Treatment Of Heterozygous Familial Hypercholesterolemia Research Articles

Review of article: Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382:1520–1530.

Review of article: Inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382:1520–1530.

Awareness, diagnosis and treatment of heterozygous familial hypercholesterolemia (HeFH) Results of a US national survey

Awareness, diagnosis and treatment of heterozygous familial hypercholesterolemia (HeFH) Results of a US national survey

The Role of Non-statin Lipid-Lowering Medications in Youth with Hypercholesterolemia.

Lifestyle modification is additive to lipid-lowering medications in the treatment of heterozygous familial hypercholesterolemia (HeFH), which does not respond sufficiently to statin therapy. While both are also important in homozygous familial hypercholesterolemia (HoFH), additional measures such as apheresis may be needed. The purpose of this review is to identify non-statin medications to lower cholesterol that are available for children and adolescents as adjunctive therapy. Ezetimibe is commonly used as second-line pharmacotherapy for treatment of HeFH and HoFH. Colesevelam, a bile acid sequestrant, may be considered for adjunct therapy. Since 2015, the PCSK9 inhibitor evolocumab has been available for adolescents, and its FDA approval has now expanded to age 10years. The ANGPTL3 inhibitor evinacumab has been approved for children age 12years and older. A clinical trial for lomitapide is in progress. Approvals for PCSK9 and ANGPTL3 inhibitors have expanded opportunities for children and adolescents with HeFH and HoFH to achieve lower LDL-C levels.

Awareness, diagnosis and treatment of heterozygous familial hypercholesterolemia (HeFH) – Results of a US national survey

HeFH is a common inherited disorder that leads to markedly elevated LDL-cholesterol from birth and premature cardiovascular disease. HeFH is frequently underdiagnosed and undertreated. To compare how well primary care physicians and cardiologists recognize and treat HeFH. The National Lipid Association surveyed 500 primary care physicians and 500 cardiologists in the US who have patients with baseline LDL-cholesterol ≥ 190 mg/dL. The survey was conducted between August 29 and September 30, 2019. For a hypothetical case of HeFH, 57% of cardiologists versus 43% of primary care physicians made the correct diagnosis (P<0.001). Among respondents, 21% of cardiologists versus 29% of primary care physicians have never made a diagnosis of HeFH in a patient with an LDL-cholesterol ≥ 190 mg/dL (P<0.004). Only 7% of cardiologists versus 5% of primary care physicians would refer to a lipid specialist (P=0.05). For additional LDL-cholesterol lowering after statins, 58% of cardiologists versus 48% of primary care physicians would prescribe a PCSK9 inhibitor (P=0.004); however, 30% of cardiologists versus 53% of primary care physicians have never prescribed a PSCK9 inhibitor in an HeFH patient (P<0.001). Although cardiologists compared to primary care physicians are somewhat more likely to recognize and treat HeFH patients according to guidelines, both physician specialties do not adequately recognize or treat HeFH. There is a need for more education and training in recognizing and treating HeFH, greater access to lipid specialists, and fewer barriers for PCSK9 inhibitor use.

Prevention of Atherosclerotic Cardiovascular Disease in Children with Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH), a common inherited disorder of LDL-C metabolism that predisposes to premature cardiovascular disease, is underdiagnosed. Despite recommendations for screening all children and initiation of lipid-lowering medication beginning at 8-10years of age, adherence to guidelines is low. Most individuals with FH are inadequately treated, especially women and children. The purpose of this review is to discuss current literature and recommendations for the diagnosis and treatment of heterozygous FH (HeFH) in the pediatric population. Twenty-year outcome data demonstrate lower rates of atherosclerotic cardiovascular disease (ASCVD) related events and death in individuals with FH who were treated with statins from childhood, compared to those who initiated statins in adulthood. While diagnosis rates of FH are slowly improving, most clinicians do not adhere to recommendations for cholesterol screening in youth. Identifying youth with FH offers the opportunity for early intervention to prevent ASCVD and identify affected relatives through reverse cascade screening.

Cascade Screening and Treatment Initiation in Young Adults with Heterozygous Familial Hypercholesterolemia.

