- Email: [email protected]
Cost-effective quantitative metabolite profiling in large-scale cardiovascular epidemiology
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Abstracts / Atherosclerosis 241 (2015) e1ee31
ile10th) and 120 high HDLc (HDLc %ile90th) individuals, and identified three ABCA8 variants exclusively in low-HDLc subjects: Proline609Arginine (in the ATP-binding domain), E17-2 A>G (disruption of essential splice site) and Threonine741Stop. Genotyping of expanded families identified additional mutation carriers and first-degree relative controls. Compared with controls, heterozygous mutation carriers showed a significant 32.6% decrease in plasma HDLc levels and 55.5% decrease HDLc percentiles (age and sex adjusted). Overexpression of human ABCA8 in mouse livers via adenoviral injection led to a 23.1% increase in HDLc levels. Wild-type ABCA8 localized at the plasma membrane and the ER. However, P609R- and T741X-ABCA8 are only present at the ER. A significant 181% increase in cholesterol efflux to lipid free APOA-I was observed with wild type ABCA8, but not with the mutants P609R or T741X. It has been described that ABCA8 regulates levels of sphingomyelin, an essential lipid in the formation and maturation of HDL. Compared to controls, HDL sphingomyelin content of ABCA8 mutation carriers was decreased, and HDL sphingomyelin levels of mice overexpressing ABCA8 in the liver was significantly increased. We show here that ABCA8 is a cholesterol transporter that modulates HDLc and sphingomyelin levels in humans and mice.
CVD prediction and novel biomarkers EAS-0166. PLASMA CHEMERIN IS A STRONG AND INDEPENDENT PREDICTOR OF CARDIOVASCULAR EVENT RISK A. Leiherer 1, A. Muendlein 1, P. Rein 2, K. Geiger 1, P. Fraunberger 3, H. Drexel 2, A. Vonbank 2, C.H. Saely 2. 1 VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; 2 Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; 3 Medical Central Laboratory, Academic Teaching Hospital Feldkirch, Feldkirch, Austria Aim: Associations of the adipokine chemerin with the metabolic syndrome (MetS) and with chronic kidney disease (CKD), two important indicators of increased cardiovascular event risk, have been described. However, the power of chemerin to predict cardiovascular events has not been investigated so far and is addressed in the present study. Methods: We measured plasma chemerin in a high-risk cohort of 495 patients undergoing coronary angiography for the evaluation of suspected or established coronary artery disease (CAD) in which cardiovascular events were prospectively recorded over 3.5±1.1 years. Significant baseline CAD was diagnosed in the presence of coronary artery stenoses 50%. Results: At baseline, plasma chemerin was significantly higher in patients with the MetS as defined by the current harmonized consensus definition (n¼147) than in non-MetS subjects (201±71 ng/ml versus 163±62 ng/ml p Conclusions: From this first prospective evaluation of the cardiovascular event risk associated with chemerin we conclude that chemerin is strongly predictive of cardiovascular events independently from standard risk factors, from the MetS, and from the baseline presence of CAD.
