequent hypoglycaemic events. We aimed to assess the safety and efficacy of insulin pump therapy with integrated continuous glucose monitoring (CGM) and a suspend-before-low feature (Medtronic MiniMed 640G with SmartGuard) in hypoglycaemia-prone adults with type 1 diabetes.
SMILE was an open-label randomised controlled trial done in people aged 24-75 years with type 1 diabetes for 10 years or longer, HbA values of 5·8-10·0% (40-86 mmol/mol), and at high risk of hypoglycaemia (recent severe hypoglycaemia or hypoglycaemia unawareness defined by a Clarke or Gold score ≥4). Participants were enrolled from 16 centres (eg, clinics, hospitals, or university medical centres) in Canada, France, Italy, the Netherlands, and the UK. After baseline run-in phase (2 weeks), participants were randomly assigned to the MiniMed 640G pump (continuous subcutaneous insulin infusion) with self-monitoring of blood glucose (control group) or to the MiniMed 640G system with the suspend-before-low feature enabled (intervention group), for 6 months. The study statistician analysing the data was masked to group assignment until final database lock; because of the nature of the intervention, participants and treating clinicians could not be masked to group assignment. The primary outcome was the mean number of sensor hypoglycaemic events, defined as 55 mg/dL (3·1 mmol/L) or lower, and was analysed on an intention-to-treat basis in all randomly assigned participants. This trial is registered with ClinicalTrials.gov, number NCT02733991, and is completed.
Between Dec 7, 2016, and March 27, 2018, 153 participants with a mean age 48·2 [12·4] years were randomly assigned: 77 to the control group (mean age 47·4 [12·5] years) and 76 to the intervention group (mean age 49·0 [12·2] years). After 6 months, the intervention group had significantly fewer hypoglycaemic events per participant per week (1·1 [SD 1·2] vs 4·1 [3·4] mean events, model-based treatment effect -2·9 [95% CI -3·5 to -2·3]; p<0·0001) and fewer severe hypoglycaemic events (instances requiring third-party assistance with carbohydrate or glucagon administration, or other resuscitative actions) overall (three vs 18; p=0·0036). The most common adverse events were hypoglycaemia (observed in ten [13%] of 77 participants in the control group vs four [5%] of 76 in the intervention group) and hyperglycaemia (observed in seven [9%] of 77 vs seven [9%] of 76). No serious adverse device effects or episodes of diabetic ketoacidosis were reported.
Insulin pump therapy with integrated CGM and a suspend-before-low feature reduced the frequency of sensor hypoglycaemic and severe hypoglycaemic events in hypoglycaemia-prone adults compared with use of continuous subcutaneous insulin infusion without real-time CGM. These results suggest that this technology could be beneficial in this high-risk population.
Medtronic International Trading Sàrl and Medtronic Canada.
低血糖意识障碍和严重低血糖会增加对低血糖的恐惧，并增加随后低血糖事件的风险。我们旨在评估在有低血糖倾向、患有 1 型糖尿病且病程 10 年以上、HbA1c 值为 5.8-10.0%（40-86mmol/mol）且有发生低血糖风险（近期发生严重低血糖或低血糖意识障碍，定义为 Clarke 或 Gold 评分≥4）的成年人中，使用具有集成连续血糖监测（CGM）和低血糖前暂停（美敦力 MiniMed 640G 与 SmartGuard）功能的胰岛素泵治疗的安全性和疗效。
SMILE 是一项开放性标签、随机对照试验，纳入了年龄在 24-75 岁之间、病程 10 年以上、HbA1c 值为 5.8-10.0%（40-86mmol/mol）且有发生低血糖风险（近期发生严重低血糖或低血糖意识障碍，定义为 Clarke 或 Gold 评分≥4）的 1 型糖尿病患者。参与者来自加拿大、法国、意大利、荷兰和英国的 16 个中心（如诊所、医院或大学医学中心）。在基线入组阶段（2 周）后，参与者被随机分配至美敦力 MiniMed 640G 泵（持续皮下胰岛素输注）联合自我血糖监测（对照组）或美敦力 MiniMed 640G 系统联合低血糖前暂停功能（干预组），治疗 6 个月。分析数据的研究统计学家在最终数据库锁定前对分组情况进行了设盲；由于干预的性质，参与者和治疗临床医生无法对分组情况进行设盲。主要结局是传感器低血糖事件的平均数量，定义为 55mg/dL（3.1mmol/L）或更低，所有随机分配的参与者均按意向治疗进行分析。该试验在 ClinicalTrials.gov 上注册，编号为 NCT02733991，现已完成。
2016 年 12 月 7 日至 2018 年 3 月 27 日期间，共有 153 名平均年龄为 48.2[12.4]岁的参与者被随机分配：77 名参与者进入对照组（平均年龄 47.4[12.5]岁），76 名参与者进入干预组（平均年龄 49.0[12.2]岁）。6 个月后，干预组参与者每周的低血糖事件发生率显著减少（每例参与者每周 1.1[1.2]次 vs 4.1[3.4]次，基于模型的治疗效果-2.9[95%CI-3.5 至-2.3]；p<0.0001），且严重低血糖事件（需要第三方协助给予碳水化合物或胰高血糖素治疗，或其他复苏措施）的总发生率也显著降低（3 例 vs 18 例；p=0.0036）。最常见的不良事件是低血糖（对照组 77 名参与者中有 10 名[13%]发生，干预组 76 名参与者中有 4 名[5%]发生）和高血糖（对照组 77 名参与者中有 7 名[9%]发生，干预组 76 名参与者中有 7 名[9%]发生）。未报告严重不良设备相关事件或糖尿病酮症酸中毒发作。
与不使用实时 CGM 的持续皮下胰岛素输注相比，具有集成 CGM 和低血糖前暂停功能的胰岛素泵治疗可降低有低血糖倾向的成年人传感器低血糖和严重低血糖事件的发生频率。这些结果表明，该技术在这一高危人群中可能有益。
美敦力国际贸易公司和美敦力加拿大公司。
