[Show abstract][Hide abstract] ABSTRACT: Familial chylomicronemia syndrome (FCS) is a rare lipid disease caused by complete lipoprotein lipase (LPL) deficiency resulting in fasting chylomicronemia and severe hypertriglyceridemia. Inhibition of diacylglycerol acyltransferase 1 (DGAT1), which mediates chylomicron triglyceride (TG) synthesis, is an attractive strategy to reduce TG levels in FCS. In this study we assessed the safety, tolerability and TG-lowering efficacy of the DGAT1 inhibitor pradigastat in patients with FCS.
Six FCS patients were enrolled in an open-label clinical study. Following a 1-week very low fat diet run-in period patients underwent baseline lipid assessments, including a low fat meal tolerance test. Patients then underwent three consecutive 21 day treatment periods (pradigastat at 20, 40 & 10 mg, respectively). Treatment periods were separated by washout periods of ≥4 weeks. Fasting TG levels were assessed weekly through the treatment periods. Postprandial TGs, ApoB48 and lipoprotein lipid content were also monitored.
Following once daily oral dosing, steady-state exposure was reached by Day 14. There was an approximately dose proportional increase in pradigastat exposure at studied doses. Pradigastat was associated with a 41% (20 mg) and 70% (40 mg) reduction in fasting triglyceride over 21 days of treatment. The reduction in fasting TG was almost entirely accounted for by a reduction in chylomicron TG. Pradigastat treatment also led to substantial reductions in postprandial TG as well as apo48 (both fasting and postprandial). Pradigastat was safe and well tolerated, with only mild, transient gastrointestinal adverse events.
The novel DGAT1 inhibitor pradigastat substantially reduces plasma TG levels in FCS patients, and may be a promising new treatment for this orphan disease.
ClinicalTrials.gov identifier NCT01146522.
Lipids in Health and Disease 12/2015; 14(1). DOI:10.1186/s12944-015-0006-5 · 2.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim:
To assess the associations between gestational diabetes mellitus (GDM) and DNA methylation levels at genes related to energy metabolism.
Patients & methods:
Ten loci were selected from our recent epigenome-wide association study on GDM. DNA methylation levels were quantified by bisulfite pyrosequencing in 80 placenta and cord blood samples (20 exposed to GDM) from an independent birth cohort (Gen3G).
We did not replicate association between DNA methylation and GDM. However, in normoglycemic women, glucose levels were associated with DNA methylation changes at LRP1B and BRD2 and at CACNA1D and LRP1B gene loci in placenta and cord blood, respectively.
These results suggest that maternal glucose levels, within the normal range, are associated with DNA methylation changes at genes related to energy metabolism and previously associated with GDM. Maternal glycemia might thus be involved in fetal metabolic programming.
[Show abstract][Hide abstract] ABSTRACT: Background
Excess visceral fat is a major risk factor for hypertension. Enhanced blood pressure (BP) reactivity and delayed BP recovery from physical and mental challenges predict future hypertension.Objectives
Determine whether visceral fat is associated with higher BP reactivity and delayed BP recovery from physical and mental challenges during adolescence.Methods
In a community-based sample of 283 male and 308 female adolescents, we measured visceral fat with magnetic resonance imaging, total body fat with bioimpedance, and beat-by-beat BP with a Finometer at rest and during physical (10-min standing) and mental (2-min math stress) challenges.ResultsMales vs. females showed greater BP reactivity and no differences in BP recovery from either type of challenges. Visceral fat was positively associated with BP reactivity to standing up only and in males only (+8.4 ± 3.6 mmHg per 1 log cm3 of visceral fat, P = 0.008), and this association was independent of total body fat. No association was seen between visceral fat and BP recovery from either type of challenge in either sex. All these associations were independent of age, puberty stage, height and initial BP.Conclusions
Adolescent males vs. females demonstrate greater BP reactivity but similar BP recovery from physical and mental challenges. Excess visceral fat enhances BP reactivity to physical but not mental challenges in males only.
