Daniel Gaudet | Université de Montréal (original) (raw)
Papers by Daniel Gaudet
European Heart Journal - Case Reports
Background Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening geneti... more Background Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening genetic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels, important xanthomatosis and increased risk of premature atherosclerotic cardiovascular disease. Management of HoFH at an early stage is recommended but conventional lipid-lowering therapies (LLTs) dependent on the LDL-receptor for clearance of LDL particles, are usually not sufficient. However, agents acting independently of the LDL-receptor, such as inhibitors of microsomal triglyceride transfer protein (MTP) or angiopoietin-like protein 3 (ANGPTL3), administered in combination, on top of standard-of-care LLT constitute a promising therapy for HoFH. Case summary The present case describes a long-term (>10 years) follow-up of a 52-year-old woman with severe HoFH, who was treated with conventional lipid-lowering medications (i.e. statins and ezetimibe) for several years before experiencing...
Journal of the Endocrine Society
Context Palmar striated xanthomas (PSX) are macular subcutaneous lesions conferring a yellow-to-o... more Context Palmar striated xanthomas (PSX) are macular subcutaneous lesions conferring a yellow-to-orange coloration of palmar and finger creases that characterize dysbetalipoproteinemia, a disease associated with sustained plasma accumulation of triglyceride-rich lipoprotein remnants. Although remnants accumulation may occur in any condition interfering with triglyceride-rich lipoprotein hydrolysis or clearance, the presence of PSX has not been systematically assessed across the spectrum of lipid disorders potentially associated with sustained or recurrent remnants accumulation. Objective The aim of this study was to assess the occurrence of (PSX) in a wide spectrum of lipid disorders ranging from very severe hypercholesterolemia (homozygous familial hypercholesterolemia) to very severe hypertriglyceridemia (chylomicronemia). Methods This study involved 3382 dyslipidemic White adult patients (1856 men and 1526 women) seen at the Chicoutimi Hospital Lipid Clinic (Quebec, Canada), cover...
Journal of Clinical Medicine, 2021
Non-alcoholic fatty liver disease (NAFLD) is frequent in patients with features of the metabolic ... more Non-alcoholic fatty liver disease (NAFLD) is frequent in patients with features of the metabolic syndrome (MetS), obesity, or type 2 diabetes. Lipoprotein lipase (LPL) is the main driver of triglyceride (TG) hydrolysis in chylomicrons and very-low density lipoproteins (VLDL). In some patients with MetS, dysfunction of this pathway can lead to plasma TG values > 10 mmol/L (multifactorial chylomicronemia or MCS). Chylomicronemia also characterizes LPL deficiency (LPLD), a rare autosomal recessive disease called familial chylomicronemia syndrome (FCS), which is associated with an increased risk of recurrent pancreatitis. This study aims to investigate the expression of NAFLD, as assessed by transient elastography, in MCS and FCS subjects. Data were obtained from 38 subjects with chylomicronemia; 19 genetically confirmed FCS and 19 sex- and age-matched MCS. All participants underwent liver ultrasonography and stiffness measurement after a 4-h fast using transient elastography (FibroS...
European Journal of Preventive Cardiology, 2020
Aims To obtain safety and efficacy data of alirocumab, a proprotein convertase subtilisin/kexin t... more Aims To obtain safety and efficacy data of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in a real-life setting in high cardiovascular (CV) risk patients with heterozygous familial hypercholesterolaemia (HeFH) or very-high low-density lipoprotein cholesterol (LDL-C) levels despite maximally tolerated dose of statin ± other lipid-lowering therapies (MTD ± LLTs). ODYSSEY APPRISE was a prospective, single-arm, Phase 3b open-label (≥12 weeks to ≤ 30 months) European/Canadian study with alirocumab. Methods and results Patients received alirocumab 75 or 150 mg every 2 weeks, with dose adjustment based on physician’s judgment. In total, 994 patients were enrolled and treated. The mean [standard deviation (SD)] duration of alirocumab exposure was 72.4 (42.5) weeks. Patients with HeFH were younger [mean (SD) age of 53.8 (11.6) vs. 61.6 (10.1) years], more likely to be female (41.7% vs. 29.1%) and had higher baseline LDL-C compared with non-familial hypercholesterolae...
The American Journal of Cardiology, 2017
Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. H... more Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).
