Cholesterol-Lowering Agents.

Cardiovascular disease (CVD) remains the leading cause of death worldwide. To date, decades of research has established LDL-C (low-density lipoprotein cholesterol) as a causal factor in the development of atherosclerotic CVD. Statin therapy, supported by a broad evidence base, has demonstrated its superior efficacy in reducing LDL-C and subsequent cardiovascular risk. It therefore currently forms the mainstay of lipid-lowering therapy as recommended by international guidelines. Statin therapy is indicated in the secondary prevention of atherosclerotic CVD, as well as genetic causes of dyslipidemia (such as familial hypercholesterolemia). Although this strategy targets those most at risk, it merely addresses those most susceptible and does not account for the fact that most cardiovascular events occur in those at moderate to low risk. In addition, there is evidence for use in primary prevention such as in those with diabetes mellitus, chronic kidney disease, and high risk of future atherosclerotic CVD as determined by risk prediction calculators. Risk prediction tools, however, are far from perfect and do not accurately account for those at low short-term but high lifelong risk. Considering the log-linear relationship between LDL-C reductions and reductions in risk of atherosclerotic CVD, even in those at very low risk of future events, a clinical question posed is can we and should we shift the entire risk distribution by treating everyone? The present review discusses these issues in more detail outlining arguments for and against each approach.

PCSK9 in context: A contemporary review of an important biological target for the prevention and treatment of atherosclerotic cardiovascular disease.

The identification of the critical role of proprotein convertase subtilisin/kexin type 9 (PCSK9) has rapidly led to the development of PCSK9 inhibition with monoclonal antibodies (mAbs). PCSK9 mAbs are already in limited clinical use and are the subject of major cardiovascular outcomes trials, which, if universally positive, could see much wider clinical application of these agents. Patients with familial hypercholesterolaemia are the most obvious candidates for these drugs, but other patients with elevated cardiovascular risk, statin intolerance or hyperlipoproteinaemia(a) may also benefit. PCSK9 mAbs, administered once or twice monthly, reduce LDL cholesterol levels by 50% to 70%, and appear to be safe and acceptable to patients over at least 2 years of treatment; however, treatment-emergent adverse effects are not always identified in clinical trials, as well-evidenced by statin myopathy. Inclisiran is a promising RNA-based therapy that promotes the degradation of PCSK9 mRNA transcripts and has similar efficacy to mAbs, but with a much longer duration of action. The cost-effectiveness and long-term safety of therapies targeted at inhibiting PCSK9 remain to be demonstrated if they are to be used widely in coronary prevention.

Beyond cascade screening: detection of familial hypercholesterolaemia at childhood immunization and other strategies.

PURPOSE OF REVIEW: Familial hypercholesterolaemia is a common genetic disorder that accelerates premature coronary heart disease. Although effective treatments are available, the majority of individuals remain undiagnosed. We review new evidence for improving the detection of familial hypercholesterolaemia. RECENT FINDINGS: Recent studies have demonstrated that universal screening of children for familial hypercholesterolaemia may be highly effective at the time of immunization if combined with reverse cascade testing of adult family members, who have a more immediate risk of a coronary event. Alerts on laboratory reports and the application of bioinformatics to electronic health records may also be useful for identifying familial hypercholesterolaemia in community settings. Effective detection, diagnosis, and codification of familial hypercholesterolaemia are essential for the development of registries. SUMMARY: Although the cost-effectiveness of screening programs for familial hypercholesterolaemia in childhood remains to be established, combining universal and reverse cascade screening, complemented by opportunistic identification of individuals in high-risk settings, use of laboratory alerts, and screening of electronic health records are likely to have a high yield in the detection of familial hypercholesterolaemia in the community.

Using human genetics to discover new therapeutic targets for plasma lipids.

Genetic variation arises through multiple different alleles that vary in frequency and severity of effect. Mutations that give rise to Mendelian disorders, such as the LDL receptor (LDLR) mutations that result in familial hypercholesterolaemia, are efficiently winnowed from the population by purifying selection and are almost inevitably rare. Conversely, alleles that are common in the population (such that homozygotes for the minor allele are present even in modest sample sizes) typically have very modest phenotypic effects. Mutations in the gene for proprotein convertase subtilisin/kexin type 9 (PCSK9) represent an unusual but informative exception in that they are relatively common but have large effects on phenotype. Loss-of-function mutations in PCSK9 occur in ~2.5% of African Americans and are associated with large reductions in coronary heart disease (CHD) risk. The development of agents to inhibit PCSK9 demonstrates the utility of translating genetics into clinical therapeutics. Attempts to identify genes responsible for hypercholesterolaemia have used traditional linkage analysis, which requires samples collected from multiple families with defects in the same gene, or genome-wide association, which requires thousands of samples from the population. More recently, whole-exome sequencing studies have revealed loss-of-function mutations in ANGPTL3 associated with pan-hypolipidemia, and in APOC3 that confer protection against CHD. The application of whole-exome sequencing to large populations or to carefully selected patients can streamline the discovery of causal genetic mutations.

