Statin Initiation and Dementia Incidence in a Large Health Care System From 1997 to 2020: A Target Trial Emulation Study

Abstract

Background and objectives: Previous research of associations between statins and Alzheimer disease and Alzheimer disease-related dementias (AD/ADRDs) has been limited by short follow-up, small samples, and confounding. We aimed to estimate the association between the 1st statin prescription and incident AD/ADRD among members of a large population-based cohort of older adults.

Methods: We used a cohort study design emulating a target trial using data from Kaiser Permanente Northern California (KPNC), an integrated health care delivery system. Participants were born before 1951 and KPNC members for 4+ years during 1997-2010. Embedded subsamples included sociodemographic and genetic data. Statin initiators were matched at first prescription ("baseline") with up to 5 "noninitiators" based on age and low-density lipoprotein cholesterol (LDL-C). Participants with extreme propensity scores were excluded. The outcome was time to incident AD/ADRD diagnosis, censoring, or the administrative end of study (December 31, 2020). Cox proportional hazard models were used to estimate hazard ratios for statin initiation on AD/ADRD incidence. Follow-up time was divided at the first year of follow-up to account for increased AD/ADRD detection in the first year due to increased interaction with the health care system after a statin prescription.

Results: Among eligible participants (n = 705,061), 264,294 individuals (37.5% of eligible participants) initiated any statin during 2001-2010 ("initiators"), of whom 249,613 (94.4%) were matched with 255,937 unique noninitiators to create the analytic sample (322,358 unique participants; mean age at baseline = 67.4 years; 55.1% female). The average follow-up was 11.8 years. In the first year after initiating statins, AD/ADRD diagnoses were elevated by 46% (hazard ratio [HR] = 1.46, 95% CI 1.42-1.53) compared with noninitiators. After 1 year, statin initiators experienced no difference in AD/ADRD incidence (full sample: HR = 1.00, 95% CI 0.99-1.01; subsample with survey covariates: HR = 1.01, 95% CI 0.98-1.06; subsample with survey and genetic covariates: HR = 0.97, 95% CI 0.91-1.07). Adjustment for sociodemographic covariates and apolipoprotein E e4 allele count did not materially change the findings.

Discussion: In this large emulated target trial, statin initiation was inconsistent with more than a 3% increase or decrease in the hazard of AD/ADRD after the first year of follow-up. This intent-to-treat analysis does not directly quantify effects of long-term exposure to statins. Associations in the first year likely reflect increased medical observation immediately after statin initiation.

Classification of evidence: This emulated trial provides Class II evidence that statin initiation is not associated with AD/ADRD or AD incidence after the first year of follow-up.

Figure 1. Flowchart of Sample Sizes

Participants eligible for inclusion were KPNC members with a continuous “run-in period” of at least 4 years during the period January 1, 1997, to December 31, 2010, after enrollment in KPNC or the beginning of the study period, whichever occurred earlier. Thus, the latest possible KPNC enrollment date was December 31, 2006. Participants were excluded if they had a dementia diagnosis, statin prescription, or end of enrollment during the run-in period. KPNC = Kaiser Permanente Northern California.

Figure 2. Matching and Follow-Up Time Schematic

Schematic showing hypothetical time lines potentially followed by statin initiators and their matched noninitiators for 4 statin initiators (A–D) and 4 potential noninitiator matches (E–H). Blue bars represent statin prescription time. Yellow bars represent follow-up time. The right-hand column describes whether the potential match would have been an eligible match for participant a.