Journal of Clinical Lipidology, 2016
Atherosclerosis Supplements, 2003
MONDAY may predispose to future coronary events including SCD, and the results may help explain w... more MONDAY may predispose to future coronary events including SCD, and the results may help explain why hp 2-2 in the metabolic syndrome is linked to an increased risk of CVD. Larger studies are warranted to confirm the present findings.
The American Journal of Cardiology, 2014
Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited tre... more Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9, alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled, phase 2 studies of 8 or 12 weeks' duration conducted in patients with hypercholesterolemia on background lipidlowering therapy (NCT01266876, NCT01288469, and NCT01288443). Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (L30.3% vs L0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that <5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol. In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering.
The Lancet, 2015
Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of... more Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the eff ect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. Methods This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia,
New England Journal of Medicine, 2008
Background Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprote... more Background Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. Methods We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. Results The primary outcome, the mean (±SE) change in the carotid-artery intima-media thickness, was 0.0058±0.0037 mm in the simvastatin-only group and 0.0111±0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P = 0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (±SD) LDL cholesterol level was 192.7±60.3 mg per deciliter (4.98±1.56 mmol per liter) in the simvastatin group and 141.3±52.6 mg per deciliter (3.65±1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. Conclusions In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097.
Human Mutation, 1998
Page 1. © 1997 WILEY-LISS, INC. HUMU 778 MUTATION IN BRIEF Identification of Three Mutations in t... more Page 1. © 1997 WILEY-LISS, INC. HUMU 778 MUTATION IN BRIEF Identification of Three Mutations in the Low-Density Lipoprotein Receptor Gene Causing Familial Hypercholesterolemia Among French Canadians Patrick ...
Gene Therapy, 2012
We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL S447X gene th... more We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL S447X gene therapy for lipoprotein lipase deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially lifethreatening pancreatitis. The LPL S447X gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ≥40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 10 11 gc/kg, and cohort 3 (n=8) received 1 × 10 12 gc/kg. Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ≥40% reduction in fasting TG between 3-12 weeks. TG subsequently returned to baseline, although sustained LPL S447X expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2013
Myotonic dystrophy type 1 (DM1) is the most common adultonset muscular dystrophy 1,2. DM1 results... more Myotonic dystrophy type 1 (DM1) is the most common adultonset muscular dystrophy 1,2. DM1 results from an unstable CtG-repeat expansion in the 3' untranslated region of a myotonic dystrophy protein kinase gene on chromosome 19q13.3 3. the [CtG]n expansion responsible for DM1 can vary from 50 to over 1000 repeats, leading to phenotypic variability and different age at onset. Myotonic dystrophy type 1 is a progressive and pleiotropic disease that can affect several systems including the muscular, respiratory, cardiac, endocrine, ocular and central nervous systems 4. Decreased strength 5 , fatigue 6 and decreased executive function 7 are the impairments in DM1 with the most significant impact on quality of life and social participation 6,8,9. DM1 is also associated with difficulty in the accomplishment of several daily activities and social roles 10 including mobility issues 11 and low educational attainment 12,13. Individuals with DM1 live in a distinctive environment characterized by poverty, lack of social support and poor housing 12,13. a more holistic approach in the management of such a chronic complex disabling disease has been ABSTRACT: Background: the prevalence of unhealthy lifestyle habits such as smoking has seldom been described in neuromuscular disorders, including myotonic dystrophy type 1 (DM1). However, it is essential to document the unhealthy lifestyle habits as they can exacerbate existing impairments and disabilities. the objectives are: 1) to determine the prevalence of risk factors among individuals with DM1; 2) to compare the prevalence among classic and mild phenotypes. Method: a survey was done on a sample of two-hundred (200) patients with DM1 as part of a larger study. Lifestyle risk factors included being overweight or obese, tobacco smoking, illicit drug use, excessive alcohol consumption and physical inactivity. a registered nurse administered the validated public health survey. Categorization of risk factors were based on national