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More evidence suggested that metformin may be protective against new-onset dementia in older adults with diabetes, a cohort study found.

Compared with routine metformin users, those who stopped the drug early for reasons other than kidney dysfunction saw a 21% higher risk for developing dementia (HR 1.21, 95% CI 1.12-1.30), found Sarah Ackley, PhD, of Boston University, and colleagues.

This link was largely independent of changes in HbA1c and insulin usage, they reported in .

Mediation analysis found HbA1c level or insulin use contributed to an acceleration of dementia diagnosis by 0.07 years (95% CI 0.02-0.13 years) 1 year after metformin termination, but by the 5-year mark had zero contribution to dementia diagnosis acceleration (0.00 years, 95% CI -0.02 to 0.02 years).

"For individuals with diabetes at particularly high risk of dementia, such as carriers of APOE4 or individuals with a family history of dementia, it may be particularly beneficial to find ways to manage or mitigate gastrointestinal adverse effects (e.g., switching to slower release formulations of metformin or taking the medication with food in the evening) instead of replacing metformin with other agents, given that participants in this study remained on anti-diabetes drugs after early termination with metformin," Ackley's group advised.

These findings track with a that found people with diabetes on metformin had 24% lower risk for developing dementia compared with patients not on metformin (HR 0.76, 95% CI 0.60-0.97). Another 2020 study found an 81% reduction in incident dementia risk in older metformin users (HR 0.19, 95% CI 0.04-0.85, P=0.030).

Here, 12,220 early terminators of metformin were included from the Kaiser Permanente Northern California health system, defined as any individuals with diabetes who stopped using metformin without prior history of abnormal kidney function. This sample included 46.2% women with an average age of 59.4 at the start of their first metformin prescription. About 63% were white, 14.9% were Hispanic, 13.4% were Asian, and 8.2% were Black.

They were compared with 29,126 routine users, who were patients remaining on metformin at the age when the matched early-terminator group stopped using it. This group had either not yet terminated metformin treatment or had terminated -- with or without restarting -- after their first abnormal estimated glomerular filtration rate (eGFR) measurement. They were comparable in terms of demographics. The mean HbA1c level at baseline was 8 and 7.7 for early terminators and routine users, respectively. All patients in both groups were born prior to 1955.

Routine metformin users were less likely to have cardiovascular disease at baseline (26.5% vs 33%) but were more likely to have a low eGFR at initiation of metformin (4.6% vs 1.6%).

Data on the reason behind metformin termination were not available, which was a limitation of the study.

As for next steps, the researchers noted that "[f]ormally evaluating the heterogeneity of the metformin estimate across known risk factors for dementia is an important extension of our work."

"Given considerable interest in drug repurposing for dementia, further confirmatory work would be required to extrapolate to prediabetic or nondiabetic populations," they said.

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