[Show abstract][Hide abstract] ABSTRACT: Apolipoprotein C-III (APOC3) is a key regulator of plasma triglyceride levels. Elevated triglyceride levels are associated with a risk of adverse cardiovascular events and pancreatitis. ISIS 304801 is a second-generation antisense inhibitor of APOC3 synthesis.
We conducted a randomized, double-blind, placebo-controlled, dose-ranging, phase 2 study to evaluate ISIS 304801 in untreated patients with fasting triglyceride levels between 350 mg per deciliter (4.0 mmol per liter) and 2000 mg per deciliter (22.6 mmol per liter) (ISIS 304801 monotherapy cohort), as well as in patients receiving stable fibrate therapy who had fasting triglyceride levels between 225 mg per deciliter (2.5 mmol per liter) and 2000 mg per deciliter (ISIS 304801-fibrate cohort). Eligible patients were randomly assigned to receive either ISIS 304801, at doses ranging from 100 to 300 mg, or placebo, once weekly for 13 weeks. The primary outcome was the percentage change in APOC3 level from baseline.
A total of 57 patients were treated in the ISIS 304801 monotherapy cohort (41 received active agent, and 16 received placebo), and 28 patients were treated in the ISIS 304801-fibrate cohort (20 received active agent, and 8 received placebo). The mean (±SD) baseline triglyceride levels in the two cohorts were 581±291 mg per deciliter (6.6±3.3 mmol per liter) and 376±188 mg per deciliter (4.2±2.1 mmol per liter), respectively. Treatment with ISIS 304801 resulted in dose-dependent and prolonged decreases in plasma APOC3 levels when the drug was administered as a single agent (decreases of 40.0±32.0% in the 100-mg group, 63.8±22.3% in the 200-mg group, and 79.6±9.3% in the 300-mg group, vs. an increase of 4.2±41.7% in the placebo group) and when it was administered as an add-on to fibrates (decreases of 60.2±12.5% in the 200-mg group and 70.9±13.0% in the 300-mg group, vs. a decrease of 2.2±25.2% in the placebo group). Concordant reductions of 31.3 to 70.9% were observed in triglyceride levels. No safety concerns were identified in this short-term study.
We found that treatment with ISIS 304801 was associated with significant lowering of triglyceride levels, among patients with a broad range of baseline levels, through selective antisense inhibition of APOC3 synthesis. (Funded by Isis Pharmaceuticals; ClinicalTrials.gov number, NCT01529424.).
New England Journal of Medicine 07/2015; 373(5):438-47. DOI:10.1056/NEJMoa1400283 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite current standard-of-care, many patients at high cardiovascular disease (CVD) risk still have elevated low-density lipoprotein cholesterol (LDL-C). Alirocumab is a fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9).
To compare LDL-C-lowering efficacy of adding alirocumab vs other common lipid-lowering strategies. Design, Patients, Interventions: Patients (n=355) with CVD and LDL-C levels ≥70 mg/dL, or CVD risk factors and LDL-C ≥100 mg/dL, on baseline atorvastatin 20 or 40 mg, were randomized to: (1) add-on alirocumab 75 mg every 2 weeks (Q2W) subcutaneously; (2) add-on ezetimibe 10 mg/day; (3) double atorvastatin dose; (4) for atorvastatin 40 mg regimen only, switch to rosuvastatin 40 mg. For patients not achieving protocol-defined LDL-C goals, alirocumab dose was increased (blinded) at week 12 to 150 mg Q2W.
Primary endpoint was % change in calculated LDL-C from baseline to 24 weeks (intent-to-treat).
Among atorvastatin 20 and 40 mg regimens respectively, add-on alirocumab reduced LDL-C levels by 44.1% and 54.0% (p<0.001 vs all comparators); add-on ezetimibe, 20.5% and 22.6%; doubling of atorvastatin dose, 5.0% and 4.8%; and switching atorvastatin 40 mg to rosuvastatin 40 mg, 21.4%. Most alirocumab-treated patients (87.2% and 84.6%) achieved their LDL-C goals. Most alirocumab-treated patients (86%) maintained their 75 mg Q2W regimen. Treatment-emergent adverse events occurred in 65.4% of alirocumab patients, vs 64.4% ezetimibe and 63.8% double atorvastatin/switch to rosuvastatin (data pooled).
Adding alirocumab to atorvastatin provided significantly greater LDL-C reductions vs adding ezetimibe, doubling atorvastatin dose, or switching to rosuvastatin, and enabled greater LDL-C goal achievement.
The Journal of Clinical Endocrinology and Metabolism 06/2015; 100(8):jc20151520. DOI:10.1210/jc.2015-1520 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and objectives
• Homozygous familial hypercholesterolemia (HoFH) is a rare genetic condition characterized by markedly elevated low-density lipoprotein cholesterol (LDL-C) levels, inadequate response to conventional drug therapy and premature-onset cardiovascular disease.1
• HoFH is most commonly caused by the occurrence of two LDL–receptor (LDL-R) gene (LDLR) mutations but can also be caused by mutations in other genes which directly or indirectly affect the LDL-C/LDL-R pathway, including the genes encoding apolipoprotein B (APOB) and proprotein convertase subtilisin/kexin type 9 (PCSK9), and LDL-receptor adapter protein 1 (LDLRAP1) (Figure 1).1
• The genotype and clinical phenotype of HoFH patients varies, and depending on the type of mutations, patients can present with untreated LDL-C levels as low as 4.4 mmol/L.1, 2
• To further explore the variability of HoFH, we examined the phenotype, genotype and baseline-treated LDL-C levels in a cohort of patients with genetically confirmed HoFH enrolled in a clinical trial.
ISA 2015 - 17th International Symposium on Atherosclerosis, Netherlands, Amsterdam; 05/2015
[Show abstract][Hide abstract] ABSTRACT: Homozygous familial hypercholesterolemia features a wide range of LDL-C levels
Abstract nr. 389
Author Stefanutti , Claudia, ‘Sapienza’ University of Rome, Rome, Italy
Co-author(s) - Blom , Dirk
Co-author(s) - Averna , Maurizio
Co-author(s) - Meagher , Emma
Co-author(s) - Theron , Hendrik du toit
Co-author(s) - Marais , David
Co-author(s) - Hegele , Robert
Co-author(s) - Sirtori , Cesare
Co-author(s) - Shah , Prediman
Co-author(s) - Gaudet , Daniel
Co-author(s) - Vigna , Giovanni
Co-author(s) - Du Plessis , Anne
Co-author(s) - Bloedon , LeAnne
Co-author(s) - Rader , Daniel
Co-author(s) - Cuchel , Marina
Topic Dyslipidemia; Lipids, Lipoproteins and Apolipoproteins
Keywords Familial Hypercholesterolemia,Genetics,Hypolipidemic Drugs,LDL
Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disease
characterized by highly elevated LDL-C levels, limited response to conventional lipid-lowering
therapies, and increased risk of premature CVD. Severe atherosclerosis may develop before the
age of 30. Traditionally, HoFH has been diagnosed according to untreated plasma LDL-C levels
>500mg/dL; or treated levels ≥300mg/dL. More recently, studies suggest that the range of LDL-C
levels in HoFH may be more variable. To explore this, we analyzed baseline LDL-C levels in a
group of treated clinical trial subjects with genetically confirmed HoFH.
Baseline characteristics of 29 HoFH patients from a multinational Phase 3 study were
collected. All subjects were ≥18 years and met the diagnosis of HoFH based on: untreated TC
>500 mg/dL and both parents with documented untreated TC >250mg/dL; documented genetic
mutations of genes known to affect LDLR functionality; or skin fibroblast LDLR activity <20%
All patients had confirmed mutations in both alleles of LDLR (n=28) or LDLRAP1 (n=1)
gene. Age range was 18-55 years. Nearly all patients (93%) had a history of CVD: CABG, 35%;
coronary angioplasty, 10%; aortic valve replacement, 10%; mitral valve replacement/repair, 10%.
