It is Time to Screen for Homozygous Familial Hypercholesterolemia in the United States.

Homozygous familial hypercholesterolemia (HoFH) is an ultra-rare inherited condition that affects approximately one in 300,000 people. The disorder is characterized by extremely high, life-threatening levels of low-density lipoprotein (LDL) cholesterol from birth, leading to significant premature cardiovascular morbidity and mortality, if left untreated. Homozygous familial hypercholesterolemia is severely underdiagnosed and undertreated in the United States (US), despite guidelines recommendations for universal pediatric lipid screening in children aged 9-11. Early diagnosis and adequate treatment are critical in averting premature cardiovascular disease in individuals affected by HoFH. Yet, an unacceptably high number of people living with HoFH remain undiagnosed, misdiagnosed, and/or receive a late diagnosis, often after a major cardiovascular event. The emergence of novel lipid-lowering therapies, along with the realization that diagnosis is too often delayed, have highlighted an urgency to implement policies that ensure timely detection of HoFH in the US. Evidence from around the world suggests that a combination of universal pediatric screening and cascade screening strategies constitutes an effective approach to identifying heterozygous familial hypercholesterolemia (HeFH). Nevertheless, HoFH and its complications manifest much earlier in life compared to HeFH. To date, little focus has been placed on the detection of HoFH in very young children and/or infants. The 2023 Updated European Atherosclerosis Society Consensus Statement on HoFH has recommended, for the first time, broadening pediatric guidelines to include lipid screening of newborn infants. Some unique aspects of HoFH need to be considered before implementing newborn screening. As such, insights from pilot studies conducted in Europe may provide some preliminary guidance. Our paper proposes a set of actionable measures that states can implement to reduce the burden of HoFH. It also outlines key research and policy gaps that need to be addressed in order to pave the way for universal newborn screening of HoFH in the US.

Sex Differences in Diagnosis, Treatment, and Cardiovascular Outcomes in Homozygous Familial Hypercholesterolemia.

Importance: Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by extremely increased low-density lipoprotein (LDL) cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Heterozygous familial hypercholesterolemia (HeFH) is more common than HoFH, and women with HeFH are diagnosed later and undertreated compared to men; it is unknown whether these sex differences also apply to HoFH. Objective: To investigate sex differences in age at diagnosis, risk factors, lipid-lowering treatment, and ASCVD morbidity and mortality in patients with HoFH. Design, Setting, and Participants: Sex-specific analyses for this retrospective cohort study were performed using data from the HoFH International Clinical Collaborators (HICC) registry, the largest global dataset of patients with HoFH, spanning 88 institutions across 38 countries. Patients with HoFH who were alive during or after 2010 were eligible for inclusion. Data entry occurred between February 2016 and December 2020. Data were analyzed from June 2022 to June 2023. Main Outcomes and Measures: Comparison between women and men with HoFH regarding age at diagnosis, presence of risk factors, lipid-lowering treatment, prevalence, and onset and incidence of ASCVD morbidity (myocardial infarction [MI], aortic stenosis, and combined ASCVD outcomes) and mortality. Results: Data from 389 women and 362 men with HoFH from 38 countries were included. Women and men had similar age at diagnosis (median [IQR], 13 [6-26] years vs 11 [5-27] years, respectively), untreated LDL cholesterol levels (mean [SD], 579 [203] vs 596 [186] mg/dL, respectively), and cardiovascular risk factor prevalence, except smoking (38 of 266 women [14.3%] vs 59 of 217 men [27.2%], respectively). Prevalence of MI was lower in women (31 of 389 [8.0%]) than men (59 of 362 [16.3%]), but age at first MI was similar (mean [SD], 39 [13] years in women vs 38 [13] years in men). Treated LDL cholesterol levels and lipid-lowering therapy were similar in both sexes, in particular statins (248 of 276 women [89.9%] vs 235 of 258 men [91.1%]) and lipoprotein apheresis (115 of 317 women [36.3%] vs 118 of 304 men [38.8%]). Sixteen years after HoFH diagnosis, women had statistically significant lower cumulative incidence of MI (5.0% in women vs 13.7% in men; subdistribution hazard ratio [SHR], 0.37; 95% CI, 0.21-0.66) and nonsignificantly lower all-cause mortality (3.0% in women vs 4.1% in men; HR, 0.76; 95% CI, 0.40-1.45) and cardiovascular mortality (2.6% in women vs 4.1% in men; SHR, 0.87; 95% CI, 0.44-1.75). Conclusions and Relevance: In this cohort study of individuals with known HoFH, MI was higher in men compared with women yet age at diagnosis and at first ASCVD event were similar. These findings suggest that early diagnosis and treatment are important in attenuating the excessive cardiovascular risk in both sexes.

