Treating homozygous familial hypercholesterolemia in a real-world setting: Experiences with lomitapide

Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by markedly elevated plasma levels of low-density lipoprotein-cholesterol (LDL-C). Lomitapide is a microsomal triglyceride transfer protein (MTP) inhibitor approved as an adjunct to other lipid-lowering therapies (LLTs), with or without lipoprotein apheresis (LA), for the treatment of adult HoFH. Diet with <20% calories from fat is required. Due to a varying genetic and phenotypic profile of patients with HoFH, individual patients may respond to therapy differently; therefore examining individual cases in a 'real-world' setting provides valuable information on the effective day-to-day management of HoFH cases. Four HoFH cases were selected for analysis and discussion: a 20-year-old female compound heterozygote; a 62-year old female homozygote; a 42-year-old female compound heterozygote; and a 36-year-old male homozygote. Each patient was commenced on lomitapide according to the prescribed protocol and subjected to routine follow-up. All four patients experienced clinically meaningful reductions in LDL-C levels of 35-73%. Three of the patients had evidence of steatosis or mildly elevated liver function tests) before lomitapide was started, but effects of lomitapide on hepatic function were not universal. Three of the patients experienced gastrointestinal adverse events, but were managed with appropriate dietary control. Lomitapide is an effective adjunct LLT in the management of patients with HoFH, with or without LA. Real-world use of lomitapide has a side-effect profile consistent with clinical trials and one that can be managed by adherence to recommendations on dose escalation, dietary modification and dietary supplements

LINEE GUIDA CLINICHE PER LA PREVENZIONE DELLA CARDIOPATIA ISCHEMICA NELLA IPERCOLESTEROLEMIA FAMILIARE Una patologia sotto-diagnosticata e sotto-trattata

AIMS. Familial hypercholesterolaemia (FH) is a common genetic cause of premature coronary heart disease (CHD) due to lifelong elevated plasma low-density lipoprotein (LDL) cholesterol levels. This paper aims to describe the problem of FH underdiagnosis and undertreatment and to promote CHD prevention providing recommendations for the screening and treatment of patients with FH. Methods and results. In many countries, less then 1% of FH patients are diagnosed, although the estimated prevalence of this condition is about 1/500 for heterozygous FH and the results of FH screening in a general population of Northern Europe suggest a prevalence of 1/200. Studies on FH patients agree on a widespread failure to achieve recommended target of LDL-cholesterol and on a 12-fold increased CHD risk. With a theoretical prevalence between 1/500 and 1/200, it is estimated that 14 to 34 million subjects worldwide have FH. With evidence of plasma cholesterol ≥8 mmol/L (≥310 mg/dL) in an adult or ≥6 mmol/L (≥230 mg/dL) in a child, premature CHD, tendon xanthomas, or sudden premature cardiac death, we recommend the screening for FH of this subject and of all first-degree relatives. The treatment of a patient with diagnosis of FH should have LDL targets of <3.5 mmol/L (<135 mg/ dL) for children, <2.5 mmol/L (<100 mg/dL) for adults, and <1.8 mmol/L (<70 mg/dL) for adults with known CHD or diabetes. Beside life-style and dietary modifications, first line therapies are statins, ezetimibe, and bile acid binding resins in children, and maximal potent statin dose, ezetimibe, bile acid binding resins, and fibrates in adults. Homozygotes FH and in treatment-resistant heterozygotes FH with CHD should be referred for LDL-apheresis. Conclusion. Familial hypercholesterolemia is a common condition that carries a high risk of CHD. The underdiagnosis and undertreatment of FH require a focused intervention that implements the screening and promote the early and aggressive treatment of these patients

Replication of linkage of familial hypobetalipoproteinemia to chromosome 3p in six kindreds

Familial hypobetalipoproteinemia (FHBL) is a genetically heterogeneous condition characterized by very low apolipoprotein B (apoB) concentrations in plasma and/or low levels of LDL-cholesterol (LDL-C) with a propensity to developing fatty liver. In a minority of cases, truncation-specifying mutations of the apoB gene (APOB) are etiologic, but the genetic basis of most cases is unknown. We previously reported linkage of FHBL to a 10 cM region on 3p21.1-22 in one kindred. The objectives of the current study were to identify other FHBL families with linkage to 3p and to narrow the FHBL susceptibility region on 3p. Six additional FHBL kindreds unlinked to the APOB region on chromosome 2 were genotyped with polymorphic markers spanning a region of approximately 13 cM on chromosome 3. Quantitative linkage analyses indicated that the FHBL in these families was linked to 3p21.1-22. Haplotype analysis identified several meiotic crossover events, allowing us to narrow the critical region from 10 cM to 2.0 cM, between markers D3S2407 and D3S1767

Statin utilization and lipid goal attainment in high or very-high cardiovascular risk patients: Insights from Italian general practice

