Efficacy and Safety of Lipid-Lowering Drugs of Different Intensity on Clinical Outcomes: A Systematic Review and Network Meta-Analysis

Abstract

There have been many meta-analyses for statins, ezetimibe and proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) to evaluate clinical outcomes, but the efficacy and safety of different intensity of these three drugs on clinical outcomes was absent. PCSK9i, ezetimibe, and statins were divided into seven interventions as follows: including PCSK9i + high-intensity statins (P9i+HT), PCSK9i + moderate-intensity statins (P9i+MT), ezetimibe + high-intensity statins (Eze+HT), ezetimibe + moderate-intensity statins (Eze+MT), high-intensity statins (HT), moderate-intensity statins (MT), and low-intensity statins (LT). The risk ratios (RR) and 95% confidence intervals (CI) were calculated to evaluate the clinical outcomes in all randomized controlled trials included. In traditional meta-analysis, the more intensive treatment had a lower risk of all-cause mortality (RR 0.91, 95% CI 0.88–0.95), cardiovascular mortality (RR 0.89, 95% CI 0.86–0.92), myocardial infarction (RR 0.79, 95% CI 0.77–0.81), coronary revascularization (RR 0.80, 95% CI 0.76-0.84), and cerebrovascular events (RR 0.84, 95% CI 0.80–0.88) compared with the less intensive treatment. However, the more intensive treatment had a higher risk of new-onset diabetes (RR 1.08, 95% CI 1.04-1.12). The network meta-analysis demonstrated that P9i+HT, P9i+MT, HT, and MT were significantly associated with a risk reduction in coronary revascularization and cerebrovascular events compared with PLBO. LT could effectively reduce the risk of cardiovascular mortality (RR 0.71, 95% CI 0.54–0.92), MI (RR 0.67, 95% CI 0.54-0.82), and coronary revascularization (RR 0.77, 95% CI 0.65–0.91) compared with PLBO. P9i+HT was superior to HT in reducing the risk of MI (RR 0.78, 95% CI 0.68–0.90), coronary revascularization (RR 0.84, 95% CI 0.73–0.96), and cerebrovascular events (RR 0.78, 95% CI 0.64–0.95). However, compared with PLBO, P9i+HT, HT, and MT could increase the risk of new-onset diabetes (RR 1.23, 95% CI 1.11–1.37; RR 1.23, 95% CI 1.14–1.33; RR 1.09, 95% CI 1.02–1.15, respectively). In conclusion, PCSK9i added to background statins may be recommended as preferred lipid-lowering therapy, and did not increase the additional risk of new-onset diabetes. The safety and efficacy of ezetimibe was not superior to that of statins. LT can be recommended as the initial therapy.

PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis

“…Our results are consistent with prior evidence on lipid-lowering therapies. For instance, a network meta-analysis by Ma et al showed larger relative risk reduction in cardiovascular outcomes by addition of PCSK9 inhibitor on statin than ezetimibe 37. Ezetimibe has been shown to reduce risk of non-fatal myocardial infarction and stroke, but not mortality (moderate to high certainty) 3435.…”

Patient versus physician preferences for lipid‐lowering drug therapy: A discrete choice experiment

“…Previous studies primarily concentrated on the comparative analysis of different lipid‐lowering drugs 5,35,36 . Nevertheless, our DCE study is unique in that it evaluates the significance of these differences from the patient and physician perspectives.…”

“…Previous studies primarily concentrated on the comparative analysis of different lipid‐lowering drugs. 5 , 35 , 36 Nevertheless, our DCE study is unique in that it evaluates the significance of these differences from the patient and physician perspectives. Despite the favourable efficacy, safety and administration frequency of PCSK9 inhibitors, our study found that subcutaneous injections were a source of distress for patients.…”

A Look to the Past - What Has Had the Biggest Impact on Lipids in the Last Four Decades? A Personal Perspective

“…Everything started with two pivotal studies – the Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) published in 1984 [ 1 ] that showed the proof-of-concept of lipid lowering and confirmed that reducing LDL-C levels can diminish the incidence of coronary heart disease (CHD) morbidity and mortality in men at high risk for CHD, and the 4S study [ 23 ] that 10 years later confirmed the role of statins in reduction of all-cause mortality. Subsequently, hundreds of studies confirmed these results, and now statins are essential drugs in both primary ( Figure 2 A ) and secondary ( Figure 2 B ) prevention of ASCVD, effectively prolonging patients’ lives [ 24 , 25 ].…”

“… The impact of statin use on the prognosis of patients in primary ( A ) and secondary ( B ) prevention [ 24 , 25 ] …”