Early metformin initiation was not associated with incident dementia: a population‐based cohort study
Bibliographic record
Abstract
Abstract Background Metformin is the first‐line pharmacotherapy for type 2 diabetes. Although metformin was previously suggested to prevent dementia, most existing epidemiologic studies did not adequately address immortal time bias or confounding due to disease severity. We aim to determine the association of metformin with dementia risk using various bias mitigation strategies. Method This population‐based retrospective cohort study utilized data housed at ICES (https://www.ices.on.ca/). Using a validated algorithm for diabetes (Specificity = 99.1%, PPV = 91.4%), residents of Ontario, Canada ≥66 years newly diagnosed with diabetes from January 1, 2008 to December 31, 2017 entered the cohort. We excluded potential type 1 diabetes or advanced diabetes cases by excluding people with insulin as the first received glucose‐lowering medication. To select people at an early disease stage who could either initiate metformin or start lifestyle interventions alone, we excluded people with hemoglobin A1c <6.5% or ≥8.0% or estimated glomerular filtration rate (eGFR) <45 mL/min/1.73m2. Using a landmark analysis to address immortal time bias, the exposure was classified into “metformin monotherapy initiation within 180 days after new diabetes diagnosis” or “no glucose‐lowering medications within 180 days”. To mitigate reverse causality, a 1‐year lag period was applied to the end of the 180‐day landmark period, and therefore follow‐up started 1.5 year after cohort entry. Incident dementia was ascertained using a validated algorithm for Alzheimer’s disease and related dementias (Sensitivity = 79.3%, Specificity = 99.1%). Adjusted hazard ratios (aHR) and confidence intervals (CI) were obtained from propensity‐score weighted Cox proportional hazard models. Result Compared to no or delayed metformin initiation (N = 22,369; 1,768 events; 117,414 person‐years), metformin initiation within 180 days (N = 12,331; 978 events; 65,761 person‐years) showed no association (aHR [95% CI] = 1.047 [0.956‐1.147]) with dementia risk over mean follow‐up of 5.28 years. The sensitivity analysis with a 1‐year landmark period also showed no association (aHR [95% CI] = 1.040 [0.942‐1.148]) when comparing metformin initiation within 1 year (N = 13,902; 1,047 events; 68,404 person‐years) to no or delayed initiation (N = 19,078; 1,433 events; 91,917 person‐years). Conclusion Early metformin initiation was not associated with a lower dementia risk. The present study does not support metformin as a drug to prevent dementia.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.006 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.002 |
| Bibliometrics | 0.001 | 0.002 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.002 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".