EAS-0450. EXTREME NONFASTING REMNANT CHOLESTEROL VERSUS EXTREME LOW-DENSITY LIPOPROTEIN CHOLESTEROL AS CONTRIBUTORS OF CARDIOVASCULAR DISEASE AND ALL-CAUSE MORTALITY IN 90,000 INDIVIDUALS FROM THE GENERAL POPULATION B.G. Nordestgaard, J.J. Freiberg, A. Varbo. Clinical Biochemistry Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark Aims: Elevated concentrations of nonfasting remnant cholesterol like elevated low-density lipoprotein(LDL) cholesterol concentrations are
causally associated with increased risk of ischemic heart disease(IHD). We tested the hypothesis that extreme concentrations of nonfasting remnant and LDL cholesterol are equal contributors of risk of IHD, myocardial infarction(MI), and all-cause mortality, which is presently unknown. Methods: We compared stepwise increasing concentrations of nonfasting remnant and LDL cholesterol for association with risk of IHD, MI, and all-cause mortality in ~90,000 individuals from the Danish general population. During up to 22 years without losses to follow-up 4,435 participants developed IHD, 1,722 developed MI, and 8,121 died. Results: Compared to participants with nonfasting remnant cholesterol concentrations <0.5mmol/L, hazard ratios for IHD ranged from 1.3(95%CI:1.1-1.5) for remnant cholesterol of 0.5-0.99mmol/L to 2.4(1.9-2.9) for remnant cholesterol 1.5mmol/L(P-trend<0.001). Compared to participants with LDL cholesterol <3.0mmol/L, hazard ratios for IHD ranged from 1.3(1.1-1.5) for LDL cholesterol of 33.99mmol/L to 2.3(1.9-2.8) for LDL cholesterol 5mmol/L(P<0.001). Corresponding hazard ratios for MI ranged from 1.8(1.4-2.3) to 3.4(2.5-4.8) for remnant cholesterol(P<0.001), and from 1.7(1.4-2.2) to 4.7(3.5-6.3) for LDL cholesterol(P<0.001), respectively. Nonfasting remnant cholesterol concentrations were also associated stepwise with all-cause mortality ranging from a hazard ratio of 1.0(0.9-1.1) to 1.6(1.4-1.9)(P<0.001); however, LDL cholesterol concentrations were associated with decreased risk of all-cause mortality in a Ushaped pattern with hazard ratios from 0.8(0.7-0.8) to 0.9(0.81.0)(P¼0.002). Conclusions: Both lipoproteins were associated equally with risk of IHD and MI; however, only nonfasting remnant cholesterol concentrations were associated stepwise with increased risk of all-cause mortality.
EAS-0809. COST-EFFECTIVE QUANTITATIVE METABOLITE PROFILING IN LARGESCALE CARDIOVASCULAR EPIDEMIOLOGY P. Würtz 1, P. Soininen 2, A.J. Kangas 1, M. Ala-Korpela 1. 1 Computational Medicine, University of Oulu, Oulu, Finland; 2 NMR Metabolomics Laboratory, University of Eastern Finland, Kuopio, Finland Aim: To quantify circulating lipids and metabolites in large prospective cohorts, and use the metabolite concentration data to uncover biomarkers for future onset of cardiovascular disease and diabetes. The method can help to uncover the aetiology of cardiometabolic diseases and improve risk prediction. Method: We have developed a serum NMR metabolomics platform optimized for the large sample amounts used in epidemiological studies and biobanks. At costs comparable to routine lipid analyses, our metabolomics platform offers robust quantification of >225 molecular measures, including the lipid concentrations and composition of 14 lipoprotein subclasses (Figure), various fatty acids, amino acids, glycolysis metabolites and ketones (Figure); (computationalmedicine.fi/platform). The absolute metabolite concentrations can be analyzed with the standard medical statistics toolset, i.e., these data can be meta-analysed and combined with other ‘omics and conventional clinical data. Results: The high-throughput metabolomics platform has been used in numerous epidemiological studies with over 5,000 individuals, and >220,000 samples have been measured in total. The detailed metabolic profiling has provided insights into the mechanisms of obesity and revealed biomarkers for cardiovascular disease, diabetes, and all-cause mortality. Applications will be exemplified for biomarker discovery, replication and improved risk prediction for incident cardiovascular disease in >15,000 individuals. Conclusions: Several large-scale studies demonstrate the value of largescale metabolomics for cardiovascular biomarker discovery and improved
Abstracts / Atherosclerosis 241 (2015) e1ee31
risk assessment. As the metabolomics platform quantifies amino acids and fatty acids simultaneously along with the standard lipid measures, the novel biomarkers could be implemented to augment risk prediction without additional clinical chemistry.
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Pediatrics, University of Padova, Padova, Italy; 14 Pediatrics, Faculty Hospital Palacky University, Olomouc, Czech Republic; 15 Pediatrics, Instytut “Pomnik e Centrum Zdrowia Dziecka”, Warszawa, Poland; 16 Pediatrics, University Hopital Necker Enfants malades and IMAGINE Institute, Paris, France; 17 Gastroenterology and Hepatology, Jikei University Hospital, Tokyo, Japan Lysosomal Acid Lipase (LAL) Deficiency is a progressive multisystem disease that is an underappreciated cause of cirrhosis, severe dyslipidemia and early onset atherosclerosis. A phase 3, double-blind, placebo-controlled trial (NCT01757184) randomized affected children and adults (N¼66) to placebo or sebelipase alfa 1 mg/kg every other week for 20 weeks. Primary endpoint was ALT normalization. Secondary endpoints included additional important efficacy assessments, safety and immunogenicity. Medically important abnormalities were common at baseline including fibrosis and cirrhosis in 100% and 31% respectively of biopsied patients (n¼32) and a median LDL of 204.0mg/dL (range 70378mg/dl). After 20 weeks, ALT normalization (ULN range 34-43 U/L) was achieved in 31% of the sebelipase alfa group and 7% of the placebo group. Multiple secondary efficacy endpoints were also met including relative reduction in LDL-C, non-HDL-c, and triglycerides and relative increase in HDL-C. Over 350 infusions of sebelipase alfa were given during the double-blind period. The number of patients with AEs was similar in each arm. During the double-blind period, most AEs were mild and unrelated to sebelipase alfa; 6 patients experienced infusionassociated reactions (4 placebo; 2 sebelipase alfa). Dosing was paused in 1 patient after an atypical infusion-related reaction following sebelipase alfa treatment. Sebelipase alfa for 20 weeks demonstrated statistically significant improvements in ALT normalization and in a number of other important disease related abnormalities including marked reductions in LDL. The safety profile appears favorable and infusions were generally well tolerated.
EAS-0563. EFFICACY OF ALIROCUMAB IN HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA OR HIGH CV RISK POPULATIONS: POOLED ANALYSES OF EIGHT PHASE 3 TRIALS
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FH and severe hyperlipidemias EAS-0197. EFFICACY AND SAFETY OF SEBELIPASE ALFA IN CHILDREN AND ADULTS WITH LYSOSOMAL ACID LIPASE DEFICIENCY: RESULTS OF A PHASE 3 TRIAL S. Rojas-Caro 1, M. Balwani 2, M. Bialer 3, C. Camarena Grande 4, A. Consuelo Sanchez 5, F.Suheyl Ezgu 6, M. Kostyleva 7, C. Laukaitis 8, V. Malinov a 9, E. Neilan 10, H. Peters 11, Y. Rahman 12, M. Scarpa 13, V. Smolka 14, J. Taybert 15, V. Valayannopoulos 16, M. Zenia 17, Y. Yang 1, S. Eckert 1, A. Quinn 1. 1 Clinical Research, Synageva BioPharma Corp, Lexington, USA; 2 Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, USA; 3 Medical Genetics, North Shore Long Island Jewish, Manhasset, USA; 4 Hepatology-Children, Hospital Universitario La Paz, Madrid, Spain; 5 Gastroenterology and Nutrition, Hospital Infantil de mez, Mexico, Mexico; 6 Pediatrics, Gazi University M exico Federico Go Medical Faculty, Ankara, Turkey; 7 Federal State Institution, Russian Children's Clinical Hospital, Moscow, Russia; 8 Medical Genetics, University of Arizona Cancer Center, Tucson, USA; 9 Pediatrics, 1st Faculty of Medicine e Charles University, Praha, Czech Republic; 10 Genetics, Boston Children's Hospital, Boston, USA; 11 Pediatrics, Royal Children's Hospital, Parkville, Australia; 12 Inherited metabolic diseases, Guy's & St Thomas' Hospital NHS Foundation Trust, London, United Kingdom;