Recent advances in the management and implementation of care for familial hypercholesterolaemia.

Familial hypercholesterolaemia (FH) is a common autosomal semi-dominant and highly penetrant disorder of the low-density lipoprotein (LDL) receptor pathway, characterised by lifelong elevated levels of low-density lipoprotein cholesterol (LDL-C) and increased risk of atherosclerotic cardiovascular disease (ASCVD). However, many patients with FH are not diagnosed and do not attain recommended LDL-C goals despite maximally tolerated doses of potent statin and ezetimibe. Over the past decade, several cholesterol-lowering therapies such as those targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) or angiopoietin-like 3 (ANGPTL3) with monoclonal antibody or ribonucleic acid (RNA) approaches have been developed that promise to close the treatment gap. The availability of new therapies with complementary modes of action of lipid metabolism has enabled many patients with FH to attain guideline-recommended LDL-C goals. Emerging therapies for FH include liver-directed gene transfer of the LDLR, vaccines targeting key proteins involved in cholesterol metabolism, and CRISPR-based gene editing of PCSK9 and ANGPTL3, but further clinical trials are required. In this review, current and emerging treatment strategies for lowering LDL-C, and ASCVD risk-stratification, as well as implementation strategies for the care of patients with FH are reviewed.

2023 Update on European Atherosclerosis Society Consensus Statement on Homozygous Familial Hypercholesterolaemia: new treatments and clinical guidance.

This 2023 statement updates clinical guidance for homozygous familial hypercholesterolaemia (HoFH), explains the genetic complexity, and provides pragmatic recommendations to address inequities in HoFH care worldwide. Key strengths include updated criteria for the clinical diagnosis of HoFH and the recommendation to prioritize phenotypic features over genotype. Thus, a low-density lipoprotein cholesterol (LDL-C) >10 mmol/L (>400 mg/dL) is suggestive of HoFH and warrants further evaluation. The statement also provides state-of-the art discussion and guidance to clinicians for interpreting the results of genetic testing and for family planning and pregnancy. Therapeutic decisions are based on the LDL-C level. Combination LDL-C-lowering therapy-both pharmacologic intervention and lipoprotein apheresis (LA)-is foundational. Addition of novel, efficacious therapies (i.e. inhibitors of proprotein convertase subtilisin/kexin type 9, followed by evinacumab and/or lomitapide) offers potential to attain LDL-C goal or reduce the need for LA. To improve HoFH care around the world, the statement recommends the creation of national screening programmes, education to improve awareness, and management guidelines that account for the local realities of care, including access to specialist centres, treatments, and cost. This updated statement provides guidance that is crucial to early diagnosis, better care, and improved cardiovascular health for patients with HoFH worldwide.

Contemporary Homozygous Familial Hypercholesterolemia in the United States: Insights From the CASCADE FH Registry.

Background Homozygous familial hypercholesterolemia (HoFH) is a rare, treatment-resistant disorder characterized by early-onset atherosclerotic and aortic valvular cardiovascular disease if left untreated. Contemporary information on HoFH in the United States is lacking, and the extent of underdiagnosis and undertreatment is uncertain. Methods and Results Data were analyzed from 67 children and adults with clinically diagnosed HoFH from the CASCADE (Cascade Screening for Awareness and Detection) FH Registry. Genetic diagnosis was confirmed in 43 patients. We used the clinical characteristics of genetically confirmed patients with HoFH to query the Family Heart Database, a US anonymized payer health database, to estimate the number of patients with similar lipid profiles in a "real-world" setting. Untreated low-density lipoprotein cholesterol levels were lower in adults than children (533 versus 776 mg/dL; P=0.001). At enrollment, atherosclerotic cardiovascular disease and supravalvular and aortic valve stenosis were present in 78.4% and 43.8% and 25.5% and 18.8% of adults and children, respectively. At most recent follow-up, despite multiple lipid-lowering treatment, low-density lipoprotein cholesterol goals were achieved in only a minority of adults and children. Query of the Family Heart Database identified 277 individuals with profiles similar to patients with genetically confirmed HoFH. Advanced lipid-lowering treatments were prescribed for 18%; 40% were on no lipid-lowering treatment; atherosclerotic cardiovascular disease was reported in 20%; familial hypercholesterolemia diagnosis was uncommon. Conclusions Only patients with the most severe HoFH phenotypes are diagnosed early. HoFH remains challenging to treat. Results from the Family Heart Database indicate HoFH is systemically underdiagnosed and undertreated. Earlier screening, aggressive lipid-lowering treatments, and guideline implementation are required to reduce disease burden in HoFH.

