122 results on '"Dirk J. Blom"'
Search Results
2. Effects of evolocumab therapy and low LDL‐C levels on vitamin E and steroid hormones in Chinese and global patients with type 2 diabetes
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Dirk J. Blom, Jiyan Chen, Zuyi Yuan, Joao L. C. Borges, Maria L. Monsalvo, Nan Wang, Andrew W. Hamer, and Junbo Ge
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diabetes ,dyslipidaemia ,hypercholesterolaemia ,PCSK9 inhibitor ,Diseases of the endocrine glands. Clinical endocrinology ,RC648-665 - Abstract
Abstract Aims We assessed the change from baseline in vitamin E, steroid hormones, adrenocorticotropic hormone (ACTH), and gonadotropins, overall and by lowest achieved low‐density lipoprotein‐cholesterol (LDL‐C) level, in patients with type 2 diabetes and dyslipidaemia after 12 weeks of treatment with evolocumab. Materials and Methods This was a prespecified analysis of vitamin E, cortisol, ACTH, gonadal hormones and gonadotropins in the 12‐week, placebo‐controlled BERSON trial of evolocumab in patients with type 2 diabetes and dyslipidaemia. In BERSON, 981 (451 in China) patients on daily atorvastatin 20 mg were randomized to placebo or one of two doses of evolocumab. We measured analyte levels at baseline and week 12 (vitamin E in all patients; steroid/gonadal hormones only in Chinese patients). Results In both the global and Chinese populations, absolute vitamin E levels decreased from baseline to week 12 by approximately 6 μmol/L (P
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- 2020
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3. Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia
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Dirk J. Blom, Marina Cuchel, Miranda Ager, and Helen Phillips
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(3–10): Homozygous familial hypercholesterolemia ,Lomitapide ,Number needed to treat ,Target ,Low-density lipoprotein cholesterol ,Major adverse cardiovascular event ,Medicine - Abstract
Abstract Background Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown. Methods We used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306). Results Twenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) – equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively. Conclusions Approximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further. Trial registration NCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009).
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- 2018
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4. PCSK9 Modulates the Secretion But Not the Cellular Uptake of Lipoprotein(a) Ex Vivo
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Elise F. Villard, PhD, Aurélie Thedrez, PhD, Jorg Blankenstein, PhD, Mikaël Croyal, BSc, Thi-Thu-Trang Tran, PhD, Bruno Poirier, PhD, Jean-Christophe Le Bail, PhD, Stéphane Illiano, PhD, Estelle Nobécourt, MD, PhD, Michel Krempf, MD, PhD, Dirk J. Blom, MD, PhD, A. David Marais, MD, Philip Janiak, PhD, Anthony J. Muslin, MD, PhD, Etienne Guillot, PhD, and Gilles Lambert, PhD
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familial hypercholesterolemia ,LDL receptor ,lipoprotein(a) ,PCSK9 ,primary human hepatocytes ,Diseases of the circulatory (Cardiovascular) system ,RC666-701 - Abstract
To elucidate how the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab modulates lipoprotein(a) [Lp(a)] plasma levels, the authors performed a series of Lp(a) uptake studies in primary human hepatocytes and dermal fibroblasts and measured Lp(a) secretion from human hepatocytes. They found that Lp(a) cellular uptake occurred in a low-density lipoprotein receptor–independent manner. Neither PCSK9 nor alirocumab altered Lp(a) internalization. By contrast, the secretion of apolipoprotein (a) from human hepatocytes was sharply increased by PCSK9, an effect that was reversed by alirocumab. They propose that PCSK9 does not significantly modulate Lp(a) catabolism, but rather enhances the secretion of Lp(a) from liver cells.
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- 2016
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5. Non-denaturing polyacrylamide gradient gel electrophoresis for the diagnosis of dysbetalipoproteinemia
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Dirk J. Blom, Pamela Byrnes, Sheena Jones, and A.David Marais
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Type III hyperlipidemia ,remnants ,apolipoprotein E ,method ,Biochemistry ,QD415-436 - Abstract
Dysbetalipoproteinemia, an uncommon but highly atherogenic mixed hyperlipidemia due to the accumulation of remnants of triglyceride-rich lipoproteins, is characterized by cholesterol-enriched VLDL that migrates in the β-position on agarose gels. The demonstration of a broad β-band on agarose gel electrophoresis of plasma is an insensitive method and ultracentrifugation is an impractical method of diagnosing this condition. Non-denaturing polyacrylamide gradient gel electrophoresis 5) was investigated as a screening method for the diagnosis of dysbetalipoproteinemia. A minigel procedure separating the Sudan Black prestained apolipoprotein B (apoB)-containing lipoproteins on a 2–8% polyacrylamide gel at 4°C overnight was analyzed for ultracentrifugally and genetically proven dysbetalipoproteinemic subjects as well as matched controls for mixed hyperlipidemia. Visual inspection revealed that the presence of only small VLDL- and IDL-like particles in untreated patients was highly sensitive (72%) and specific (95%) for dysbetalipoproteinemia. Videodensitometric analysis of area under the curve for large and small VLDL, as well as IDL and LDL, permitted even better discrimination in subjects whose profiles included some staining in the LDL-like region. A ratio of area under the curve of more than 0.5 for IDL-LDL allowed for a specificity of 100% and a sensitivity of 89% for the diagnosis of dysbetalipoproteinemia.This modified PGGE system may be useful in screening for dysbetalipoproteinemia.
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- 2003
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6. Genetic and Mechanistic Insights into the Modulation of Circulating Lipoprotein (a) Concentration by Apolipoprotein E Isoforms
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Kévin Chemello, Dirk J. Blom, A. David Marais, Gilles Lambert, and Valentin Blanchard
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Adult ,Apolipoproteins E ,Genotype ,Hyperlipoproteinemia Type III ,Humans ,Protein Isoforms ,Cardiology and Cardiovascular Medicine ,Lipoprotein(a) - Abstract
Lipoprotein (a) [Lp(a)] is a highly atherogenic lipoprotein species. A unique feature of Lp(a) is the strong genetic determination of its concentration. The LPA gene is responsible for up to 90% of the variance in Lp(a), but other genes also have an impact.Genome-wide associations studies indicate that the APOE gene, encoding apolipoprotein E (apoE), is the second most important locus modulating Lp(a) concentrations. Population studies clearly show that carriers of the apoE2 variant (ε2) display reduced Lp(a) levels, the lowest concentrations being observed in ε2/ε2 homozygotes. This genotype can lead predisposed adults to develop dysbetalipoproteinemia, a lipid disorder characterized by sharp elevations in cholesterol and triglycerides. However, dysbetalipoproteinemia does not significantly modulate circulating Lp(a). Mechanistically, apoE appears to impair the production but not the catabolism of Lp(a). These observations underline the complexity of Lp(a) metabolism and provide key insights into the pathways governing Lp(a) synthesis and secretion.
