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Xuechun Li,1 Dennis Steenhuis,1 Maarten J Bijlsma,1,2 Stijn de Vos,1 Sumaira Mubarik,1 Jens HJ Bos,1 Catharina CM Schuiling-Veninga,1 Eelko Hak1 1Pharmacotherapy, Epidemiology and Economics, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, the Netherlands; 2Laboratory of Population Health, Max Planck Institute for Demographic Research, Rostock, GermanyCorrespondence: Xuechun Li, PhD Research Fellow, Pharmacotherapy, Epidemiology and Economics, Groningen Research Institute of Pharmacy, University of Groningen, 9713 AV Groningen, the Netherlands, Tel +31 649019602, Email xuechen.li@rug.nlPurpose: Anti-hyperlipidemic drug treatments are effective in reducing the risk of cardiovascular disease. In a long-term retrospective inception cohort study, we aimed to assess the real-world comparative effectiveness of anti-hyperlipidemic monotherapies for primary prevention of cardiovascular events.Patients and Methods: Patients aged 18 years and older, who initiated primary prevention with anti-hyperlipidemic monotherapy, were selected from the University of Groningen IADB.nl dispensing database. In intention-to-treat (ITT) analysis we included all patients, whereas in per-protocol (PP) analysis we included both all patients independent of adherence (PPIA) and adherent patients (PPA). Study outcome was the time to first prescription of acute cardiac drug therapy measured by valid drug proxies to identify a first major cardiovascular event. We applied inverse probability of treatment-weighted (IPTW) analysis using Cox regression and time-varying Cox regression with simvastatin as the reference category to estimate the average treatment effect hazard ratios (HR) and their corresponding 95% confidence intervals (CI).Results: Atorvastatin users had significantly higher hazards compared to simvastatin users (HR range: 1.27 to 1.47, 95% CI: 1.15 to 1.69). Similarly, Pravastatin users also exhibited increased hazards compared to simvastatin users (HR range: 1.41 to 1.56, 95% CI: 1.14 to 2.04). Similar patterns were observed in patients with diabetes, rheumatoid arthritis, and asthma/COPD. No differences were found in the hazards of rosuvastatin, fluvastatin, fibrates, and simvastatin.Conclusion: Atorvastatin and pravastatin users had higher long-term rates of cardiovascular events compared to simvastatin monotherapy in primary prevention, the difference may be attributed to the confounding by severity, but also possibly due to differences in drug mechanisms or patient response. These findings could influence current guideline recommendations, suggesting a potential preference for simvastatin in primary prevention, underscoring the need for further research to explore long-term impacts and underlying mechanisms, especially in diverse populations. Keywords: acute cardiac drug therapy, time-varying confounding, inverse probability treatment weighting, Cox regression