Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial.
Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial.
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DOI：
10.1136/bmj.c2181
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发表时间：
2010-05-20
期刊：
影响因子：
--
通讯作者：
Stehouwer CD
中科院分区：
文献类型：
--
作者：
de Jager J;Kooy A;Lehert P;Wulffelé MG;van der Kolk J;Bets D;Verburg J;Donker AJ;Stehouwer CD
目的研究二甲双胍对接受胰岛素治疗的2型糖尿病患者维生素B-12缺乏（<150 pmol/l）、低浓度维生素B-12（150-220 pmol/l）、叶酸和同型半胱氨酸浓度的影响。设计多中心随机安慰剂对照试验。设置在荷兰的三个非学术医院门诊。研究对象390例接受胰岛素治疗的2型糖尿病患者。干预850 mg二甲双胍或安慰剂，每天三次，持续4.3年。主要观察指标：4、17、30、43和52个月时维生素B-12、叶酸和同型半胱氨酸浓度相对于基线的百分比变化。结果与安慰剂相比，二甲双胍治疗与维生素B-12浓度平均降低−19%相关（95%置信区间为−24%至−14%; P<0.001），叶酸浓度为−5%（95% CI-10%至-0.4%; P=0.033），同型半胱氨酸浓度增加5%（95% CI-1%至11%; P=0.091）。校正体重指数和吸烟后，二甲双胍对叶酸浓度无显著影响。维生素B-12缺乏的绝对风险二甲双胍组在研究结束时的血糖水平（<150 pmol/l）比安慰剂组高7.2个百分点（95% CI 2.3至12.1; P=0.004），每4.3年需要13.8例伤害（95% CI 43.5至8.3）。二甲双胍组在研究结束时维生素B-12浓度低（150-220 pmol/l）的绝对风险高11.2个百分点（95% CI 4.6 - 17.9; P=0.001），每4.3年需要8.9例损害（95% CI 21.7 - 5.6）。研究结束时维生素B-12缺乏患者的平均同型半胱氨酸水平为23.7 µmol/l（95% CI 18.8 - 30.0 µmol/l），而平均同型半胱氨酸水平为18.1 µmol/l（95% CI 16.7 - 19.6 µmol/l; P=0.003），对于维生素B-12浓度低且14.9 µmol/l的患者维生素B-12浓度正常（>220 pmol/l）的患者（95% CI 14.3 - 15.5 µmol/l;与维生素B-12缺乏相比P<0.001;与维生素B-12低水平相比P=0.005）。结论长期二甲双胍治疗增加了维生素B-12缺乏的风险，从而导致同型半胱氨酸浓度升高。维生素B-12缺乏症是可以预防的;因此，我们的研究结果表明，应强烈考虑在长期二甲双胍治疗期间定期测量维生素B-12浓度。试用注册Clinicaltrials.gov NCT 00375388。
Objectives To study the effects of metformin on the incidence of vitamin B-12 deficiency (<150 pmol/l), low concentrations of vitamin B-12 (150-220 pmol/l), and folate and homocysteine concentrations in patients with type 2 diabetes receiving treatment with insulin. Design Multicentre randomised placebo controlled trial. Setting Outpatient clinics of three non-academic hospitals in the Netherlands. Participants 390 patients with type 2 diabetes receiving treatment with insulin. Intervention 850 mg metformin or placebo three times a day for 4.3 years. Main outcome measures Percentage change in vitamin B-12, folate, and homocysteine concentrations from baseline at4, 17, 30, 43, and 52 months. Results Compared with placebo, metformin treatment was associated with a mean decrease in vitamin B-12 concentration of −19% (95% confidence interval −24% to −14%; P<0.001) and in folate concentration of −5% (95% CI −10% to −0.4%; P=0.033), and an increase in homocysteine concentration of 5% (95% CI −1% to 11%; P=0.091). After adjustment for body mass index and smoking, no significant effect of metformin on folate concentrations was found. The absolute risk of vitamin B-12 deficiency (<150 pmol/l) at study end was 7.2 percentage points higher in the metformin group than in the placebo group (95% CI 2.3 to 12.1; P=0.004), with a number needed to harm of 13.8 per 4.3 years (95% CI 43.5 to 8.3). The absolute risk of low vitamin B-12 concentration (150-220 pmol/l) at study end was 11.2 percentage points higher in the metformin group (95% CI 4.6 to 17.9; P=0.001), with a number needed to harm of 8.9 per 4.3 years (95% CI 21.7 to 5.6). Patients with vitamin B-12 deficiency at study end had a mean homocysteine level of 23.7 µmol/l (95% CI 18.8 to 30.0 µmol/l), compared with a mean homocysteine level of 18.1 µmol/l (95% CI 16.7 to 19.6 µmol/l; P=0.003) for patients with a low vitamin B-12 concentration and 14.9 µmol/l (95% CI 14.3 to 15.5 µmol/l; P<0.001 compared with vitamin B-12 deficiency; P=0.005 compared with low vitamin B-12) for patients with a normal vitamin B-12 concentration (>220 pmol/l). Conclusions Long term treatment with metformin increases the risk of vitamin B-12 deficiency, which results in raised homocysteine concentrations. Vitamin B-12 deficiency is preventable; therefore, our findings suggest that regular measurement of vitamin B-12 concentrations during long term metformin treatment should be strongly considered. Trial registration Clinicaltrials.gov NCT00375388.
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