Background and aims: Statin utilization and lipid goal achievement were estimated in a large sample of Italian patients at high/very-high cardiovascular (CV) risk. Methods: Patients aged â¥18 years with a valid low-density lipoprotein cholesterol (LDL-C) measurement in 2015 were selected from the IMS Health Real World Data database; non-high-density lipoprotein cholesterol (non-HDL-C) was assessed in those with available total cholesterol measurements. Index dates were defined as the last valid lipid measurement in 2015. Patients were hierarchically classified into mutually exclusive risk categories: heterozygous familial hypercholesterolemia (primary and secondary prevention), atherosclerotic CV disease (including recent acute coronary syndrome [ACS], chronic coronary heart disease, stroke, and peripheral arterial disease), and diabetes mellitus (DM) alone. Statin and non-statin lipid-modifying therapy (LMT) use, and European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline-recommended goal attainment, were assessed. Results: Among 66,158 patients meeting selection criteria, the overall rate of LMT prescriptions was 53.3%, including 7.7% on high-intensity statin therapy. Statin use was highest for recent ACS and lowest for DM alone. LDL-C goal attainment was 16.0% for <1.8 mmol/l and 45.0% for <2.5 mmol/l; 24.3% reached non-HDL-C <2.6 mmol/l and 52.2% were at <3.3 mmol/l. Goal achievement was greatest with high-intensity statin use. Conclusions: Statin use in this cohort was consistent with previous reports in Italian patients at high/very-high CV risk, and low relative to statin use in other European countries. The low rate of ESC/EAS lipid goal attainment observed was consistent with outcomes of other European studies

treatment effect of alirocumab according to age group smoking status and hypertension pooled analysis from 10 randomized odyssey studies

Background Age, smoking, hypercholesterolemia, and hypertension are major risk factors for atherosclerotic cardiovascular disease. Objective We examined whether the effects of alirocumab on low-density lipoprotein cholesterol (LDL-C) differed according to age, hypertension, or smoking status. Methods Data were pooled from 10 Phase 3 ODYSSEY randomized trials (24–104 weeks' duration) in 4983 people with heterozygous familial hypercholesterolemia (FH) or non–familial hypercholesterolemia (3188 on alirocumab, 1795 on control [620 on ezetimibe and 1175 on placebo]). Most participants received concomitant maximum tolerated statin therapy. In 8 trials, the alirocumab dose was increased from 75 mg every 2 weeks (Q2W) to 150 mg Q2W at Week 12 if predefined risk-based LDL-C goals were not achieved at Week 8 (≥70 mg/dL in very high cardiovascular risk; ≥100 mg/dL in moderate or high cardiovascular risk). Two trials compared alirocumab 150 mg Q2W vs placebo. The efficacy and safety of alirocumab were assessed post hoc in subgroups stratified by age ( Results Alirocumab reduced LDL-C by 23.7% (75/150 mg vs ezetimibe + statin) to 65.4% (150 mg vs placebo + statin) from baseline to Week 24 vs control. Subgroup analyses confirmed no significant interactions in response to alirocumab between age group, hypertension, or smoking status. Overall rates of treatment-emergent adverse events were similar between alirocumab and control groups. Conclusions In this pooled analysis from 10 trials, alirocumab led to substantial LDL-C reductions vs control in every age group and regardless of hypertension or smoking status. Alirocumab was well tolerated in all subgroups

Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society

AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH. METHODS AND RESULTS: Early diagnosis of HoFH and prompt initiation of diet and lipid-lowering therapy are critical. Genetic testing may provide a definitive diagnosis, but if unavailable, markedly elevated LDL-C levels together with cutaneous or tendon xanthomas before 10 years, or untreated elevated LDL-C levels consistent with heterozygous FH in both parents, are suggestive of HoFH. We recommend that patients with suspected HoFH are promptly referred to specialist centres for a comprehensive ACVD evaluation and clinical management. Lifestyle intervention and maximal statin therapy are the mainstays of treatment, ideally started in the first year of life or at an initial diagnosis, often with ezetimibe and other lipid-modifying therapy. As patients rarely achieve LDL-C targets, adjunctive lipoprotein apheresis is recommended where available, preferably started by age 5 and no later than 8 years. The number of therapeutic approaches has increased following approval of lomitapide and mipomersen for HoFH. Given the severity of ACVD, we recommend regular follow-up, including Doppler echocardiographic evaluation of the heart and aorta annually, stress testing and, if available, computed tomography coronary angiography every 5 years, or less if deemed necessary. CONCLUSION: This EAS Consensus Panel highlights the need for early identification of HoFH patients, prompt referral to specialized centres, and early initiation of appropriate treatment. These recommendations offer guidance for a wide spectrum of clinicians who are often the first to identify patients with suspected HoFH

Exome sequencing in suspected monogenic dyslipidemias

Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias

Behavior of the total antioxidant status in a group of subjects with metabolic syndrome.

AIM: Our purpose was to examine the total antioxidant status (TAS) in subjects with metabolic syndrome (MS) subdivided according to the presence or not of diabetes mellitus. METHODS: We enrolled 106 subjects (45 women, 61 men) with MS subsequently subdivided in diabetics (14 women, 29 men) and nondiabetics (31 women, 29 men). TAS was obtained using an Assay kit which relies on the ability of plasma antioxidant substances to inhibit the oxidation of 2,2'-azino-bis(3-ethylbenzthiazoline sulfonic acid) to the radical ABTS+. RESULTS: In the group of MS subjects a significant decrease in TAS (p<0.05) in comparison with normal controls was evident. This difference was present between normal subjects and nondiabetic subjects with MS (p<0.001) but not between normal and diabetic subjects with MS. Examining the linear regression among TAS, age, anthropometric profile, blood pressure values and glycometabolic pattern, conflicting data were found. CONCLUSIONS: Although we know that TAS includes several enzymatic and non enzymatic antioxidants, we retain that the difference observed in the two subgroups of subjects with MS must be looked in particular into two pathophysiological aspects regarding bilirubin and uric acid

Exome Sequencing in Suspected Monogenic Dyslipidemias

Abstract BACKGROUND: -Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. METHODS AND RESULTS: -We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families despite follow-up analyses. We identified three factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. CONCLUSIONS: -We identified the genetic basis of disease in nine of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies