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Clinical Trial Summary | Neurology, Endocrinology
Metformin Cessation and Dementia Incidence
Time to read: 06:30 minute
Time to listen: 07:34
Source: JAMA Network Open
Original Published : 25 October 2023
Type of article: Clinical Research Summary
MedED Catalogue Reference: MPECS012
Cross-reference: Diabetes, Neurology
Keywords: neurology, diabetes, T2T, type 2 diabetes, dementia, metformin, renal function, morbidity, mortality
Key Take Aways
1. This study found that early termination was associated with a 1.21 times higher hazard of dementia diagnosis when compared to users who had not terminated
2. The association between early metformin termination and dementia was largely independent of changes in HbA1c level and insulin usage
2. The research has implications for diabetes treatment in later life, in particular for those patients who are carriers of APOE ε4 or individuals with a family history of dementia
Overview | Objectives | Study Design | Findings | Conclusion | Original Research | Limitations | Declaration of Interests|
This summarises an original research article published in JAMA Network Open on 25 October 2024, and reproduced under the CC BY License. This is a summary in no way represents as an original research article. Unless otherwise indicated, all work contained here is implicitly referenced to the original author and trial. Links to all original material can be found at the end of this summary.
Overview
Metformin (dimethylbiguanide) has been the preferred first-line agent for type 2 diabetes since its approval for use in the US in 2006.
While numerous trials have suggested that individuals with type 2 diabetes exhibit improved cognitive function and reduced dementia risk when treated with metformin compared to other antidiabetic medications, the precise mechanism underlying these neuroprotective effects remains inconclusive.
Some studies attribute these benefits specifically to metformin use compared to other antidiabetic treatments whilst several trials propose that the overall reduction in glucose levels, irrespective of the specific therapeutic agent used, contributes to the observed decrease in dementia risk
The ACCORD-MIND trial compared an intensive glucose control strategy (HbA1c] levels below 6.0%) involving increased exposure to antidiabetes drugs, including metformin, to a less intensive approach (HbA1c target of 7.0% to 7.9%), and found no cognitive advantage in patients on the intensive control program
Users terminate metformin for various reasons, including in cases of kidney dysfunction, as it is associated with increased mortality in these patients. Less severe side effects, particularly gastrointestinal side effects, are commonly experienced by metformin users, leading to low adherence rates and the replacement of metformin with other antidiabetes agents.
In light of these confounding factors, it was challenging to determine whether there was an association between the incidence of dementia in individuals with type 2 diabetes who did not have renal disease and who had terminated their metformin treatments and, if such an association did exist, whether the dementia incidence was mediated by factors such as haemoglobin A1c (HbA1c) levels or insulin.
Objectives
The researchers aimed to explore whether terminating metformin in type 2 patients who did not have kidney disease was associated with dementia incidence.
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Study Design & Methods
Participant Selection
This study was conducted at Kaiser Permanente Northern California in the US among a cohort of metformin users who were born before 1955 and who had no history of diagnosed kidney disease when metformin treatment was initiated.
Dementia follow-up began with the implementation of electronic health records in 1996.
Study Interventions
12,220 early terminator patients were compared with 29,126 routine metformin users.
Early terminators were classified as individuals who ceased metformin usage without a prior history of abnormal kidney function (normal estimated glomerular filtration rate (eGFR).
46.2% (5640)were women, and the mean age of starting metformin was 59.4 [9.0] years.
A routine user was any individual who remained on metformin at the age when the matched early terminator ceased using metformin. 46.6% (3 582) were women, the mean age of whom was 51.1 [8.9] years at the start of the first metformin prescription.
Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration.
The age at which the first documented abnormal kidney function occurred after the initiation of metformin was determined for each participant in the metformin user cohort.
Causal mediation analysis was utilized to investigate whether changes in HbA1c levels or adjustments in insulin prescription status, evaluated approximately one year after the premature discontinuation of metformin, played a role in mediating the association between early termination of metformin and dementia.
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Findings
The researchers reported the following:
Early terminators exhibited a 1.21 times higher hazard of dementia diagnosis compared to routine users (hazard ratio, 1.21; 95% CI, 1.12 to 1.30).
In mediation analysis, the influence of changes in HbA1c level or insulin use on this association varied, ranging from no contribution for insulin use five years after termination to 0.07 years for HbA1c level 1 year after termination.
The findings suggest that the association between early metformin termination and dementia was largely independent of changes in HbA1c level and insulin usage.
Conclusion
Based on their findings, the researchers concluded that terminating metformin treatment was associated with increased dementia incidence in a diverse cohort of older adults.
Much of this association cannot be accounted for by increases in HbA1c levels or insulin use 1 or 5 years after cessation of metformin treatment.
The findings have implications for diabetes treatment in later life, in particular for those patients who are carriers of APOE ε4 or individuals with a family history of dementia. According to their findings, the researchers suggest that for patients encountering gastrointestinal (GIT) side effects with metformin, exploring ways to manage or alleviate those effects might be more beneficial than opting for a treatment replacement.
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Limitations
The study had several limitations, including:
- Dementia diagnosis relied on medical records, which could delay the recording of dementia onset
- A complete case analysis was used, with differences in sample size between the main and mediation analyses
- Several potential axes of heterogeneity, like race and ethnicity, were not explored
- The study couldn't ascertain precise reasons for metformin termination
- Data limitations hindered addressing every potential bias source, such as deprescribing for quality-of-life improvement
- Calendar time and age as the time scale may introduce bias, and assumptions about adverse effects and diabetes progression may impact results
Reproduced under CC-BY License
Disclosures
Conflict of Interest Disclosures:
• Mr. Zimmerman reported stock ownership in AbbVie Inc, Gilead Sciences LLC, CRISPR Therapeutics, and Abbott Laboratories outside the submitted work.
Funding/Support:
Role of the Funder/Sponsor:
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