二甲双胍预防痴呆优于其他降糖药

波士顿——研究者在国际阿尔茨海默病协会2013年大会上报告，接受二甲双胍治疗的年龄较大的成年2型糖尿病患者，5年内发生痴呆的风险显著低于接受其他口服降糖药治疗的患者。

北加州Kaiser Permanente研究部门的Rachel Whitmer博士指出，据估计，在年龄超过65岁的人群中，12%~25%患有2型糖尿病，与同龄非糖尿病人群相比，2型糖尿病患者发生痴呆的风险增加约50%。几乎所有老年2型糖尿病患者都会从某个时间点开始使用某种降糖药。“很多研究提示，胰岛素（尤其是胰岛素抵抗）在阿尔茨海默病中发挥一定作用，一些高质量的动物模型和细胞培养研究特别关注了二甲双胍。”结果提示，二甲双胍可减轻神经元胰岛素抵抗，并与神经再生相关。并且，因为二甲双胍与心肌梗死和卒中风险降低相关，故可能对血管性痴呆也有保护作用。

Whitmer博士及其同事利用Kaiser Permanente数据库检出在1999年10月~2001年11月间开始接受糖尿病药物治疗且无痴呆病史的14,891例年龄≥55岁的成年2型糖尿病患者。

结果显示，总体上，9.9%的患者在5年随访期间被诊断为痴呆，包括：二甲双胍组8,528例患者中的9.5%、磺脲类药物组3,383例患者中的19.9%、噻唑烷二酮类药物(TZD)组2,095例患者中的9.8%和胰岛素组905例患者中的11.1%。在校正年龄、种族、教育和糖尿病病程的多变量模型中发现，与TZD相比，二甲双胍与任何痴呆的危险比（HR）为0.77相关。磺脲类药物或胰岛素治疗均不伴有风险显著降低。当将血糖控制(HbA1c)因素追加入模型后，发现二甲双胍预防痴呆效果仍显著优于TZD(HR，0.84)，而其他药物预防痴呆的效果均不显著优于TZD。相似的，在一个将磺脲类药物作为参照的模型中，二甲双胍预防痴呆的效果显著优于磺脲类药物，在不纳入和纳入HbA1c的模型中，经校正的HR分别为0.79和 0.80。按照痴呆亚组的效果分析中也显示，二甲双胍预防阿尔茨海默病(HR，0.70)和血管性痴呆(HR，0.75)的效果显著优于磺脲类药物。在糖尿病病程不足5年的患者中，二甲双胍使用者的痴呆风险较磺脲类药物使用者降低40%，在糖尿病病程至少为10年的患者中，二甲双胍使用者的风险较磺脲类药物使用者降低19%。

该研究由国家糖尿病、消化病与肾病研究所以及Kaiser Permanente资助。Whitmer博士受雇于北加州Kaiser Permanente。

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By: NEIL OSTERWEIL, Clinical Neurology News Digital Network

BOSTON – Older adults with type 2 diabetes who were taking metformin had a significantly lower 5-year risk for dementia than did peers who were taking other oral antidiabetic agents, investigators reported at the Alzheimer’s Association International Conference 2013.

A retrospective study of nearly 15,000 adults aged 55 years and older who started on single-agent drug therapy for type 2 diabetes between 1999 and 2001 showed that 5 years after starting therapy, patients who started on metformin had a 23% lower 5-year risk for dementia compared with patients who started on a thiazolidinedione (TZD) such as rosiglitazone (Avandia), reported Rachel Whitmer, Ph.D., an investigator in the research division of Kaiser Permanente Northern California, Oakland.

Metformin users also had a 20% lower risk for any dementia compared with those on a sulfonylurea such as glyburide. Among patients with a diabetes duration of less than 5 years, metformin users had a 40% lower dementia risk than did sulfonylurea users, and among those with a diabetes duration of at least 10 years, the risk for metformin users was 19% lower.

The differences between the drug types held up after adjustment for race, sex, education, and hemoglobin A1c (HbA1c) levels, Dr. Whitmer said.

It is estimated that 12%-25% of people over age 65 have type 2 diabetes, putting them at about a 50% increase in risk for dementia, compared with nondiabetic people of the same age. Nearly all elderly patients with type 2 diabetes will be started on some antidiabetic agent at some point, she noted.

"A lot of work out there [indicates] that insulin, and specifically insulin resistance, may play a role in Alzheimer’s disease, and there has been some nice work from animal models and cell-culture studies looking at metformin specifically," Dr. Whitmer said.

Metformin appears to lessen neuronal insulin resistance and is associated with neurogenesis. In addition, because it is associated with reduced risk of myocardial infarction and stroke, metformin may protect against vascular dementias, she added.

Dr. Whitmer and her colleagues delved into the Kaiser Permanente database to identify 14,891 patients aged 55 years and up with no history of dementia who were started on new diabetes pharmacotherapy between October 1999 and November 2001.

In all, 9.9% of patients in the sample were diagnosed with dementia during 5 years of follow-up, including 9.5% of 8,528 patients on metformin, 19.9% of 3,383 patients on a sulfonylurea, 9.8% of 2,095 patients on a TZD, and 11.1% of 905 patients on insulin.

In multivariate models adjusting for age, race, education, and diabetes duration, metformin was associated with a hazard ratio (HR) for any dementia of 0.77, compared with a TZD. Neither sulfonylureas nor insulin was associated with a significant reduction in risk. When glycemic control (HbA1c) was added to the model, metformin remained significantly better (HR, 0.84) at protecting against dementia, whereas the other agents were not significantly better than a TZD.

Similarly, in a model with sulfonylureas as the referent, metformin was significantly better, with adjusted HRs of 0.79 and 0.80 in models without and with HbA1c, respectively.

An analysis of effect by dementia subtype also showed significant benefit for metformin vs. sulfonylurea for protection against Alzheimer’s disease (HR, 0.70) and vascular dementia (HR, 0.75).

The investigators plan to examine relationships between dose and dementia, and to look at the effects of combination therapies.

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases, and by Kaiser Permanente. Dr. Whitmer is employed by Kaiser Permanente Northern California.