M. Farnier 1, D. Gaudet 2, V. Valcheva 3, P. Minini 4, K. Miller 5, B. epartement d'Endocrinologie et de Lipidologie, Point Cariou 6. 1 D e de Medical, Dijon, France; 2 Department of Medicine, Universit Montr eal The ECOGENE-21 Clinical Research Center and Lipid Clinic, Chicoutimi, Canada; 3 Global Medical Affairs, Sanofi, Paris, France; 4 Biostatistics and Programming, Sanofi, Chilly-Mazarin, France; 5 Biostatistics and Data Management, Regeneron Pharmaceuticals Inc, Tarrytown, USA; 6 Department of Endocrinology l'Institut du Thorax, Nantes University Hospital, Nantes, France Aims: Despite standard-of-care statin therapy, many patients with heterozygous familial hypercholesterolemia (HeFH) or at high CV risk (coronary heart disease or risk equivalents) do not achieve low-density lipoprotein cholesterol (LDL-C) goals. We summarize alirocumab efficacy from eight Phase 3 trials in patients with HeFH or high CV risk on statin ± other lipid-lowering therapy (LLT). Methods: Six trials evaluated alirocumab 75 mg every 2 weeks (Q2W) increasing to 150mg Q2W at W12 if W8 LDL-C 1.8 or 2.6 mmol/L (depending on CV risk): placebo comparator in 3 trials, ezetimibe in the other 3. Two trials evaluated 150 mg Q2W vs placebo. Results: Alirocumab reduced LDL-C from baseline to W24 by 49% in studies of 75/150 mg Q2W, and by 60% in studies of alirocumab 150mg Q2W (p Conclusions: Alirocumab demonstrated significantly greater LDL-C reductions vs control and enabled a majority of HeFH or high CV-risk patients on statin ± other LLT to achieve LDL-C goals. Favourable changes in other lipids were also observed.
Abstracts / Atherosclerosis 241 (2015) e1ee31
ile10th) and 120 high HDLc (HDLc %ile90th) individuals, and identified three ABCA8 variants exclusively in low-HDLc subjects: Proline609Arginine (in the ATP-binding domain), E17-2 A>G (disruption of essential splice site) and Threonine741Stop. Genotyping of expanded families identified additional mutation carriers and first-degree relative controls. Compared with controls, heterozygous mutation carriers showed a significant 32.6% decrease in plasma HDLc levels and 55.5% decrease HDLc percentiles (age and sex adjusted). Overexpression of human ABCA8 in mouse livers via adenoviral injection led to a 23.1% increase in HDLc levels. Wild-type ABCA8 localized at the plasma membrane and the ER. However, P609R- and T741X-ABCA8 are only present at the ER. A significant 181% increase in cholesterol efflux to lipid free APOA-I was observed with wild type ABCA8, but not with the mutants P609R or T741X. It has been described that ABCA8 regulates levels of sphingomyelin, an essential lipid in the formation and maturation of HDL. Compared to controls, HDL sphingomyelin content of ABCA8 mutation carriers was decreased, and HDL sphingomyelin levels of mice overexpressing ABCA8 in the liver was significantly increased. We show here that ABCA8 is a cholesterol transporter that modulates HDLc and sphingomyelin levels in humans and mice.
