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New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk?

      Highlights

      • New personalized drug modalities are needed to reduce the residual CVD risk.
      • Major therapies aimed at reducing TRLs involve targeting ANGPTL3 or apoC-III.
      • Targeting ANGPTL3 reduces all serum lipoproteins; Phase III trials are expected with enthusiasm.
      • Targeting apoC-III reduces TG and elevates HDL; Phase III trials on hyper-TG subjects are ongoing.
      • The present TRL therapies hold a lot of promise, however, genome editing may revolutionize the field.

      Abstract

      Remarkably good results have been achieved in the treatment of atherosclerotic cardiovascular diseases (CVD) by using statin, ezetimibe, antihypertensive, antithrombotic, and PCSK9 inhibitor therapies and their proper combinations. However, despite this success, the remaining CVD risk is still high. To target this residual risk and to treat patients who are statin-intolerant or have an exceptionally high CVD risk for instance due to familial hypercholesterolemia (FH), new therapies are intensively sought. One pathway of drug development is targeting the circulating triglyceride-rich lipoproteins (TRL) and their lipolytic remnants, which, according to the current view, confer a major CVD risk. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are at present the central molecular targets for therapies designed to reduce TRL, and there are new drugs emerging that suppress their expression or inhibit the function of these two key proteins. The medications targeting these components are biological, either human monoclonal antibodies or antisense oligonucleotides. In this article, we briefly review the mechanisms of action of ANGPTL3 and apoC-III, the reasons why they have been considered promising targets of novel therapies for CVD, as well as the current status and the most important results of their clinical trials.

      Keywords

      Abbreviations:

      ANGPTL3 (angiopoietin-like protein 3), apoB (apolipoprotein B), apoC-III (apolipoprotein C-III), ASO (antisense oligonucleotide), C (cholesterol), CAD (coronary artery disease), CVD (cardiovascular disease), FH (familial hypercholesterolemia), HDL (high-density lipoprotein), LDL (low-density lipoprotein), LOF (loss-of-function), Lp(a) (lipoprotein (a)), LPL (lipoprotein lipase), MI (myocardial infarction), PCSK9 (proprotein convertase subtilisin/kexin type 9), TG (triglyceride), TRL (triglyceride-rich lipoprotein), VLDL (very-low-density lipoprotein)
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