standards and compared with provincial and regional prevalences. Results: 50% of DM1 patients were overweight or obese, 23.6% were regular smokers, and 76% were physically inactive. Except for overweight and obesity, significant differences were observed between patients with classic and mild phenotypes for all the other lifestyle risk factors: those with the classic phenotype being more often regular smokers, consuming more often illicit drugs and being less physically active. Conclusions: the results of this study will provide guidance for the development of better adapted and focussed health promotion interventions in the future. RÉSUMÉ: Prévalence des facteurs de risque liés aux habitudes de vie dans la dystrophie myotonique de type 1. Contexte : La prévalence d'habitudes de vie non favorables à la santé comme le tabagisme a rarement été décrite dans les maladies neuromusculaires dont la dystrophie myotonique de type 1 (DM1). Cependant, il est essentiel de les documenter puisse qu'elles peuvent exacerber les déficiences et les incapacités. Les objectifs de l'étude étaient de déterminer la prévalence de facteurs de risque chez les patients atteints de DM1 et de comparer leur prévalence chez les patients qui présentent un phénotype classique et léger. Méthode : L'étude porte sur un échantillon de deux cent patients atteints de DM1, dans le cadre d'une étude plus vaste. Les facteurs de risque liés aux habitudes de vie incluaient l'embonpoint ou l'obésité, le tabagisme, l'utilisation de drogues illégales, la consommation d'alcool et la sédentarité. Une infirmière administrait le questionnaire de santé publique. Les facteurs de risque étaient classés selon les standards nationaux et leur prévalence était comparée aux prévalences provinciales et régionales. Résultats : Cinquante pourcent des patients atteints de DM1 souffraient d'embonpoint ou étaient obèses, 23,6% étaient fumeurs et 76% étaient sédentaires. Des différences significatives ont été observées entre les patients atteints du phénotype classique et ceux du phénotype léger pour tous les facteurs de risque liés aux habitudes de vie, sauf pour l'embonpoint et l'obésité : il y avait plus de fumeurs réguliers chez ceux qui présentaient le phénotype classique, plus d'utilisateurs de drogues illégales et ils étaient moins actifs. Conclusions : Les résultats de notre étude pourront servir de guide dans l'élaboration d'interventions de promotion de la santé qui sont plus ciblées et mieux adaptées.
Endocrine Journal
A fasting triglyceridemia >10 mmol/L is associated with chylomicronemia (CM) and an increased rec... more A fasting triglyceridemia >10 mmol/L is associated with chylomicronemia (CM) and an increased recurrent acute pancreatitis (RAP) risk. The number of pancreatitis episodes varies significantly between patients with CM. The objective of this study was to investigate gene expression profiles of RAP in patients with CM. A total of 47 CM subjects participated in this study. Prior to the analyses, all patients were divided into three groups covering a wide spectrum of RAP: 0 (n = 21), 1-3 (n = 10) or >4 (n = 16) pancreatitis episodes. Gene expression profiles were compared to those of 15 healthy normolipidemic controls. Differential expression moderated T-tests between studied groups were performed using a linear model of the Bioconductor package Limma. The False discovery rate was controlled using the Benjamini-Hochberg procedure. At a pvalue <0.01, a false discovery rate of 5% and a >2-fold change expression significance levels, a set of 41 probes have been found differentially expressed in CM subjects with no pancreatitis, 103 in the CM group with 1 to 3 pancreatitis, and 94 in the group with ≥4 pancreatitis compared to healthy controls. Of the identified annotated probes, 14 are shared by all CM groups; 3 are specific to CM with no pancreatitis; 11 are specific to CM with 1 to 3 pancreatitis, and 17 are specific to CM with ≥4 pancreatitis. Most of the annotated biomarkers are involved in inflammatory, immune, lipoprotein kinetics or signalling biological pathways. These results reveal gene expression signatures of RAP in patients with CM.
Journal of Clinical Medicine
Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated low-d... more Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated low-density lipoprotein-cholesterol (LDL-C) concentrations appearing at birth and is associated with increased risk of premature atherosclerotic cardiovascular disease (CVD). However, in some cases, FH subjects over 70 years of age have surprisingly never experienced any CVD symptoms throughout their entire lives. The objective of this study consists of identifying biological and environmental markers acting as cardioprotective factors and associated with unexpected survival in FH. Upon age and reported cardiovascular events (CVE) stratification, we identified a total of 458 French–Canadian FH subjects with premature reported CVE, and 1297 young adults as well as 24 elderly subjects (≥70 years) who have never reported CVE requiring hospitalization. Logistic regression models were used to depict cardioprotective markers among FH survivors (≥70 years). Regression analyses of the FH cohort showe...
