Statins and Nonstatin LDL-Lowering Medications

Study Questions:

What is the clinical impact of more-intensive versus less-intensive low-density lipoprotein cholesterol (LDL-C) lowering by means of statins and currently recommended nonstatin medications in secondary prevention?


The authors performed a meta-analysis using Medline, EMBASE, and Cochrane databases for randomized controlled trials of statins, ezetimibe, PCSK9 inhibitors, or bile acid sequestrants with >500 patients followed for ≥1 year. Random-effects models using risk ratios (RRs) were used to compare outcomes. Nineteen trials were included (15 of statins, 3 of PCSK9 inhibitors, and 1 of ezetimibe) with 152,507 patients randomly assigned to more-intensive (n = 76,678) or less-intensive (n = 75,829) treatment.


More-intensive treatment was associated with a 19% relative risk reduction for the primary outcome, major vascular events (MVEs) (RR, 0.81). Risk reduction was greater across higher baseline levels and greater achieved reductions of LDL-C. The clinical benefit was significant across varying types of more-intensive treatment and was consistent for statins (RR, 0.81) and nonstatin agents (PCSK9 inhibitors and ezetimibe; RR, 0.85) as active (more-intensive) intervention (p-interaction = 0.38). Each 1.0 mmol/L (~40 mg/dl) reduction in LDL-C was associated with a 19% relative decrease in MVEs. Death, cardiovascular death, myocardial infarction, stroke, and coronary revascularization also favored more-intensive treatment.


Reduction of MVEs is proportional to the magnitude of LDL-C lowering across a broad spectrum of on-treatment levels in secondary prevention. Statin intensification and add-on treatment with PCSK9 inhibitors or ezetimibe are associated with significant reduction of cardiovascular morbidity in this very high-risk population.


The conclusion would be that the available lipid-lowering agents for secondary prevention produce results proportionate to reduction in LDL-C and do not have other properties that make them unique. The authors point out that meta-regression techniques on a trial level require cautious interpretation. ‘Although random-effects pooling reduces heterogeneity, the heterogeneity observed among studies with different baseline cardiovascular risk and background therapy is substantial.’ This meta-analysis does not refute the possibility that certain agents may have more or less benefit based on the anti-inflammatory effects or reduction in lipoprotein (a).

Clinical Topics: Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Cardiac Surgery and Arrhythmias, Advanced Lipid Testing, Lipid Metabolism, Nonstatins, Novel Agents, Statins

Keywords: Bile Acids and Salts, Cholesterol, LDL, Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Lipoprotein(a), Myocardial Infarction, Myocardial Revascularization, Primary Prevention, Risk Factors, Risk Reduction Behavior, Secondary Prevention, Stroke, Treatment Outcome, Vascular Diseases

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