CVD prediction and novel biomarkers EAS-0166. PLASMA CHEMERIN IS A STRONG AND INDEPENDENT PREDICTOR OF CARDIOVASCULAR EVENT RISK A. Leiherer 1, A. Muendlein 1, P. Rein 2, K. Geiger 1, P. Fraunberger 3, H. Drexel 2, A. Vonbank 2, C.H. Saely 2. 1 VIVIT-Institute, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; 2 Medicine and Cardiology, Academic Teaching Hospital Feldkirch, Feldkirch, Austria; 3 Medical Central Laboratory, Academic Teaching Hospital Feldkirch, Feldkirch, Austria Aim: Associations of the adipokine chemerin with the metabolic syndrome (MetS) and with chronic kidney disease (CKD), two important indicators of increased cardiovascular event risk, have been described. However, the power of chemerin to predict cardiovascular events has not been investigated so far and is addressed in the present study. Methods: We measured plasma chemerin in a high-risk cohort of 495 patients undergoing coronary angiography for the evaluation of suspected or established coronary artery disease (CAD) in which cardiovascular events were prospectively recorded over 3.5±1.1 years. Significant baseline CAD was diagnosed in the presence of coronary artery stenoses 50%. Results: At baseline, plasma chemerin was significantly higher in patients with the MetS as defined by the current harmonized consensus definition (n¼147) than in non-MetS subjects (201±71 ng/ml versus 163±62 ng/ml p Conclusions: From this first prospective evaluation of the cardiovascular event risk associated with chemerin we conclude that chemerin is strongly predictive of cardiovascular events independently from standard risk factors, from the MetS, and from the baseline presence of CAD.
EAS-0450. EXTREME NONFASTING REMNANT CHOLESTEROL VERSUS EXTREME LOW-DENSITY LIPOPROTEIN CHOLESTEROL AS CONTRIBUTORS OF CARDIOVASCULAR DISEASE AND ALL-CAUSE MORTALITY IN 90,000 INDIVIDUALS FROM THE GENERAL POPULATION B.G. Nordestgaard, J.J. Freiberg, A. Varbo. Clinical Biochemistry Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark Aims: Elevated concentrations of nonfasting remnant cholesterol like elevated low-density lipoprotein(LDL) cholesterol concentrations are
causally associated with increased risk of ischemic heart disease(IHD). We tested the hypothesis that extreme concentrations of nonfasting remnant and LDL cholesterol are equal contributors of risk of IHD, myocardial infarction(MI), and all-cause mortality, which is presently unknown. Methods: We compared stepwise increasing concentrations of nonfasting remnant and LDL cholesterol for association with risk of IHD, MI, and all-cause mortality in ~90,000 individuals from the Danish general population. During up to 22 years without losses to follow-up 4,435 participants developed IHD, 1,722 developed MI, and 8,121 died. Results: Compared to participants with nonfasting remnant cholesterol concentrations <0.5mmol/L, hazard ratios for IHD ranged from 1.3(95%CI:1.1-1.5) for remnant cholesterol of 0.5-0.99mmol/L to 2.4(1.9-2.9) for remnant cholesterol 1.5mmol/L(P-trend<0.001). Compared to participants with LDL cholesterol <3.0mmol/L, hazard ratios for IHD ranged from 1.3(1.1-1.5) for LDL cholesterol of 33.99mmol/L to 2.3(1.9-2.8) for LDL cholesterol 5mmol/L(P<0.001). Corresponding hazard ratios for MI ranged from 1.8(1.4-2.3) to 3.4(2.5-4.8) for remnant cholesterol(P<0.001), and from 1.7(1.4-2.2) to 4.7(3.5-6.3) for LDL cholesterol(P<0.001), respectively. Nonfasting remnant cholesterol concentrations were also associated stepwise with all-cause mortality ranging from a hazard ratio of 1.0(0.9-1.1) to 1.6(1.4-1.9)(P<0.001); however, LDL cholesterol concentrations were associated with decreased risk of all-cause mortality in a Ushaped pattern with hazard ratios from 0.8(0.7-0.8) to 0.9(0.81.0)(P¼0.002). Conclusions: Both lipoproteins were associated equally with risk of IHD and MI; however, only nonfasting remnant cholesterol concentrations were associated stepwise with increased risk of all-cause mortality.