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- 2022
7. A Case Series Assessing the Effects of Lomitapide on Carotid Intima-Media Thickness in Adult Patients with Homozygous Familial Hypercholesterolaemia in a Real-World Setting
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Dirk J. Blom, Daniel Gaudet, Robert A. Hegele, Dharmesh S. Patel, Jaimini Cegla, Genovefa Kolovou, and Luis Masana Marin
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Pharmacology (medical) ,General Medicine - Published
- 2022
8. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk
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Aruna, Das Pradhan, Robert J, Glynn, Jean-Charles, Fruchart, Jean G, MacFadyen, Elaine S, Zaharris, Brendan M, Everett, Stuart E, Campbell, Ryu, Oshima, Pierre, Amarenco, Dirk J, Blom, Eliot A, Brinton, Robert H, Eckel, Marshall B, Elam, João S, Felicio, Henry N, Ginsberg, Assen, Goudev, Shun, Ishibashi, Jacob, Joseph, Tatsuhiko, Kodama, Wolfgang, Koenig, Lawrence A, Leiter, Alberto J, Lorenzatti, Boris, Mankovsky, Nikolaus, Marx, Børge G, Nordestgaard, Dénes, Páll, Kausik K, Ray, Raul D, Santos, Handrean, Soran, Andrey, Susekov, Michal, Tendera, Koutaro, Yokote, Nina P, Paynter, Julie E, Buring, Peter, Libby, Paul M, Ridker, and Maureen, McClelland
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Hypertriglyceridemia ,Apolipoprotein C-III ,Cholesterol, HDL ,Hyperlipidemias ,General Medicine ,Cholesterol, LDL ,Cholesterol ,Diabetes Mellitus, Type 2 ,Double-Blind Method ,Cardiovascular Diseases ,Heart Disease Risk Factors ,Risk Factors ,PROMINENT Investigators ,General & Internal Medicine ,Humans ,PPAR alpha ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,11 Medical and Health Sciences ,Triglycerides ,Hypolipidemic Agents - Abstract
Background High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. Methods In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. Results Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. Conclusions Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)
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- 2022
9. Worldwide experience of homozygous familial hypercholesterolaemia:retrospective cohort study
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Tycho R Tromp, Merel L Hartgers, G Kees Hovingh, Antonio J Vallejo-Vaz, Kausik K Ray, Handrean Soran, Tomas Freiberger, Stefano Bertolini, Mariko Harada-Shiba, Dirk J Blom, Frederick J Raal, Marina Cuchel, Tycho R. Tromp, Merel L. Hartgers, G. Kees Hovingh, Antonio J. Vallejo-Vaz, Kausik K. Ray, Stefano A. Bertolini, Jing Pang, Gerald F. Watts, Susanne Greber-Platzer, Martin Mäser, Thomas M. Stulnig, Christoph F. Ebenbichler, Khalid Bin Thani, David Cassiman, Olivier S. Descamps, Daisy Rymen, Peter Witters, Raul D. Santos, Liam R. Brunham, Gordon A. Francis, Jacques Genest, Robert A. Hegele, Brooke A. Kennedy, Isabelle Ruel, Mark H. Sherman, Long Jiang, Luya Wang, Željko Reiner, Vladimir Blaha, Richard Ceska, Jana Dvorakova, Lubomir Dlouhy, Pavel Horak, Vladimir Soska, Lukas Tichy, Robin Urbanek, Helena Vaverkova, Michal Vrablik, Stanislav Zemek, Lukas Zlatohlavek, Sameh Emil, Tarek Naguib, Ashraf Reda, Sophie Béliard, Eric Bruckert, Antonio Gallo, Moses S. Elisaf, Genovefa Kolovou, Hofit Cohen, Ronen Durst, Eldad J. Dann, Avishay Elis, Osama Hussein, Eran Leitersdorf, Daniel Schurr, Nitika Setia, Ishwar C. Verma, Mohammed D. Alareedh, Mutaz Al-Khnifsawi, Ali F. Abdalsahib Al-Zamili, Sabah H. Rhadi, Foaad K. Shaghee, Marcello Arca, Maurizio Averna, Andrea Bartuli, Marco Bucci, Paola S. Buonuomo, Paolo Calabrò, Sebastiano Calandra, Manuela Casula, Alberico L. Catapano, Angelo B. Cefalù, Arrigo F.G. Cicero, Sergio D'Addato, Laura D'Erasmo, Alessia Di Costanzo, Tommaso Fasano, Marta Gazzotti, Antonina Giammanco, Gabriella Iannuzzo, Anastasia Ibba, Emanuele A. Negri, Andrea Pasta, Chiara Pavanello, Livia Pisciotta, Claudio Rabacchi, Carlo Ripoli, Tiziana Sampietro, Francesco Sbrana, Fulvio Sileo, Patrizia Suppressa, Patrizia Tarugi, Chiara Trenti, Maria G. Zenti, Mika Hori, Mahmoud H. Ayesh, Sami T. Azar, Fadi F. Bitar, Akl C. Fahed, Elie M. Moubarak, Georges Nemer, Hapizah M. Nawawi, Ramón Madriz, Roopa Mehta, Arjen J. Cupido, Joep C. Defesche, M. Doortje Reijman, Jeanine E. Roeters-van Lennep, Erik S.G. Stroes, Albert Wiegman, Linda Zuurbier, Khalid Al-Waili, Fouzia Sadiq, Krzysztof Chlebus, Mafalda Bourbon, Isabel M. Gaspar, Katarina S. Lalic, Marat V. Ezhov, Andrey V. Susekov, Urh Groselj, Min-Ji Charng, Weerapan Khovidhunkit, Melih Aktan, Bulent B. Altunkeser, Sinan Demircioglu, Melis Kose, Cumali Gokce, Osman Ilhan, Meral Kayikcioglu, Leyla G. Kaynar, Irfan Kuku, Erdal Kurtoglu, Harika Okutan, Osman I. Ozcebe, Zafer Pekkolay, Saim Sag, Osman Z. Salcioglu, Ahmet Temizhan, Mustafa Yenercag, Mehmet Yilmaz, Hamiyet Yilmaz Yasar, Olena Mitchenko, Alexander R.M. Lyons, Christophe A.T. Stevens, Julie A. Brothers, Lisa C. Hudgins, Christina Nguyen, Rano Alieva, Aleksandr Shek, Doan-Loi Do, Ngoc-Thanh Kim, Hong-An Le, Thanh-Tung Le, Mai-Ngoc T. Nguyen, Thanh-Huong Truong, Dirk J. Blom, Frederick J. Raal, VU University medical center, Tromp T.R., Hartgers M.L., Hovingh G.K., Vallejo-Vaz A.J., Ray K.K., Soran H., Freiberger T., Bertolini S., Harada-Shiba M., Blom D.J., Raal F.J., Cuchel M., Bertolini S.A., Pang J., Watts G.F., Greber-Platzer S., Maser M., Stulnig T.M., Ebenbichler C.F., Bin Thani K., Cassiman D., Descamps O.S., Rymen D., Witters P., Santos R.D., Brunham L.R., Francis G.A., Genest J., Hegele R.A., Kennedy B.A., Ruel I., Sherman M.H., Jiang L., Wang L., Reiner Z., Blaha V., Ceska R., Dvorakova J., Dlouhy L., Horak P., Soska V., Tichy L., Urbanek R., Vaverkova H., Vrablik M., Zemek S., Zlatohlavek L., Emil S., Naguib T., Reda A., Beliard S., Bruckert E., Gallo A., Elisaf M.S., Kolovou G., Cohen H., Durst R., Dann E.J., Elis A., Hussein O., Leitersdorf E., Schurr D., Setia N., Verma I.C., Alareedh M.D., Al-Khnifsawi M., Abdalsahib Al-Zamili A.F., Rhadi S.H., Shaghee F.K., Arca M., Averna M., Bartuli A., Bucci M., Buonuomo P.S., Calabro P., Calandra S., Casula M., Catapano A.L., Cefalu A.B., Cicero A.F.G., D'Addato S., D'Erasmo L., Di Costanzo A., Fasano T., Gazzotti M., Giammanco A., Iannuzzo G., Ibba A., Negri E.A., Pasta A., Pavanello C., Pisciotta L., Rabacchi C., Ripoli C., Sampietro T., Sbrana F., Sileo F., Suppressa P., Tarugi P., Trenti C., Zenti M.G., Hori M., Ayesh M.H., Azar S.T., Bitar F.F., Fahed A.C., Moubarak E.M., Nemer G., Nawawi H.M., Madriz R., Mehta R., Cupido A.J., Defesche J.C., Reijman M.D., Roeters-van Lennep J.E., Stroes E.S.G., Wiegman A., Zuurbier L., Al-Waili K., Sadiq F., Chlebus K., Bourbon M., Gaspar I.M., Lalic K.S., Ezhov M.V., Susekov A.V., Groselj U., Charng M.-J., Khovidhunkit W., Aktan M., Altunkeser B.B., Demircioglu S., Kose M., Gokce C., Ilhan O., Kayikcioglu M., Kaynar L.G., Kuku I., Kurtoglu E., Okutan H., Ozcebe O.I., Pekkolay Z., Sag S., Salcioglu O.Z., Temizhan A., Yenercag M., Yilmaz M., Yilmaz Yasar H., Mitchenko O., Lyons A.R.M., Stevens C.A.T., Brothers J.A., Hudgins L.C., Nguyen C., Alieva R., Shek A., Do D.-L., Kim N.-T., Le H.-A., Le T.-T., Nguyen M.-N.T., Truong T.