Heterozygous familial hypercholesterolemia (HeFH) creates elevated low-density lipoprotein cholesterol (LDL-C), causing premature atherosclerotic cardiovascular disease (ASCVD). Guidelines recommend cascade screening relatives and starting statin therapy at 8–10 years old, but adherence to these recommendations is low. Our purpose was to measure self-reported physician practices for cascade screening and treatment initiation for HeFH using a survey of 500 primary care physicians and 500 cardiologists: 54% “always” cascade screen relatives of an individual with FH, but 68% would screen individuals with “strong family history of high cholesterol or premature ASCVD”, and 74% would screen a child of a patient with HeFH. The most likely age respondents would start statins was 18–29 years, with few willing to prescribe to a pediatric male (17%) or female (14%). Physicians who reported previously diagnosing a patient with HeFH were more likely to prescribe to a pediatric patient with HeFH, either male (OR = 1.34, 95% CI = 0.99–1.81) or female (OR = 1.31, 95% CI = 0.99–1.72). Many physicians do not cascade screen and are less likely to screen individuals with family history of known HeFH compared to “high cholesterol or premature ASCVD”. Most expressed willingness to screen pediatric patients, but few would start treatment at recommended ages. Further education is needed to improve diagnosis and treatment of HeFH.

Efficacy of PCSK9 inhibitors in the treatment of heterozygous familial hypercholesterolemia: A clinical practice experience

PCSK9 inhibitors are a treatment option for patients with familial hypercholesterolemia not on low-density lipoprotein cholesterol goals despite the use of maximally tolerated high intensity-statins dose. To evaluate the efficacy of alirocumab and evolocumab in LDL-C reduction and targets attainment in patients with heterozygous familial hypercholesterolemia in clinical practice setting. SAFEHEART is an open, long-term prospective study of a cohort of subjects with molecular diagnosis of familial hypercholesterolemia. This study analyze subjects ≥ 20 years of age on stable lipid-lowering therapy, who received PCSK9 inhibitors during the period 2016 to January 2020. 433 patients (mean age 55 years, 53% male, 39% with cardiovascular disease) were included and followed-up for a median of 2.5 years (IQR 1.6-3.0). Median LDL-C level prior to PCSK9 inhibitors was 145mg/dL (IQR 125-173). The addition of PCSK9 inhibitors (211 alirocumab, 222 evolocumab) reduced LDL-C by 58% (IQR 41-70) p<0.001, in men and women, achieving a median LDL-C level of 62mg/dL (IQR 44-87) without differences between both PCSK9 inhibitors. Out of them 67% with and 80% without cardiovascular disease reached 2016 ESC/EAS LDL-C targets, and 46% very high risk and 50% high risk patients achieved 2019 ESC/EAS LDL-C goals. Independent predictor factors for attainment of 2019 ESC/EAS LDL-C goals were to be male, smoking and the use of statins with ezetimibe. Both inhibitors were well tolerated. PCSK9 inhibitors on top of maximum lipid-lowering treatment significantly reduced LDL-C levels in patients with familial hypercholesterolemia and improved the achievement of LDL-C targets.

ATP citrate lyase inhibitor Bempedoic Acid alleviate long term HFD induced NASH through improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes and improvement in NAS score

Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH) are chronic liver disorders, the prevalence of which is increasing worldwide. Long term High Fat Diet (HFD) induced NASH animal models closely mimic the characteristics of human NASH and hence used by investigators as a model system for studying the mechanism of action of new drugs. Bempedoic acid (ETC-1002), a ATP citrate lyase (ACLY) inhibitor that lowers the LDL cholesterol was recently approved by US FDA for the treatment of heterozygous familial hypercholesterolemia (HeFH) and established atherosclerotic cardiovascular disease (ASCVD). ACLY is one of the genes modulated in NASH patients and hence we studied the effect of ACLY inhibitor Bempedoic acid in long term HFD induced NASH animal model to understand the pharmacological benefits and the associated mechanism of action of this newly approved drug in NASH. Mice fed with 60% Kcal High Fat Diet for 32 weeks were used for the study and the animals were given Bempedoic acid for 5 weeks at doses of 10 ​mg ​kg−1, po, qd, and 30 ​mg ​kg−1, po, qd. Bempedoic acid treatment resulted in inhibition of body weight gain and improved the glycemic control. Bempedoic acid treated group showed statistically significant reduction in plasma ALT, AST, hepatic triglycerides (TG) and total cholesterol (TC), along with statistically significant reduction in steatosis score by histological analysis. Hepatic gene expression analysis showed significant reduction in inflammatory and fibrotic genes such as Mcp-1/Ccl2, Timp-1 &Col1α1. Histological analysis showed significant improvement in NAS score. Overall, Bempedoic acid alleviated HFD induced Non-Alcoholic Steatohepatitis through inhibition of body weight gain, improvement in glycemic control, reduction of hepatic triglycerides & total cholesterol, modulation of inflammatory & fibrotic genes, and improvement in NAS score. Hence, Bempedoic acid can be a potential therapeutic option for metabolic syndrome and NASH.

