The report in JAMA Network Open discussed a recent cohort study of 12,220 early terminators and 29,126 routine users of metformin. The researchers found that cessation of metformin therapy without abnormal kidney function markers was associated with 1.21 times the hazard of dementia diagnosis compared with continuation of therapy or cessation with abnormal kidney function markers. According to authors from the University of California San Francisco, Kaiser Permanente and Boston University, the association was only minimally mediated by increases in HbA1c level and was not mediated by insulin use 1 or 5 years after metformin cessation.
“Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends,” the study pointed out. “Cessation of metformin therapy in people with diabetes typically occurs due to signs of kidney dysfunction but sometimes is due to less serious adverse effects associated with metformin.”
This cohort study was conducted at Kaiser Permanente Northern California, a large integrated healthcare delivery system, among a cohort of metformin users born prior to 1955 without a history of diagnosed kidney disease at metformin initiation. Dementia follow-up began with the implementation of electronic health records in 1996 and continued to 2020. Data were analyzed from November 2021 through September 2023.
The study team compared 12,220 early terminators, patients who stopped metformin with normal estimated glomerular filtration rate (eGFR), were compared with routine metformin users who had not yet terminated metformin treatment or had terminated (with or without restarting) after their first abnormal eGFR measurement. The study noted that early terminators were matched with 29,126 routine users of the same age and gender who had diabetes for the same duration.
All-cause incident dementia was considered the outcome of interest for the early terminators (46.2% women with a mean age of 59.4 years when initiating metformin) and routine users (46.6% women with a mean age of 61.1 years when starting metformin).
Results indicate that early terminators had 1.21 times the hazard of dementia diagnosis compared with routine users (hazard ratio, 1.21; 95% CI, 1.12 to 1.30). “In mediation analysis, contributions to this association by changes in HbA1c level or insulin use ranged from no contribution (0.00 years; 95% CI, 0.02 to 0.02 years) for insulin use at 5 years after termination to 0.07 years (95% CI, 0.02 to 0.13 years) for HbA1c level at 1 year after termination, suggesting that the association was largely independent of changes in HbA1c level and insulin usage,” the researchers advised.
The authors suggest their findings “may have important implications for clinical treatment of adults with diabetes and provide additional evidence that metformin is associated with reduced dementia risk.”
Background information in the article points out that type 2 diabetes “occurs among an increasing fraction of people aged older than 65 years in the U.S., and diabetes is associated with increased dementia risk.” It added that metformin (dimethylbiguanide) gained FDA approval in 1995 and has been the preferred first-line agent for type 2 diabetes since 2006.
“Metformin treatment reduces incidence of diabetes complications and diabetes-related and all-cause mortality,” the authors explain. “Metformin may also reduce dementia risk by improved glucose control or by mechanisms unrelated to diabetes, including activation of adenosine monophosphate–activated protein kinase, which may mimic starvation, or by inhibition of aromatase, which may be associated with lower blood pressure.”
The study added that gastrointestinal adverse effects are more common with metformin than with other antidiabetes agents, which often leads to lower adherence and replacement with other medications in about 20% of users. It also is sometimes terminated because it is associated with increased mortality in people with kidney dysfunction, a common type 2 diabetes complication. Current recommendations are to discontinue metformin when the eGFR decreases to less than 30 or 45 mL/min/1.73 m2 of height, depending on the benefits and risks of continued use.
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