-H., University of Amsterdam, University of Pennsylvania, European Atherosclerosis Society, Experimental Vascular Medicine, Graduate School, Vascular Medicine, ACS - Atherosclerosis & ischemic syndromes, Human Genetics, Paediatric Metabolic Diseases, ACS - Diabetes & metabolism, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, ACS - Heart failure & arrhythmias, R Tromp, Tycho, L Hartgers, Merel, Kees Hovingh, G, J Vallejo-Vaz, Antonio, K Ray, Kausik, Soran, Handrean, Freiberger, Toma, A Bertolini, Stefano, Harada-Shiba, Mariko, Pang, Jing, F Watts, Gerald, Greber-Platzer, Susanne, Mäser, Martin, M Stulnig, Thoma, F Ebenbichler, Christoph, Bin Thani, Khalid, Cassiman, David, S Descamps, Olivier, Rymen, Daisy, Witters, Peter, D Santos, Raul, R Brunham, Liam, A Francis, Gordon, Genest, Jacque, A Hegele, Robert, A Kennedy, Brooke, Ruel, Isabelle, H Sherman, Mark, Jiang, Long, Wang, Luya, Reiner, Željko, Blaha, Vladimir, Ceska, Richard, Dvorakova, Jana, Dlouhy, Lubomir, Horak, Pavel, Soska, Vladimir, Tichy, Luka, Urbanek, Robin, Vaverkova, Helena, Vrablik, Michal, Zemek, Stanislav, Zlatohlavek, Luka, Emil, Sameh, Naguib, Tarek, Reda, Ashraf, Béliard, Sophie, Bruckert, Eric, Gallo, Antonio, S Elisaf, Mose, Kolovou, Genovefa, Cohen, Hofit, Durst, Ronen, J Dann, Eldad, Elis, Avishay, Hussein, Osama, Leitersdorf, Eran, Schurr, Daniel, Setia, Nitika, C Verma, Ishwar, D Alareedh, Mohammed, Al-Khnifsawi, Mutaz, F Abdalsahib Al-Zamili, Ali, H Rhadi, Sabah, K Shaghee, Foaad, Arca, Marcello, Averna, Maurizio, Bartuli, Andrea, Bucci, Marco, S Buonuomo, Paola, Calabrò, Paolo, Calandra, Sebastiano, Casula, Manuela, L Catapano, Alberico, B Cefalù, Angelo, G Cicero, Arrigo F, D'Addato, Sergio, D'Erasmo, Laura, Di Costanzo, Alessia, Fasano, Tommaso, Gazzotti, Marta, Giammanco, Antonina, Iannuzzo, Gabriella, Ibba, Anastasia, A Negri, Emanuele, Pasta, Andrea, Pavanello, Chiara, Pisciotta, Livia, Rabacchi, Claudio, Ripoli, Carlo, Sampietro, Tiziana, Sbrana, Francesco, Sileo, Fulvio, Suppressa, Patrizia, Tarugi, Patrizia, Trenti, Chiara, G Zenti, Maria, Hori, Mika, H Ayesh, Mahmoud, T Azar, Sami, F Bitar, Fadi, C Fahed, Akl, M Moubarak, Elie, Nemer, George, M Nawawi, Hapizah, Madriz, Ramón, Mehta, Roopa, J Cupido, Arjen, C Defesche, Joep, Doortje Reijman, M, E Roeters-van Lennep, Jeanine, G Stroes, Erik S, Wiegman, Albert, Zuurbier, Linda, Al-Waili, Khalid, Sadiq, Fouzia, Chlebus, Krzysztof, Bourbon, Mafalda, M Gaspar, Isabel, S Lalic, Katarina, V Ezhov, Marat, V Susekov, Andrey, Groselj, Urh, Charng, Min-Ji, Khovidhunkit, Weerapan, Aktan, Melih, B Altunkeser, Bulent, Demircioglu, Sinan, Kose, Meli, Gokce, Cumali, Ilhan, Osman, Kayikcioglu, Meral, G Kaynar, Leyla, Kuku, Irfan, Kurtoglu, Erdal, Okutan, Harika, I Ozcebe, Osman, Pekkolay, Zafer, Sag, Saim, Z Salcioglu, Osman, Temizhan, Ahmet, Yenercag, Mustafa, Yilmaz, Mehmet, Yilmaz Yasar, Hamiyet, Mitchenko, Olena, M Lyons, Alexander R, T Stevens, Christophe A, A Brothers, Julie, C Hudgins, Lisa, Nguyen, Christina, Alieva, Rano, Shek, Aleksandr, Do, Doan-Loi, Kim, Ngoc-Thanh, Le, Hong-An, Le, Thanh-Tung, T Nguyen, Mai-Ngoc, Truong, Thanh-Huong, J Blom, Dirk, J Raal, Frederick, and Cuchel, Marina
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Adult ,Male ,Homozygous Familial Hypercholesterolemia ,Adolescent ,retrospective study ,CHILDREN ,Doenças Cardio e Cérebro-vasculares ,Cohort Studies ,Young Adult ,Medicine, General & Internal ,General & Internal Medicine ,Cardiovascular Disease ,Humans ,Registries ,LIPOPROTEIN-APHERESIS ,Child ,11 Medical and Health Sciences ,Retrospective Studies ,Homozygous Familial Hypercholesterolaemia International Clinical Collaborators ,Science & Technology ,GUIDANCE ,clinical characteristic ,EVOLOCUMAB ,Homozygous familial hypercholesterolemia ,Worldwide ,Therapies ,Cardiovascular disease ,General Medicine ,CARE ,OPEN-LABEL ,EFFICACY ,INSIGHTS ,Child, Preschool ,outcome ,Female ,genetic ,Familial Hypercholesterolaemia ,Life Sciences & Biomedicine - Abstract
[Background]: Homozygous familial hypercholesterolaemia (HoFH) is a rare inherited disorder resulting in extremely elevated low-density lipoprotein cholesterol levels and premature atherosclerotic cardiovascular disease (ASCVD). Current guidance about its management and prognosis stems from small studies, mostly from high-income countries. The objective of this study was to assess the clinical and genetic characteristics, as well as the impact, of current practice on health outcomes of HoFH patients globally., [Methods]: The HoFH International Clinical Collaborators registry collected data on patients with a clinical, or genetic, or both, diagnosis of HoFH using a retrospective cohort study design. This trial is registered with ClinicalTrials.gov, NCT04815005., [Findings]: Overall, 751 patients from 38 countries were included, with 565 (75%) reporting biallelic pathogenic variants. The median age of diagnosis was 12∙0 years (IQR 5∙5–27∙0) years. Of the 751 patients, 389 (52%) were female and 362 (48%) were male. Race was reported for 527 patients; 338 (64%) patients were White, 121 (23%) were Asian, and 68 (13%) were Black or mixed race. The major manifestations of ASCVD or aortic stenosis were already present in 65 (9%) of patients at diagnosis of HoFH. Globally, pretreatment LDL cholesterol levels were 14∙7 mmol/L (IQR 11∙6–18∙4). Among patients with detailed therapeutic information, 491 (92%) of 534 received statins, 342 (64%) of 534 received ezetimibe, and 243 (39%) of 621 received lipoprotein apheresis. On-treatment LDL cholesterol levels were lower in high-income countries (3∙93 mmol/L, IQR 2∙6–5∙8) versus non-highincome countries (9∙3 mmol/L, 6∙7–12∙7), with greater use of three or more lipid-lowering therapies (LLT; highincome 66% vs non-high-income 24%) and consequently more patients attaining guideline-recommended LDL cholesterol goals (high-income 21% vs non-high-income 3%). A first major adverse cardiovascular event occurred a decade earlier in non-high-income countries, at a median age of 24∙5 years (IQR 17∙0–34∙5) versus 37∙0 years (29∙0–49∙0) in high-income countries (adjusted hazard ratio 1∙64, 95% CI 1∙13–2∙38)., [Interpretation]: Worldwide, patients with HoFH are diagnosed too late, undertreated, and at high premature ASCVD risk. Greater use of multi-LLT regimens is associated with lower LDL cholesterol levels and better outcomes. Significant global disparities exist in treatment regimens, control of LDL cholesterol levels, and cardiovascular event-free survival, which demands a critical re-evaluation of global health policy to reduce inequalities and improve outcomes for all patients with HoFH., Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; and European Atherosclerosis Society
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- 2022
10. Familial Hypercholesterolemia Identification by Machine Learning Using Lipid Profile Data Performs as Well as Clinical Diagnostic Criteria
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Reinhardt Hesse, Frederick J. Raal, Dirk J. Blom, and Jaya A. George
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Hyperlipoproteinemia Type II ,Machine Learning ,Area Under Curve ,Mutation ,Humans ,Cholesterol, LDL ,General Medicine - Abstract