Statins in the Management of Pediatric Dyslipidemia.

Hypercholesterolemia is a major concern in the USA, with studies identifying children as young as 2years old with early-stage atherosclerosis. Genetics play a major role in the dyslipidemia of children, but other factors, such as diet and lack of physical activity, confound the problem. Familial hypercholesterolemia (FH) is a genetic condition that causes lifelong elevations in low-density lipoprotein cholesterol (LDL-C). The heterozygous form of the disease affects around 1 in 200 people, and the homozygous form of the disease affects around 1 in 160,000-300,000 people. Early identification and appropriate management of patients with FH are essential to reduce cardiovascular disease morbidity and mortality. Consequently, US dyslipidemia guidelines recommend routine screening of all children aged 9-11years, and that LDL-C levels should be <110mg/dL in children and adolescents. The primary management strategy in all children with dyslipidemia is diet and lifestyle; a healthy diet (including fruits, vegetables, fish, and whole grains) and increased physical activity should be encouraged. Most patients with FH will also require pharmacotherapy to reduce LDL-C levels to ≤130mg/dL. Statins are recommended as first-line therapy due to their proven efficacy in reducing LDL-C and improving other lipid parameters in children. They have also been shown to have a positive effect on atherosclerosis. Safety is of particular concern with children; however, studies have so far shown that the side-effect profile of statins in children is similar to that in adults. Despite improvements in disease management, FH remains underdiagnosed and undertreated, highlighting the need for greater awareness and understanding.

Recent advances in the understanding and care of familial hypercholesterolaemia: significance of the biology and therapeutic regulation of proprotein convertase subtilisin/kexin type 9.

Familial hypercholesterolaemia (FH) is an autosomal co-dominant disorder that markedly raises plasma low-density lipoprotein-cholesterol (LDL-C) concentration, causing premature atherosclerotic coronary artery disease (CAD). FH has recently come under intense focus and, although there is general consensus in recent international guidelines regarding diagnosis and treatment, there is debate about the value of genetic studies. Genetic testing can be cost-effective as part of cascade screening in dedicated centres, but the full mutation spectrum responsible for FH has not been established in many populations, and its use in primary care is not at present logistically feasible. Whether using genetic testing or not, cholesterol screening of family members of index patients with an abnormally raised LDL-C must be used to determine the need for early treatment to prevent the development of CAD. The metabolic defects in FH extend beyond LDL, and may affect triacylglycerol-rich and high-density lipoproteins, lipoprotein(a) and oxidative stress. Achievement of the recommended targets for LDL-C with current treatments is difficult, but this may be resolved by new drug therapies. Lipoprotein apheresis remains an effective treatment for severe FH and, although expensive, it costs less than the two recently introduced orphan drugs (lomitapide and mipomersen) for homozygous FH. Recent advances in understanding of the biology of proprotein convertase subtilisin/kexin type 9 (PCSK9) have further elucidated the regulation of lipoprotein metabolism and led to new drugs for effectively treating hypercholesterolaemia in FH and related conditions, as well as for treating many patients with statin intolerance. The mechanisms of action of PCSK9 inhibitors on lipoprotein metabolism and atherosclerosis, as well as their impact on cardiovascular outcomes and cost-effectiveness, remain to be established.

Aligning policy to promote cascade genetic screening for prevention and early diagnosis of heritable diseases.

Cascade genetic screening is a methodology for identifying and testing close blood relatives of individuals at increased risk for heritable conditions and follows a sequential process, minimizing testing costs and the number of family members who need to be tested. It offers considerable potential for cost savings and increased awareness of heritable conditions within families. CDC-classified Tier 1 genomic applications for hereditary breast and ovarian cancer syndrome (HBOC), Lynch Syndrome (LS), and familial hypercholesterolemia (FH) are recommended for clinical use and support the use of cascade genetic screening. Most individuals are unaware of their increased risk for heritable conditions such as HBOC, LS, and FH. Consistent implementation of cascade genetic screening could significantly increase awareness and prevention of heritable conditions. Limitations to effective implementation of cascade genetic screening include: insufficient genetic risk assessment and knowledge by a majority of healthcare providers without genetics credentials; a shortage of genetic specialists, especially in rural areas; a low rate of reimbursement for comprehensive genetic counseling services; and an individual focus on prevention by clinical guidelines and insurance coverage. The family-centric approach of cascade genetic screening improves prevention and early diagnosis of heritable diseases on a population health level. Cascade genetic screening could be better supported and augmented through changes in health policy.

