Safety and efficacy of low-density lipoprotein-lowering drugs in the elderly: a network meta-analysis of randomized controlled trials

BACKGROUND Balancing the efficacy of low-density lipoprotein (LDL) reduction with safety presents a significant challenge in the elderly care. While guidelines recommended high-intensity statins as the optimal strategy to lower LDL in high-risk individuals, there are prevailing concerns regarding its side effects and subsequent fatality rate. The effectiveness of different LDL-lowering therapies in this population is also unclear. This study aims to compare the safety and efficacy of various LDL-lowering strategies in elderly population. METHODS A systematic search was conducted through six databases until March 2025. Randomized controlled trials (RCTs) that evaluate LDL-lowering agents were included. The primary outcome was adverse effects, while secondary outcomes included composite cardiovascular disease (CVD) events, CVD related mortality, all-cause mortality, and LDL level reduction. Risk of bias was assessed using the RoB-2 tool. A network meta-analyses were performed to compare the safety and efficacy with subgroup analysis based on underlying CVD under the cumulative ranking values. RESULTS Sixteen RCTs (n = 43,625) with low to moderate risk of bias were included. Among interventions evaluated for adverse events, moderate-intensity pitavastatin had the highest probability of being the safest. Ezetimibe demonstrated the most favorable safety profile for reducing CVD mortality, while evolocumab was most effective in lowering all-cause mortality. For LDL reduction, the combination of moderate-intensity pitavastatin and ezetimibe was the most effective, followed by moderate-intensity rosuvastatin plus ezetimibe. Subgroup analyses revealed significant differences between CVD and non-CVD populations in CVD mortality (P = 0.0059), CVD events (P = 0.0096), and LDL reduction (P = 0.0100), with more pronounced effects in the non-CVD group, suggesting greater efficacy in primary prevention. CONCLUSIONS Moderate-intensity pitavastatin showed the highest safety profile, while its combination with ezetimibe was the most effective for LDL reduction.