Unveiling Familial Hypercholesterolemia—Review, Cardiovascular Complications, Lipid-Lowering Treatment and Its Efficacy

**Background** Familial hypercholesterolemia (FH) is one of the most prevalent hereditary disorders worldwide, characterized by high circulating LDL-C levels that predispose patients to premature atherosclerosis and coronary heart disease (CHD). Heterozygous FH occurs in 1 in 250–300 individuals, while homozygous FH occurs in 1 in 250,000–360,000. Despite its prevalence, FH remains largely underdiagnosed and undertreated. If left untreated, men develop coronary artery disease (CAD) before age 55 and women before age 60. The paper reviews the genetic underpinnings, cardiovascular complications, and both pharmacological and non-pharmacological treatment options for FH.

**Methods** This is a narrative review that synthesizes findings from multiple clinical trials, observational studies, and guideline documents. The authors discuss diagnostic criteria (Dutch Lipid Clinic Network, Simon Broome, MEDPED), genetic mechanisms (monogenic and polygenic), and evidence for various lipid-lowering therapies. Key trials cited include IMPROVE-IT, ODYSSEY FH I/II, RUTHERFORD 2, ORION-9, CLEAR Harmony/Wisdom, and others. The review also covers non-pharmacological approaches such as diet, lipoprotein apheresis, liver transplant, and emerging gene-editing technologies.

**Key Results** - Statins reduce LDL-C by 50–60% with high-intensity therapy; an observational study found statin therapy reduced cardiovascular events in FH patients by 76%. - Ezetimibe added to statins provides an additional 20% LDL-C reduction (IMPROVE-IT trial). - PCSK9 inhibitors (alirocumab, evolocumab) reduce LDL-C by approximately 60% when combined with statins. - Inclisiran (siRNA) reduced LDL-C by an additional 48% in FH patients (ORION-9 trial). - Bempedoic acid reduced LDL-C by about 22.3% in HeFH patients (CLEAR Harmony/Wisdom). - Evinacumab reduced LDL-C by 49% in HoFH patients regardless of LDLR variant status. - Lomitapide reduced LDL-C by 50% in HoFH patients. - Lipoprotein apheresis reduces plasma LDL-C by 50–75%. - Despite combination therapy, only 53.84% of genetically confirmed FH patients achieved the 2019 ESC/EAS LDL-C target (<1.4 mmol/L for very-high-risk patients). - The ESC/EAS recommends LDL-C goals of <1.4 mmol/L (<55 mg/dL) for very-high-risk FH patients and <1.8 mmol/L (<70 mg/dL) for high-risk FH patients.

**Clinical Implications** The review underscores that early diagnosis and aggressive lipid-lowering therapy are critical to reducing the cardiovascular burden in FH. Statins remain first-line therapy, but most patients require combination therapy with ezetimibe and often PCSK9 inhibitors to reach targets. Newer agents like inclisiran, bempedoic acid, and evinacumab offer additional options, especially for HoFH or statin-intolerant patients. Non-pharmacological treatments such as lipoprotein apheresis and liver transplant are reserved for severe cases. The authors note that despite advances, many patients still do not achieve guideline-recommended LDL-C levels, highlighting the need for more effective treatment strategies and better adherence. Emerging gene-editing technologies (e.g., CRISPR-Cas9) are in preclinical stages and may offer future curative potential.