Ng Tze Pin, Feng Liang, Yap Keng Bee, Lee Tih Shih, Tan Chay Hoon, Winblad Bengt
Gerontology Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
Gerontology Research Programme, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore Department of Geriatric Medicine, Alexandra Hospital, Singapore, Singapore.
J Alzheimers Dis. 2014;41(1):61-8. doi: 10.3233/JAD-131901.
Evidence strongly supports the important role of insulin resistance in cognitive decline and dementia and suggests that insulin sensitizers may protect against cognitive decline in diabetic and pre-diabetic individuals. Inconclusive results have been reported in clinical trials of rosiglitazone, an insulin sensitizer that also increases cardiovascular mortality risks. No study has yet reported a protective cognitive effect of metformin, an insulin-sensitizing biguanide widely used in diabetic patients. We studied 365 older persons aged 55 and over in the population-based Singapore Longitudinal Aging Study with diabetes who were followed up over 4 years. The odds ratios (OR) of association of metformin use (n = 204) versus non-use (n = 161) with cognitive impairment (Mini-Mental State Exam ≤ 23), and by duration: up to 6 years (n = 114) and more than 6 years (n = 90) were evaluated in cross-sectional and longitudinal multivariate analyses. Controlling for age, education, diabetes duration, fasting blood glucose, vascular and non-vascular risk factors, metformin use showed a significant inverse association with cognitive impairment in longitudinal analysis (OR = 0.49, 95% CI 0.25-0.95). Metformin use showed significant linear trends of association across duration of use in cross-sectional and longitudinal analyses (p = 0.018 and p = 0.002, respectively), with use for more than 6 years significantly associated with lowest risk of cognitive impairment in both cross-sectional analysis (OR = 0.30, 95% CI 0.11-0.80) and in longitudinal analysis (OR = 0.27, 95% CI 0.12-0.60). No significant interactive effects of metformin use with APOE-ε4, depression, or fasting glucose level were observed. Among individuals with diabetes, long-term treatment with metformin may reduce the risk of cognitive decline. Further studies should establish the role of hyperglycemia and insulin resistance, and the protective role of metformin in the risk of cognitive decline and dementia.
有充分证据支持胰岛素抵抗在认知功能减退和痴呆中起重要作用，并表明胰岛素增敏剂可能预防糖尿病患者和糖尿病前期个体的认知功能减退。罗格列酮是一种胰岛素增敏剂，但在临床试验中其结果尚无定论，该药物还会增加心血管疾病死亡风险。二甲双胍是一种广泛用于糖尿病患者的胰岛素增敏双胍类药物，目前尚无研究报道其对认知功能有保护作用。我们在基于人群的新加坡纵向老龄化研究中，对365名年龄在55岁及以上的糖尿病老年人进行了为期4年的随访。在横断面和纵向多变量分析中，评估了使用二甲双胍（n = 204）与未使用二甲双胍（n = 161）的人群发生认知障碍（简易精神状态检查表≤23）的比值比（OR），以及使用时间：长达6年（n = 114）和超过6年（n = 90）的情况。在控制年龄、教育程度、糖尿病病程、空腹血糖、血管和非血管危险因素后，纵向分析显示二甲双胍的使用与认知障碍呈显著负相关（OR = 0.49，95%可信区间0.25 - 0.95）。在横断面和纵向分析中，二甲双胍的使用在使用期间均呈现出显著的线性关联趋势（分别为p = 0.018和p = 0.002），在横断面分析（OR = 0.30，95%可信区间0.11 - 0.80）和纵向分析（OR = 0.27，95%可信区间0.12 - 0.60）中，使用超过6年与认知障碍风险最低显著相关。未观察到二甲双胍的使用与APOE-ε4、抑郁或空腹血糖水平之间存在显著的交互作用。在糖尿病患者中，长期使用二甲双胍可能降低认知功能减退的风险。进一步的研究应明确高血糖和胰岛素抵抗的作用，以及二甲双胍在认知功能减退和痴呆风险中的保护作用。
