双相、基础-餐时或基础胰岛素类似物治疗对2型糖尿病患者颈动脉内膜中层厚度的影响：随机化哥本哈根胰岛素与二甲双胍治疗（CIMT）试验

Effects of biphasic, basal-bolus or basal insulin analogue treatments on carotid intima-media thickness in patients with type 2 diabetes mellitus: the randomised Copenhagen Insulin and Metformin Therapy (CIMT) trial.

作者信息

Lundby-Christensen Louise, Vaag Allan, Tarnow Lise, Almdal Thomas P, Lund Søren S, Wetterslev Jørn, Gluud Christian, Boesgaard Trine W, Wiinberg Niels, Perrild Hans, Krarup Thure, Snorgaard Ole, Gade-Rasmussen Birthe, Thorsteinsson Birger, Røder Michael, Mathiesen Elisabeth R, Jensen Tonny, Vestergaard Henrik, Hedetoft Christoffer, Breum Leif, Duun Elsebeth, Sneppen Simone B, Pedersen Oluf, Hemmingsen Bianca, Carstensen Bendix, Madsbad Sten

机构信息

Steno Diabetes Center, Gentofte, Denmark Department of Endocrinology, Hvidovre, Copenhagen University Hospital, Hvidovre, Denmark Copenhagen Trial Unit, Centre for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark Department of Paediatrics, Hvidovre, Copenhagen University Hospital, Hvidovre, Denmark.

Steno Diabetes Center, Gentofte, Denmark Department of Endocrinology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark University of Copenhagen, Copenhagen, Denmark.

出版信息

BMJ Open. 2016 Feb 25;6(2):e008377. doi: 10.1136/bmjopen-2015-008377.

OBJECTIVE

To assess the effect of 3 insulin analogue regimens on change in carotid intima-media thickness (IMT) in patients with type 2 diabetes.

DESIGN AND SETTING

Investigator-initiated, randomised, placebo-controlled trial with a 2 × 3 factorial design, conducted at 8 hospitals in Denmark.

PARTICIPANTS AND INTERVENTIONS

Participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol), body mass index >25 kg/m(2)) were, in addition to metformin versus placebo, randomised to 18 months open-label biphasic insulin aspart 1-3 times daily (n=137) versus insulin aspart 3 times daily in combination with insulin detemir once daily (n=138) versus insulin detemir alone once daily (n=137), aiming at HbA1c ≤ 7.0% (≤ 53 mmol/mol).

OUTCOMES

Primary outcome was change in mean carotid IMT (a marker of subclinical cardiovascular disease). HbA1c, insulin dose, weight, and hypoglycaemic and serious adverse events were other prespecified outcomes.

RESULTS

Carotid IMT change did not differ between groups (biphasic -0.009 mm (95% CI -0.022 to 0.004), aspart+detemir 0.000 mm (95% CI -0.013 to 0.013), detemir -0.012 mm (95% CI -0.025 to 0.000)). HbA1c was more reduced with biphasic (-1.0% (95% CI -1.2 to -0.8)) compared with the aspart+detemir (-0.4% (95% CI -0.6 to -0.3)) and detemir (-0.3% (95% CI -0.4 to -0.1)) groups (p<0.001). Weight gain was higher in the biphasic (3.3 kg (95% CI 2.7 to 4.0) and aspart+detemir (3.2 kg (95% CI 2.6 to 3.9)) compared with the detemir group (1.9 kg (95% CI 1.3 to 2.6)). Insulin dose was higher with detemir (1.6 IU/kg/day (95% CI 1.4 to 1.8)) compared with biphasic (1.0 IU/kg/day (95% CI 0.9 to 1.1)) and aspart+detemir (1.1 IU/kg/day (95% CI 1.0 to 1.3)) (p<0.001). Number of participants with severe hypoglycaemia and serious adverse events did not differ.

CONCLUSIONS

Carotid IMT change did not differ between 3 insulin regimens despite differences in HbA1c, weight gain and insulin doses. The trial only reached 46% of planned sample size and lack of power may therefore have affected our results.

TRIAL REGISTRATION NUMBER

NCT00657943.

目的

评估3种胰岛素类似物治疗方案对2型糖尿病患者颈动脉内膜中层厚度（IMT）变化的影响。

设计与背景

由研究者发起的、采用2×3析因设计的随机、安慰剂对照试验，在丹麦的8家医院进行。

参与者与干预措施

2型糖尿病患者（糖化血红蛋白（HbA1c）≥7.5%（≥58 mmol/mol），体重指数>25 kg/m²），除了给予二甲双胍或安慰剂外，还被随机分为三组，分别接受为期18个月的开放标签治疗：每日1 - 3次双相门冬胰岛素（n = 137）、每日3次门冬胰岛素联合每日1次地特胰岛素（n = 138）、每日1次单独使用地特胰岛素（n = 137），目标是使HbA1c≤7.0%（≤53 mmol/mol）。

观察指标

主要观察指标是平均颈动脉IMT的变化（亚临床心血管疾病的一个标志物）。HbA1c、胰岛素剂量、体重以及低血糖和严重不良事件是其他预先设定的观察指标。

结果

各组之间颈动脉IMT变化无差异（双相门冬胰岛素组-0.009 mm（95%可信区间-0.022至0.004），门冬胰岛素+地特胰岛素组0.000 mm（95%可信区间-0.013至0.013），地特胰岛素组-0.012 mm（95%可信区间-0.025至0.000））。与门冬胰岛素+地特胰岛素组（-0.4%（95%可信区间-0.6至-0.3））和地特胰岛素组（-0.3%（95%可信区间-0.4至-0.1））相比，双相门冬胰岛素组HbA1c降低幅度更大（-1.0%（95%可信区间-1.2至-0.8））（p<0.001）。与地特胰岛素组（1.9 kg（95%可信区间1.3至2.6））相比，双相门冬胰岛素组（3.3 kg（95%可信区间2.7至4.0））和门冬胰岛素+地特胰岛素组（3.2 kg（95%可信区间2.6至3.9））体重增加更多。与双相门冬胰岛素组（1.0 IU/kg/天（95%可信区间0.9至1.1））和门冬胰岛素+地特胰岛素组（1.1 IU/kg/天（95%可信区间1.0至1.3））相比，地特胰岛素组胰岛素剂量更高（1.6 IU/kg/天（95%可信区间1.4至1.8））（p<0.001）。严重低血糖和严重不良事件的参与者数量无差异。

结论

尽管在HbA1c、体重增加和胰岛素剂量方面存在差异，但3种胰岛素治疗方案在颈动脉IMT变化上无差异。该试验仅达到计划样本量的46%，因此可能是检验效能不足影响了我们的结果。

试验注册号

NCT00657943。