New algorithms for treating homozygous familial hypercholesterolemia.

PURPOSE OF REVIEW: We reviewed current and future therapeutic options for patients with homozygous familial hypercholesterolemia (HoFH) and place this evidence in context of an adaptable treatment algorithm. RECENT FINDINGS: Lowering LDL-C levels to normal in patients with HoFH is challenging, but a combination of multiple lipid-lowering therapies (LLT) is key. Patients with (near) absence of LDL receptor expression are most severely affected and frequently require regular lipoprotein apheresis on top of combined pharmacologic LLT. Therapies acting independently of the LDL receptor pathway, such as lomitapide and evinacumab, are considered game changers for many patients with HoFH, and may reduce the need for lipoprotein apheresis in future. Liver transplantation is to be considered a treatment option of last resort. Headway is being made in gene therapy strategies, either aiming to permanently replace or knock out key lipid-related genes, with first translational steps into humans being made. Cardiovascular disease risk management beyond LDL-C, such as residual Lp(a) or inflammatory risk, should be evaluated and addressed accordingly in HoFH. SUMMARY: Hypercholesterolemia is notoriously difficult to control in most patients with HoFH, but multi-LLT, including newer drugs, allows reduction of LDL-C to levels unimaginable until a few years ago. Cost and availability of these new therapies are important future challenges to be addressed.

Advancements in the Treatment of Homozygous Familial Hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder with extreme elevations of low-density lipoprotein cholesterol (LDL-C) leading to premature atherosclerotic cardiovascular disease (ASCVD) as early as in childhood. Management of HoFH centers around aggressive and adequate reduction of LDL-C levels to slow the trajectory of ASCVD development. Historically, lowering LDL-C levels in HoFH has been challenging because of both the markedly elevated LDL-C levels (often ＞400 mg/dL) and reduced response to treatment options, such as statins, for which the mechanism of action requires a functional LDL receptor. However, the treatment landscape for HoFH has rapidly progressed over the last decade. While statins and ezetimibe remain first-line treatment, patients often require addition of multiple therapies to achieve goal LDL-C levels. The PCSK9 inhibitors are an important recent addition to the available treatment options, along with lomitapide, bile acid sequestrants, and, possibly, bempedoic acid. Additionally, ANGPTL3 has emerged as an important therapeutic target, with evinacumab being the first available ANGPTL3 inhibitor on the market for the treatment of patients with HoFH. For patients who cannot achieve adequate LDL-C reduction, lipoprotein apheresis may be necessary, with the added benefit of reducing lipoprotein(a) levels that carries an added risk if also elevated in patients with HoFH. Finally, gene therapy and genome editing using CRISPR/Cas-9 are moving through clinical development and may dramatically alter the future landscape of treatment for HoFH.

A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia.

PURPOSE: Family-based cascade screening from index probands is considered an effective way of identifying undiagnosed individuals with familial hypercholesterolemia (FH). The role of genetic testing of the proband in the success of cascade screening for FH is unknown. METHODS: We randomized 240 individuals with a clinical diagnosis of FH to genetic testing for FH (n = 160) or usual care with lipid testing alone (n = 80). The primary study endpoint was the proportion of probands with at least one relative enrolled in the study within one year after the notification of results. RESULTS: Proband median age was 59 (47-67) and 71% were female. Only 28 (12%) probands succeeded in enrolling a relative. While the genetic testing group had a higher proportion of probands with relatives enrolled (13.1%) compared with the usual care group (8.8%), this difference was not significant (p = 0.40). In subgroup analyses, enrollment of a relative was higher in the pathogenic variant group (22.7%) compared to the no pathogenic variant (9.5%) and usual care groups (8.8%) (p = 0.04). CONCLUSION: We observed a low rate of family participation in cascade screening despite repeated recommendations to probands. Compared to usual care, genetic testing did not improve family participation in cascade screening for FH. CLINICAL TRIAL NUMBER: NCT04526457.

