Hypercholesterolemia Diagnosis, Treatment Patterns, and 12-Month Target Achievement in Clinical Practice in Germany in Patients with Familial Hypercholesterolemia.
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ABSTRACT: Background
Familial hypercholesterolemia (FH) is a highly prevalent disorder and a risk factor for early coronary artery disease. The objective of this registry was to document the clinical characteristics of patients with definite FH in Germany and to document lipid profiles, lipid-lowering therapy, and lipid target achievement during longitudinal follow-up.Methods
HYDRA-FH was a national, prospective, multicenter, non-interventional registry conducted in 35 centers in Germany. Consecutive adult patients with definite FH were included (n = 241).Results
In the cross-sectional analysis (n = 233), lipid-lowering therapy involved statins (82.0%), ezetimibe (31.8%), and PCSK9 antibodies (18.5%); 11.2% of patients were receiving no lipid-lowering drugs. Median lipid levels were: low-density lipoprotein cholesterol (LDL-C) 134 mg/dL (3.5 mmol/L), high-density lipoprotein cholesterol (HDL-C) 48 mg/dL (1.2 mmol/L), triglycerides 160 mg/dL (1.9 mmol/L), total cholesterol 211 mg/dL (5.5 mmol/L). Values were above the normal threshold (150 mg/dL) for LDL-C in 72.9%, total cholesterol in 29.7%, and triglycerides in 45.0% of patients. After the 12-month follow-up (n = 145), only 17.2% had LDL-C < 70 mg/dL, and 20.7% had either LDL-C < 70 mg/dL or a reduction of ≥50% versus baseline.Conclusion
This study provides insight into the clinical characteristics and current treatment status of patients with FH in Germany. Many patients with FH do not achieve recommended lipid levels.
SUBMITTER: Gitt AK
PROVIDER: S-EPMC9267207 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Familial hypercholesterolemia (FH) is considered the genetic cause of coronary heart disease and ischemic stroke. FH is mainly an autosomal codominant pattern-based disorder and is primarily determined by point mutations within the low-density lipoprotein receptor, apolipoprotein B, and proprotein convertase subtilisin/kexin type 9 genes, causing increased low-density lipoprotein cholesterol levels in the serum of untreated individuals. The accumulation will eventually lead to atherosclerotic cardiovascular disease. Although clinical criteria comprising several prognosis scores, such as the Simon Broome, Dutch Lipid Clinic Network, Make Early Diagnosis to Prevent Early Death, and the recently proposed Montreal-FH-SCORE, are the conventional basis of diagnosing FH, the genetic diagnosis made by single nucleotide polymorphism genotyping, multiplex ligation-dependent probe amplification analysis, and sequencing (both Sanger and Next-Generation sequencing) offers unequivocal diagnosis. Given the heterogeneity of known mutations, the genetic diagnosis of FH is often difficult to establish, despite the growing evidence of the causative mutations, as well as the polygenic aspect of this pathology and the importance of cascade screening of the FH patient‚s healthy family members. This review article details different genetic techniques that can be used in FH identification when there is a clinical FH suspicion based on criteria comprised in prognosis scores, knowing that none of these are exhaustive in the diagnosis, yet they efficaciously overlap and complement each other for confirming the disease at the molecular level.
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Project description:IntroductionAchieving target low-density lipoprotein-cholesterol (LDL-C) levels remains challenging when treating homozygous familial hypercholesterolemia (HoFH). Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) are prescribed in addition to statins and ezetimibe, but patients' response varies and depends on residual low-density lipoprotein receptor (LDLR) function.MethodsA multicenter, retrospective observational analysis evaluated LDL-C target achievement in response to PCSK9i treatment in 28 patients with HoFH from the Middle East/North Africa region. Effect of genotype was investigated. Demographic and clinical information was retrospectively obtained from medical records. Patient response to PCSK9i treatment was assessed by calculating percentage changes in lipid levels from pre-PCSK9i treatment baseline to most recent follow-up visit where patients were recorded as receiving PCSK9i on top of standard of care lipid-lowering therapies (LLTs; i.e., statins/ezetimibe) and assessing European Atherosclerosis Society (EAS) target achievement up to January 31, 2022. Lowest LDL-C level while receiving PCSK9i was identified.ResultsThe cohort (n = 28) had a mean age (standard deviation; SD) of 22.8 (9.8) years (n = 28) and was 51% female (n = 27). Baseline LDL-C data were available in 24/28 (85.7%) patients (mean [SD] 14.0 [3.0] mmol/L). Median (interquartile range) duration of PCSK9i treatment was 12.0 months (4.0-19.1) months and mean (SD) % change in LDL-C after PCSK9i treatment was - 8.6% (12.1). LDL-C reduction from baseline was below 15% in 17/24 patients (70.8%). In the full cohort, mean (SD) minimum LDL-C during PCSK9i treatment was 11.9 (2.8; n = 28) mmol/L. No patient achieved EAS target LDL-C while receiving PCSK9i; genotype analysis suggested LDLR-null/null patients were most refractory to PCSK9i.ConclusionResponse to PCSK9i was minimal in this cohort of patients with HoFH. No patients achieved EAS LDL-C targets, and most failed to reach the EAS-recommended 15% LDL-C reduction for PCSK9i therapy continuation. These results suggest additional LLTs are necessary to achieve LDL-C targets in HoFH.
