Individualized Dose-Response to Statins Associated with Cardiovascular Disease Outcomes

Statins reduce low-density lipoprotein cholesterol (LDL-C) and are efficacious in the prevention of atherosclerotic cardiovascular disease (ASCVD). Dose-response to statins varies among patients and can be modeled using three distinct pharmacological properties: (1) E₀ (baseline LDL-C), (2) ED₅₀ (potency: median dose achieving 50% reduction in LDL-C); and (3) E_max (efficacy: maximum LDL-C reduction). However, individualized dose-response and its association with ASCVD events remains unknown.

We analyze the relationship between ED₅₀ and E_max with real-world cardiovascular disease outcomes.

We leveraged de-identified electronic health record data to identify individuals exposed to multiple doses of the three most commonly prescribed statins (atorvastatin, simvastatin, or rosuvastatin) within the context of their longitudinal healthcare. We derived ED₅₀ and E_max to quantify the relationship with a composite outcome of ASCVD events and all-cause mortality.

We estimated ED₅₀ and E_max for 3,033 unique individuals (atorvastatin: 1,632, simvastatin: 1,089, and rosuvastatin: 312) using a nonlinear, mixed effects dose-response model. Time-to-event analyses revealed that ED₅₀ and E_max are independently associated with the primary endpoint. Hazard ratios were 0.85 (p < 0.01), 0.83 (p < 0.01), and 0.87 (p = 0.10) for ED₅₀ and 1.13 (p < 0.001), 1.06 (p < 0.001), and 1.15 (p = 0.009) for E_max in the atorvastatin, simvastatin, and rosuvastatin cohorts, respectively.

The class-wide association of ED₅₀ and E_max with clinical outcomes indicates that these measures influence the risk for ASCVD events in patients on statins.