Communicating risk with relatives in a familial hypercholesterolemia cascade screening program: a summary of the evidence.

BACKGROUND: Familial hypercholesterolemia (FH) is the most common inherited, potentially deadly disease, affecting an estimated 600 000 people in the United States. When FH is undiagnosed and untreated, it is linked with early coronary heart disease in more than 50% of men by age 50 years and 30% of women by age 60 years. Cascade screening is the most cost effective method available to identify family members with this disease; however, cascade screening guidelines do not specify best methods to use when contacting relatives. Therefore, I conducted an exhaustive search of the literature to find the most successful communication methods used in contact tracing and cascade screening. PURPOSE: The purpose of this summary of the evidence was to identify the communication method with greatest impact in having at-risk populations present to a provider for disease screening. These findings will inform clinicians of the most successful methods to implement when cascade screening relatives of known FH patients. CONCLUSIONS: Most studies support direct contact of relatives via letter, mailed from the provider. Provider-initiated communication more often resulted in relatives being tested when compared with other methods of communication. CLINICAL IMPLICATIONS: On the basis of the literature, family members of current FH patients will be more likely to present to a provider for cascade screening if they receive written communication from the provider.

Do long-chain n-3 fatty acids reduce arterial stiffness? A meta-analysis of randomised controlled trials.

Fish oils, rich in long-chain n-3 PUFA, are known to reduce various risk factors for CVD. However, conclusive evidence regarding the benefits of n-3 on arterial stiffness, a risk factor for CVD, has not yet been established. Consequently, we conducted the first study aimed to quantify the effects of n-3 supplementation on arterial stiffness through meta-analysis. Multiple databases and clinical trial registries were systematically searched up until September 2010 for randomised and controlled adult human clinical trials to investigate the effects of long-chain n-3 fatty acids on arterial stiffness. No limits were set on dosage sizes or sample characteristics. A total of ten n-3 trials met the final inclusion criteria; four using pulse wave velocity (PWV) and six using arterial compliance, measured as capacitive compliance or systemic arterial compliance, as respective outcome measures. Meta-analysis revealed that n-3 was statistically significant in effectively improving both PWV (g = 0·33; 95 % CI 0·12, 0·56; P < 0·01) and arterial compliance (g = 0·48; 95 % CI 0·24, 0·72; P < 0·001). There was no evidence of heterogeneity or publication bias. Results were not influenced by changes in blood pressure, heart rate or BMI. The findings of the present study reveal that supplementation with n-3 offers a scientifically supported means of reducing arterial stiffness. Reduction in arterial stiffness by n-3 may account for some of its purported cardioprotective effects.

GPs have key role in detecting familial hypercholesterolaemia.

Currently the vast majority of people with familial hypercholesterolaemia (FH) in the U.K. remain undiagnosed, probably 85% of the predicted 120,000 cases. FH is a common inherited disorder of lipid metabolism causing high levels of LDL cholesterol which leads to early CHD. It has an autosomal dominant pattern of inheritance so siblings and children of a patient with FH will have a 50% chance of inheriting the condition. FH is present in the heterozygous form in 1 in 500 of the population. The homozygous form is very rare, affecting 1 in 1,000,000. Around half of men with FH, if untreated, will have developed clinically evident CHD by the age of 55 years, and approximately one third of women by the age of 60. A significant reduction in the mortality and morbidity of the disease can be achieved through changes in lifestyle and the use of statins to lower cholesterol. NICE recommends that clinical management of FH patients should primarily be carried out in lipid clinics. When cascade testing from lipid clinics is underway, GPs will be approached by relatives who have been identified as being at 50% risk of having FH, because they have an affected first-degree relative with the disorder. They will then need to take a blood sample for cholesterol measurement, and often will also be asked to provide a sample for DNA testing. A preliminary investigation in the surgery of a family member would involve a full lipid profile to calculate LDL cholesterol. If this is not elevated in an adult, cut-off value 4.9 mmol/L, FH is highly unlikely. Even if an FH patient is young, currently does not have CHD and may have no other CHD risk factors, the Framingham risk charts should not be used. These individuals are at increased CHD risk which warrants treatment with statins. The vascular health check screening programme recommends that where a total cholesterol of > 7.5 mmol/L is found FH should be considered.