EAS-0809. COST-EFFECTIVE QUANTITATIVE METABOLITE PROFILING IN LARGESCALE CARDIOVASCULAR EPIDEMIOLOGY P. Würtz 1, P. Soininen 2, A.J. Kangas 1, M. Ala-Korpela 1. 1 Computational Medicine, University of Oulu, Oulu, Finland; 2 NMR Metabolomics Laboratory, University of Eastern Finland, Kuopio, Finland Aim: To quantify circulating lipids and metabolites in large prospective cohorts, and use the metabolite concentration data to uncover biomarkers for future onset of cardiovascular disease and diabetes. The method can help to uncover the aetiology of cardiometabolic diseases and improve risk prediction. Method: We have developed a serum NMR metabolomics platform optimized for the large sample amounts used in epidemiological studies and biobanks. At costs comparable to routine lipid analyses, our metabolomics platform offers robust quantification of >225 molecular measures, including the lipid concentrations and composition of 14 lipoprotein subclasses (Figure), various fatty acids, amino acids, glycolysis metabolites and ketones (Figure); (computationalmedicine.fi/platform). The absolute metabolite concentrations can be analyzed with the standard medical statistics toolset, i.e., these data can be meta-analysed and combined with other ‘omics and conventional clinical data. Results: The high-throughput metabolomics platform has been used in numerous epidemiological studies with over 5,000 individuals, and >220,000 samples have been measured in total. The detailed metabolic profiling has provided insights into the mechanisms of obesity and revealed biomarkers for cardiovascular disease, diabetes, and all-cause mortality. Applications will be exemplified for biomarker discovery, replication and improved risk prediction for incident cardiovascular disease in >15,000 individuals. Conclusions: Several large-scale studies demonstrate the value of largescale metabolomics for cardiovascular biomarker discovery and improved
Abstracts / Atherosclerosis 241 (2015) e1ee31
risk assessment. As the metabolomics platform quantifies amino acids and fatty acids simultaneously along with the standard lipid measures, the novel biomarkers could be implemented to augment risk prediction without additional clinical chemistry.
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Pediatrics, University of Padova, Padova, Italy; 14 Pediatrics, Faculty Hospital Palacky University, Olomouc, Czech Republic; 15 Pediatrics, Instytut “Pomnik e Centrum Zdrowia Dziecka”, Warszawa, Poland; 16 Pediatrics, University Hopital Necker Enfants malades and IMAGINE Institute, Paris, France; 17 Gastroenterology and Hepatology, Jikei University Hospital, Tokyo, Japan Lysosomal Acid Lipase (LAL) Deficiency is a progressive multisystem disease that is an underappreciated cause of cirrhosis, severe dyslipidemia and early onset atherosclerosis. A phase 3, double-blind, placebo-controlled trial (NCT01757184) randomized affected children and adults (N¼66) to placebo or sebelipase alfa 1 mg/kg every other week for 20 weeks. Primary endpoint was ALT normalization. Secondary endpoints included additional important efficacy assessments, safety and immunogenicity. Medically important abnormalities were common at baseline including fibrosis and cirrhosis in 100% and 31% respectively of biopsied patients (n¼32) and a median LDL of 204.0mg/dL (range 70378mg/dl). After 20 weeks, ALT normalization (ULN range 34-43 U/L) was achieved in 31% of the sebelipase alfa group and 7% of the placebo group. Multiple secondary efficacy endpoints were also met including relative reduction in LDL-C, non-HDL-c, and triglycerides and relative increase in HDL-C. Over 350 infusions of sebelipase alfa were given during the double-blind period. The number of patients with AEs was similar in each arm. During the double-blind period, most AEs were mild and unrelated to sebelipase alfa; 6 patients experienced infusionassociated reactions (4 placebo; 2 sebelipase alfa). Dosing was paused in 1 patient after an atypical infusion-related reaction following sebelipase alfa treatment. Sebelipase alfa for 20 weeks demonstrated statistically significant improvements in ALT normalization and in a number of other important disease related abnormalities including marked reductions in LDL. The safety profile appears favorable and infusions were generally well tolerated.