Journal of the Endocrine Society
Familial chylomicronemia syndrome (FCS) is a rare disorder associated with chylomicronemia (CM) a... more Familial chylomicronemia syndrome (FCS) is a rare disorder associated with chylomicronemia (CM) and an increased risk of pancreatitis. Most individuals with CM do not have FCS but exhibit multifactorial CM (MCM), which differs from FCS in terms of risk and disease management. This study aimed to investigate clinical and gene expression profiles of FCS and MCM patients. Anthropometrics, clinical, and biochemical variables were analyzed in 57 FCS and 353 MCM patients. Gene expression analyses were performed in a subsample of 19 FCS, 28 MCM, and 15 normolipidemic controls. Receiver operating characteristic (ROC) curve analyses were performed to analyze the capacity of variables to discriminate FCS from MCM. Sustained fasting triglycerides ≥20 mmol/L (>15 mmol/L with eruptive xanthomas), history of pancreatitis, poor response to fibrates, diagnosis of CM at childhood, body mass index <22 kg/m2, and delipidated apolipoprotein B or glycerol levels <0.9 g/L and <0.05 mmol/L, re...
Lipids in Health and Disease
Background Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder charact... more Background Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by persistent extreme hypertriglyceridemia as a result of lipoprotein lipase deficiency. Canada is an important region for FCS research due to the high prevalence rates. The burden of illness and quality of life of Canadian patients, however, have been inadequately addressed in the literature. Objective To understand the burden of illness of FCS on Canadian patients’ lives. Methods IN-FOCUS is a global web-based survey open to patients with FCS, including patients in Canada. This survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions. Results A total of 37 Canadian patients completed the IN-FOCUS survey. Patients saw a mean of 4 physicians before their FCS diagnosis despite 89% reporting an FCS family history. Patients experience multiple physical, emotional, and cognitive symptoms in addition to FC...
Expert Opinion on Drug Discovery
European Heart Journal - Case Reports
Background Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening geneti... more Background Homozygous familial hypercholesterolaemia (HoFH) is a rare and life-threatening genetic disease characterized by extremely elevated low-density lipoprotein cholesterol (LDL-C) levels, important xanthomatosis and increased risk of premature atherosclerotic cardiovascular disease. Management of HoFH at an early stage is recommended but conventional lipid-lowering therapies (LLTs) dependent on the LDL-receptor for clearance of LDL particles, are usually not sufficient. However, agents acting independently of the LDL-receptor, such as inhibitors of microsomal triglyceride transfer protein (MTP) or angiopoietin-like protein 3 (ANGPTL3), administered in combination, on top of standard-of-care LLT constitute a promising therapy for HoFH. Case summary The present case describes a long-term (>10 years) follow-up of a 52-year-old woman with severe HoFH, who was treated with conventional lipid-lowering medications (i.e. statins and ezetimibe) for several years before experiencing...
Journal of the Endocrine Society
Context Palmar striated xanthomas (PSX) are macular subcutaneous lesions conferring a yellow-to-o... more Context Palmar striated xanthomas (PSX) are macular subcutaneous lesions conferring a yellow-to-orange coloration of palmar and finger creases that characterize dysbetalipoproteinemia, a disease associated with sustained plasma accumulation of triglyceride-rich lipoprotein remnants. Although remnants accumulation may occur in any condition interfering with triglyceride-rich lipoprotein hydrolysis or clearance, the presence of PSX has not been systematically assessed across the spectrum of lipid disorders potentially associated with sustained or recurrent remnants accumulation. Objective The aim of this study was to assess the occurrence of (PSX) in a wide spectrum of lipid disorders ranging from very severe hypercholesterolemia (homozygous familial hypercholesterolemia) to very severe hypertriglyceridemia (chylomicronemia). Methods This study involved 3382 dyslipidemic White adult patients (1856 men and 1526 women) seen at the Chicoutimi Hospital Lipid Clinic (Quebec, Canada), cover...
Journal of Clinical Medicine, 2021
Non-alcoholic fatty liver disease (NAFLD) is frequent in patients with features of the metabolic ... more Non-alcoholic fatty liver disease (NAFLD) is frequent in patients with features of the metabolic syndrome (MetS), obesity, or type 2 diabetes. Lipoprotein lipase (LPL) is the main driver of triglyceride (TG) hydrolysis in chylomicrons and very-low density lipoproteins (VLDL). In some patients with MetS, dysfunction of this pathway can lead to plasma TG values > 10 mmol/L (multifactorial chylomicronemia or MCS). Chylomicronemia also characterizes LPL deficiency (LPLD), a rare autosomal recessive disease called familial chylomicronemia syndrome (FCS), which is associated with an increased risk of recurrent pancreatitis. This study aims to investigate the expression of NAFLD, as assessed by transient elastography, in MCS and FCS subjects. Data were obtained from 38 subjects with chylomicronemia; 19 genetically confirmed FCS and 19 sex- and age-matched MCS. All participants underwent liver ultrasonography and stiffness measurement after a 4-h fast using transient elastography (FibroS...