Regional Variations in Alirocumab Dosing Patterns in Patients with Heterozygous Familial Hypercholesterolemia During an Open-Label Extension Study

PurposeDuring the alirocumab open-label extension study ODYSSEY OLE (open-label extension; NCT01954394), physicians could adjust alirocumab dosing for enrolled patients, who were diagnosed with heterozygous familial hypercholesterolemia (HeFH) and who had completed previous phase III clinical trials with alirocumab. This post hoc analysis evaluated the differences in physician–patient dosing decisions between the regions of Western Europe, Eastern Europe, North America, and the rest of the world (ROW).MethodsPatients (n = 909) who received starting dose alirocumab 75 mg every 2 weeks (Q2W) during ODYSSEY OLE (patients from FH I, FH II, and LONG TERM parent studies) were included. Low-density lipoprotein cholesterol (LDL-C) levels were blinded until week 8; subsequently, LDL-C values were communicated to physicians. From week 12, dose adjustment from 75 to 150 mg Q2W, or vice versa, was possible.ResultsMean LDL-C values used for the decision to increase dose from 75 to 150 mg Q2W were higher in Eastern Europe (3.7 mmol/L; 144.0 mg/dL) and ROW (3.8 mmol/L; 145.2 mg/dL) compared with Western Europe (3.1 mmol/L; 118.6 mg/dL) and North America (3.3 mmol/L; 126.6 mg/dL). Irrespective of region, the mean LDL-C at the time of decision to maintain at 75 mg Q2W was approximately 1.8 mmol/L (70 mg/dL). During ODYSSEY OLE (median treatment duration of 131.7 weeks), alirocumab was shown to have no unexpected long-term safety concerns.ConclusionsIn this OLE study, the observed variations in clinical treatment decisions suggest that physicians may perceive the severity of HeFH and/or the treatment of HeFH differently depending on their region.

HOW WELL DO CARDIOLOGISTS AND PRIMARY CARE PHYSICIANS RECOGNIZE AND TREAT HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA: A SURVEY FROM THE NATIONAL LIPID ASSOCIATION

Heterozygous Familial Hypercholesterolemia (HeFH) is an inherited disorder that leads to very high levels of LDL-C from birth and premature cardiovascular disease. However, HeFH is often undiagnosed and undertreated in clinical practice. We sought to compare awareness and treatment of HeFH between

Impact of specialty pharmacist involvement on patient access to PCSK9 inhibitors

Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel antilipemic agents commonly associated with barriers to access for patients. They are indicated as adjunctive therapy for the treatment of heterozygous familial hypercholesterolemia, homozygous familial hypercholesterolemia, and atherosclerotic cardiovascular disease needing additional low-density lipoprotein cholesterol (LDL-C) lowering. On average, annual therapy costs total approximately $14,000 per year. Due to high cost and specific indications, rates of prescription coverage denial are high for patients prescribed these medications with approximately 50% of prescriptions ultimately being rejected.Objectives: The purpose of this study is to demonstrate the impact of specialty pharmacist involvement on patient access to PCSK9 inhibitors.Methods: This was a retrospective study of patients over the age of 18 who were prescribed a PCSK9 inhibitor by a Medical University of South Carolina (MUSC) provider, with additional training in lipid management or cardiology, from 1 January to 30 June 2017. Patients were excluded if they were actively enrolled in a clinical trial at the time of PCSK9 inhibitor prescribing, or they were pregnant or lactating.Results: A total of 76 prescription orders were included in the analysis. The results were divided into three categories and compared to industry standards via chi-squared goodness of fit tests. Overall, 34/38 (89.5%) prescriptions were eligible to be filled at MUSC, statistically significantly higher than the expected 30.9% overall fill rate (p < .001). Additionally, 50/57 (87.7%) of prescriptions requiring a prior authorization (PA) and sent to MUSC received approval, statistically significantly higher than the expected 47.29% approval rate (p < .001). Lastly, 28/31 (90.3%) of patients received medication and a PA, statistically significant compared to 65.3% expected (p = .003). Regarding clinical outcomes, 35/38 patients (92.1%) in the MUSC eligible fill group did not have an unplanned cardiovascular-related emergency department visit or admission.Conclusions: As specialty pharmacy continues to grow and diversify, costly medications, like PCSK9 inhibitors, will continue to require added steps to obtain them. In this study, dedicated specialty pharmacists increased patient access to PCSK9 inhibitors by 58.6% compared to expected. This not only demonstrated improved quality of care, but also positive impacts on clinical outcomes, especially in patients who maintain the continuum of care through the health system.