Therapy included statins (93%; 76% with ezetimibe) and apheresis (62%). Treated LDL-C levels
were in the range 152-564mg/dL; 38% had LDL-C <300mg/dL and 14% <200mg/dL (Table). There
were no differences in LDL-C levels between subjects who were receiving apheresis treatment
and those who were not.
Consistent with other recent studies, this analysis provides additional evidence of the
heterogeneity of on-treatment LDL-C values in patients with genetically defined HoFH. Diagnosis
of HoFH should not rely solely on treated LDL-C >300 mg/dL, but should also include other clinical
or genetic factors.
Table of baseline characteristics
Subdivision 3. Clinical Studies
Presentation Preference Electronic poster presentation
17th triennial congress of the International Atherosclerosis Society, Netherlands, Amsterdam; 05/2015
[Show abstract][Hide abstract] ABSTRACT: (EN): The invention relates to traceable metallic products, methods of uses and methods of making same. The metallic products may be made traceable for integrity purposes, identification purposes, counterfeit avoidance and the like. The invention also relates to metallic supports for nanostorage of various compounds and samples.
(FR): L'invention concerne des produits métalliques traçables, des procédés d'utilisation et des procédés de fabrication de ceuxci. Ces produits métalliques peuvent être rendus traçables à des fins d'intégrité, d'identification, de lutte contre la contrefaçon et analogue. L'invention concerne également des supports métalliques pour le nanostockage de divers composés et échantillons.
[Show abstract][Hide abstract] ABSTRACT: Objective: Hypertension and osteoporosis are age-related health risks differentially expressed in men and women. Here we have analysed their prevalence in a randomly selected cross-sectional cohort [CARTaGENE (CaG) of Quebec, Canada and explored their existing relationships along with height, arterial stiffness and bone fractures.
Methods: The principal cohort CaG included 20 007 individuals of age 40–70 years. Participants were subjected to an extensive phenotyping and a questionnaire of medical history and habits.
Results: We determined the differences in height of participants and their relation to hypertension status and sex in this cohort and validated it in two other cohorts (The Canadian Heart Health Study and a family cohort from the Saguenay Lac Saint-Jean, a region of Quebec). In all three cohorts, we found that at younger age individuals with hypertension are taller than normotensive individuals, but they have a shorter stature at an older age compared with normotensive individuals. In CaG, we observed that hypertension, low bone mineral density (BMD) and arterial stiffness are strongly associated with height when adjusted for antihypertensive medications (P < 0.0001). Fractures are the net outcome of low BMD, and a significant association is observed (odds ratio = 2.34, confidence interval = 2.12–2.57); this relation was stronger in hypertensive individuals compared with normotensive individuals particularly in younger hypertensive individuals. In addition, we observed that increased arterial stiffness was significantly correlated with a low BMD in both men and women at all ages.
Conclusion: Shorter stature in elderly, low BMD and fractures correlated with increased arterial stiffness and hypertension. We propose that hypertension and osteoporosis share components of accelerated aging.
Journal of Hypertension 04/2015; 33(4):727-735. DOI:10.1097/HJH.0000000000000475 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a pivotal Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of lomitapide
Existing lipid-lowering therapy, including apheresis, was to remain stable from Week –6 to Week 26. Lomitapide dose was escalated on the basis of individual safety/tolerability from 5 mg to a maximum of 60 mg a day. The primary endpoint was mean percent change in LDL-C from baseline to Week 26 (efficacy phase), after which patients remained on lomitapide through Week 78 for safety assessment and further evaluation of efficacy. During this latter period, apheresis could be adjusted. We analysed the potential impact of apheresis on LDL-C reductions in patients receiving lomitapide
Of the 29 patients that entered the efficacy phase, 18 (62%) were receiving apheresis at baseline. Twenty-three patients (13 receiving apheresis) completed the Week-26 evaluation. Of the six patients who discontinued in the first 26 weeks, five were receiving apheresis. There were no significant differences in percent change from baseline of LDL-C at Week 26 in patients treated (–48%) and not treated (–55%) with apheresis (p=0.545). Lp(a) levels did not change in either group
The LDL-C lowering efficacy of lomitapide is independent of lipoprotein apheresis