European Journal of Preventive Cardiology, 2020
Aims To obtain safety and efficacy data of alirocumab, a proprotein convertase subtilisin/kexin t... more Aims To obtain safety and efficacy data of alirocumab, a proprotein convertase subtilisin/kexin type 9 inhibitor, in a real-life setting in high cardiovascular (CV) risk patients with heterozygous familial hypercholesterolaemia (HeFH) or very-high low-density lipoprotein cholesterol (LDL-C) levels despite maximally tolerated dose of statin ± other lipid-lowering therapies (MTD ± LLTs). ODYSSEY APPRISE was a prospective, single-arm, Phase 3b open-label (≥12 weeks to ≤ 30 months) European/Canadian study with alirocumab. Methods and results Patients received alirocumab 75 or 150 mg every 2 weeks, with dose adjustment based on physician’s judgment. In total, 994 patients were enrolled and treated. The mean [standard deviation (SD)] duration of alirocumab exposure was 72.4 (42.5) weeks. Patients with HeFH were younger [mean (SD) age of 53.8 (11.6) vs. 61.6 (10.1) years], more likely to be female (41.7% vs. 29.1%) and had higher baseline LDL-C compared with non-familial hypercholesterolae...
The American Journal of Cardiology, 2017
Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. H... more Elevated lipoprotein(a) [Lp(a)] is independently associated with increased cardiovascular risk. However, treatment options for elevated Lp(a) are limited. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, reduced low-density lipoprotein cholesterol (LDL-C) by up to 62% from baseline in phase 3 studies, with adverse event rates similar between alirocumab and controls. We evaluated the effect of alirocumab on serum Lp(a) using pooled data from the phase 3 ODYSSEY program: 4,915 patients with hypercholesterolemia from 10 phase 3 studies were included. Eight studies evaluated alirocumab 75 mg every 2 weeks (Q2W), with possible increase to 150 mg Q2W at week 12 depending on LDL-C at week 8 (75/150 mg Q2W); the other 2 studies evaluated alirocumab 150-mg Q2W from the outset. Comparators were placebo or ezetimibe. Eight studies were conducted on a background of statins, and 2 studies were carried out with no statins. Alirocumab was associated with significant reductions in Lp(a), regardless of starting dose and use of concomitant statins. At week 24, reductions from baseline were 23% to 27% with alirocumab 75/150-mg Q2W and 29% with alirocumab 150-mg Q2W (all comparisons p <0.0001 vs controls). Reductions were sustained over 78 to 104 weeks. Lp(a) reductions with alirocumab were independent of race, gender, presence of familial hypercholesterolemia, baseline Lp(a), and LDL-C concentrations, or use of statins. In conclusion, in addition to marked reduction in LDL-C, alirocumab leads to a significant and sustained lowering of Lp(a).
Journal of Clinical Lipidology, 2016
Atherosclerosis Supplements, 2003
MONDAY may predispose to future coronary events including SCD, and the results may help explain w... more MONDAY may predispose to future coronary events including SCD, and the results may help explain why hp 2-2 in the metabolic syndrome is linked to an increased risk of CVD. Larger studies are warranted to confirm the present findings.
The American Journal of Cardiology, 2014
Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited tre... more Lipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease, with limited treatment options. This analysis evaluated the effect of a monoclonal antibody to proprotein convertase subtilisin/kexin 9, alirocumab 150 mg every 2 weeks (Q2W), on Lp(a) levels in pooled data from 3 double-blind, randomized, placebo-controlled, phase 2 studies of 8 or 12 weeks' duration conducted in patients with hypercholesterolemia on background lipidlowering therapy (NCT01266876, NCT01288469, and NCT01288443). Data were available for 102 of 108 patients who received alirocumab 150 mg Q2W and 74 of 77 patients who received placebo. Alirocumab resulted in a significant reduction in Lp(a) from baseline compared with placebo (L30.3% vs L0.3%, p <0.0001). Median percentage Lp(a) reductions in the alirocumab group were of a similar magnitude across a range of baseline Lp(a) levels, resulting in greater absolute reductions in Lp(a) in patients with higher baseline levels. Regression analysis indicated that <5% of the variance in the reduction of Lp(a) was explained by the effect of alirocumab on low-density lipoprotein cholesterol. In conclusion, pooled data from 3 phase 2 trials demonstrate substantive reduction in Lp(a) with alirocumab 150 mg Q2W, including patients with baseline Lp(a) >50 mg/dl. Reductions in Lp(a) only weakly correlated with the magnitude of low-density lipoprotein cholesterol lowering.
