Alirocumab efficacy in patients with double heterozygous, compound heterozygous, or homozygous familial hypercholesterolemia

Background Mutations in the genes for the low-density lipoprotein receptor ( LDLR ), apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 have been reported to cause heterozygous and homozygous familial hypercholesterolemia (FH). Objective The objective is to examine the influence of double heterozygous, compound heterozygous, or homozygous mutations underlying FH on the efficacy of alirocumab. Methods Patients from 6 alirocumab trials with elevated low-density lipoprotein cholesterol (LDL-C) and FH diagnosis were sequenced for mutations in the LDLR , apolipoprotein B, proprotein convertase subtilisin/kexin type 9, LDLR adaptor protein 1 ( LDLRAP1 ), and signal-transducing adaptor protein 1 genes. The efficacy of alirocumab was examined in patients who had double heterozygous, compound heterozygous, or homozygous mutations. Results Of 1191 patients sequenced, 20 patients were double heterozygotes (n = 7), compound heterozygotes (n = 10), or homozygotes (n = 3). Mean baseline LDL-C levels were similar between patients treated with alirocumab (n = 11; 198 mg/dL) vs placebo (n = 9; 189 mg/dL). All patients treated with alirocumab 75/150 or 150 mg every 2 weeks had an LDL-C reduction of ≥15% at either week 12 or 24. At week 12, 1 patient had an increase of 7.1% in LDL-C, whereas in others, LDL-C was reduced by 21.7% to 63.9% (corresponding to 39–114 mg/dL absolute reduction from baseline). At week 24, LDL-C was reduced in all patients by 8.8% to 65.1% (10–165 mg/dL absolute reduction from baseline). Alirocumab was generally well tolerated in the 6 trials. Conclusion Clinically meaningful LDL-C–lowering activity was observed in patients receiving alirocumab who were double heterozygous, compound heterozygous, or homozygous for genes that are causative for FH

Achieved LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia: A model that explores the efficacy of conventional and novel lipid-lowering therapy

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PCSK9 inhibitors in clinical practice: Delivering on the promise?

In clinical trials, protein convertase subtilisin/kexin type 9 (PCSK9) inhibitors robustly lowered LDL-cholesterol (LDL-c) and had a favorable tolerability and safety profile. Based on these findings, PCSK9 inhibitors are incorporated in updates of clinical treatment guidelines. However, trial results do not necessarily predict the effectiveness under real-world conditions. The aim of the current study is to determine the efficacy and tolerability of PCSK9 inhibitors in routine outpatient care. The cohort comprised all patients who were prescribed evolocumab or alirocumab at the outpatient clinic of a large university hospital in the Netherlands. Eligible patients required additional lipid-lowering despite maximally tolerated statin therapy and ezetimibe, or were statin intolerant. Data were systematically collected during routine outpatient visits. The study included 238 patients of whom 67.2% had familial hypercholesterolemia (FH) and 42.9% were statin intolerant. The mean LDL-c reduction was 55.0% from a baseline of 4.4 mmol/L. LDL-c goals were attained by 62.3% of patients. Side effects were reported by 15.5% of patients and 2.5% discontinued treatment. No meaningful differences in efficacy or tolerability were observed between patients with FH or statin intolerance, or across treatment regimens. The observed lipid reductions and side effects profile of PCSK9 inhibitors in a routine care setting were comparable to observations in clinical trial

The clinical and molecular diversity of homozygous familial hypercholesterolemia in children: Results from the GeneTics of clinical homozygous hypercholesterolemia (GoTCHA)study

Background: Homozygous familial hypercholesterolemia (hoFH)is either diagnosed on the identification of pathogenic genetic variants in LDLR, APOB, or PCSK9 or by phenotypic parameters of which an extremely elevated LDL-C level >13 mmol/L (>500 mg/dL)is the most prominent hallmark. Little is known about the clinical spectrum in children with hoFH. Objective: We set out to investigate the phenotypical spectrum of genetically defined hoFH in our pediatric cohort and evaluated how many pediatric patients, now classified as heterozygous, carry a second mutation, which would reclassify these patients as hoFH. Methods: We analyzed the data of a total of 1903 children with molecularly proven FH. Subsequently we performed candidate gene sequencing in the cohort of heterozygous familial hypercholesterolemia children in whom the LDL-C level was above the lowest level measured in the pediatric patients with hoFH. Results: Of our 13 hoFH children, 8 (62%)had LDL-C levels below the clinical hoFH criteria of 13 mmol/L (500 mg/dL). In the remaining 1890 patients with heterozygous familial hypercholesterolemia, 64 (3.4%)had LDL-C levels equal to or above the lowest LDL-C level in a patient with hoFH carrying 2 deleterious variants (8.36 mmol/L or 323.3 mg/dL). No additional pathogenic variants in LDLR and APOB were identified. In 2 related patients, a PCSK9 gain of function mutation was found. Conclusion: We show that LDL-C levels vary among pediatric patients with molecularly proven hoFH, and that most of these patients do not meet the clinical LDL-C criteria for hoFH. The levels overlap with LDL-C levels in true heterozygous patients. This warrants a critical reappraisal of the current LDL-C cutoffs for the phenotypic diagnosis of hoFH in children

