© 2019 Elsevier Inc. Statin therapy is effective in primary and secondary prevention, but substantial residual risk remains on statin treatment, especially among high risk and very high risk patients. Add-on therapy with ezetimibe and proprotein convertase subtilisin /kexin type 9 (PCSK9) inhibitors provides additional risk reduction through further reduction in low density lipoprotein cholesterol. Elevated triglycerides/triglyceride rich lipoproteins contribute to atherogenesis and to the residual risk on statin therapy. Addition of icosapent ethyl to statins has recently been shown to markedly lower risk of ASCVD events in patients with established atherosclerotic CVD (ASCVD) and high risk patients with type II diabetes mellitus. These data are discussed in the context of current guidelines and synthesized in a decision pathway to guide combination lipid-lowering therapy in patients at high ASCVD risk.