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Roeters Van Lennep J.,Erasmus Medical Center | Averna M.,University of Palermo | Alonso R.,Lipid Clinic | Alonso R.,Lipid Unit
Journal of Clinical Lipidology | Year: 2015

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. © 2015 National Lipid Association. All rights reserved.

Toledo E.,Public University of Navarra | Salas-Salvado J.,University of Cambridge | Donat-Vargas C.,Public University of Navarra | Buil-Cosiales P.,Nutricion Institute Salud Carlos III | And 16 more authors.
JAMA Internal Medicine | Year: 2015

IMPORTANCE Breast cancer is the leading cause of female cancer burden, and its incidence has increased by more than 20%worldwide since 2008. Some observational studies have suggested that the Mediterranean dietmay reduce the risk of breast cancer. OBJECTIVE To evaluate the effect of 2 interventions with Mediterranean diet vs the advice to follow a low-fat diet (control) on breast cancer incidence. DESIGN, SETTING, AND PARTICIPANTS The PREDIMED study is a 1:1:1 randomized, single-blind, controlled field trial conducted at primary health care centers in Spain. From 2003 to 2009, 4282 women aged 60 to 80 years and at high cardiovascular disease risk were recruited after invitation by their primary care physicians. INTERVENTIONS Participants were randomly allocated to a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). MAIN OUTCOMES AND MEASURES Breast cancer incidencewas a prespecified secondary outcome of the trial for women without a prior history of breast cancer (n = 4152). RESULTS After a median follow-up of 4.8 years, we identified 35 confirmed incident cases of breast cancer. Observed rates (per 1000 person-years) were 1.1 for the Mediterranean diet with extra-virgin olive oil group, 1.8 for the Mediterranean diet with nuts group, and 2.9 for the control group. The multivariable-adjusted hazard ratios vs the control group were 0.32 (95%CI, 0.13-0.79) for the Mediterranean diet with extra-virgin olive oil group and 0.59 (95% CI, 0.26-1.35) for the Mediterranean diet with nuts group. In analyses with yearly cumulative updated dietary exposures, the hazard ratio for each additional 5%of calories from extra-virgin olive oil was 0.72 (95%CI, 0.57-0.90). CONCLUSIONS AND RELEVANCE This is the first randomized trial finding an effect of a long-term dietary intervention on breast cancer incidence. Our results suggest a beneficial effect of a Mediterranean diet supplemented with extra-virgin olive oil in the primary prevention of breast cancer. These results come from a secondary analysis of a previous trial and are based on few incident cases and, therefore, need to be confirmed in longer-term and larger studies. Copyright © 2015 American Medical Association. All rights reserved.

Heier I.,University of Oslo | Soyland E.,Section for Climate Therapy | Krogstad A.-L.,Section for Climate Therapy | Rodriguez-Gallego C.,Lipid Clinic | And 4 more authors.
British Journal of Dermatology | Year: 2011

Background Interferon (IFN)-α-producing plasmacytoid dendritic cells (pDCs), inflammatory CD11c+CD1c- myeloid dendritic cells (mDCs) and macrophages have been found to contribute to the pathogenesis of psoriasis. Heliotherapy is a well-established treatment modality of this disease, although the details of how the effects are mediated are unknown. Objectives To test the hypothesis that exposure to natural sun affects pathogenic DC subsets in lesional skin. Methods Skin biopsies were obtained from lesional and nonlesional skin in 10 patients with moderate to severe psoriasis subjected to controlled sun exposure on Gran Canaria. Biopsies were obtained at baseline, day 2 and day 16 and examined by immunohistochemistry. Results Sixteen days of heliotherapy had excellent clinical effect on patients with psoriasis, with significant reductions in Psoriasis Area and Severity Index (PASI) scores. In lesional skin pDC numbers and expression of MxA, a surrogate marker for IFN-α, were rapidly reduced. Inflammatory CD11c+CD1c- mDCs were significantly reduced whereas resident dermal CD11c+CD1c+ mDCs were unaffected. Expression levels of the maturation marker DC-LAMP (CD208) on mDCs were significantly reduced after sun exposure, as were the numbers of lesional dermal macrophages. A decrease of dermal DC subsets and macrophages was already observed after 1 day of sun exposure. An additional finding was that DC-SIGN (CD209) is primarily expressed on CD163+ macrophages and not DCs. Conclusions The clinical improvement in psoriasis following sun exposure is associated with rapid changes in dermal DC populations and macrophages in lesional skin, preceding the clinical effect. These findings support the concept that these DC subsets are involved in the pathogenesis of psoriasis and suggest that sun-induced clinical benefit may partly be explained by its effect on dermal DCs. © 2011 British Association of Dermatologists.

