二甲双胍与安慰剂联合胰岛素类似物治疗2型糖尿病患者——随机、双盲的哥本哈根胰岛素与二甲双胍治疗（CIMT）试验

Metformin versus placebo in combination with insulin analogues in patients with type 2 diabetes mellitus-the randomised, blinded Copenhagen Insulin and Metformin Therapy (CIMT) trial.

作者信息

Lundby-Christensen Louise, Tarnow Lise, Boesgaard Trine W, Lund Søren S, 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, Gluud Christian, Wetterslev Jørn, Vaag Allan, Almdal Thomas P

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 Cardiology, Nephrology and Endocrinology, Nordsjællands University Hospital-Hillerød, Hillerød, Denmark Department of Health, University of Aarhus, Denmark.

出版信息

BMJ Open. 2016 Feb 25;6(2):e008376. doi: 10.1136/bmjopen-2015-008376.

OBJECTIVE

To assess the effect of metformin versus placebo both in combination with insulin analogue treatment on changes 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 eight hospitals in Denmark.

PARTICIPANTS AND INTERVENTIONS

412 participants with type 2 diabetes (glycated haemoglobin (HbA1c) ≥ 7.5% (≥ 58 mmol/mol); body mass index >25 kg/m2) were in addition to open-labelled insulin treatment randomly assigned 1:1 to 18 months blinded metformin (1 g twice daily) versus placebo, aiming at an HbA1c ≤ 7.0% (≤ 53 mmol/mol).

OUTCOMES

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

RESULTS

Change in the mean carotid IMT did not differ significantly between the groups (between-group difference 0.012 mm (95% CI -0.003 to 0.026), p=0.11). HbA1c was more reduced in the metformin group (between-group difference -0.42% (95% CI -0.62% to -0.23%), p<0.001)), despite the significantly lower insulin dose at end of trial in the metformin group (1.04 IU/kg (95% CI 0.94 to 1.15)) compared with placebo (1.36 IU/kg (95% CI 1.23 to 1.51), p<0.001). The metformin group gained less weight (between-group difference -2.6 kg (95% CI -3.3 to -1.8), p<0.001). The groups did not differ with regard to number of patients with severe or non-severe hypoglycaemic or other serious adverse events, but the metformin group had more non-severe hypoglycaemic episodes (4347 vs 3161, p<0.001).

CONCLUSIONS

Metformin in combination with insulin did not reduce carotid IMT despite larger reduction in HbA1c, less weight gain, and smaller insulin dose compared with placebo plus insulin. However, the trial only reached 46% of the planned sample size and lack of power may therefore have affected our results.

TRIAL REGISTRATION NUMBER

NCT00657943; Results.

目的

评估二甲双胍与安慰剂联合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（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，在丹麦的八家医院进行。

参与者与干预措施

412例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），除接受开放标签的胰岛素治疗外，按1:1随机分配，接受为期18个月的二甲双胍（每日两次，每次1 g）或安慰剂盲法治疗，目标是使HbA1c≤7.0%（≤53 mmol/mol）。

结局指标

主要结局指标是平均颈动脉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结局指标。

结果

两组间平均颈动脉IMT的变化无显著差异（组间差异0.012 mm（95%CI -0.003至0.026），p = 0.11）。二甲双胍组的HbA1c降低幅度更大（组间差异-0.42%（95%CI -0.62%至-0.23%），p<0.001），尽管试验结束时二甲双胍组的胰岛素剂量（1.04 IU/kg（95%CI 0.94至1.15））显著低于安慰剂组（1.36 IU/kg（95%CI 1.23至1.51），p<0.001）。二甲双胍组体重增加较少（组间差异-2.6 kg（95%CI -3.3至-1.8），p<0.001）。两组在严重或非严重低血糖或其他严重不良事件患者数量方面无差异，但二甲双胍组的非严重低血糖发作次数更多（4347次对3161次，p<0.001）。

结论

与安慰剂加胰岛素相比，二甲双胍联合胰岛素虽能更大程度降低HbA1c、减少体重增加且降低胰岛素剂量，但并未降低颈动脉IMT。然而，该试验仅达到计划样本量的46%，因此可能因检验效能不足影响了结果。

试验注册号

NCT00657943；结果