Background: Familial hypercholesterolemia (FH) is a common genetic disorder and, if not diagnosed and treated early, results in premature cardiovascular disease. Most individuals with FH are undiagnosed and machine learning offers a new prospect to improve FH identification. Our objective was to create a machine learning model from basic lipid profile data with better screening performance than LDL-C (low-density lipoprotein cholesterol) cutoff levels and diagnostic performance comparable to the Dutch Lipid Clinic Network criteria. Methods: The model was developed combining logistic regression, deep learning, and random forest classification and trained on a 70% split of a data set of individuals clinically suspected of having FH. Model performance, as well as that of the LDL-C cutoff and Dutch Lipid Clinic Network criteria, were assessed on the internal 30% testing data set and an external data set by comparing the area under the receiver operator characteristic (AUROC) curves. All methodologies were measured against the gold standard of FH diagnosis by mutation identification. Furthermore, the model was also tested on 2 lower prevalence data sets. Results: The machine learning model achieved an AUROC curve of 0.711 on the external data set (n=1376; FH prevalence=64%), which was superior to the LDL-C cutoff (AUROC=0.642) and comparable to the Dutch Lipid Clinic Network criteria (AUROC=0.705). The model performed even better when tested on the medium-prevalence (n=2655; FH prevalence=20%) and low-prevalence (n=1616; FH prevalence=1%) data sets, with AUROC curve values of 0.801 and 0.856, respectively. Conclusions: Despite absence of clinical information, the model better identified genetically confirmed FH in a cohort of individuals suspected of having FH than LDL-C cutoff values and was comparable to the Dutch Lipid Clinic Network criteria. The model achieved higher accuracy when tested on 2 cohorts with lower FH prevalence. The application of machine learning is, therefore, a promising tool in both the screening for, and diagnosis of, individuals with FH.
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- 2022
11. COVID-19–Associated Graft Loss From Renal Infarction in a Kidney Transplant Recipient
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Dharshnee Rama Chetty, Bianca Davidson, Zunaid Barday, Dirk J. Blom, Christine Webb, Nicola Wearne, and Erika Jones
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kidney transplant ,medicine.medical_specialty ,2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Renal infarction ,Graft loss ,lcsh:Diseases of the genitourinary system. Urology ,lcsh:RC870-923 ,Gastroenterology ,Kidney transplant ,Kidney transplant recipient ,kidney infarction ,Nephrology ,Internal medicine ,medicine ,acute kidney injury (AKI) ,Kidney infarction ,Nephrology Rounds ,business ,graft loss ,renal complications of COVID-19 - Published
- 2021
12. The therapeutic management of South African dyslipidaemic patients at very high cardiovascular risk (CARDIO TRACK): a cross-sectional study
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Rory Leisegang, Hemant Makan, Pankaj S. Joshi, Julien Shane Trokis, Naresh Ranjith, Dirk J. Blom, Alet van Tonder, Shaifali Joshi, Poobalan Naidoo, Frederick J. Raal, and Moji Ganiyat Musa
- Subjects
Male ,medicine.medical_specialty ,Time Factors ,Statin ,medicine.drug_class ,Cross-sectional study ,Population ,Down-Regulation ,Comorbidity ,Overweight ,Risk Assessment ,South Africa ,Ezetimibe ,Internal medicine ,Diabetes mellitus ,Prevalence ,medicine ,Humans ,Risk factor ,education ,Aged ,Dyslipidemias ,education.field_of_study ,medicine.diagnostic_test ,business.industry ,Anticholesteremic Agents ,Cardiovascular Topics ,PCSK9 Inhibitors ,Cholesterol, LDL ,General Medicine ,Middle Aged ,medicine.disease ,Cross-Sectional Studies ,Treatment Outcome ,Cardiovascular Diseases ,Heart Disease Risk Factors ,Drug Therapy, Combination ,Female ,lipids (amino acids, peptides, and proteins) ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,Lipid profile ,business ,Biomarkers ,medicine.drug - Abstract
Background Dyslipidaemia is a major modifiable risk factor for atherosclerotic cardiovascular disease. At the time the study was conducted, guidelines recommended a low-density lipoprotein cholesterol (LDL-C) target of less than 1.8 mmol/l and a reduction of at least 50% if the baseline LDL-C was between 1.8 and 3.5 mmol/l in patients with either very high cardiovascular risk or established atherosclerosis. In South Africa, there is a paucity of data on attainment of LDL-C goal in patients with very high cardiovascular risk who are on maximum tolerated statin with or without ezetimibe. Objective The aim was to assess the percentage of very high cardiovascular risk South African patients with dyslipidaemia not reaching an LDL-C goal of less than 1.8 mmol/l, despite maximum tolerated statin with or without ezetimibe. Methods This was a multi-centre, observational, cross-sectional study conducted at 15 private healthcare sector sites and one public sector site. Adults (> 18 years) with very high cardiovascular risk of familial hypercholesterolaemia receiving stable, maximum-tolerated statin therapy for at least four weeks prior to their latest lipid profile were enrolled into the study, and electronic case report forms were completed after written informed consent was provided. LDL-C goal attainment was modelled, first assuming an increase in the statin dose to the registered maximum, followed by the addition of ezetimibe or a PCSK9-inhibitor. Results In total, 507 patients were screened, of whom 492 were eligible for study participation. One patient was excluded from the analysis because of a missing LDL-C value. Most participants were male (male 329, 67%; female 162, 33%). Most patients were either obese (223, 46.0%) or overweight (176, 36.3%). Hypertension and diabetes mellitus were frequent co-morbidities and were found in 381 (77.6%) and 316 (64.4%) patients, respectively. Eighty (16.3%) patients reported current smoking. Only 68 (13.8%) patients were taking ezetimibe in addition to a statin. Reasons for not using ezetimibe included no requirement for ezetimibe in the opinion of the treating physician (229, 48.7%), cost (149, 31.7%), Physician's choice (39, 8.3%), or other (53, 11.3%). Only 161 (32.8%) of the patients attained their goal LDL-C level. In our modelling analysis, increasing the statin dose to the registered maximum and adding ezetimibe brought an additional 34.5% of patients to goal, while adding a PCSK9-inhibitor, irrespective of any other changes to lipid-lowering therapy brought over 90% of not-at-goal patients to goal. Conclusions Most study participants were not at LDL-C goal despite maximum-tolerated statin, highlighting the need for treatment intensification in this high-risk population. Although intensifying treatment by adding a PCSK9-inhibitor brought more patients to goal, the initial addition of ezetimibe would be more reasonable, given the cost of PCSK9-inhibitors.