The Lancet, 2015
Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of... more Background Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the eff ect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. Methods This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia,
New England Journal of Medicine, 2008
Background Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprote... more Background Ezetimibe, a cholesterol-absorption inhibitor, reduces levels of low-density lipoprotein (LDL) cholesterol when added to statin treatment. However, the effect of ezetimibe on the progression of atherosclerosis remains unknown. Methods We conducted a double-blind, randomized, 24-month trial comparing the effects of daily therapy with 80 mg of simvastatin either with placebo or with 10 mg of ezetimibe in 720 patients with familial hypercholesterolemia. Patients underwent B-mode ultrasonography to assess the intima-media thickness of the walls of the carotid and femoral arteries. The primary outcome measure was the change in the mean carotid-artery intima-media thickness, which was defined as the average of the means of the far-wall intima-media thickness of the right and left common carotid arteries, carotid bulbs, and internal carotid arteries. Results The primary outcome, the mean (±SE) change in the carotid-artery intima-media thickness, was 0.0058±0.0037 mm in the simvastatin-only group and 0.0111±0.0038 mm in the simvastatin-plus-ezetimibe (combined-therapy) group (P = 0.29). Secondary outcomes (consisting of other variables regarding the intima-media thickness of the carotid and femoral arteries) did not differ significantly between the two groups. At the end of the study, the mean (±SD) LDL cholesterol level was 192.7±60.3 mg per deciliter (4.98±1.56 mmol per liter) in the simvastatin group and 141.3±52.6 mg per deciliter (3.65±1.36 mmol per liter) in the combined-therapy group (a between-group difference of 16.5%, P<0.01). The differences between the two groups in reductions in levels of triglycerides and C-reactive protein were 6.6% and 25.7%, respectively, with greater reductions in the combined-therapy group (P<0.01 for both comparisons). Side-effect and safety profiles were similar in the two groups. Conclusions In patients with familial hypercholesterolemia, combined therapy with ezetimibe and simvastatin did not result in a significant difference in changes in intima-media thickness, as compared with simvastatin alone, despite decreases in levels of LDL cholesterol and C-reactive protein. (ClinicalTrials.gov number, NCT00552097.
Human Mutation, 1998
Page 1. © 1997 WILEY-LISS, INC. HUMU 778 MUTATION IN BRIEF Identification of Three Mutations in t... more Page 1. © 1997 WILEY-LISS, INC. HUMU 778 MUTATION IN BRIEF Identification of Three Mutations in the Low-Density Lipoprotein Receptor Gene Causing Familial Hypercholesterolemia Among French Canadians Patrick ...