A Deep Intronic Variant in LDLR in Familial Hypercholesterolemia

BACKGROUND: Familial hypercholesterolemia (FH) is an inherited disorder characterized by high plasma LDL-C (low-density lipoprotein-cholesterol) levels. The vast majority of FH patients carry a mutation in the coding region of LDLR, APOB, or PCSK9. We set out to identify the culprit genetic defect in a large family with clinical FH, in whom no mutations were identified in the coding regions of these FH genes. METHODS: Whole genome sequencing was performed in 5 affected and 4 unaffected individuals from a family with an unexplained autosomal dominant FH trait. The effect on splicing of the identified novel intronic LDLR mutation was ascertained by cDNA sequencing. The prevalence of the novel variant was assessed in 1 245 FH patients without an FH causing mutation identified by Sanger sequencing and in 2 154 patients referred for FH analysis by next-generation sequencing (covering the intronic region). RESULTS: A novel deep intronic variant in LDLR (c.2140+103G>T) was found to cosegregate with high LDL-C in 5 patients, but was not present in 4 unaffected family members. The variant was shown to result in a 97 nucleotides insertion leading to a frameshift and premature stop codon in exon 15 of LDLR. The prevalence of the intronic variant was 0.24% (3/1245) in a cohort of FH patients without a known FH causing mutation and 0.23% (5/2154) in a population of FH patients referred for analysis by next-generation sequencing. Cosegregation analysis of a second family showed full penetrance of the novel variant with the FH phenotype over 3 generations. CONCLUSIONS: The c.2140+103G>T mutation in LDLR is a novel intronic variant identified in FH that cosegregates with the FH phenotype. Our findings underline the need to analyze the intronic regions of LDLR in patients with FH, especially those in whom no mutation is found in the coding regions of LDLR, APOB, or PCSK9

Achieved LDL cholesterol levels in patients with heterozygous familial hypercholesterolemia: A model that explores the efficacy of conventional and novel lipid-lowering therapy

Background: A large proportion of patients with heterozygous familial hypercholesterolemia (heFH) do not reach low-density lipoprotein cholesterol (LDL-c) levels advocated by international guidelines (<70 mg/dL or <100 mg/dL). Objective: We set out to model which proportion of patients reach targets using conventional and novel therapies. Methods: We performed a cross-sectional analysis in a large cohort of genetically identified heFH patients and calculated the proportion reaching treatment targets in four scenarios: (1) after 50% LDL-c reduction (representing maximal dose statin); (2) after 70% LDL-c reduction (maximal dose statin + ezetimibe); (3) additional 40% LDL-c reduction representing cholesteryl ester transfer protein inhibitor (CETPi); and (4) 60% LDL-c reduction (proprotein convertase subtilisin/kexin type 9 inhibitors [PCSK9i]), on top of scenario 2. We applied 100% adherence rates and literature-based adherence rates from 62% to 80%. Results: We included 1,059 heFH patients with and 9,420 heFH patients without coronary heart disease (CHD). With maximal dose statin, 8.3% and 48.1% of patients with and without CHD would reach their recommended LDL-c targets, respectively. This increases to 54.3% and 93.2% when ezetimibe is added. Addition of CETPi increases these numbers to 95.7% and 99.7%, whereas adding PCSK9i would result in 99.8% and 100% goal attainment. Using literature-based adherence rates, these numbers decrease to 3.8% and 27.3% for maximal dose statin, 5.8% and 38.9% combined with ezetimibe, 31.4% and 81.2% when adding CETPi, and 40.3% and 87.1% for addition of PCSK9i. Conclusions: Less than 10% with and 50% of heFH patients without CHD would reach treatment targets with maximal dose statin, but this substantially increases on addition of ezetimibe, CETPi, or PCSK9i. However, considering recently published adherence data, this might be lower in real life, especially in heFH patients with CHD

Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study.

Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5-27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6-18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6-5·8) versus non-high-income countries (9·3 mmol/L, 6·7-12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0-34·5) versus 37·0 years (29·0-49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13-2·38). Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH. Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society

Worldwide experience of homozygous familial hypercholesterolaemia: retrospective cohort study

Background: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally. Methods: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005. Findings: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12·0 years (IQR 5·5–27·0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14·7 mmol/L (IQR 11·6–18·4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3·93 mmol/L, IQR 2·6–5·8) versus non-high-income countries (9·3 mmol/L, 6·7–12·7), with greater use of three or more lipid-lowering therapies (LLT; high-income 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24·5 years (IQR 17·0–34·5) versus 37·0 years (29·0–49·0) in high-income countries (adjusted hazard ratio 1·64, 95% CI 1·13–2·38). Interpretation: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH. Funding: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Societ