- Published
- 2020
13. A report card for healthy aging in South Africa
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Dirk J, Blom
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Healthy Aging ,South Africa ,Humans ,General Medicine ,Cardiology and Cardiovascular Medicine - Published
- 2022
14. PCSK9 Inhibitors: From Nature’s Lessons to Clinical Utility
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Célia Bouharati, Rory Forseth Leisegang, Nelusha Shunmoogam, Iftikhar O. Ebrahim, Robert J. Chilton, Frederick J. Raal, Poobalan Naidoo, Alet van Tonder, Sumanth Karamchand, Naresh Ranjith, Virendra Rambiritch, Dirk J. Blom, and Moji Ganiyat Musa
- Subjects
Oncology ,medicine.medical_specialty ,Acute coronary syndrome ,Statin ,medicine.drug_class ,Endocrinology, Diabetes and Metabolism ,Hypercholesterolemia ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,Ezetimibe ,Internal medicine ,medicine ,Animals ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Hypolipidemic Agents ,business.industry ,PCSK9 ,PCSK9 Inhibitors ,Absolute risk reduction ,Atherosclerosis ,medicine.disease ,Proprotein convertase ,Tolerability ,Cardiovascular Diseases ,LDL receptor ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,medicine.drug - Abstract
Background: Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors are a novel class of non-statin lipid lowering therapy that reduce LDL-cholesterol by 50 - 60%. PCSK9 inhibitors decrease LDL-cholesterol by preventing intracellular degradation of LDL receptors; subsequently, a greater number of LDL-receptors are available on the cell surface to extract circulating LDL. Objective: To describe the origins of PCSK9 inhibitors and their current use in clinical practice. Methods: We performed a narrative review of the PCSK9 inhibitor class of drugs. Results: Current data indicate that PCSK9 inhibitors effectively reduce LDL-cholesterol and are well tolerated and safe. PCSK9 inhibitors have also been shown to reduce cardiovascular event rates in patients with stable atherosclerotic cardiovascular disease and in patients with a recent (up to one year) acute coronary syndrome. Given the costs, chronicity of the treatment and the potential budget impact, PCSK9 inhibitors are often limited to patients with the highest absolute risk for major adverse cardiovascular events despite optimal treatment with high-intensity statin and ezetimibe. Conclusion: PCSK9 inhibitors have a favorable safety, efficacy and tolerability profile. Postmarketing safety surveillance and real-world studies are needed to further support the long-term safety profile of this class of medicine.
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- 2020
15. Homozygous familial hypercholesterolemia and its treatment by inclisiran
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A. David Marais, Frederick J. Raal, and Dirk J. Blom
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Ldl cholesterol ,medicine.medical_specialty ,business.industry ,Health Policy ,PCSK9 ,Genetic disorder ,Hepatic clearance ,Familial hypercholesterolemia ,medicine.disease ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Inclisiran ,Autosomal Recessive Hypercholesterolemia ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,lipids (amino acids, peptides, and proteins) ,Pharmacology (medical) ,business ,Pharmacology, Toxicology and Pharmaceutics (miscellaneous) ,030217 neurology & neurosurgery - Abstract
Homozygous familial hypercholesterolemia (hoFH), a genetic disorder characterized by markedly impaired hepatic clearance of LDL and LDL cholesterol concentration exceeding 12 mmol/L, causes coronar...
- Published
- 2020
16. Abstract 12027: Low-Density Lipoprotein Cholesterol in Patients With Homozygous Familial Hypercholesterolemia Who Participated in Sequential Studies of Alirocumab and Evinacumab
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Frederick J Raal, Robert S Rosenson, Genovefa Kolovou, Mariko Harada-shiba, Olena Mitchenko, Paolo Rubba, shazia ali, Poulabi Banerjee, Nagwa Khilla, Jennifer McGinniss, robert pordy, and Dirk J Blom
- Subjects
Physiology (medical) ,Cardiology and Cardiovascular Medicine - Abstract
Background: Homozygous familial hypercholesterolemia (HoFH) is characterized by markedly elevated levels of low-density lipoprotein cholesterol (LDL-C) and premature cardiovascular disease. This analysis evaluated LDL-C changes in patients with HoFH who sequentially participated in interventional trials with alirocumab (NCT03156621) and evinacumab (NCT03399786). Methods: A total of 25 patients completed the alirocumab trial and entered the evinacumab trial and were randomized to intravenous evinacumab 15 mg/kg (n=16) or placebo (n=9) every 4 weeks. The primary outcome for the evinacumab trial was percent change in LDL-C from baseline to week 24. Results: Baseline characteristics were generally well balanced. Among patients who participated in the alirocumab trial, a reduction in LDL-C of –44.6% and –1.1% was observed at week 24 in patients treated with evinacumab versus placebo, respectively. Overall, mean total reductions in LDL-C (Figure) and apolipoprotein B of -62.9% and -54.9%, respectively, were observed in patients treated with the combination of alirocumab and evinacumab; and triglycerides were lowered by -54.5%. The absolute LDL-C reduction from their baseline in patients treated with the combination of alirocumab and evinacumab was -216.3 mg/dL. No new safety signals were observed when treated with alirocumab and evinacumab, and were consistent with the respective trial results. Conclusions: Combination therapy with alirocumab and evinacumab reduced LDL-C by more than 60% in patients with HoFH and was well tolerated.
- Published
- 2021
17. A Case Series Assessing the Effects of Lomitapide on Carotid Intima-Media Thickness in Adult Patients with Homozygous Familial Hypercholesterolaemia in a Real-World Setting
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Dirk J, Blom, Daniel, Gaudet, Robert A, Hegele, Dharmesh S, Patel, Jaimini, Cegla, Genovefa, Kolovou, and Luis Masana, Marin
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Hyperlipoproteinemia Type II ,Homozygous Familial Hypercholesterolemia ,Anticholesteremic Agents ,Homozygote ,Humans ,Benzimidazoles ,Cholesterol, LDL ,Atherosclerosis ,Carotid Intima-Media Thickness - Abstract
Homozygous familial hypercholesterolaemia (HoFH) is characterised by extremely elevated levels of low-density lipoprotein cholesterol (LDL-C) and results from multiple mutations in genes affecting the LDL receptor pathway. Patients are at risk of premature atherosclerotic cardiovascular disease (ASCVD) and premature death. Lomitapide is a microsomal triglyceride transfer protein inhibitor developed to treat HoFH, but cardiovascular outcome data are lacking.We evaluated detailed data from five HoFH patients and one patient with heterozygous FH (HeFH) and a very severe phenotype. We also analysed confirmatory data from a further 8 HoFH cases. In total, we analysed data from patients in seven global centres in six countries who were all treated with lomitapide with long-term follow-up. Carotid intima-media thickness (CIMT) imaging was recorded on an ad hoc basis to monitor ASCVD in HoFH.Lomitapide resulted in marked decreases in LDL-C of 56.8-93.9% [77.7-93.9% in the 6 initial cases (mean nadir 64.8 ± 30.1 mg/dL); 56.8-86.0% in the 8 confirmatory cases (mean nadir 131.4 ± 38.2 mg/dL)]. CIMT regressed in 50% of cases (mean follow-up 5.0 ± 3.1 years in initial six cases, and 4.4 ± 1.4 years in confirmatory cases). In the remaining patients, CIMT showed little further change. In patients where assessments of plaque area were available, regression or stabilisation in CIMT was accompanied by clinically significant regression of plaque area.Lomitapide reduces LDL-C levels in patients with HoFH and severe LDL-C phenotypes, and results in stabilisation and/or regression of CIMT, which is an established marker of ASCVD risk. Additional data are needed to determine if this confers a survival benefit in these very high-risk patients.
- Published
- 2021
18. Long-term safety and efficacy of alirocumab in South African patients with heterozygous familial hypercholesterolaemia: the ODYSSEY Open-Label Extension study
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Poobalan Naidoo, Frederick J. Raal, Graham Ellis, Dirk J. Blom, Eugene van der Walt, Prashilla Soma, Alet van Tonder, Lesley J. Burgess, Johannes Breedt, and Iftikhar O. Ebrahim
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medicine.medical_specialty ,Statin ,medicine.drug_class ,business.industry ,Cardiovascular Topics ,Extension study ,General Medicine ,030204 cardiovascular system & hematology ,Discontinuation ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,lipids (amino acids, peptides, and proteins) ,In patient ,Long term safety ,Open label ,Cardiology and Cardiovascular Medicine ,business ,Lipoprotein cholesterol ,Alirocumab - Abstract
Background Alirocumab reduces low-density lipoprotein cholesterol (LDL-C) levels by up to 61%. The ODYSSEY Open-Label Extension study investigated the effect of alirocumab in patients with heterozygous familial hypercholesterolaemia (HeFH) over 144 weeks. Methods Eligible patients with HeFH had completed an earlier double-blind, randomised, placebo-controlled parent study. Patients were initiated on 75 mg alirocumab Q2W subcutaneous (SC) unless baseline LDL-C was > 8.9 mmol/l, in which case they received 150 mg alirocumab Q2W. Dose titration to 150 mg Q2W was at the investigator's discretion. Results The study enrolled 167 patients and the parent study mean (± SD) baseline LDL-C level was 3.65 ± 1.9 mmol/l. Mean LDL-C level was reduced by 48.7% at week 144; mean on-treatment LDL-C was 2.30 ± 1.24 mmol/l. Eight patients reported injection-site reactions, with one treatment discontinuation. Treatment emergent anti-drug antibodies were identified in five patients but these did not affect the efficacy. Conclusions Alirocumab effectively and safely reduced LDL-C in these patients.
- Published
- 2019
19. Management of low-density lipoprotein cholesterol levels in South Africa: the International ChoLesterol management Practice Study (ICLPS)
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Poobalan Naidoo, Yen-Yu Evelyn Lai, Aslam Amod, Dirk J. Blom, and Frederick J. Raal
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Statin ,Combination therapy ,medicine.drug_class ,Low density lipoprotein cholesterol ,030204 cardiovascular system & hematology ,Risk Assessment ,South Africa ,03 medical and health sciences ,0302 clinical medicine ,Risk Factors ,Internal medicine ,medicine ,Humans ,Goal achievement ,Practice Patterns, Physicians' ,Aged ,Dyslipidemias ,Cholesterol management ,business.industry ,Guideline adherence ,Cholesterol, LDL ,General Medicine ,Guideline ,Middle Aged ,Cross-Sectional Studies ,Treatment Outcome ,Cardiovascular Diseases ,Practice Guidelines as Topic ,European atherosclerosis society ,Drug Therapy, Combination ,Female ,lipids (amino acids, peptides, and proteins) ,Guideline Adherence ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
The International Cholesterol Management Practice Study (ICLPS) South Africa investigated achievement of European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline low-density lipoprotein cholesterol (LDL-C) targets in real-world clinical practice. Demographic data, clinical characteristics, cardiovascular risk factors, lipid-modifying medications, lipid values and investigator's assessment of cardiovascular risk were recorded for 396 patients on stable lipid-modifying therapy. Most (98.7%) patients received statins; 25.1% of statin-treated patients were receiving high-intensity statins. Overall, 41.4% of patients achieved their LDL-C target; among 354 (89.4%) patients in whom cardiovascular disease risk, based on ESC Systematic Coronary Risk Estimation (SCORE) was calculated, achievement rate was 14.3% for moderate-risk (n = 7), 59.3% for high-risk (n = 123) and 32.3% for very high-risk patients (n = 223). Half of Asian (54.7%) and black African (53.2%) patients were at LDL-C target compared with 29.8% of European/Caucasian and 27.3% of 'other' patients. Improved guideline adherence and greater use of combination therapy may increase LDL-C goal achievement.
- Published
- 2019
20. Novel PCSK9 (Proprotein Convertase Subtilisin Kexin Type 9) Variants in Patients With Familial Hypercholesterolemia From Cape Town
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Rosemary J. Jooste, Asier Benito-Vicente, Kévin Chemello, Dee Blackhurst, Zorena Behardien, César Martín, Merel L. Hartgers, G. Kees Hovingh, Joep C. Defesche, Dirk J. Blom, Karen H. Wolmarans, Kepa B. Uribe, Annemiek G. de Jong, Gabriele Solomon, A. David Marais, Gilles Lambert, Brigitte C. Brice, Roeland Huijgen, Regeneron Pharmaceuticals, Fritz Thyssen Foundation, Amsterdam Stollings Foundation, Amsterdam University Funds, Atheros Foundation, Academic Medical Center Foundation, Agence Nationale de la Recherche (France), Eusko Jaurlaritza, Blom, Dirk, Benito-Vicente, Asier, Blackhurst, Dee M., Kees Hovingh, G., Martín, César, Vascular Medicine, Human Genetics, ACS - Atherosclerosis & ischemic syndromes, and Experimental Vascular Medicine
- Subjects
0301 basic medicine ,Male ,Heredity ,Time Factors ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,medicine.disease_cause ,chemistry.chemical_compound ,South Africa ,0302 clinical medicine ,Mutation ,Hep G2 Cells ,Middle Aged ,Lipids ,Progression-Free Survival ,Pedigree ,Cholesterol ,Phenotype ,Cardiovascular Diseases ,Kexin ,Female ,lipids (amino acids, peptides, and proteins) ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,Adult ,medicine.medical_specialty ,Hypercholesterolemia ,Risk Assessment ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,Young Adult ,Internal medicine ,medicine ,Humans ,In patient ,Genetic Predisposition to Disease ,Genetic Association Studies ,Aged ,business.industry ,PCSK9 ,Subtilisin ,Proprotein convertase ,medicine.disease ,030104 developmental biology ,Endocrinology ,HEK293 Cells ,chemistry ,Heart Disease Risk Factors ,Gain of function ,business ,Biomarkers - Abstract
Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein-cholesterol and markedly increased cardiovascular risk. In patients with a genetic diagnosis, low-density lipoprotein receptor (LDLR) mutations account for >90% of cases, apolipoprotein B (APOB) mutations for ≈5% of cases, while proprotein convertase subtilisin kexin type 9 (PCSK9) gain of function mutations are rare (T) was found in 5 index patients and cascade screening identified 15 additional carriers. Low-density lipoprotein-cholesterol levels were higher in these 15 carriers compared with the 27 noncarriers (236±73 versus 124±35 mg/dL; P, This work was funded by Regeneron: R727-CL-1555. Grants received from the Fritz Thyssen Foundation, Amsterdam Stollings Foundation, that is, the Jan Wouter ten Cate Prize, Amsterdam University Funds, and the Atheros Foundation to R. Huijgen. Grants received from Academic Medical Center Young Talent Fund, grant received by the Academic Medical Center Foundation, and the Atheros Foundation to M.L. Hartgers. Grants received from Programme de Recherche Hospitalière en Santé ANR-16-RHUS-0007 to K. Chemello and G. Lambert. Grants received from Basque Government (Grupos Consolidados IT1264-19) to A. Benito-Vicente, K.B. Uribe, and C. Martin.