EAS-0563. EFFICACY OF ALIROCUMAB IN HETEROZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA OR HIGH CV RISK POPULATIONS: POOLED ANALYSES OF EIGHT PHASE 3 TRIALS
Ă
FH and severe hyperlipidemias EAS-0197. EFFICACY AND SAFETY OF SEBELIPASE ALFA IN CHILDREN AND ADULTS WITH LYSOSOMAL ACID LIPASE DEFICIENCY: RESULTS OF A PHASE 3 TRIAL S. Rojas-Caro 1, M. Balwani 2, M. Bialer 3, C. Camarena Grande 4, A. Consuelo Sanchez 5, F.Suheyl Ezgu 6, M. Kostyleva 7, C. Laukaitis 8, V. Malinov a 9, E. Neilan 10, H. Peters 11, Y. Rahman 12, M. Scarpa 13, V. Smolka 14, J. Taybert 15, V. Valayannopoulos 16, M. Zenia 17, Y. Yang 1, S. Eckert 1, A. Quinn 1. 1 Clinical Research, Synageva BioPharma Corp, Lexington, USA; 2 Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, USA; 3 Medical Genetics, North Shore Long Island Jewish, Manhasset, USA; 4 Hepatology-Children, Hospital Universitario La Paz, Madrid, Spain; 5 Gastroenterology and Nutrition, Hospital Infantil de mez, Mexico, Mexico; 6 Pediatrics, Gazi University M exico Federico Go Medical Faculty, Ankara, Turkey; 7 Federal State Institution, Russian Children's Clinical Hospital, Moscow, Russia; 8 Medical Genetics, University of Arizona Cancer Center, Tucson, USA; 9 Pediatrics, 1st Faculty of Medicine e Charles University, Praha, Czech Republic; 10 Genetics, Boston Children's Hospital, Boston, USA; 11 Pediatrics, Royal Children's Hospital, Parkville, Australia; 12 Inherited metabolic diseases, Guy's & St Thomas' Hospital NHS Foundation Trust, London, United Kingdom;
M. Farnier 1, D. Gaudet 2, V. Valcheva 3, P. Minini 4, K. Miller 5, B. epartement d'Endocrinologie et de Lipidologie, Point Cariou 6. 1 D e de Medical, Dijon, France; 2 Department of Medicine, Universit Montr eal The ECOGENE-21 Clinical Research Center and Lipid Clinic, Chicoutimi, Canada; 3 Global Medical Affairs, Sanofi, Paris, France; 4 Biostatistics and Programming, Sanofi, Chilly-Mazarin, France; 5 Biostatistics and Data Management, Regeneron Pharmaceuticals Inc, Tarrytown, USA; 6 Department of Endocrinology l'Institut du Thorax, Nantes University Hospital, Nantes, France Aims: Despite standard-of-care statin therapy, many patients with heterozygous familial hypercholesterolemia (HeFH) or at high CV risk (coronary heart disease or risk equivalents) do not achieve low-density lipoprotein cholesterol (LDL-C) goals. We summarize alirocumab efficacy from eight Phase 3 trials in patients with HeFH or high CV risk on statin ± other lipid-lowering therapy (LLT). Methods: Six trials evaluated alirocumab 75 mg every 2 weeks (Q2W) increasing to 150mg Q2W at W12 if W8 LDL-C 1.8 or 2.6 mmol/L (depending on CV risk): placebo comparator in 3 trials, ezetimibe in the other 3. Two trials evaluated 150 mg Q2W vs placebo. Results: Alirocumab reduced LDL-C from baseline to W24 by 49% in studies of 75/150 mg Q2W, and by 60% in studies of alirocumab 150mg Q2W (p Conclusions: Alirocumab demonstrated significantly greater LDL-C reductions vs control and enabled a majority of HeFH or high CV-risk patients on statin ± other LLT to achieve LDL-C goals. Favourable changes in other lipids were also observed.