Department of Ophthalmology, Academic Medical Center, Amsterdam, Netherlands.
BMJ. 2010 May 20;340:c2181. doi: 10.1136/bmj.c2181.
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.
Multicentre randomised placebo controlled trial.
Outpatient clinics of three non-academic hospitals in the Netherlands.
390 patients with type 2 diabetes receiving treatment with insulin.
850 mg metformin or placebo three times a day for 4.3 years.
Percentage change in vitamin B-12, folate, and homocysteine concentrations from baseline at 4, 17, 30, 43, and 52 months.
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 micromol/l (95% CI 18.8 to 30.0 micromol/l), compared with a mean homocysteine level of 18.1 micromol/l (95% CI 16.7 to 19.6 micromol/l; P=0.003) for patients with a low vitamin B-12 concentration and 14.9 micromol/l (95% CI 14.3 to 15.5 micromol/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).
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.
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 缺乏症（<150 pmol/l）、低维生素 B-12 浓度（150-220 pmol/l）、叶酸和同型半胱氨酸浓度发生率的影响。
多中心随机安慰剂对照试验。
荷兰三家非学术医院的门诊。
390 名接受胰岛素治疗的 2 型糖尿病患者。
每天服用 850 毫克二甲双胍或安慰剂，持续 4.3 年。
从基线到第 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的百分比变化。
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%（95%置信区间 -24%至-14%；P<0.001）和叶酸浓度降低 5%（95%置信区间 -10%至-0.4%；P=0.033）有关，同型半胱氨酸浓度升高 5%（95%置信区间 -1%至 11%；P=0.091）。在调整体重指数和吸烟后，发现二甲双胍对叶酸浓度没有显著影响。研究结束时，与安慰剂组相比，接受二甲双胍治疗的患者维生素 B-12 缺乏症（<150 pmol/l）的绝对风险增加了 7.2 个百分点（95%置信区间 2.3 至 12.1；P=0.004），每 4.3 年需要治疗的人数为 13.8 人（95%置信区间 43.5 至 8.3）。研究结束时，与安慰剂组相比，接受二甲双胍治疗的患者维生素 B-12 浓度较低（150-220 pmol/l）的绝对风险增加了 11.2 个百分点（95%置信区间 4.6 至 17.9；P=0.001），每 4.3 年需要治疗的人数为 8.9 人（95%置信区间 21.7 至 5.6）。研究结束时维生素 B-12 缺乏症患者的同型半胱氨酸水平平均为 23.7 μmol/l（95%置信区间 18.8 至 30.0 μmol/l），而维生素 B-12 浓度较低患者的同型半胱氨酸水平平均为 18.1 μmol/l（95%置信区间 16.7 至 19.6 μmol/l；P=0.003 与维生素 B-12 缺乏症相比；P=0.005 与维生素 B-12 缺乏症相比，P<0.001 与维生素 B-12 缺乏症相比）。浓度正常（>220 pmol/l）的患者。
长期使用二甲双胍会增加维生素 B-12 缺乏症的风险，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，在长期使用二甲双胍治疗期间，应强烈考虑定期测量维生素 B-12 浓度。试验注册 Clinicaltrials.gov NCT00375388。