- Published
- 2021
21. Worldwide perspective on homozygous familial hypercholesterolemia diagnosis, treatment and outcome – results from the HICC registry
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Dirk J. Blom, Tycho R Tromp, G.K. Hovingh, Frederick J. Raal, Merel L. Hartgers, and Marina Cuchel
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Pediatrics ,medicine.medical_specialty ,Diagnosis treatment ,business.industry ,Perspective (graphical) ,medicine ,Familial hypercholesterolemia ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business ,Outcome (game theory) - Published
- 2021
22. Lipoprotein Metabolism in Familial Hypercholesterolemia
- Author
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Dirk J. Blom, César Martín, Kévin Chemello, Gilles Lambert, Antonio Gallo, Javier García-Nafría, Gestionnaire, Hal Sorbonne Université, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Instituto de Biocomputación y Física de Sistemas Complejos = Institute for Biocomputation and Physics of Complex Systems (BIFI), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Universidad del Pais Vasco / Euskal Herriko Unibertsitatea [Espagne] (UPV/EHU), University of Cape Town, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], Interreg, Conseil Régional de la Réunion, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Fondation pour la Recherche Médicale, Eusko Jaurlaritza, Agence Nationale de la Recherche (France), Fondation de France, and Blom, Dirk
- Subjects
0301 basic medicine ,Apolipoprotein B ,[SDV]Life Sciences [q-bio] ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Biochemistry ,0302 clinical medicine ,Endocrinology ,ANGPTL3 ,GOF, gain-of-function ,HoFH, homozygous familial hypercholesterolemia ,apoB, apolipoprotein B ,TRL, TG-rich lipoprotein ,biology ,TG, triglyceride ,familial hypercholesterolemia ,LDLR, LDL receptor ,Lipoprotein(a) ,3. Good health ,[SDV] Life Sciences [q-bio] ,PCSK9, proprotein convertase subtilisin kexin type 9 ,Autosomal Recessive Hypercholesterolemia ,Cardiovascular Diseases ,LDL cholesterol ,lipids (amino acids, peptides, and proteins) ,Proprotein Convertase 9 ,medicine.medical_specialty ,ARH, autosomal recessive hypercholesterolemia ,ANGPTL3, angiopoietin-like 3 ,apo(a), apolipoprotein (a) ,HeFH, heterozygous familial hypercholesterolemia ,apoB100, apolipoprotein B100 ,QD415-436 ,apoA1, apolipoprotein A1 ,FH, familial hypercholesterolemia ,03 medical and health sciences ,Internal medicine ,medicine ,CVDs ,REDUCE-IT, Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial ,LDL-C ,FCR, fractional catabolic rate ,business.industry ,PCSK9 ,lipoprotein (a) ,FDB, familial defective apolipoprotein B ,LDLRAP1, LDLR adapter protein 1 ,Thematic Review Series ,Cell Biology ,medicine.disease ,JELIS, Japan EPA Lipid Intervention Study ,Lp(a), lipoprotein (a) ,lipoproteins ,030104 developmental biology ,ASCVD, atherosclerotic CVD ,LDL receptor ,biology.protein ,business ,TESLA, Trial Evaluating PCSK9 Antibody in Subjects With LDL Receptor Abnormalities ,Lipoprotein - Abstract
Familial hypercholesterolemia (FH) is one of the most common genetic disorders in humans. It is an extremely atherogenic metabolic disorder characterized by lifelong elevations of circulating LDL-C levels often leading to premature cardiovascular events. In this review, we discuss the clinical phenotypes of heterozygous and homozygous FH, the genetic variants in four genes (LDLR/APOB/PCSK9/LDLRAP1) underpinning the FH phenotype as well as the most recent in vitro experimental approaches used to investigate molecular defects affecting the LDL receptor pathway. In addition, we review perturbations in the metabolism of lipoproteins other than LDL in FH, with a major focus on lipoprotein (a). Finally, we discuss the mode of action and efficacy of many of the currently approved hypocholesterolemic agents used to treat patients with FH, with a special emphasis on the treatment of phenotypically more severe forms of FH., K. C. received a scholarship from the European Union (European Regional Development Fund INTERREG V) and the Région Réunion (Saint-Denis, Réunion, France); J. G.-N. is a recipient of a Ramón y Cajal fellowship from the Spanish Ministerio de Ciencia, Innovación y Universidades; A. G. has received a postdoctoral fellowship from the Fondation pour la Recherche Médicale; C. M. has received research grants from the Basque Government Grupos Consolidados IT-1264-19; GL Research Group is funded by the Agence Nationale de la Recherche (Paris, France) Program Grant CHolesterol Personalized Innovation ANR-16-RHUS-0007 and project grant KRINGLE2 ANR-20-CE14-0009 as well as from La Fondation de France (project grant: 00096274).
- Published
- 2021
23. Global perspective of familial hypercholesterolaemia: a cross-sectional study from the EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC)
- Author
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Jie Lin, Snejana Tisheva, Ishwar C. Verma, Francesco Cipollone, Liam R. Brunham, Florentina Predica, Perla A.C. Gonzalez, Jocelyne Inamo, André R. Miserez, Belma Pojskic, Michel Farnier, Avishay Ellis, Katia Bonomo, Ibrahim Al-Zakwani, Maria Grazia Zenti, Humberto A. Lopez, Khairul Shafiq Ibrahim, Erkin M. Mirrakhimov, Alexey Meshkov, Jose P. de Moura, Muthukkaruppan Annamalai, Raul D. Santos, F. Paillard, Maria Del Ben, Jan Lacko, Miguel T. Rico, Ximena Reyes, Laura E.G. de Leon, Noor Shafina Mohd Nor, Ulrich Julius, Mohammed A. Batais, Dieter Böhm, Ta-Chen Su, Takuya Kobayashi, Magdalena Chmara, Marco Gebauer, Marcos M. Lima-Martínez, Ravshanbek D. Kurbanov, Daisaku Masuda, Amro El-Hadidy, Melanie Schüler, Francisco Fuentes, Florian J. Mayer, Helena Vaverkova, F. Ulrich Beil, Juraj Bujdak, Mario Stoll, Isabelle Ruel, Elena Dorn, Thomas M. Stulnig, Abubaker Elfatih, Rano B. Alieva, Jiri Vesely, Valérie Carreau, Cristina M. Sibaja, Sophie Béliard, Olivier Ziegler, Adriana Branchi, Daniel Schurr, G.B. John Mancini, Tai E. Shyong, Eric L.T. Siang, Mafalda Bourbon, Zerrin Yigit, Meral Kayıkçıoğlu, Jacques Genest, Wei Yu, Michal Vrablík, Shavkat U. Hoshimov, Dan Gaita, Antonio Pipolo, Ashraf H.A. AlQudaimi, Walter Speidl, Gianfranco Parati, Zaliha Ismail, Victoria M. Zubieta, René Valéro, Tomas Salek, Hana Halamkova, Gustavs Latkovskis, Nicole Allendorf-Ostwald, Agnes Perrin, Vladimir Soska, Anastasia Garoufi, Francisco Araujo, Nacu C. Portilla, Thomas Segiet, Charalambos Koumaras, Hila Knobler, Fatih Sivri, Hani Altaradi, Ivan Pećin, Long Jiang, Alexander