Real-world impact of lipophilic statins on survival outcomes in polycythemia vera and essential thrombocythemia

Abstract Background: Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative neoplasms frequently associated with JAK2 mutations, which lead to constitutive activation of the JAK-STAT signaling pathway and uncontrolled hematopoietic proliferation. Preclinical studies have suggested that lipophilic statins—such as simvastatin, lovastatin, and atorvastatin—may disrupt membrane lipid rafts, thereby interfering with JAK2-V617F–mediated signaling. In this study, we evaluated the association between lipophilic statin use and survival outcomes in patients with PV or ET. Methods: We conducted a retrospective, propensity score–matched cohort study using the TriNetX Analytics Network, a global research platform with de-identified electronic health records from over 120 healthcare organizations. Adult patients diagnosed with polycythemia vera (PV) or essential thrombocythemia (ET) between January 1, 2012, and June 30, 2024, were included. The statin cohort comprised patients who received a lipophilic statin (simvastatin, lovastatin, or atorvastatin) within one year before or after PV/ET diagnosis. The non-statin cohort included patients without statin exposure during the same period. Patients with prior JAK inhibitor use or a history of acute myeloid leukemia (AML) were excluded. Propensity score matching was performed in a 1:1 ratio based on age, sex, race, presence of metastatic disease, and comorbid conditions. The index date was defined as the date of PV/ET diagnosis, with patients followed for one year. The primary outcome was all-cause mortality. Secondary outcomes included subsequent JAK inhibitor use and transformation to AML. Results: We identified 225,374 patients who met eligibility criteria. A total of 21,959 patients in the lipophilic statin cohort were successfully matched 1:1 to patients in the non-statin cohort. In Cox proportional hazards analyses, lipophilic statin use was associated with a significantly lower risk of all-cause mortality (hazard ratio [HR], 0.77 [95% CI: 0.73–0.82]) compared to non-use. There was no significant difference between the two cohorts in the subsequent use of JAK inhibitors (HR, 1.08 [95% CI: 0.81–1.43]) or in the risk of transformation to acute myeloid leukemia (HR, 1.15 [95% CI: 0.87–1.51]). Conclusion: In this large, real-world cohort study, lipophilic statin use was associated with a significant reduction in all-cause mortality among patients with polycythemia vera or essential thrombocythemia. These findings highlight the potential role of statins as adjunctive therapy in myeloproliferative neoplasms and warrant further prospective evaluation.