The comparison of lipid-lowering agents targeting low-density cholesterol on cardiovascular outcomes and safety: A systematic review and network meta-analysis

초록

Background: The concept of 'the lower, the better' regarding lipid levels and cardiovascular (CV) outcomes has been widely accepted. More potent drugs lowering low-density cholesterol (LDL) levels have been investigated. However, the optimal regimen for preventing CV outcomes and safety issues remains uncertain. This study aims to compare the efficacy and safety of different lipidlowering agents targeting LDL levels and their combinations using a Bayesian network meta-analysis (NMA). Methods: Randomized controlled trials (RCT) comparing different intensities of statins, ezetimibe, PCSK-9 inhibitor, and their combinations were searched in MEDLINE, EMBASE, and the Cochrane Library from January 2002 to September 2022. The primary outcome was a composite of any stroke, myocardial infarction (MI), and vascular death. Secondary outcomes included MI, vascular death, any stroke, ischemic stroke, and hemorrhagic stroke. Safety outcomes were myositis, elevated liver function test (LFT), and new-onset diabetes mellitus (DM). Each treatment was compared using relative risk ratios (RR) and 95% credible intervals (CrI). Results: This study included 66 RCTs with eight interventions involving 308,981 participants. The combination of a high-intensity statin and PCSK-9i demonstrated the most significant risk reduction (RR 0.59, 95% CrI 0.51-0.68, p<0.001) for the primary outcome, followed by high-intensity statin monotherapy (RR 0.71, 95% CrI 0.64-0.78, p<0.001). PCSK-9i plus high-intensity statin regimen consistently showed the greatest risk reduction in non-fatal MI, vascular death, any stroke, and ischemic stroke. However, hemorrhagic stroke risk is increased in the moderate statin plus ezetimibe group. (RR 1.38, 95% CrI 1.01-1.89, p=0.043). Regarding safety outcomes, the regimens involving high-intensity statins showed the highest increased risk of myositis, elevated LFT, and newonset DM. Conclusion: A high-intensity statin plus PCSK-9i regimen was most effective for the risk reduction of ischemic CV events and vascular death. On the other hand, the risk of safety outcomes was increased in regimens with high-intensity statins.