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In older patients with diabetes, use of metformin was linked with slower cognitive decline and reduced risk of dementia, according to a prospective observational study.

In more than 1,000 patients followed for 6 years, the rate of decline in global cognition was significantly slower in patients with diabetes treated with metformin compared with those treated with other therapies (P=0.032), and the same was true for decline in executive function (P=0.006). In fact, the rates for both were similar to that of patients without diabetes, said Katherine Samaras, PhD, of the Garvan Institute of Medical Research in New South Wales, Australia, and colleagues.

Their study, online in also found that metformin use was associated with an 81% reduction in incident dementia risk (HR 0.19, 95% CI 0.04-0.85, P=0.030) in a statistical model that adjusted for factors including age, sex, body-mass index, cardiovascular disease, blood pressure, smoking, and apolipoprotein E (APOE) genotype.

As many as 60% of patients with type 2 diabetes develop dementia, the researchers noted, explaining that the mechanism is thought to involve neurodegeneration caused by hyperglycemia, hyperinsulinemia, and oxidative stress. Previous research has suggested that diabetes medications including metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like 1 peptide agonists, sodium-glucose co-transporter 2 inhibitors, and sulfonylureas can slow cognitive decline in patients with diabetes.

"We've revealed the promising new potential for a safe and widely used medication, which could be life-changing for patients at risk of dementia and their families," Samaras said in a statement. "For those with type 2 diabetes, metformin may add something extra to standard glucose lowering in diabetes care: a benefit for cognitive health."

Previous epidemiological studies and two pilot randomized clinical trials reported cognitive benefits associated with metformin use. However, few of those studies controlled for covariates that significantly contribute to dementia risk -- most notably APOE genotype, which has been strongly linked with risk of Alzheimer's disease, Samaras and colleagues said.

For the new study, they prospectively analyzed data on 1,073 community-dwelling adults ages 70-90 from the longitudinal . The vast majority (98%) were white, and none had dementia at baseline. Cognitive function was assessed every 2 years with neuropsychological tests that measured executive function, memory, attention/speed, language, and other parameters.

Incident dementia was ascertained by a multidisciplinary panel. Other data was collected every 2 years via interviews that covered medical conditions, sociodemographic factors, and all medications used, including dosage and duration of use.

At baseline, 123 study participants had diabetes. Of those, 67 received metformin. Approximately half of these received metformin alone and the other half received it in combination with other drugs, most often sulfonylureas. The patients with diabetes not being treated with metformin were most often being treated with diet alone. Other medications included sulfonylureas, glitazones, and insulin.

Follow-up was 6 years. The researchers used Cox regression and other statistical analyses to examine links between metformin use and incident dementia and cognitive decline. The team also measured brain volume by magnetic resonance imaging at baseline and every 2 years; however, the results showed no differences in brain volume outcomes, the investigators reported.

Asked for his perspective, Robert Eckel, MD, of the University of Colorado Anschutz Medical Campus in Aurora, who was not involved with the study, called the results "quite interesting" in an email to MedPage Today -- "particularly the impact of metformin on executive function in DM [diabetes mellitus] vs DM without metformin, and potentially very important for such a commonly used drug," he said.

However, the study's sample size was small and the participants were mostly white, and therefore the results need further validation, Eckel noted. In addition, "use of anti-hypertensives and lipid-lowering medications were not stated or evaluated, and this could be important in either direction, for less or more cognitive dysfunction/dementia."

Additional limitations of the study, the researchers said, included the potential for selection bias and survivor bias. Participants who dropped out of the study had lower cognitive performance at baseline compared with those who remained in the study. "These participants also had higher rates of the dementia risk factors of heart disease and stroke," Samaras and co-authors wrote. "Thus, the cohort may have included survivor bias, in which case our estimates of the association between diabetes and cognitive decline and incident dementia may have been underestimated."

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