Anti-PCSK9 antibodies for the treatment of heterozygous familial hypercholesterolemia: patient selection and perspectives.

Heterozygous familial hypercholesterolemia (FH) is a genetic disorder characterized by high low-density lipoprotein cholesterol levels from birth, which exposes the arteries to high levels of atherogenic lipoproteins lifelong and results in a significantly increased risk of premature cardiovascular events. The diagnosis of FH, followed by an appropriate and early treatment is critical to reduce the cardiovascular burden in this population. Phase I–III clinical trials showed the benefit of proprotein convertase subtilisin kexin 9 inhibitors, both alirocumab and evolocumab, in these patients with an average low-density lipoprotein cholesterol reduction ranging from −40% to −60%. The aim of this review is to address the unmet needs in cholesterol management, elucidate the biology and the clinical benefit of proprotein convertase subtilisin kexin 9 inhibition and finally discuss the open gaps and future directions in the treatment of patients with heterozygous FH.

Treatment of Heterozygous Familial Hypercholesterolemia in Children and Adolescents: An Unsolved Problem

Treatment of Heterozygous Familial Hypercholesterolemia in Children and Adolescents: An Unsolved Problem

Cost-effectiveness of evolocumab in treatment of heterozygous familial hypercholesterolaemia in Bulgaria: measuring health benefit by effectively treated patient-years*

ABSTRACTBackground: An elevated level of low-density lipoprotein cholesterol (LDL-C) constitutes one of the most important modifiable risk factors for cardiovascular disease (CVD). Individuals with heterozygous familial hypercholesterolaemia (HeFH) are particularly vulnerable to CVD events. The addition of evolocumab to statins has shown marked reductions in LDL-C levels. The objective of this analysis is to demonstrate the clinical and economic value of LDL-C lowering with evolocumab from the Bulgarian public health care perspective.Methods: A disease-specific measure of health benefit was devised: Effectively treated patient-years (ETPYs) combine length of life with the likelihood of attaining best-practice recommendations on LDL-C lowering. “Effective treatment” was defined as a reduction in LDL-C levels of ≥50%. A Markov cohort state-transition model was adapted, considering a life-long treatment duration. Demographics, baseline characteristics and efficacy data were taken from the RUTHERFORD-2 trial. The model uses the relationship between LDL-C lowering and reduced CVD event rates observed in the meta-analyses conducted by the Cholesterol Treatment Trialists’ Collaboration. Outcomes and costs (from year 2015) were discounted at an annual rate of 5%. Sensitivity analyses were conducted to assess uncertainty surrounding the results.Results: The total incremental costs of evolocumab added to statins versus statins alone are BGN 120,329 while adding 9.30 ETPYs over lifetime. These results imply an incremental cost per ETPY of BGN 12,937 (US$ 7,215; € 6,604). The use of evolocumab is associated with a relative reduction in the CVD event rate by 38% (18% per 1 mmol/L).Conclusions: Adding evolocumab to statins may be considered cost-effective in light of an additional expense per patient-year gained in which individuals with HeFH receive effective treatment under the terms of international prevention guidelines. ETPYs are an intuitive and clinically meaningful measure of patient benefit that, in relation to costs, can support health care decision-making that considers quality of care.

An online questionnaire survey of UK general practitioners’ knowledge and management of familial hypercholesterolaemia

ObjectiveEarly diagnosis and treatment of heterozygous familial hypercholesterolaemia (HeFH) is known to be associated with reduced mortality from premature coronary artery disease, but HeFH remains underdiagnosed. This survey aims to...