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Project description:Background Evidence suggests that LPA risk genotypes are a possible contributor to the clinical diagnosis of familial hypercholesterolemia (FH). This study aimed at determining the prevalence of LPA risk variants in adult individuals with FH enrolled in the Italian LIPIGEN (Lipid Transport Disorders Italian Genetic Network) study, with (FH/M+) or without (FH/M-) a causative genetic variant. Methods and Results An lp(a) [lipoprotein(a)] genetic score was calculated by summing the number risk-increasing alleles inherited at rs3798220 and rs10455872 variants. Overall, in the 4.6% of 1695 patients with clinically diagnosed FH, the phenotype was not explained by a monogenic or polygenic cause but by genotype associated with high lp(a) levels. Among 765 subjects with FH/M- and 930 subjects with FH/M+, 133 (17.4%) and 95 (10.2%) were characterized by 1 copy of either rs10455872 or rs3798220 or 2 copies of either rs10455872 or rs3798220 (lp(a) score ≥1). Subjects with FH/M- also had lower mean levels of pretreatment low-density lipoprotein cholesterol than individuals with FH/M+ (t test for difference in means between FH/M- and FH/M+ groups <0.0001); however, subjects with FH/M- and lp(a) score ≥1 had higher mean (SD) pretreatment low-density lipoprotein cholesterol levels (223.47 [50.40] mg/dL) compared with subjects with FH/M- and lp(a) score=0 (219.38 [54.54] mg/dL for), although not statistically significant. The adjustment of low-density lipoprotein cholesterol levels based on lp(a) concentration reduced from 68% to 42% the proportion of subjects with low-density lipoprotein cholesterol level ≥190 mg/dL (or from 68% to 50%, considering a more conservative formula). Conclusions Our study supports the importance of measuring lp(a) to perform the diagnosis of FH appropriately and to exclude that the observed phenotype is driven by elevated levels of lp(a) before performing the genetic test for FH.
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Project description:Familial hypercholesterolemia (FH) is an inherited disorder of lipid metabolism characterized by premature cardiovascular disease. It is one of the most common metabolic disorders affecting humans. There are two clinical manifestations: the milder heterozygous form and more severe homozygous form. Despite posing a significant health risk, FH is inadequately diagnosed and managed. As the clinical outcome is related to the degree and duration of exposure to elevated low-density lipoprotein cholesterol (LDL-C) levels, early treatment is vital. Diagnosis can usually be made using a combination of clinical characteristics such as family history, lipid levels, and genetic testing. Mutations in the gene encoding the LDL receptor (LDLR), apolipoprotein B, the pro-protein convertase subtilisin/kexin 9 (PCSK9), and LDLR adaptor protein are the commonest abnormalities. Early identification and treatment of patients, as well as screening of relatives, helps significantly reduce the risk of premature disease. Although statins remain the first-line therapy in most cases, monotherapy is usually inadequate to control elevated LDL-C levels. Additional therapy with ezetimibe and bile acid sequestrants may be required. Newer classes of pharmacotherapy currently under investigation include lomitapide, mipomersen, and monoclonal antibodies to PCSK9. Lipoprotein apheresis may be required when multiple pharmacotherapies are inadequate, especially in the homozygous form. Effective early detection and treatment of the index individual and initiation of cascade screening will help reduce the complications associated with FH. In this article, we review the disease of FH, complexity of diagnosis and management, and the challenges faced in preventing the significant morbidity and mortality associated with it.