Lipoprotein apheresis.

PURPOSE OF REVIEW: Lipoprotein apheresis is being performed with increasing frequency, but better data collection and recording of clinical outcomes are needed. Setting up registries would facilitate this process. RECENT FINDINGS: This review appraises recent articles that discuss the need for national registries and requirements for setting them up, the efficacy of lipoprotein apheresis in homozygous familial hypercholesterolaemia and patients with coronary disease secondary to raised levels of lipoprotein (a), and its role in the management of acute pancreatitis secondary to severe hypertriglyceridaemia. SUMMARY: Lipoprotein apheresis seems to be going through a growth spurt, presumably reflecting better implementation of treatment guidelines or a broadening of indications for its use.

Switching from lipoprotein apheresis to evolocumab in FH siblings on hemodialysis: case reports and discussion.

Familial hypercholesterolemia (FH) and chronic kidney disease, especially end-stage renal disease (ESRD), are common and put patients at a high risk of developing atherosclerotic cardiovascular disease (ASCVD). ESRD concomitant with FH may further increase the risk of ASCVD. Achieving target levels of low-density lipoprotein cholesterol (LDL-C) is difficult owing to the limitations of statin administration due to its side effects in ESRD. Therefore, some FH patients with ESRD require lipoprotein apheresis for the prevention of secondary ASCVD events. Although proprotein convertase subtilisin kexin 9 (PCSK9) inhibitors may offer a safe and effective option for lowering lipid levels in such patients, no guidelines are available for their use. Here, we report the case of two male siblings with FH in secondary prevention undergoing hemodialysis combined with PCSK9 inhibitor treatment. The siblings, who showed a heterozygous c.1846-1G>A mutation in the LDLR gene, underwent hemodialysis. In combination with the lipoprotein apheresis, siblings were administered evolocumab, a PCSK9 inhibitor. Both the siblings had coronary artery disease, diabetes, and ESRD, and received hemodialysis. Their LDL-C levels did not reach the target values despite administering statin, ezetimibe, and biweekly lipoprotein apheresis. On the introduction of evolocumab treatment, their LDL-C levels were significantly reduced without any adverse effects, resulting in successful withdrawal from lipoprotein apheresis therapy. Although the effects of switching from lipoprotein apheresis to PCSK9 inhibitors for cardiovascular protection remain unclear in FH patients with and without ESRD, our case report will be helpful in guiding future therapeutic decisions.

Calcium homeostasis and skeletal integrity in individuals with familial hypercholesterolemia and aortic calcification.

BACKGROUND: Familial hypercholesterolemia (FH) due to mutations in the low-density lipoprotein receptor (LDLR) gene exhibit severe, premature aortic calcification in a gene-dosage, age-dependent fashion. We sought to determine potential associations with mineral and skeletal indices. METHODS: We obtained computed tomography (CT) scan aortic calcium scores (AoCSs) in 19 (age 49 [SD 14] years) FH patients heterozygous for the 15-kb deletion at the LDLR gene and examined associations with various indices of mineral and skeletal homeostasis. RESULTS: We found that mean bone mineral density (BMD) at the femoral neck in these patients did not differ from age-, sex-, and province-matched mean BMD, and we observed no association of AoCS with any marker of bone resorption. However, there were negative correlations between AoCS and serum concentrations of osteocalcin, a marker of bone formation (r = -0.64, P = 0.0034), urinary calcium (r = -0.59, P = 0.0085), and estimated glomerular filtration rate (r = -0.67, P = 0.0019). CONCLUSIONS: We found that LDLR-deficient FH was not associated with obvious bone loss or a major disturbance in calcium homeostasis. The lack of LDLR, however, may modify osteoblast function or extracellular calcium distribution, manifesting as lower bone formation, and reduced calcium excretion, resulting in increased deposition in calcifying vascular tissue.

Familial Hypercholesterolemia and Atherosclerosis: Animal Models and Therapeutic Advances.

Familial hypercholesterolemia (FH), mainly arising from loss-of-function mutation of the low-density lipoprotein receptor (LDLR), is a life-threatening inherited cardiometabolic disorder with limited therapies. In a recent study, Zhao et al. created a new model of FH and demonstrate that LDLR gene editing protects against both FH and atherosclerosis.

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

Importance: 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.