ANGPTL3 Inhibition With Evinacumab Results in Faster Clearance of IDL and LDL apoB in Patients With Homozygous Familial Hypercholesterolemia-Brief Report.

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Hypoglycemia and Islet Dysfunction Following Oral Glucose Tolerance Testing in Pancreatic-Insufficient Cystic Fibrosis.

CONTEXT: Oral glucose tolerance test (OGTT)-related hypoglycemia is common in pancreatic-insufficient cystic fibrosis (PI-CF), but its mechanistic underpinnings are yet to be established. OBJECTIVE: To delineate the mechanism(s) underlying OGTT-related hypoglycemia. DESIGN AND SETTING: We performed 180-minute OGTTs with frequent blood sampling in adolescents and young adults with PI-CF and compared results with those from a historical healthy control group. Hypoglycemia (Hypo[+]) was defined as plasma glucose <65 mg/dL. We hypothesized that CF-Hypo[+] would demonstrate impaired early phase insulin secretion and persistent late insulin effect compared with control-Hypo[+], and explored the contextual counterregulatory response. MAIN OUTCOME MEASURE: OGTT 1-hour and nadir glucose, insulin, C-peptide, and insulin secretory rate (ISR) incremental areas under the curve (AUC) between 0 and 30 minutes (early) and between 120 and 180 minutes (late), and Δglucagon120-180min and Δfree fatty acids (FFAs)120-180min were compared between individuals with CF and control participants with Hypo[+]. RESULTS: Hypoglycemia occurred in 15/23 (65%) patients with CF (43% female, aged 24.8 [14.6-30.6] years) and 8/15 (55%) control participants (33% female, aged 26 [21-38] years). The CF-Hypo[+] group versus the control-Hypo[+] group had higher 1-hour glucose (197 ± 49 vs 139 ± 53 mg/dL; P = 0.05) and lower nadir glucose levels (48 ± 7 vs 59 ± 4 mg/dL; P < 0.01), while insulin, C-peptide, and ISR-AUC0-30 min results were lower and insulin and C-peptide, and AUC120-180min results were higher (P < 0.05). Individuals with CF-Hypo[+] had lower Δglucagon120-180min and ΔFFA120-180min compared with the control-Hypo[+] group (P < 0.01). CONCLUSIONS: OGTT-related hypoglycemia in PI-CF is associated with elevated 1-hour glucose, impaired early phase insulin secretion, higher late insulin exposure, and less increase in glucagon and FFAs. These data suggest that hypoglycemia in CF is a manifestation of islet dysfunction including an impaired counterregulatory response.

Homozygous familial hypercholesterolemia: what treatments are on the horizon?

PURPOSE OF REVIEW: Homozygous familial hypercholesterolemia (HoFH) is a rare disorder associated with early atherosclerotic disease due to impairment of the LDL receptor (LDLR) pathway. Because of their molecular defect, current treatment options have limited success in bringing HoFH patient to LDL-C target and morbidity and mortality remain high. We review current and upcoming therapies directed at HoFH, including gene therapy. RECENT FINDINGS: Recent real-world studies have confirmed the strength in lomitapide as a treatment adjunct to statins and other lipid-lowering therapies in HoFH patients. The approval of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor monoclonal antibodies has also been a welcome addition to the treatment armamentarium offering an additional average reduction in LDL-C levels of 24% when added to background lipid-lowering therapies in this population. Although achieving adequate LDL-C levels in this population is difficult, there are several therapies on the horizon that may help more patients reach goal. Evinacumab, a monoclonal antibody against ANGPTL3, has been shown to substantially reduce LDL-C of an average of 49%, independently of residual LDLR activity. RNA interference targeting PCSK9 and ANGPTL3 shows promise in clinical trials. Adeno-associated virus-mediated gene transfer and gene editing techniques are in early clinical and preclinical development. SUMMARY: LDL-C lowering in HoFH patients remains very challenging. However, novel treatment options are emerging. Upcoming therapies directed at PCSK9 and ANPTL3 may offer additional LDL-C reduction, to help patients achieve adequate LDL-C levels. Gene therapy and gene editing techniques, if proven effective, may offer a unique opportunity to treat patients with a one-time treatment.