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Project description:ImportanceFamilial hypercholesterolemia (FH) is the most common inherited cardiovascular disease and carries significant morbidity and mortality risks. Genetic testing can identify affected individuals, but some array-based assays screen only a small subset of known pathogenic variants.ObjectiveTo identify the number of clinically significant variants associated with FH that would be missed by an array-based, limited-variant screen when compared with next-generation sequencing (NGS)-based comprehensive testing.Design, setting, and participantsThis cross-sectional study compared comprehensive genetic test results for clinically significant variants associated with FH with results for a subset of 24 variants screened by a limited-variant array. Data were deidentified next-generation sequencing results from indication-based or proactive gene panels. Individuals receiving next-generation sequencing-based genetic testing, either for an FH indication between November 2015 and June 2020 or as proactive health screening between February 2016 and June 2020 were included. Ancestry was reported by clinicians who could select from preset options or enter free text on the test requisition form.Main outcomes and measuresNumber of pathogenic or likely pathogenic (P/LP) variants identified.ResultsThis study included 4563 individuals who were referred for FH diagnostic testing and 6482 individuals who received next-generation sequencing of FH-associated genes as part of a proactive genetic test. Among individuals in the indication cohort, the median (interquartile range) age at testing was 49 (32-61) years, 55.4% (2528 of 4563) were female, and 63.6% (2902 of 4563) were self-reported White/Caucasian. In the indication cohort, the positive detection rate would have been 8.4% (382 of 4563) for a limited-variant screen compared with the 27.0% (1230 of 4563) observed with the next-generation sequencing-based comprehensive test. As a result, 68.9% (848 of 1230) of individuals with a P/LP finding in an FH-associated gene would have been missed by the limited screen. The potential for missed findings in the indication cohort varied by ancestry; among individuals with a P/LP finding, 93.7% (59 of 63) of self-reported Black/African American individuals and 84.7% (122 of 144) of Hispanic individuals would have been missed by the limited-variant screen, compared with 33.3% (4 of 12) of Ashkenazi Jewish individuals. In the proactive cohort, the prevalence of clinically significant FH variants was approximately 1:191 per the comprehensive test, and 61.8% (21 of 34) of individuals with an FH-associated P/LP finding would have been missed by a limited-variant screen.Conclusions and relevanceLimited-variant screens may falsely reassure the majority of individuals at risk for FH that they do not carry a disease-causing variant, especially individuals of self-reported Black/African American and Hispanic ancestry.
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Project description:BackgroundData on treatment results of lipid-lowering therapy (LLT) in familial hypercholesterolemia (FH) are limited, particularly in Asian patients.HypothesisWe sought to evaluate the target achievement rate and associated variables in Korean patients with FH after maximal statin-based LLT.MethodsWe enrolled 146 patients with heterozygous FH, and 90 patients were finally analyzed. Patients were initially prescribed rosuvastatin 10 mg or atorvastatin 20 mg, and the regimen was adjusted to achieve the low-density lipoprotein cholesterol (LDL-C) target of 100 mg/dL. The primary evaluation point was the achievement rate of the LDL-C targets at 12 months: LDL-C < 100 mg/dL and ≥50% LDL-C reduction. The associations between clinical variables and target achievement were also analyzed.ResultsAt 12 months, 58% of patients were receiving high-intensity regimens, whereas 46% were receiving combination therapy. The mean pre- and post-treatment LDL-C levels were 229 and 118 mg/dL, respectively. Twenty-eight percent of patients achieved LDL-C < 100 mg/dL, and 47% achieved ≥50% LDL-C reduction. Pretreatment LDL-C and high-intensity regimens indicated a negative tendency toward the attainment of LDL-C < 100 mg/dL. Conversely, pretreatment LDL-C and diabetes mellitus were positively associated with a higher rate of ≥50% LDL-C reduction.ConclusionsThe target achievement of LDL-C < 100 mg/dL was low, and 50% LDL-C reduction was moderately achieved in Korean patients with FH receiving maximal statin-based LLT. Pretreatment LDL-C levels and diabetes mellitus were associated with target achievement. Our results provide rare and informative data on FH treatment in Asian patients.
