Lipid-Lowering Drug Therapy: Critical Approach for Implementation in Clinical Practice

Maddalena Rossi; Enrico Fabris; Davide Barbisan; Laura Massa; Gianfranco Sinagra


Am J Cardiovasc Drugs. 2022;22(2):141-155. 

In This Article

Abstract and Introduction


Increased levels of low-density lipoprotein cholesterol (LDL-C) are recognized as a primary risk factor for atherosclerotic cardiovascular disease, which remains the leading cause of death worldwide. Lowering LDL-C levels clearly reduces the risk of cardiovascular events, with benefits related to both absolute reduction and duration of treatment; however, a threshold below which low LDL-C levels can be dangerous has never been established. Since the discovery of statins, cardiovascular research has focused on developing new lipid-lowering agents. Ezetimibe and proprotein convertase subtilisin–kexin type 9 inhibitors have been found to further reduce LDL-C values and subsequent cardiovascular risk. Novel recently approved inclisiran and bempedoic acid, currently being tested in cardiovascular outcomes studies, are further expanding our pharmacological armamentarium, enabling the clinician to diminish residual risk related to LDL-C. Moreover, new agents are paving the way to successful treatment of homozygous familial hypercholesterolemia. This review summarizes the main characteristics of current and emerging lipid-lowering therapies to assist with comprehensive evidence-based decision making.


Introduction: Why do we Need new Lipid-lowering Therapies?

Accounting for 30% of the world's total deaths, atherosclerotic cardiovascular disease (ASCVD) is considered the leading cause of morbidity and mortality all over the world.[1] In Europe, it causes more than 4 million deaths annually, with an estimated global economic cost of €196 billion per year, in terms of direct healthcare costs, loss of work productivity, and informal family care.[2]

It is well-known that low-density lipoprotein cholesterol (LDL-C) represents the key initiating event in atherogenesis as it enters the subendothelial space, accumulates in the arterial wall, and promotes a local inflammatory response.[3] A consistent body of evidence from randomized controlled trials (RCTs) confirms that elevated LDL-C is associated with the highest odds ratio for ASCVD among all modifiable cardiovascular risk factors,[4] with an "effect size" proportional to both LDL-C blood levels and the total time of exposure. Moreover the positive association between ASCVD and LDL-C extends to even very low levels of LDL-C,[5] and lowering LDL-C and apolipoprotein B (apoB) reduces the risk of major atherosclerotic vascular events, with benefits directly and positively correlated with the incrementally achieved absolute LDL-C reduction and duration of treatment.[6–8] Most importantly, a threshold below which LDL-C reduction is dangerous has never been detected, so there is no lower limit for achievable LDL-C values.[7]

Given this, the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias have further lowered LDL-C goals for each cardiovascular risk class, thus paving the way for implementation of new pharmacological approaches.