Metformin Cessation and Dementia Incidence

Abstract

Importance: Prior studies suggested that metformin may be associated with reduced dementia incidence, but associations may be confounded by disease severity and prescribing trends. 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.

Objective: To investigate the association of terminating metformin treatment for reasons unrelated to kidney dysfunction with dementia incidence.

Design, setting, and participants: This cohort study was conducted at Kaiser Permanente Northern California, a large integrated health care delivery system, among a cohort of metformin users born prior to 1955 without 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.

Exposures: A total of 12 220 early terminators, individuals 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. Early terminators were matched with routine users of the same age and gender who had diabetes for the same duration.

Main outcomes and measures: The outcome of interest was all-cause incident dementia. Follow-up for early terminators and their matched routine users was started at age of termination for the early terminator. Survival models adjusted for sociodemographic characteristics and comorbidities at the time of metformin termination (or matched age). Mediation models with HbA1c level and insulin usage 1 and 5 years after termination tested whether changes in blood glucose or insulin usage explained associations between early termination of metformin and dementia incidence.

Results: The final analytic sample consisted of 12 220 early terminators (5640 women [46.2%]; mean [SD] age at start of first metformin prescription, 59.4 [9.0] years) and 29 126 routine users (13 582 women [46.6%]; mean [SD] age at start of first metformin prescription, 61.1 [8.9] years). 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.

Conclusions and relevance: In this study, terminating metformin treatment was associated with increased dementia incidence. This finding may have important implications for clinical treatment of adults with diabetes and provides additional evidence that metformin is associated with reduced dementia risk.

Figure 1.. Matching Procedure Showing Timelines for 7 Hypothetical Study Participants

The timeline for participant 1 represents the index, the early terminator for whom matches were sought. Other timelines represent the candidate pool of individuals matched exactly to the index based on age at metformin initiation, gender, and whether metformin was the first diabetes drug prescribed in the Kaiser Permanente Northern California (KPNC) health care system. Orange boxes indicate the person-time that would be contributed for each participant if matched, with follow-up time starting at the age of metformin termination for the index. Blue boxes indicate metformin prescriptions, and black squares indicate the end of contributed person-time due to censoring. eGFR indicates estimated glomerular filtration rate.

Figure 2.. Study Flowchart

The flowchart displays inclusions and exclusions for the analytic sample in the Kaiser Permanente Northern California (KPNC) cohort and exposure definition for early terminators and matched routine users. The final sample eligible for matching is shown in the 2 boxes at the bottom. Note that this does not match the sample sizes in Table 1 given that not every early terminator could be matched and some early terminators were matched with other early terminators prior to early termination. eGFR indicates estimated glomerular filtration rate.

Figure 3.. Mediation Analysis Results

Sample sizes differed across mediation analyses due to data availability for mediators.