Unmet Needs in LDL-C Lowering: When Statins Won't Do!

Abstract

The use of low-density lipoprotein cholesterol (LDL-C)-lowering medications has led to a significant reduction of cardiovascular risk in both primary and secondary prevention. Statin therapy, one of the cornerstones for the prevention and treatment of cardiovascular disease (CVD), has been demonstrated to be effective in lowering LDL-C levels and in reducing the risk for CVD and is generally well-tolerated. However, compliance with statins remains suboptimal. One of the main reasons is limitations by adverse events, notably myopathies, which can lead to non-compliance with the prescribed statin regimen. Reducing the burden of elevated LDL-C levels is critical in patients with CVD as well as in patients with very high baseline levels of LDL-C (e.g. patients with familial hypercholesterolaemia), as statin therapy is insufficient for optimally reducing LDL-C below target values. In this review, we discuss alternative treatment options after maximally tolerated doses of statin therapy, including ezetimibe, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and cholesteryl ester transfer protein (CETP) inhibitors. Difficult-to-treat patients may benefit from combination therapy with ezetimibe or a PCSK9 inhibitor (evolocumab or alirocumab, which are now available). Updates of treatment guidelines are needed to guide the management of patients who will best benefit from these new treatments.

Fig. 1

Trafficking of LDLR in the presence of PCSK9 (a) or following PCSK9 inhibition by a monoclonal antibody (b). a Secreted PCSK9 binds to LDLR on the liver cell surface and mediates the lysosomal degradation of the complex formed by PCSK9, LDLR, and LDL [68]. b In the presence of a monoclonal antibody that binds to PCSK9, the PCSK9-mediated degradation of LDLR is inhibited, resulting in an increased uptake of LDL-cholesterol by LDLR as more LDLR are recycled at the cell surface [72]. LDL low-density lipoprotein, LDLR low-density lipoprotein receptor, PCSK9 proprotein convertase subtilisin/kexin type 9

Fig. 2

Impact of statins on cholesterol metabolism. Statins inhibit the biosynthesis of intracellular cholesterol by inhibiting HMG-CoA reductase. This results in low levels of intracellular cholesterol, leading to increased SREBP-2 activity, which promotes the production of PCSK9 and LDLR, the degradation of which is mediated by PCSK9 [72]. HMG CoA 3-hydroxy-3-methyl-glutaryl-CoA, LDL low-density lipoprotein, LDLR low density lipoprotein receptor, mRNA messenger RNA, PCSK9 proprotein convertase subtilisin/kexin type 9, SREBP-2 sterol-regulatory element-binding protein