Gene Therapy, 2012
We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL S447X gene th... more We describe the 2-year follow-up of an open-label trial (CT-AMT-011-01) of AAV1-LPL S447X gene therapy for lipoprotein lipase deficiency (LPLD), an orphan disease associated with chylomicronemia, severe hypertriglyceridemia, metabolic complications and potentially lifethreatening pancreatitis. The LPL S447X gene variant, in an adeno-associated viral vector of serotype 1 (alipogene tiparvovec), was administered to 14 adult LPLD patients with a prior history of pancreatitis. Primary objectives were to assess the long-term safety of alipogene tiparvovec and achieve a ≥40% reduction in fasting median plasma triglyceride (TG) at 3-12 weeks compared with baseline. Cohorts 1 (n=2) and 2 (n=4) received 3 × 10 11 gc/kg, and cohort 3 (n=8) received 1 × 10 12 gc/kg. Cohorts 2 and 3 also received immunosuppressants from the time of alipogene tiparvovec administration and continued for 12 weeks. Alipogene tiparvovec was well tolerated, without emerging safety concerns for 2 years. Half of the patients demonstrated a ≥40% reduction in fasting TG between 3-12 weeks. TG subsequently returned to baseline, although sustained LPL S447X expression and long-term changes in TG-rich lipoprotein characteristics were noted independently of the effect on fasting plasma TG. Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques, 2013
Myotonic dystrophy type 1 (DM1) is the most common adultonset muscular dystrophy 1,2. DM1 results... more Myotonic dystrophy type 1 (DM1) is the most common adultonset muscular dystrophy 1,2. DM1 results from an unstable CtG-repeat expansion in the 3' untranslated region of a myotonic dystrophy protein kinase gene on chromosome 19q13.3 3. the [CtG]n expansion responsible for DM1 can vary from 50 to over 1000 repeats, leading to phenotypic variability and different age at onset. Myotonic dystrophy type 1 is a progressive and pleiotropic disease that can affect several systems including the muscular, respiratory, cardiac, endocrine, ocular and central nervous systems 4. Decreased strength 5 , fatigue 6 and decreased executive function 7 are the impairments in DM1 with the most significant impact on quality of life and social participation 6,8,9. DM1 is also associated with difficulty in the accomplishment of several daily activities and social roles 10 including mobility issues 11 and low educational attainment 12,13. Individuals with DM1 live in a distinctive environment characterized by poverty, lack of social support and poor housing 12,13. a more holistic approach in the management of such a chronic complex disabling disease has been ABSTRACT: Background: the prevalence of unhealthy lifestyle habits such as smoking has seldom been described in neuromuscular disorders, including myotonic dystrophy type 1 (DM1). However, it is essential to document the unhealthy lifestyle habits as they can exacerbate existing impairments and disabilities. the objectives are: 1) to determine the prevalence of risk factors among individuals with DM1; 2) to compare the prevalence among classic and mild phenotypes. Method: a survey was done on a sample of two-hundred (200) patients with DM1 as part of a larger study. Lifestyle risk factors included being overweight or obese, tobacco smoking, illicit drug use, excessive alcohol consumption and physical inactivity. a registered nurse administered the validated public health survey. Categorization of risk factors were based on national standards and compared with provincial and regional prevalences. Results: 50% of DM1 patients were overweight or obese, 23.6% were regular smokers, and 76% were physically inactive. Except for overweight and obesity, significant differences were observed between patients with classic and mild phenotypes for all the other lifestyle risk factors: those with the classic phenotype being more often regular smokers, consuming more often illicit drugs and being less physically active. Conclusions: the results of this study will provide guidance for the development of better adapted and focussed health promotion interventions in the future. RÉSUMÉ: Prévalence des facteurs de risque liés aux habitudes de vie dans la dystrophie myotonique de type 1. Contexte : La prévalence d'habitudes de vie non favorables à la santé comme le tabagisme a rarement été décrite dans les maladies neuromusculaires dont la dystrophie myotonique de type 1 (DM1). Cependant, il est essentiel de les documenter puisse qu'elles peuvent exacerber les déficiences et les incapacités. Les objectifs de l'étude étaient de déterminer la prévalence de facteurs de risque chez les patients atteints de DM1 et de comparer leur prévalence chez les patients qui présentent un phénotype classique et léger. Méthode : L'étude porte sur un échantillon de deux cent patients atteints de DM1, dans le cadre d'une étude plus vaste. Les facteurs de risque liés aux habitudes de vie incluaient l'embonpoint ou l'obésité, le tabagisme, l'utilisation de drogues illégales, la consommation d'alcool et la sédentarité. Une infirmière administrait le questionnaire de santé publique. Les facteurs de risque étaient classés selon les standards nationaux et leur prévalence était comparée aux prévalences provinciales et régionales. Résultats : Cinquante pourcent des patients atteints de DM1 souffraient d'embonpoint ou étaient obèses, 23,6% étaient fumeurs et 76% étaient sédentaires. Des différences significatives ont été observées entre les patients atteints du phénotype classique et ceux du phénotype léger pour tous les facteurs de risque liés aux habitudes de vie, sauf pour l'embonpoint et l'obésité : il y avait plus de fumeurs réguliers chez ceux qui présentaient le phénotype classique, plus d'utilisateurs de drogues illégales et ils étaient moins actifs. Conclusions : Les résultats de notre étude pourront servir de guide dans l'élaboration d'interventions de promotion de la santé qui sont plus ciblées et mieux adaptées.
