PCSK9 Inhibitors as Adjunctive Therapies in Hypercholesterolemia: Benefits, Limitations, and Possible Alternatives

The clinical application of statins as anti-hypercholesterolemia medications, while very beneficial, remains limited by intolerance and side effects. Statins increase the production of proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades low-density lipoprotein (LDL) receptor and limits circulating LDL cholesterol (LDLC) uptake. PCSK9 also promotes cardiomyocyte and vascular smooth muscle cell apoptosis and vascular injury. Several PCSK9 inhibitors (evolocumab, alirocumab, and inclisiran) are highly effective at reducing plasma LDLC levels and moderately effective at protecting against cardiovascular disease. However, their long-term use needs to take the following issues into account: i) PCSK9 deficiency leads to various pathologies like heart failure and liver steatosis, ii) PCSK9 regulates lipid homeostasis, iii) depletion of circulating PCSK9 may itself upregulate PCSK9 expression, and iv) the cost of available inhibitors is beyond the reach of most people. Therefore, the long-term safety and affordability of PCSK9 inhibitors needs to be revisited and additional therapeutic options need to be explored.