Sleep Insufficiency as a Determinant of Residual Inflammatory Risk and Major Cardiovascular Events in Statin-Treated Individuals

Background Despite achievement of guideline-recommended LDL cholesterol targets, substantial residual cardiovascular disease (CVD) risk persists. Inflammation is a recognized contributor to this risk, yet upstream modifiable determinants remain incompletely defined. Sleep insufficiency has been associated with cardiometabolic dysfunction, but its role in residual inflammatory risk among statin-treated individuals is unclear. Purpose To investigate whether sleep insufficiency is associated with residual systemic inflammation and incident major adverse cardiovascular events (MACE) among statin-treated individuals achieving LDL targets, and to evaluate the mediating role of inflammation. Methods We conducted a retrospective cohort study within the Mass General Brigham Biobank. Adults on statin therapy who achieved LDL ≤70 mg/dL (established CVD) or ≤100 mg/dL (no CVD) between 2010–2020 were included. Sleep insufficiency was defined as self-reported sleep <7 hours/night or documented insomnia; individuals with other sleep disorders were excluded. C-reactive protein (CRP) values were averaged over the observation window. The primary outcome was incident MACE (myocardial infarction, unstable angina, coronary/peripheral revascularization, stroke, or heart failure). Multivariable linear and Cox regression models adjusted for demographics, traditional cardiovascular risk factors, obesity, history of malignancy, and common inflammatory conditions were used. Mediation analyses quantified the indirect effect of CRP. Results Among 3,631 statin-treated participants (median age 68 years; 56% male), sleep insufficiency was present in 55%. Despite LDL control, median CRP was 3.9 mg/L. Sleep insufficiency was independently associated with higher CRP in the primary adjusted model (β=5.44; 95%CI 1.55–9.33; p=0.006, Table 1), remaining significant after further adjustment for obesity, inflammatory conditions, cancer, and prevalent CVD. Over follow-up (457 MACE events occurred), sleep insufficiency was associated with higher incident MACE risk (adjusted HR 1.50; 95%CI 1.23–1.83; p<0.001, Figure 1). Residual inflammation was also independently associated with MACE (standardized HR per SD CRP 1.26; 95%CI 1.18–1.35; p<0.001). Mediation analysis demonstrated that CRP partially mediated the sleep–MACE association (indirect effect β=0.032; 95%CI 0.005–0.071), accounting for 5.9% of total risk, while a substantial direct association persisted. Conclusion Among statin-treated individuals achieving LDL targets, sleep insufficiency is common and independently associated with residual systemic inflammation and increased long-term cardiovascular risk. Inflammation partially mediates this relationship, suggesting both inflammatory and non-inflammatory pathways. These findings identify sleep health as a potentially actionable target to reduce residual cardiovascular risk beyond lipid lowering.