PURPOSE OF REVIEW: After the approval of alirocumab and evolocumab, the first two monoclonal antibodies (mAbs) targeting proprotein convertase subtilisin kexin type 9 (PCSK9), this review provides an update on recent PCSK9 inhibitors data and describes recommendations for the use before the results of the ongoing cardiovascular endpoint trials. RECENT FINDINGS: New studies and complementary analysis of phase III trials have consistently shown that alirocumab and evolocumab are highly effective in reducing LDL-cholesterol and to some extent lipoprotein (a). Some preliminary findings coming from exploratory and post-hoc analyses of the longer-term safety phase III trials and meta-analyses suggest that these mAbs can decrease the incidence of cardiovascular events. Whether or not mAbs targeting PCSK9 definitively reduce the incidence of cardiovascular events without safety concerns shall be demonstrated with the ongoing cardiovascular outcome trials. Waiting these outcome trials and given the high cost of these mAbs, groups of experts have proposed as priorities groups of patients with familial hypercholesterolemia and with atherosclerotic cardiovascular disease who have substantially elevated LDL-cholesterol on maximally tolerated statin/ezetimibe therapy. SUMMARY: Before the results of large cardiovascular outcome trials, PCSK9 inhibitors should be only used in some categories of patients with familial hypercholesterolemia and/or with atherosclerotic cardiovascular disease. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

Caballero P.,Hospital Of La Princesa | Alonso R.,Lipid Clinic | Rosado P.,Hospital Of La Princesa | Fernandez-Friera L.,National Research Center Cardiovascular | And 3 more authors.
Atherosclerosis | Year: 2012

Objectives: To investigate the extent of subclinical atherosclerosis in asymptomatic familial hypercholesterolemia (FH) patients using non-invasive images techniques. Patients, methods and results: The atherosclerotic burden of 36 molecularly defined FH patients (18 males, 45.7 ± 10.9 years) without evidence of cardiovascular disease receiving lipid-lowering treatment and 19 (47.8 ± 11.3 years) controls was investigated. Descending thoracic aorta magnetic resonance imaging (MRI) was performed in a 1.5. T equipment with T1 and T2 sequences to characterize atherosclerotic plaques and to measure aortic wall volumen. Carotid intima-media thickness (cIMT) and presence of plaques were measured using B-mode carotid ultrasound.Mean aortic wall volumen, cIMT and atherosclerotic plaques in aorta were significantly higher in FH cases (P< 0.001). A significant correlation between aortic wall volume and cIMT was observed (P< 0.01). Aortic MRI detected plaques in 94% and carotid ultrasound in 14% of cases. Lipid-rich plaques were observed only in FH cases (33%) and were associated with family history of premature coronary artery disease (P< 0.05). Conclusions: Asymptomatic middle-aged FH patients have significantly higher atherosclerotic burden than controls. cIMT has shown a significant correlation with aortic wall volume and MRI allowed the detection of lipid-rich plaques in FH subjects that were associated with family history of premature coronary artery disease. © 2012 Elsevier Ireland Ltd.

Farnier M.,Lipid Clinic
Expert Review of Cardiovascular Therapy | Year: 2015

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in lipoprotein metabolism, mainly by modulating LDL receptor activity. Alirocumab is a fully human IgG1 monoclonal antibody that binds PCSK9, increases the number of LDL receptors and decreases the levels of LDL cholesterol. The efficacy of alirocumab has been evaluated in more than 6000 subjects with primary hypercholesterolemia; in Phase III trials, alirocumab consistently reduced LDL-cholesterol up to 62% with every 2 weeks dosing compared with placebo and up to 36% compared with ezetimibe. Two doses, 75 and 150 mg, have been developed to propose a tailored approach in the treatment of hypercholesterolemic patients not controlled by maximally tolerated lipid-lowering therapy. Alirocumab was generally well-tolerated, with an acceptable safety profile. The ongoing ODYSSEY OUTCOMES trial will provide definitive evidence on the effect of alirocumab on cardiovascular morbidity and mortality and complementary data on the long-term safety and tolerability. Moreover, a cost-effectiveness analysis would be useful to determine the appropriate price of alirocumab. © 2015 Taylor & Francis.

Alonso R.,Lipid Clinic | Mata P.,Lipid Clinic | Mata P.,Spanish Familial Hypercholesterolemia Foundation | Zambon D.,University of Barcelona | And 2 more authors.
Expert Review of Cardiovascular Therapy | Year: 2013

Familial hypercholesterolemia (FH) is the most frequent inherited disorder associated with premature coronary artery disease. Early identification and treatment of patients will reduce cardiovascular outcomes. Identification of index cases and then cascade testing in first-degree relatives using lipid levels and genetic test is the most cost-effective strategy implemented in some countries. FH patients are considered at high cardiovascular risk. Imaging techniques such as coronary computed tomography angiography could identify subjects that will require more intensive treatments. Recent guidelines recommend an LDL-C below 100 mg/dl or at least 50% LDL-C reduction if the first goal is not attained as treatment targets in heterozygous FH. Statins are the first-line agents in almost all patients, and several options exist to obtain larger LDL-C reductions like the addition of ezetimibe and/or colesevelam. Novel agents like microsomal triglyceride transfer protein inhibitors, apolipoprotein B100 antisense or PCSK9-specific monoclonal antibodies, if approved by regulatory agencies, will reduce LDL-C levels and potentially reduce cardiovascular risk in homozygous and severe heterozygous FH patients. © 2013 Expert Reviews Ltd.

