Metformin Cessation and Dementia Incidence

Key Take Aways

1. Metformin has been linked to the reduced incidence of dementia, hinting at its neuroprotective benefits. 
2. It was unknown whether such benefits are independent of HbA1c levels or insulin usage.
3. Early termination of metformin is relatively common, most often related to gastrointestinal side effects
4. 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
5. The association between early metformin termination and dementia was largely independent of changes in HbA1c level and insulin usage
6. 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
 

Top

This summarises an original research article reproduced under the CC BY License. It does not replace the original work, which has been linked below.

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
• 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. Metformin is terminated in case of kidney dysfunction as it is associated with increased mortality in these patients. Less severe side effects, in particular 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 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 exister whether the dementia incidence was mediated by factors such as haemoglobin A1c (HbA1c) levels or insulin.
 

Objectives

---

 

Study Design & Methods

Participant Selection

This cohort 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.

 

---

Intervention

This cohort study compared 12 220 early terminator patients 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.

For each participant in the metformin user cohort, the age at which the first documented abnormal kidney function occurred after the initiation of metformin was determined. 

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.

 

Learn more| Adherence and persistence rates of major antidiabetic medications: a review

Lee, D.S.U., Lee, H. Adherence and persistence rates of major antidiabetic medications: a review. Diabetol Metab Syndr 14, 12 (2022). https://doi.org/10.1186/s13098-022-00785-1

Back to top
 

---

Findings 

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.

Back to top  

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 treatment with metformin.

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.
 

Learn more| Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases

Dai, J., Ports, K. D., Corrada, M. M., Odegaard, A. O., O'Connell, J., & Jiang, L. (2022). Metformin and Dementia Risk: A Systematic Review with Respect to Time Related Biases. Journal of Alzheimer's disease reports, 6(1), 443–459. https://doi.org/10.3233/ADR-220002

Limitations

•  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 

Back to top
 

 Disclosures

 

Disclaimer
This article is in no way presented as an original work.  Every effort has been made to attribute quotes and content correctly. Where possible, all information has been independently verified. The Medical Education Network bears no responsibility for any inaccuracies which may occur from the use of third-party sources. If you have any queries regarding this article contact us 

Fact-checking Policy
The Medical Education Network makes every effort to review and fact-check the articles used as source material in our summaries and original material. We have strict guidelines in relation to the publications we use as our source data, favouring peer-reviewed research wherever possible. Every effort is made to ensure that the information contained here accurately reflects the original material. Should you find inaccuracies, out-of-date content or have any additional issues with our articles, please make use of the contact us form to notify us.