Effectiveness and safety of atorvastatin/ ezetimibe fixed-dose combination in hypercholesterolemia: a systematic review and network meta-analysis

Background Many patients fail to achieve low-density lipoprotein cholesterol (LDL-C) targets with statin monotherapy, calling for a combination of statins and ezetimibe. This systematic review and network meta-analysis evaluated the comparative effectiveness and safety of atorvastatin monotherapy, atorvastatin/ezetimibe free-equivalent combination (AS/EZ FEC), and fixed-dose combination (AS/EZ FDC) in patients with hypercholesterolemia. Methods Randomized controlled trials were retrieved from electronic databases. Primary outcomes were the percentage change in LDL-C from baseline and LDL-C goal attainment, analyzed using mean difference (MD) and risk ratio (RR) with 95% confidence intervals (CI). Treatments were ranked via surface under the cumulative ranking curve (SUCRA). The two combination therapies were compared to AS alone for their safety profiles and tolerability. Forty-six trials ( n = 10,567) were included. Results AS/EZ FDC reduced LDL-C more than AS alone (MD −13.94%, 95% CI [−18.90% to −9.10%]), with similar results for AS/EZ FEC (MD −12.41%, 95% CI [−14.61% to −10.22%]). SUCRA rankings for LDL-C reduction were FDC (86.2%), FEC (63.8%), and AS (0.0%). For LDL-C goal attainment, the RR was 1.87 (95% CI [1.47–2.39]) for FEC vs. monotherapy, 1.80 (95% CI [0.85–3.81]) for FDC vs. monotherapy. No significant differences in safety profiles were observed between treatments. Conclusion AS/EZ combination therapies provide greater improvements in LDL-C reduction and goal attainment compared with AS monotherapy, with FDC ranking highest in LDL-C reduction. Treatment with AS/EZ FEC or FDC did not increase the risk of adverse events compared to AS monotherapy and was well tolerated. These findings support FDC use when intensive LDL-C lowering is required.