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

Efficacy of statins in familial hypercholesterolaemia: a long term cohort study

Objective To determine the efficacy of statin treatment on risk of coronary heart disease in patients with familial hypercholesterolaemia

A retrospective observational study to determine baseline characteristics and early prescribing patterns for patients receiving Alirocumab in UK clinical practice

Background Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9) and has been previously shown, in the phase III ODYSSEY clinical trial program, to provide significant lowering of lowdensity lipoprotein cholesterol (LDL-C) and reduction in risk of major adverse cardiovascular events. However, real-world evidence to date is limited. Objective The primary objective was to describe baseline characteristics, clinical history, and prior lipid-lowering therapy (LLT) use of patients initiated on alirocumab in UK clinical practice following publication of health technology appraisal (HTA) body recommendations. Secondary objectives included description of alirocumab use and lipid parameter outcomes over a 4-month follow-up period. Methods In this retrospective, single-arm, observational, multicenter study, data were collected for 150 patients initiated on alirocumab. Results Mean (standard deviation; SD) age of patients was 61.4 (10.5) years and baseline median (interquartile range; IQR) LDL-C level was 4.8 (4.2–5.8) mmol/l. Alirocumab use occurred predominantly in patients with heterozygous familial hypercholesterolemia (HeFH) (n = 100/150, 66%) and those with statin intolerance (n = 123/150, 82%). Most patients started on alirocumab 75 mg (n = 108/150 [72%]) and 35 (23.3%) were up-titrated to 150 mg. Clinically significant reductions in atherogenic lipid parameters were observed with alirocumab, including LDL-C (median [IQR] change from baseline, − 53.6% [− 62.9 to − 34.9], P < 0.001). Conclusion This study highlights the unmet need for additional LLT in patients with uncontrolled hyperlipidemia and demonstrates the clinical utility of alirocumab in early real-world practice, where dosing flexibility is an important attribute of this therapeutic option

Relationship between moderate-to-vigorous physical activity, abdominal fat and immunometabolic markers in postmenopausal women

AbstractObjectsTo assess the burden of levels of physical activity, non-esterified fatty acids (NEFA), triacylglycerol and abdominal fat on the immunometabolic profile of postmenopausal women.Study designForty-nine postmenopausal women [mean age 59.43 (standard deviation 5.61) years] who did not undertake regular physical exercise participated in this study. Body composition was assessed using dual-energy X-ray absorptiometry, and levels of NEFA, tumour necrosis factor-α, adiponectin, insulin and triacylglycerol were assessed using fasting blood samples. The level of physical activity was assessed using an accelerometer (Actigraph GTX3x), and reported as counts/min, time spent undertaking sedentary activities and time spent undertaking moderate-to-vigorous physical activity (MVPA). The following conditions were considered to be risk factors: (i) sedentary lifestyle (<150min of MVPA per week); (ii) high level (above median) of abdominal fat; and (iii) hypertriacylglycerolaemia (<150mg/dl of triacylglycerol).ResultsIn comparison with active women, sedentary women had higher levels of body fat (%) (p=0.041) and NEFA (p=0.064). Women with higher levels of abdominal fat had impaired insulin resistance (HOMA-IR) (p=0.016) and spent more time undertaking sedentary activities (p=0.043). Moreover, the women with two risk factors or more had high levels of NEFA and HOMA-IR (p<0.05), as well as an eight-fold higher risk of a high level of NEFA, independent of age (p<0.05). No significant relationship was found between levels of physical activity, abdominal fat, tumour necrosis factor-α and adiponectin (p>0.05).ConclusionPostmenopausal women with a combination of hypertriacylglycerolaemia, a high level of abdominal fat and a sedentary lifestyle are more likely to have metabolic disturbances

Reducing the Clinical and Public Health Burden of Familial Hypercholesterolemia A Global Call to Action

Q1Q1Artículo completoE1-E13IMPORTANCE Familial hypercholesterolemia (FH) is an underdiagnosed and undertreated genetic disorder that leads to premature morbidity and mortality due to atherosclerotic cardiovascular disease. Familial hypercholesterolemia affects 1 in 200 to 250 people around the world of every race and ethnicity. The lack of general awareness of FH among the public and medical community has resulted in only 10% of the FH population being diagnosed and adequately treated. The World Health Organization recognized FH as a public health priority in 1998 during a consultation meeting in Geneva, Switzerland. The World Health Organization report highlighted 11 recommendations to address FH worldwide, from diagnosis and treatment to family screening and education. Research since the 1998 report has increased understanding and awareness of FH, particularly in specialty areas, such as cardiology and lipidology. However, in the past 20 years, there has been little progress in implementing the 11 recommendations to prevent premature atherosclerotic cardiovascular disease in an entire generation of families with FH. OBSERVATIONS In 2018, the Familial Hypercholesterolemia Foundation and the World Heart Federation convened the international FH community to update the 11 recommendations. Two meetings were held: one at the 2018 FH Foundation Global Summit and the other during the 2018 World Congress of Cardiology and Cardiovascular Health. Each meeting served as a platform for the FH community to examine the original recommendations, assess the gaps, and provide commentary on the revised recommendations. The Global Call to Action on Familial Hypercholesterolemia thus represents individuals with FH, advocacy leaders, scientific experts, policy makers, and the original authors of the 1998 World Health Organization report. Attendees from 40 countries brought perspectives on FH from low-, middle-, and high-income regions. Tables listing country-specific government support for FH care, existing country-specific and international FH scientific statements and guidelines, country-specific and international FH registries, and known FH advocacy organizations around the world were created. CONCLUSIONS AND RELEVANCE By adopting the 9 updated public policy recommendations created for this document, covering awareness; advocacy; screening, testing, and diagnosis; treatment; family-based care; registries; research; and cost and value, individual countries have the opportunity to prevent atherosclerotic heart disease in their citizens carrying a gene associated with FH and, likely, all those with severe hypercholesterolemia as well

Beyond the Usual Suspects: Expanding on Mutations and Detection for Familial Hypercholesterolemia

Introduction: Familial hypercholesterolemia (FH) is a highly prevalent condition, predisposing individuals to premature cardiovascular disease and with a genetic basis more complex than initially thought. Advances in molecular technologies have provided novel insights into the role of next-generation-sequencing, the assessment and classification of newly found variants, the complex genotype-phenotype correlation, and the position of FH in the context of other dyslipidaemias. Areas covered: Understanding the scope of genetic determinants of FH has expanded substantially. This article reviews the current literature on the complexity that comes with this incremental knowledge and highlights the added value of genetic testing as an addition to phenotypic diagnosis of FH. Moreover, we discuss the broad genetic basis of FH, with a focus on the three main FH genes, but we also pay attention to polygenic hypercholesterolemia as well as minor and modulator genes involved in FH. Expert opinion: Both the availability and the need for genetic analysis of FH are on the rise as costs of sequencing continue to drop and new therapies require a genetic diagnosis for reimbursement. However, greater use of genetic testing requires more education of healthcare professionals, since molecular technologies will allow for rapid and accurate evaluation of large numbers of detected variants