Proportion of High-Risk/Very High-Risk Patients in Europe with Low-Density Lipoprotein Cholesterol at Target According to European Guidelines: A Systematic Review.

OBJECTIVE: Assess achievement of low-density lipoprotein cholesterol (LDL-C) targets in European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines. DESIGN: Systematic literature review. DATA SOURCES: Medline, EMBASE, Cumulated Index to Nursing and Allied Health Literature. ELIGIBILITY CRITERIA: Observational studies reporting LDL-C levels/target attainment, measured between 1 August 2006 to 31 August 2017, in European adults with established cardiovascular disease (CVD), diabetes with target organ damage, familial hypercholesterolaemia (FH) or 10-year risk of fatal CVD ≥ 5% (assessed by Systematic Coronary Risk Evaluation [SCORE]). DATA EXTRACTION AND SYNTHESIS: Two reviewers independently extracted relevant studies and assessed study quality using the Risk of Bias for Non-Randomised Studies-Interventions (ROBINS-I) tool. Primary outcome was the proportion of patients achieving LDL-C targets in the 2011/2016 ESC/EAS guidelines. Where available, patient characteristics were presented as means weighted by sample size. The proportions of patients achieving LDL-C targets in the 5 years before and after publication of the 2011 guidelines were compared using a chi-square test. RESULTS: Across 81 eligible studies (303,534 patients), achievement of LDL-C < 1.8 mmol/L was poor among patients with established CVD (16%; range 9-56%) and at very high risk of CVD (SCORE ≥ 10% [18%; 14-25%]). In individuals with FH, SCORE 5-10%, or diabetes and target organ damage, LDL-C < 2.5 mmol/L was achieved by 15% (9-22%), 46% (21-55%) and 13% (6-34%), respectively. Comparing the 5 years before/after publication of the 2011 guidelines, target achievement increased significantly over time but remained suboptimal (LDL-C < 1.8, 22% versus 15%; LDL-C < 2.5, 68% versus 61%; both p < 0.001; established CVD group only). CONCLUSIONS: These data show suboptimal LDL-C control among European patients at high risk of CVD. Those at greatest overall risk (clinically established CVD or at least a 10% 10-year risk of fatal CVD) had the lowest achievement of 2011/2016 EAS/ESC LDL-C targets. With lower LDL-C targets advocated in 2019 ESC/EAS guidelines, this unmet need will increase. PROTOCOL REGISTRATION: PROSPERO registration number; CRD77844.

Proposed low-density lipoprotein cholesterol goals for secondary prevention and familial hypercholesterolemia in India with focus on PCSK9 inhibitor monoclonal antibodies: Expert consensus statement from Lipid Association of India.

BACKGROUND: Rates of atherosclerotic cardiovascular disease (ASCVD) are strikingly high in India compared to Western countries and are increasing. Moreover, ASCVD events occur at a younger age with only modest hypercholesterolemia, most commonly with low levels of high-density lipoprotein cholesterol. The course of ASCVD also appears to be more fulminant with higher mortality. OBJECTIVE: In light of these issues, the Lipid Association of India (LAI) endeavored to develop revised guidelines with more aggressive low-density lipoprotein cholesterol (LDL-C) goals in secondary prevention and for patients with familial hypercholesterolemia compared to guidelines in the United States and other countries. METHODS: Owing to the paucity of clinical outcomes data in India, it was necessary to place major emphasis on expert opinion as a complement to randomized placebo-controlled data generated mostly in non-Indian cohorts. To facilitate this process, the LAI conducted a series of 19 meetings among 162 lipid specialists in 13 cities throughout India over a period of 11 months before formulating this expert consensus statement. RESULTS: The LAI recommends an LDL-C goal <50 mg/dL in all patients in secondary prevention or very high-risk primary prevention but proposes an optional goal ≤30 mg/dL in category A extreme-risk patients (eg, coronary artery disease + familial hypercholesterolemia) and a recommended goal ≤30 mg/dL in category B extreme-risk patients [coronary artery disease + (1) diabetes and polyvascular disease/≥3 major ASCVD risk factors/end organ damage, or (2) recurrent acute coronary syndrome within 12 months despite LDL-C <50 mg/dL, or (3) homozygous familial hypercholesterolemia]. CONCLUSIONS: More aggressive LDL-C goals are needed for prevention of ASCVD in India, as described in this expert consensus statement. Use of statins and ezetimibe needs to increase in India in combination with improved control of other ASCVD risk factors. Proprotein convertase subtilisin kexin type 9 inhibitors can improve LDL-C goal achievement in patients with refractory hypercholesterolemia.