Qualitative and Quantitative Effects of PCSK9 Inhibitors in familial Hypercholesterolemia: a Synthetic Review

Familial hypercholesterolemia (FH) is an autosomal dominant disease caused most commonly by mutations in the gene coding for LDL receptors. This results in increased circulating cholesterol, and clinical consequences of premature stroke, myocardial infarction, etc. FH remains underdiagnosed and thus undertreated, leading to a high health care burden. A newer group of agents, the PCSK9 inhibitors, effectively reduces plasma cholesterol, especially when combined with other lipid lowering agents. The purpose of this narrative review is to synthesize all existing qualitative and quantitative data on the utility of PCSK9 inhibitors in familial hypercholesterolemia, in order to clarify standards of care and identify areas needing further research. Through PubMed/MEDLINE keyword searching, we identified 12 existing randomized controlled trials comparing PCSK9 inhibitor to placebo in FH patients, and pooled their outcomes across a total 2533 patients. We also reviewed quantitative effect on ASCVD outcomes and cost/benefit ratios. In FH patients, PCSK9 inhibitors caused a mean LDL reduction of -49.1%, compared to -3.5% with placebo (weighted average was calculated to account for different study sizes). These findings are comparable to trial results in the non-FH ASCVD population. However, there are no data on PCSK9 inhibitors' effect on hard cardiovascular outcomes in FH. Furthermore, in order for PCSK9 inhibitors to qualify as high-value care, price must be significantly reduced or LDL goals increased. PCSK9 inhibitors are potent reducers of LDL in FH patients. However, dedicated randomized trials are needed to assess whether this translates into statistically significant ASCVD prevention long-term.