Comparison of the burden of familial hypercholesterolemia between two cohorts of French Canadians hospitalized 25 years apart for coronary heart disease.

BACKGROUND: Familial hypercholesterolemia (FH) is associated with lifelong elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). Clinical recommendations and treatments have emerged to facilitate the management of FH patients. Their impact on the burden of FH is however not well documented. OBJECTIVE: To compare the burden of FH between patients hospitalized for a CHD event 25 years apart in the French-Canadian founder population. METHODS: Lipid profiles, cardiovascular risk factors, treatments and FH status of 2,029 patients consecutively hospitalized for an acute CHD event between 2017 and 2022 (2022 Cohort) were compared to those of 2,506 patients with angiographically-confirmed CHD who were admitted between 1995 and 1998 (1998 Cohort). RESULTS: At the time of admission, 24.6 % of CHD patients had LDL-C levels >5.0 mmol/L in 1998 compared to 1.4 % in 2022, and FH was diagnosed in 9.6 % of patients in the 1998 cohort compared to 5.5 % in 2022 (p<0.001). FH patients hospitalized for a CHD event were older in 2022 than in 1998 (p <0.001). The prevalence of premature CHD requiring a hospitalization significantly decreased from 1998 to 2022 (64.3% vs. 44.1 %, p<0.001). At the moment of admission, 18.2 % of FH patients had LDL-C concentration <2.0 mmol/L in 2022 vs 0 % in 1998 (p <0.001). CONCLUSIONS: Over 25 years, FH patients tend to be older and contribute to a lower proportion of hospitalizations for CHD in the French-Canadian founder population. Despite significant improvement in diagnosis and treatment, FH management remains however sub-optimal.

Atherosclerotic plaque regression in homozygous familial hypercholesterolaemia: a case report of a long-term lipid-lowering therapy involving LDL-receptor-independent mechanisms.

Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening genetic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels, important xanthomatosis and increased risk of premature atherosclerotic cardiovascular disease. Management of HoFH at an early stage is recommended but conventional lipid-lowering therapies (LLTs) dependent on the LDL-receptor for clearance of LDL particles, are usually not sufficient. However, agents acting independently of the LDL-receptor, such as inhibitors of microsomal triglyceride transfer protein (MTP) or angiopoietin-like protein 3 (ANGPTL3), administered in combination, on top of standard-of-care LLT constitute a promising therapy for HoFH. Case summary: The present case describes a long-term (>10 years) follow-up of a 52-year-old woman with severe HoFH, who was treated with conventional lipid-lowering medications (i.e. statins and ezetimibe) for several years before experiencing the risks and benefits that were encountered with the use of LDL-receptor-independent agents (MTP and ANGPTL3 inhibitors). This combination therapy demonstrated a good long-term safety and efficacy profile, while continuous monitoring of hepatic enzymes (sometimes requiring dose adjustments) and fat accumulation is recommended when using lomitapide. Discussion: Treating this HoFH patient with an LLT involving the combination of MTP and ANGPTL3 LDL-receptor-independent inhibitors (lomitapide and evinacumab, respectively) showed remarkable improvement in LDL-C levels, disappearance of xanthomatosis and regression in atherosclerotic plaques. In addition to safety and efficacy, one should question the affordability and access hurdle that emerging combination of expensive therapies might constitute in the future for the payers. These challenges could eventually limit the clinical use of those innovative treatments despite their clinical benefit.

Lessons learned from the evinacumab trials in the treatment of homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a life-threatening disease characterized by extremely elevated LDL cholesterol (LDL-C) levels which result in premature atherosclerotic cardiovascular disease. As conventional lipid-lowering therapies, which mainly depend on LDL receptors for LDL particle clearance, remain insufficient for reaching the recommended LDL-C levels in HoFH, agents acting independently of LDL receptors, such as ANGPTL3 inhibitors, constitute a promising target. Evinacumab, a monoclonal antibody directed against ANGPTL3, was approved in the USA in 2021 for treating patients with HoFH. Evinacumab has shown an adequate safety profile with strong LDL-lowering efficacy. This review highlights the development path of evinacumab and provides insight on the lessons learned from trials as well as the hurdles facing accessibility.

Homozygous familial hypercholesterolemia (HoFH) is a life-threatening rare genetic disorder characterized by extremely elevated 'bad' cholesterol and resulting in heart disease at a young age. As the current treatments that tend to lower the levels of 'bad' cholesterol remain insufficient for treating patients with this disease, emerging agents, such as inhibitors of the protein ANGPTL3, follow different biological pathways than the ones targeted by the traditional therapies and constitute a promising target for HoFH. Evinacumab, which is highly selective for ANGPTL3 inhibition, was approved in the USA in 2021 for treating patients with HoFH. Evinacumab has been shown to be safe and well tolerated, with a strong effect on decreasing 'bad' cholesterol levels. This review highlights the development path of evinacumab and provides insight into the lessons learned from trials as well as the hurdles facing accessibility.