Endocrine Journal
A fasting triglyceridemia >10 mmol/L is associated with chylomicronemia (CM) and an increased rec... more A fasting triglyceridemia >10 mmol/L is associated with chylomicronemia (CM) and an increased recurrent acute pancreatitis (RAP) risk. The number of pancreatitis episodes varies significantly between patients with CM. The objective of this study was to investigate gene expression profiles of RAP in patients with CM. A total of 47 CM subjects participated in this study. Prior to the analyses, all patients were divided into three groups covering a wide spectrum of RAP: 0 (n = 21), 1-3 (n = 10) or >4 (n = 16) pancreatitis episodes. Gene expression profiles were compared to those of 15 healthy normolipidemic controls. Differential expression moderated T-tests between studied groups were performed using a linear model of the Bioconductor package Limma. The False discovery rate was controlled using the Benjamini-Hochberg procedure. At a pvalue <0.01, a false discovery rate of 5% and a >2-fold change expression significance levels, a set of 41 probes have been found differentially expressed in CM subjects with no pancreatitis, 103 in the CM group with 1 to 3 pancreatitis, and 94 in the group with ≥4 pancreatitis compared to healthy controls. Of the identified annotated probes, 14 are shared by all CM groups; 3 are specific to CM with no pancreatitis; 11 are specific to CM with 1 to 3 pancreatitis, and 17 are specific to CM with ≥4 pancreatitis. Most of the annotated biomarkers are involved in inflammatory, immune, lipoprotein kinetics or signalling biological pathways. These results reveal gene expression signatures of RAP in patients with CM.
Journal of Clinical Medicine
Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated low-d... more Familial hypercholesterolemia (FH) is an autosomal dominant trait characterized by elevated low-density lipoprotein-cholesterol (LDL-C) concentrations appearing at birth and is associated with increased risk of premature atherosclerotic cardiovascular disease (CVD). However, in some cases, FH subjects over 70 years of age have surprisingly never experienced any CVD symptoms throughout their entire lives. The objective of this study consists of identifying biological and environmental markers acting as cardioprotective factors and associated with unexpected survival in FH. Upon age and reported cardiovascular events (CVE) stratification, we identified a total of 458 French–Canadian FH subjects with premature reported CVE, and 1297 young adults as well as 24 elderly subjects (≥70 years) who have never reported CVE requiring hospitalization. Logistic regression models were used to depict cardioprotective markers among FH survivors (≥70 years). Regression analyses of the FH cohort showe...
Journal of the Endocrine Society
Familial chylomicronemia syndrome (FCS) is a rare disorder associated with chylomicronemia (CM) a... more Familial chylomicronemia syndrome (FCS) is a rare disorder associated with chylomicronemia (CM) and an increased risk of pancreatitis. Most individuals with CM do not have FCS but exhibit multifactorial CM (MCM), which differs from FCS in terms of risk and disease management. This study aimed to investigate clinical and gene expression profiles of FCS and MCM patients. Anthropometrics, clinical, and biochemical variables were analyzed in 57 FCS and 353 MCM patients. Gene expression analyses were performed in a subsample of 19 FCS, 28 MCM, and 15 normolipidemic controls. Receiver operating characteristic (ROC) curve analyses were performed to analyze the capacity of variables to discriminate FCS from MCM. Sustained fasting triglycerides ≥20 mmol/L (>15 mmol/L with eruptive xanthomas), history of pancreatitis, poor response to fibrates, diagnosis of CM at childhood, body mass index <22 kg/m2, and delipidated apolipoprotein B or glycerol levels <0.9 g/L and <0.05 mmol/L, re...
Lipids in Health and Disease
Background Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder charact... more Background Familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder characterized by persistent extreme hypertriglyceridemia as a result of lipoprotein lipase deficiency. Canada is an important region for FCS research due to the high prevalence rates. The burden of illness and quality of life of Canadian patients, however, have been inadequately addressed in the literature. Objective To understand the burden of illness of FCS on Canadian patients’ lives. Methods IN-FOCUS is a global web-based survey open to patients with FCS, including patients in Canada. This survey captured information on diagnostic experience, symptoms, comorbidities, disease management, and impact on multiple life dimensions. Results A total of 37 Canadian patients completed the IN-FOCUS survey. Patients saw a mean of 4 physicians before their FCS diagnosis despite 89% reporting an FCS family history. Patients experience multiple physical, emotional, and cognitive symptoms in addition to FC...
Expert Opinion on Drug Discovery