Metformin Discontinuation and Dementia Risk

Researchers examined whether metformin medication is connected with a lower incidence of all-cause dementia in patients with type 2 diabetes (T2D) in a recent cohort study published in JAMA Network Open.
The researchers investigated whether this link is mediated by mechanisms other than improved glucose control, such as hemoglobin A1c (HbA1c) levels.

Background

Metformin (dimethylbiguanide) has been the first-line treatment for type 2 diabetes since 2006. Metformin medication may lessen the incidence of dementia in people with type 2 diabetes, according to research.
Patients, on the other hand, frequently discontinue metformin treatment for reasons like as gastrointestinal side effects and kidney problems. In fact, one-fifth of early users substitute metformin for other diabetes medications.

When the estimated glomerular filtration rate (eGFR) falls below a certain level, consumers should carefully assess the advantages vs dangers of metformin medication, according to current recommendations.

About the Study – Metformin discontinuation

The current investigation looked into whether stopping metformin treatment for reasons other than renal disease (eGFR rates falling below the acceptable threshold) was connected with an increase in dementia incidence.

They looked at the electronic health records (EHRs) of metformin users who were members of Kaiser Permanente Northern California (KPNC), one of the largest integrated healthcare delivery organizations in the United States of America (USA), with over 4.6 million members.

These people were born before January 1, 1955 (older adults), used metformin, did not have dementia, and completed one of two health surveys before enrolling in this study.

The dementia incidence follow-up began with the deployment of their EHRs in 1996 and will continue until 2020. Participants were censored at the age of 90, death, dementia diagnosis, or the start of a 90-day membership gap.

They obtained death dates from the KPNC mortality database, while race and ethnicity information was self-reported. Participants identified themselves as Asians, Blacks, Hispanic/Latino, White, and other or unclear. The race and ethnicity of those who did not endorse a group were confirmed using KPNC health plan databases.

This cohort study employed an imitated trial design, which reproduced key aspects of an RCT. As a result, the scientists estimated associations similar to intent-to-treat (ITT) estimates while comparing early metformin terminators to the group of routine metformin users.

The researchers had a 1:4 ratio of early terminators to routine metformin users. They were the same age, gender, and had diabetes for the same amount of time.

All derived P values were two-sided, and the statistical significance level for the proportional hazard assumptions was set at =.05. Between November 2021 and September 2023, the data was evaluated.

To examine whether changes in HbA1c levels or insulin prescription status mediated the links between early metformin discontinuation and all-cause dementia, a causal mediation analysis was undertaken.

Mean HbA1c levels were measured 8-16 months after metformin discontinuation and at the same age in matched routine users. They employed changes in insulin prescription status and HbA1c levels measured five years after early metformin discontinuation as factors in further analyses.

The researchers used accelerated failure time (AFT) models to conduct mediation studies, which gave a more straightforward interpretation of the observed relationships.

Furthermore, they used Cox proportional regression modeling to calculate hazard ratios (HRs) for dementia diagnosis using time since metformin discontinuation as the time scale, stratified by age when metformin medication was initiated and gender.

The researchers also ran sensitivity analyses utilizing creatinine instead of eGFR and gender-specific cutoffs. They also conducted data analysis on those who adhered to their treatment regimen.

In further sensitivity analyses, the researchers limited disparities between early and routine users by excluding differences in HbA1c levels greater than 0.1% and diabetes duration greater than one year.

They also looked at data from those who had started metformin within the previous two years and had no diabetic development.

Results and Conclusions

In total, 12,220 early terminators (46.2% women) and 29,126 routine users (46.6% women) were studied, with mean ages of 59.4 and 61.1 years at the start of the first metformin prescription, respectively.

Early terminators were 1.21 times more likely to be diagnosed with dementia than comparable routine users.

Mediation analysis revealed that changes in HbA1c level or insulin use contributed to the association between early metformin discontinuation and all-cause dementia, with no contribution for insulin use five years after metformin discontinuation and 0.07 years for HbA1c level one year after termination, implying that they only minimally mediated the association. The results of the sensitivity analyses matched those of the primary analysis.

Overall, this metformin cohort analysis in older persons essentially confirmed past observational evidence showing starting metformin was related with a lower incidence of dementia.

Because of the large sample size and lengthy follow-up period, the researchers were able to make precise estimations of the link between early metformin discontinuation and all-cause dementia. Furthermore, the study design reduced the possibility of cohort effects and confounding by indication.

This work has substantial implications for diabetes clinical care, particularly in elderly persons.

Individuals with diabetes who are at a higher risk of dementia, such as bearers of the apolipoprotein E (APOE) 4 allele, may benefit more from minimizing bad effects rather than discontinuing metformin or switching to another medicine.

To avoid gastrointestinal side effects, some individuals may choose to try different metformin formulations (e.g., slower-release metformin).

Future research could look into the heterogeneity of metformin’s observed connection with dementia risk variables. The study findings could also be extrapolated to pre-diabetic groups.

For more information: Metformin Cessation and Dementia Incidence. JAMA Netw Open

DOI:10.1001/jamanetworkopen.2023.39723.