Association between statin use and risk of incident cancer in healthy older adults: a target trial emulation using data from a multicentre, randomised trial of community-dwelling older adults in Australia and the USA

Background: The evidence on whether statin use affects cancer incidence is inconclusive and limited among apparently healthy older adults. This study emulated a target trial comparing statin initiators versus non-initiators, with further analyses stratified by statin lipophilicity. Methods: We conducted a target trial emulation using ASPREE (ASPirin in Reducing Events in the Elderly) and its extended observational data (ASPREE-XT). ASPREE was a placebo-controlled trial of low-dose aspirin in 19,114 older adults predominantly ≥70 years of age in Australia and the United States, who had no cardiovascular events, dementia, and independence-limiting physical disability at enrolment. We emulated a target trial of statin initiators versus non-initiators, following a prespecified target protocol. Key exclusion criteria were prior cardiovascular or cerebrovascular disease, high bleeding risk, conditions likely to limit 5-year survival, and anemia. The primary outcome was any-incident cancer and site-specific cancer, as adjudicated by an expert panel. Inverse probability weighting (IPW) was applied to adjust for predefined confounders including sociodemographic, clinical, and anthropometric factors, comorbidities, and co-medications to achieve balance between treatment groups. Findings: Participants were enrolled from March 01, 2010, to December 31, 2014, with follow-up to June 12, 2017, during the trial phase and then extended to January 08, 2022, as observational study. Of 12,557 eligible participants, 1596 (12.7%) initiated statin, including 882 (7.0% lipophilic and 714 (5.7%) hydrophilic statin. Over a median follow-up of 8.3 years (IQR; 6.5-9.5), the cumulative incidence of cancer per 1000 person-years was 16.0 (95% CI: [13.8-18.3]) in statin initiators and 21.6 (95% CI: [20.6-22.6]) in the non-initiators. Statin use was associated with a lower risk of cancer (Sub-distribution Hazard Ratio (SHR): 0.70 95% CI [0.59-0.82]), metastatic (SHR: 0.70 95% CI [0.52-0.93]) and non-metastatic (SHR: 0.71 95% CI [0.58-0.87]) cancers. This association remained significant for lipophilic statins (metastatic (SHR: 0.65 95% CI [0.45-0.94]) and non-metastatic (SHR: 0.64 95% CI [0.49-0.84]) cancers), but not for hydrophilic statins (metastatic (SHR: 0.77 95% CI [0.52-1.13]) and non-metastatic (SHR: 0.80 95% CI [0.61-1.06]) cancers). Among site-specific cancers, prostate cancer (SHR 0.67; 95% CI 0.47-0.95) and breast cancer (SHR 0.55; 95% CI 0.33-0.93) showed significant association. The estimated number needed to treat associated with statin use was 31 (95% CI: 25-47) for any cancer, 56 (95% CI: 44-87) metastatic cancer, and 72 (95% CI: 46-100) non-metastatic cancer over a median follow-up of 8.3 years. Interpretation: In this target trial emulation, statin use was associated with lower cancer incidence in older adults, with potential differences by cancer type and statin lipophilicity. These findings highlight the need for long-term randomised control trial to confirm this association. Potential for unmeasured confounding and bias due to the non-randomised observational design was a study limitation, and the inclusion of healthy participants may limit the generalizability of the findings.