Эффективность и безопасность Мертенила (розувастатина) 40 мг/сут у пациентов с семейной гиперхолестеринемией

Familial hypercholesterolemia (FH) is an inherited disease that results in high levels of total cholesterol, causing the risk of early ischemic heart disease (IHD). Rosuvastatin is the high-potency hypolipidemic agent of HMG-CoA reductase inhibitors which is approved for clinical use.The goal of our research is to study efficacy, safety Mertenil (rosuvastatin) acceptability of maximal course dose of 40 mg in patients with phenotypic FH. Materials and methods. The 16-week open study was prospective. The study included 40 men and women at the age of 18 years and older with phenotypic FH. 18 patients had the Arg3500Gln mutation in APOB100 gene. Men accounted for 40% of total number of patients. The average age of patients was 55,9 years and average LDL cholesterol (LDL-c) level was 7,2 (1,2) mmol/l. Patients did not accept statins before the inclusion in this study (for a period no less than 3 months).Results. Rosuvastatin40 mg monotherapy 16 weeks study contributed to decrease LDL-c by 50% (p<0,001) and ApoB-100 by 45,1% (p<0,001), TG by 20,1% (p<0,01). Aspartate aminotransferase, alanintransferase and creatinekinase activity were not statistically significant from the base values and were not exceed 1,5 superior normal limit after 16-weeks study. Through 16 weeks of therapy the identified reduction of hsCRP and uric acid were observed (p<0,05). Side-effects were not observed throughout the period of treatment.Conclusion. Therapy of Mertenil (rosuvastatin) 40 mgis available and effective in treatment of heterozygous FH.

Diagnostyka i leczenie heterozygotycznej postaci hipercholesterolemii rodzinnej u dzieci – doniesienie wstępne

Diagnostyka i leczenie heterozygotycznej postaci hipercholesterolemii rodzinnej u dzieci – doniesienie wstępne

Clinical efficacy and safety of cerivastatin in the treatment of heterozygous familial hypercholesterolemia

Patients with heterozygous familial hypercholesterolemia are at especially high risk of premature coronary artery disease and usually require aggressive long-term lipid-lowering drug therapy to decrease plasma low-density lipoprotein (LDL) cholesterol concentrations to normal levels. In the present study, the lipid-lowering effects of cerivastatin in combination with cholestyramine and probucol were investigated in 20 patients with heterozygous familial hypercholesterolemia over a 20-week treatment period. After an initial 4-week treatment with once-daily 0.2 mg cerivastatin, serum total cholesterol and LDL cholesterol levels had decreased by a significant 22% and 25%, respectively (p <0.01). The addition of 8 g/day cholestyramine or 1 g/day probucol to ongoing cerivastatin therapy produced further significant reductions in total cholesterol of 16% and 16%, respectively, and in LDL cholesterol of 22% and 15%, respectively (p <0.01), over the 12-week combination therapy period. The potent lipid-lowering effects of combined treatment were accompanied by excellent toleration of study drugs. Only 2 patients experienced gastrointestinal side effects associated with cholestyramine therapy. There was no evidence of any abnormalities in creatine phosphokinase in either treatment group and only 2 patients exhibited minor increases in hepatic transaminases. This study has shown that cerivastatin can be safely combined with either cholesytramine or probucol to provide a safe and highly effective hypolipidemic treatment regimen for patients with heterozygous familial hypercholesterolemia.

4.P.411 Diet only and diet plus simvastatin in the treatment of heterozygous familial hypercholesterolemia in childhood

4.P.411 Diet only and diet plus simvastatin in the treatment of heterozygous familial hypercholesterolemia in childhood

Gender-related response to fluvastatin in patients with heterozygous familial hypercholesterolaemia.

Hydroxymethylglutaryl coenzyme A (HMG CoA) reductase inhibitors are potent cholesterol reducing agents that have been successfully used for the treatment of heterozygous familial hypercholesterolaemia (FH). A recent investigation revealed that several constitutional and genetic factors significantly determined the response of plasma lipids and lipoproteins to the HMG CoA reductase inhibitor fluvastatin. Gender has been identified through multivariate analysis as a major determinant of the plasma high density lipoprotein (HDL) cholesterol response. The current analysis was undertaken to determine possible gender-related fluvastatin dose-response differences. The analysis revealed that for HDL cholesterol, gender-related differences reach statistical significance only at the highest fluvastatin dose of 40 mg/day (females 22.9%, males 12.9%, p < 0.01). In parallel, the change in low density lipoprotein (LDL) cholesterol: HDL cholesterol ratio, an indicator of ischaemic heart disease risk, was also found to be affected by gender (females -38.4%, males -32.2%, p < 0.01). For LDL cholesterol, no consistent gender-related differences were found. In conclusion, the response of plasma lipid levels to fluvastatin in heterozygote FH patients is significantly affected by gender, with females achieving a more marked overall response, as indicated by higher HDL cholesterol levels and a lower LDL cholesterol: HDL cholesterol ratio.