Toleikyte I.,University of Oslo | Retterstol K.,Lipid Clinic | Leren T.P.,University of Oslo | Iversen P.O.,University of Oslo
Circulation | Year: 2011

Background-: Women with familial hypercholesterolemia (FH) are prone to early cardiovascular disease and death. It is unknown whether FH adversely affects pregnant women and birth outcomes. We determined whether heterozygous FH women are at higher risk of premature birth (<37 gestational weeks), delivering children with low birth weight (<2500 g) and/or with congenital malformations compared to women in general. Methods and Results-: We linked information from the Medical Genetics Laboratory with that of the Medical Birth Registry of Norway. We included 1869 FH women (≥14 years) from the Medical Genetics Laboratory and about 2 million (general population) from the Medical Birth Registry of Norway during the period 1967 to 2006. The registry match resulted in analysis of 2319 births of 1093 women with heterozygous FH. The mean (SD) prepregnancy total cholesterol concentration was 9.59 (2.06) mmol/L (370 [80 mg/dL]), whereas the concentration of total cholesterol was not available during pregnancy. The frequencies of prematurity, low birth weight, and congenital malformations for the 40-year period in the FH population were 6.8, 5.0, and 3.3, respectively. The corresponding values for the general population were 6.2, 5.2, and 3.2. The corresponding odds ratios were 1.11 (95 confidence interval 0.94-1.31; P=0.23), 0.96 (0.79-1.15; P=0.64), and 1.09 (0.87-1.37; P=0.45). Conclusions-: Women with FH do not appear to have a higher risk of preterm delivery or of having infants with low birth weight or congenital malformations than women in general, but, although this is unlikely, some undetected bias may obscure the real differences. © 2011 American Heart Association, Inc.

Farnier M.,Lipid Clinic
Current Cardiology Reports | Year: 2016

Low-density lipoproteins (LDL) play a causal role in the development of atherosclerosis, and reduction of LDL cholesterol with a statin is a cornerstone in prevention of cardiovascular disease. However, it remains an unmet need to reduce the residual risk on maximally tolerated statin alone or in combination with other drugs such as ezetimibe. Among the new LDL-lowering therapies, PCSK9 inhibitors appear the most promising class. Genetic studies suggest that triglyceride-rich lipoproteins are associated with cardiovascular risk and several promising triglyceride-lowering therapies are at various stages of development. At the opposite end, high-density lipoprotein (HDL) cholesterol seems to not be causally associated with cardiovascular risk, and thus far, trials designed to reduce cardiovascular risk by mainly raising HDL cholesterol levels have been disappointing. Nevertheless, new drugs targeting HDL are still in development. This review describes the new drugs reducing LDL, apolipoprotein(a), and triglyceride-rich lipoproteins, and the strategies to modulate HDL metabolism. © 2016, Springer Science+Business Media New York.

Mata N.,Madrid Health Authority | Alonso R.,Lipid Clinic | Banegas J.R.,Autonomous University of Madrid | Zambon D.,Hospital Clinic | And 2 more authors.
European Journal of Public Health | Year: 2014

Objectives: This study describes health-related quality of life (HRQL) in a large sample of molecularly defined familial hypercholesterolemia (FH) patients compared with unaffected relatives. Study design and setting: Cross-sectional study of cases recruited in the Spanish FH cohort study. A total of 1947 subjects 18 years were included-1321 FH and 626 unaffected relatives. HRQL was assessed by 12-Item Short-Form Health Survey questionnaire. Main outcomes were as follows: Self-perceived health, physical summary component, mental summary component and their independent covariates. Results: Mean age was 45.3 years in FH subjects and 40.4 years in control subjects (P < 0.001). Cardiovascular disease (CVD) was present in 14.1% of FH patients and in 3.2% of control subjects (P < 0.001). Frequency of optimal self-perceived health, mean physical summary component and mental summary component of FH patients (81.5%, 52.1 and 51.1, respectively), were similar to those of control subjects (83.1%, 53.1 and 51.1, respectively). Factors independently associated with a worse HRQL in FH patients were as follows: CVD, female gender, older age, depression, obesity, lower educational level, lower physical activity and xanthomas. Conclusions: HRQL of FH patients was similar to control subjects, despite their higher burden of premature CVD. The most important factors with a negative impact in quality of life in FH are CVD, female gender and older age. © 2012 The Author.

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