Evolocumab for high cardiovascular risk patients without previous stroke: a network meta-analysis of randomized controlled trials

Background High cardiovascular (CV) risk patients with no previous stroke could benefit from an intensive lipid-lowering strategy beyond statins alone. However, the comparative efficacy of non-statin treatments in this population remains unclear. Purpose To investigate the efficacy and safety of non-statin treatments—including evolocumab, alirocumab, enlicitide, inclisiran, evinacumab, omega-3 fatty acids, and ezetimibe—in high CV risk patients without previous stroke. Method A literature search was conducted in PubMed, Scopus, and the Cochrane Library from inception through January 2026. High CV risk was defined according to standard guidelines. Only studies in which fewer than 10% of patients had a documented history of stroke were eligible. The primary endpoints included major adverse cardiovascular events (MACE)—defined as the composite endpoint of CV mortality, myocardial infarction, stroke, and coronary revascularization—along with CV mortality and stroke incidence evaluated independently. The secondary endpoints were changes in low-density lipoprotein cholesterol (LDL-C) levels (mg/dL) and lipoprotein(a) [Lp(a)] levels (%). Results A total of 15 RCTs comprising 78,146 patients (23,626 females [30.2%]; mean age 63.7± 9.2 years) were included. Among the non-statin options, evolocumab demonstrated the greatest reduction in MACE, CV mortality, and stroke incidence, with ORs of 0.75 (95% CI 0.64–0.88, p <0.001), 0.79 (95% CI 0.64–0.98, p = 0.030), and 0.79 (95% CI 0.62–1.01, p = 0.058), respectively, and the highest P-scores of 0.98, 0.91, and 0.84. The top three treatments for LDL-C reduction were evolocumab (MD −55.1 mg/dL, 95% CI −80.3 to −30.0, p <0.001; P-score 0.86), inclisiran (MD −54.1 mg/dL, 95% CI −89.4 to −18.8, p = 0.002; P-score 0.84), and alirocumab (MD −46.3 mg/dL, 95% CI −66.8 to −25.8, p <0.001; P-score 0.76). For Lp(a) reduction, evolocumab ranked highest (MD −26.9%, 95% CI −27.0 to −26.8, p <0.001; P-score 0.91), followed by enlicitide (MD −27.5%, 95% CI −34.4 to −20.7, p <0.001; P-score 0.87) and alirocumab (MD −26.1%, 95% CI −26.5 to −25.7, p <0.001; P-score 0.72). Conclusions Evolocumab had the potential to be the first-line non-statin option for high CV risk patients without previous stroke due to its efficacy in reducing MACE, CV mortality, LDL-C, and Lp(a).Figure 1Figure 2