Longitudinal low density lipoprotein cholesterol goal achievement and cardiovascular outcomes among adult patients with familial hypercholesterolemia: The CASCADE FH registry.

BACKGROUND AND AIMS: There are limited data from the US on outcomes of patients in specialty care for familial hypercholesterolemia (FH). METHODS: CASCADE FH Registry data were analyzed to assess longitudinal changes in medication usage, in low density lipoprotein cholesterol (LDL-C) levels, and the rate of major adverse cardiovascular events (MACE (myocardial infarction, coronary revascularization, stroke or transient ischemic attack) in adults with FH followed in US specialty clinics. RESULTS: The cohort consisted of 1900 individuals (61% women, 87% Caucasian), with mean age of 56 ±â€¯15 years, 37% prevalence of ASCVD at enrollment, mean pretreatment LDL-C 249 ±â€¯68 mg/dl, mean enrollment LDL-C 145 mg/dl and 93% taking lipid lowering therapy. Over follow up of 20 ±â€¯11 months, lipid lowering therapy use increased (mean decrease in LDL-C of 32 mg/dl (p < 0.001)). Only 48% of participants achieved LDL-C < 100 mg/dl and 22% achieved LDL-C < 70 mg/dl; ASCVD at enrollment was associated with greater likelihood of goal achievement. MACE event rates were almost 6 times higher among patients with prior ASCVD compared to those without (4.6 vs 0.8/100 patient years). Also associated with incident MACE were markers of FH severity and conventional ASCVD risk factors. CONCLUSIONS: With care in FH specialized clinics, LDL-C decreased, but LDL-C persisted >100 mg/dl in 52% of patients. High ASCVD event rates suggest that adults with FH warrant designation as having an ASCVD risk equivalent. Earlier and more aggressive therapy of FH is needed to prevent ASCVD events.

ATP binding cassette family A protein 1 determines hexosylceramide and sphingomyelin levels in human and mouse plasma.

Sphingolipids, including ceramide, SM, and hexosylceramide (HxCer), are carried in the plasma by lipoproteins. They are possible markers of metabolic diseases, but little is known about their control. We previously showed that microsomal triglyceride transfer protein (MTP) is critical to determine plasma ceramide and SM, but not HxCer, levels. In human plasma and mouse models, we examined possible HxCer-modulating pathways, including the role of ABCA1 in determining sphingolipid plasma concentrations. Compared with control samples, plasma from patients with Tangier disease (deficient in ABCA1) had significantly lower HxCer (-69%) and SM (-40%) levels. Similarly, mice deficient in hepatic and intestinal ABCA1 had significantly reduced HxCer (-79%) and SM (-85%) levels. Tissue-specific ablation studies revealed that hepatic ABCA1 determines plasma HxCer and SM levels; that ablation of MTP and ABCA1 in the liver and intestine reduces plasma HxCer, SM, and ceramide levels; and that hepatic and intestinal MTP contribute to plasma ceramide levels, whereas only hepatic MTP modulates plasma SM levels. These results identify the contribution of ABCA1 to plasma SM and HxCer levels and suggest that MTP and ABCA1 are critical determinants of plasma sphingolipid levels.

Clinical Genetic Testing for Familial Hypercholesterolemia: JACC Scientific Expert Panel.

Although awareness of familial hypercholesterolemia (FH) is increasing, this common, potentially fatal, treatable condition remains underdiagnosed. Despite FH being a genetic disorder, genetic testing is rarely used. The Familial Hypercholesterolemia Foundation convened an international expert panel to assess the utility of FH genetic testing. The rationale includes the following: 1) facilitation of definitive diagnosis; 2) pathogenic variants indicate higher cardiovascular risk, which indicates the potential need for more aggressive lipid lowering; 3) increase in initiation of and adherence to therapy; and 4) cascade testing of at-risk relatives. The Expert Consensus Panel recommends that FH genetic testing become the standard of care for patients with definite or probable FH, as well as for their at-risk relatives. Testing should include the genes encoding the low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9); other genes may also need to be considered for analysis based on patient phenotype. Expected outcomes include greater diagnoses, more effective cascade testing, initiation of therapies at earlier ages, and more accurate risk stratification.

Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia.

BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown. METHODS: We used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306). RESULTS: Twenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) - equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively. CONCLUSIONS: Approximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further. TRIAL REGISTRATION: NCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009).