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Project description:BackgroundPrevious studies have observed that high level of lipoprotein (a) [Lp(a)] was common in the phenotypic familial hypercholesterolemia (FH) and may explain part of the clinical diagnosis of FH.HypothesisWe aim to develop a modified model including Lp(a) and compare its diagnostic performance with Dutch Lipid Clinic Network (DLCN) criteria.MethodsData of 10?449 individuals were utilized for the model establishment (7806 for derivation and 2643 for validation) from January 2011 to March 2018. The novel score model was modified on the basis of DLCN. Furthermore, 718 patients were screened for LDLR, APOB, and PCSK9 gene mutations.ResultsThe novel modified model consisted of untreated low-density lipoprotein cholesterol (LDL-C) level, Lp(a), personal premature coronary heart disease (CHD), tendon xanthomas and family history of CHD and/or hypercholesterolemia. It has shown high discrimination (area under curve [AUC] 0.991, 95% confidence interval [CI[ 0.988-0.994, P?<?.001) for distinguishing clinical FH from non-FH diagnosed using DLCN. Furthermore, a concordance analysis was performed to compare the modified model with DLCN and it showed a good agreement with DLCN (? = 0.765). External validation of the novel model also showed good accordance (? = 0.700). Further genetic analysis showed that the agreements between the new model and mutation improved a little compared to that between DLCN and mutation.ConclusionsThe novel modified model, including Lp(a), could provide new insights into FH diagnosis in Chinese population with more concerns on the patients with high level of Lp(a).
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Project description:BackgroundThe deeper understanding of the complex hereditary basis of familial hypercholesterolemia (FH) has raised the rationale of genetic testing, which has been underutilized in clinical practice.ObjectivesThe present study aimed to explore the variant spectrum of FH in an expanding manner and compare its diagnostic performance.MethodsA total of 169 Chinese individuals (124 index cases and 45 relatives) with clinical definite/probable FH were consecutively enrolled. Next-generation sequencing was performed for genetic analysis of 9 genes associated with hypercholesterolemia (major genes: LDLR, APOB, and PCSK9; minor genes: LDLRAP1, LIPA, STAP1, APOE, ABCG5, and ABCG8) including the evaluations of small-scale variants and large-scale copy number variants (CNVs).ResultsAmong the 169 clinical FH patients included, 98 (58.0%) were men. A total of 85 (68.5%) index cases carried FH-associated variants. The proportion of FH caused by small-scale variants in LDLR, APOB, and PCSK9 genes was 62.1% and then increased by 6.5% when other genes and CNVs were further included. Furthermore, the variants in LDLR, APOB, and PCSK9 genes occupied 75% of all FH-associated variants. Of note, there were 8 non-LDLR CNVs detected in the present study.ConclusionsLDLR, APOB, and PCSK9 genes should be tested in the initial genetic screening, although variants in minor genes also could explain phenotypic FH, suggesting that an expanding genetic testing may be considered to further explain phenotypic FH.
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Project description:Familial hypercholesterolemia is an autosomal dominant inherited disease characterized by elevated plasma low-density lipoprotein cholesterol (LDL-C). It is mainly caused by mutations of the low-density lipoprotein receptor (LDLR) gene. Currently, the methods of whole genome sequencing or whole exome sequencing for screening mutations in familial hypercholesterolemia are not applicable in China due to high cost. We performed targeted exome sequencing of 167 genes implicated in the homozygous phenotype of a proband pedigree to identify candidate mutations, validated them in the family of the proband, studied the functions of the mutant protein, and followed up serum lipid levels after treatment. We discovered that exon 9 c.1268 T>C and exon 8 c.1129 T>G compound heterozygous mutations in the LDLR gene in the proband derived from the mother and father, respectively, in which the mutation of c.1129 T>G has not been reported previously. The mutant LDL-R protein had 57% and 52% binding and internalization functions, respectively, compared with that of the wild type. After 6 months of therapy, the LDL-C level of the proband decreased by more than 50% and the LDL-C of the other family members with heterozygous mutation also reduced to normal. Targeted exome sequencing is an effective method for screening mutation genes in familial hypercholesterolemia. The exon 8 and 9 mutations of the LDLR gene were pedigree mutations. The functions of the mutant LDL-R protein were decreased significantly compared with that of the wild type. Simvastatin plus ezetimibe was proven safe and effective in this preschool-age child.
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