Abstract
The recent introduction of inhibitors of proprotein convertase subtilisin/kexin 9 to lower low-density lipoprotein (LDL) cholesterol on top of statins or as monotherapy is rapidly changing the landscape of treatment of atherosclerotic cardiovascular disease (ASCVD). However, existing lipid-lowering drugs have little impact on lipoprotein(a) (Lp(a)) or plasma triglycerides, two other risk factors for ASCVD. This review summarizes the evidence and the rationale to target Lp(a) and triglycerides and provides an overview of currently tested strategies to lower Lp(a), apolipoprotein C-III and angiopoietin-like protein 3. In addition, it summarizes new findings on the use of omega-3 fatty acids (OM3FA) to fight ASCVD. With the exception of OM3FA supplementation, the promise of the experimental drugs discussed here depends on the long-term safety and efficacy of monoclonal antibodies and/or antisense oligonucleotides Clinical outcome trials will ultimately prove whether these new therapeutic modalities will reduce ASCVD risk.
Highlights
Even though mortality and morbidity from atherosclerotic cardiovascular disease (ASCVD) have been markedly reduced over the past decades, this reduction decelerates at a decreased rate and ASCVD remains the leading cause of death worldwide [1]
This review provides an update on recent data to reduce Lp(a) and to reduce TG through targeting hepatic production of apolipoprotein C-III and angiopoietin-like protein 3 (ANGPTL3)
Additional studies in mice have demonstrated that apoC-III attenuates TG hydrolysis through inhibiting lipoprotein lipase (LPL) and hepatic lipase (HL), and through increasing TG incorporation into very-low-density lipoproteins (VLDL) in the liver (Figure 3) [51,52,53,54]
Summary
Even though mortality and morbidity from atherosclerotic cardiovascular disease (ASCVD) have been markedly reduced over the past decades, this reduction decelerates at a decreased rate and ASCVD remains the leading cause of death worldwide [1]. Monoclonal antibodies against proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce LDL cholesterol with 51% on top of statins or as monotherapy with an additional risk reduction of 15% [5,6] Despite high costs, these drugs are currently becoming more widely available to patients. Mendelian randomization studies have in this regard recently established that elevated plasma levels of Lp(a) and triglycerides (TG) should be considered as independent causal risk factors for ASCVD [7,8,9] These statistical analyses may be interpreted with care in view of the interrelationship between plasma lipids. Reduced TG levels, inflammation, oxidative properties of atherogenic lipoproteins and increases plaque instability
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