Dressel, Marlena Woś, Jana Franekova, D. Agapakis, Quitéria Rato, Dirk J. Blom, Marcin A. Bartlomiejczyk, Krzysztof Dyrbuś, Maurizio Averna, Phivos Symeonides, Yung A. Chua, Asim Rana, András Nagy, Juan C.G. Cuellar, Alexander Jäkel, Maya Safarova, Neama Luqman, Amalia-Despoina Koutsogianni, Patrick Tounian, Jose A. Alvarez, Ada Cuevas, Corinna Richter, Sybil Charrieres, Vitaliy Zafiraki, Michalis Doumas, Angela Lux, Thanh Huong Truong, Elaine Chow, José Luis Díaz-Díaz, Jesus R.H. Almada, Sabine Füllgraf-Horst, Gustavo G. Retana, Claudio Borghi, Gianni Biolo, Ivajlo Tzvetkov, Patrícia Pais, Mehmet Akbulut, Kumiko Nagahama, Oner Ozdogan, Frank Leistikow, Jianxun He, Alexander R.M. Lyons, Poranee Ganokroj, Luis E.S. Mendia, Ann-Cathrin Koschker, Gabriela A.G. Ramirez, Dainus Gilis, Karin Balinth, José Ramiro Cruz, Paolo Calabrò, Alberico L. Catapano, Emmanouil Skalidis, Hamida Al-Barwani, Genovefa Kolovou, Carolyn S.P. Lam, Yoto Yotov, Yaacov Henkin, Gabriella Iannuzzo, Aimi Z. Razman, Alma B.M. Rodriguez, Hans Dieplinger, Darlington E. Obaseki, Ursulo J. Herrera, Arcangelo Iannuzzi, Christoph Säly, Elena Olmastroni, Francisco G. Padilla, S.A. Nazli, Ioanna Gouni-Berthold, Miriam Kozárová, Urh Groselj, Igor Shaposhnik, Lorenzo Iughetti, Nawal Rwaili, Cinthia E. 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Rahmat R., Hamzan N.S., Azzopardi C., Mehta R., Martagon A.J., Ramirez G.A.G., Villa N.E.A., Vazquez A.V., Elias-Lopez D., Retana G.G., Rodriguez B., Macias J.J.C., Zazueta A.R., Alvarado R.M., Portano J.D.M., Lopez H.A., Sauque-Reyna L., Herrera L.G.G., Mendia L.E.S., Aguilar H.G., Cooremans E.R., Aparicio B.P., Zubieta V.M., Gonzalez P.A.C., Ferreira-Hermosillo A., Portilla N.C., Dominguez G.J., Garcia A.Y.R., Cazares H.E.A., Gonzalez J.R., Valencia C.V.M., Padilla F.G., Prado R.M., De los Rios Ibarra M.O., Villicana R.D.A., Rivera K.J.A., Carrera R.A., Alvarez J.A., Martinez J.C.A., de los Reyes Barrera Bustillo M., Vargas G.C., Chacon R.C., Andrade M.H.F., Ortega A.F., Alcala H.G., de Leon L.E.G., Guzman B.G., Garcia J.J.G., Cuellar J.C.G., Cruz J.R.G., Garcia A.H., Almada J.R.H., Herrera U.J., Sobrevilla F.L., Rodriguez E.M., Sibaja C.M., Rodriguez A.B.M., Oyervides J.C.M., Vazquez D.I.P., Rodriguez E.A.R., Osorio M.L.R., Saucedo J.R., Tamayo M.T., Talavera L.A.V., Arroyo L.E.V., Carrillo E.A.Z., Isara A., Obaseki D.E., Al-Waili K., Al-Zadjali F., Al-Zakwani I., Al-Kindi M., Al-Mukhaini S., Al-Barwani H., Rana A., Shah L.S.U., Starostecka E., Konopka A., Lewek J., Bartlomiejczyk M., Gasior M., Dyrbus K., Jozwiak J., Gruchala M., Pajkowski M., Romanowska-Kocejko M., Zarczynska-Buchowiecka M., Chmara M., Wasag B., Parczewska A., Gilis-Malinowska N., Borowiec-Wolna J., Strozyk A., Wos M., Michalska-Grzonkowska A., Medeiros A.M., Alves A.C., Silva F., Lobarinhas G., Palma I., de Moura J.P., Rico M.T., Rato Q., Pais P., Correia S., Moldovan O., Virtuoso M.J., Salgado J.M., Colaco I., Dumitrescu A., Lengher C., Mosteoru S., Meshkov A., Ershova A., Rozkova T., Korneva V., Yu K.T., Zafiraki V., Voevoda M., Gurevich V., Duplyakov D., Ragino Y., Safarova M., Shaposhnik I., Alkaf F., Khudari A., Rwaili N., Al-Allaf F., Alghamdi M., Batais M.A., Almigbal T.H., Kinsara A., AlQudaimi A.H.A., Awan Z., Elamin O.A., Altaradi H., Rajkovic N., Popovic L., Singh S., Stosic L., Rasulic I., Lalic N.M., Lam C., Le T.J., Siang E.L.T., Dissanayake S., I-Shing J.T., Shyong T.E., Jin T.C.S., Balinth K., Buganova I., Fabryova L., Kadurova M., Klabnik A., Kozarova M., Sirotiakova J., Battelino T., Kovac J., Mlinaric M., Sustar U., Podkrajsek K.T., Fras Z., Jug B., Cevc M., Pilcher G.J., Blom D.J., Wolmarans K.H., Brice B.C., Muniz-Grijalvo O., Diaz-Diaz J.L., de Isla L.P., Fuentes F., Badimon L., Martin F., Lux A., Chang N.-T., Ganokroj P., Akbulut M., Alici G., Bayram F., Can L.H., Celik A., Ceyhan C., Coskun F.Y., Demir M., Demircan S., Dogan V., Durakoglugil E., Dural I.E., Gedikli O., Hacioglu A., Ildizli M., Kilic S., Kirilmaz B., Kutlu M., Oguz A., Ozdogan O., Onrat E., Ozer S., Sabuncu T., Sahin T., Sivri F., Sonmez A., Temizhan A., Topcu S., Tuncez A., Vural M., Yenercag M., Yesilbursa D., Yigit Z., Yildirim A.B., Yildirir A., Yilmaz M.B., Atallah B., Traina M., Sabbour H., Hay D.A., Luqman N., Elfatih A., Abdulrasheed A., Kwok S., Oca N.D., Reyes X., Alieva R.B., Kurbanov R.D., Hoshimov S.U., Nizamov U.I., Ziyaeva A.V., Abdullaeva G.J., Do D.L., Nguyen M.N.T., Kim N.T., Le T.T., Le H.A., Tokgozoglu L., Catapano A.L., Ray K.K., Vallejo-Vaz, A. J., Stevens, C. A. T., Lyons, A. R. M., Dharmayat, K. I., Freiberger, T., Hovingh, G. K., Mata, P., Raal, F. J., Santos, R. D., Soran, H., Watts, G. F., Abifadel, M., Aguilar-Salinas, C. A., Alhabib, K. F., Alkhnifsawi, M., Almahmeed, W., Alnouri, F., Alonso, R., Al-Rasadi, K., Al-Sarraf, A., Al-Sayed, N., Araujo, F., Ashavaid, T. F., Banach, M., Beliard, S., Benn, M., Binder, C. J., Bogsrud, M. P., Bourbon, M., Chlebus, K., Corral, P., Davletov, K., Descamps, O. S., Durst, R., Ezhov, M., Gaita, D., Genest, J., Groselj, U., Harada-Shiba, M., Holven, K. B., Kayikcioglu, M., Khovidhunkit, W., Lalic, K., Latkovskis, G., Laufs, U., Liberopoulos, E., Lima-Martinez, M. M., Lin, J., Maher, V., Marais, A. D., Marz, W., Mirrakhimov, E., Miserez, A. R., Mitchenko, O., Nawawi, H., Nordestgaard, B. G., Panayiotou, A. G., Paragh, G., Petrulioniene, Z., Pojskic, B., Postadzhiyan, A., Raslova, K., Reda, A., Sadiq, F., Sadoh, W. E., Schunkert, H., Shek, A. B., Stoll, M., Stroes, E., Su, T. -C., Subramaniam, T., Susekov, A. V., Tilney, M., Tomlinson, B., Truong, T. H., Tselepis, A. D., Tybjaerg-Hansen, A., Vazquez Cardenas, A., Viigimaa, M., Wang, L., Yamashita, S., Kastelein, J. J. P., Bruckert, E., Vohnout, B., Schreier, L., Pang, J., Ebenbichler, C., Dieplinger, H., Innerhofer, R., Winhofer-Stockl, Y., Greber-Platzer, S., Krychtiuk, K., Speidl, W., Toplak, H., Widhalm, K., Stulnig, T., Huber, K., Hollerl, F., Rega-Kaun, G., Kleemann, L., Maser, M., Scholl-Burgi, S., Saly, C., Mayer, F. J., Sablon, G., Tarantino, E., Nzeyimana, C., Pojskic, L., Sisic, I., Nalbantic, A. D., Jannes, C. E., Pereira, A. C., Krieger, J. E., Petrov, I., Goudev, A., Nikolov, F., Tisheva, S., Yotov, Y., Tzvetkov, I., Baass, A., Bergeron, J., Bernard, S., Brisson, D., Brunham, L. R., Cermakova, L., Couture, P., Francis, G. A., Gaudet, D., Hegele, R. A., Khoury, E., Mancini, G. B. J., Mccrindle, B. W., Paquette, M., Ruel, I., Cuevas, A., Asenjo, S., Wang, X., Meng, K., Song, X., Yong, Q., Jiang, T., Liu, Z., Duan, Y., Hong, J., Ye, P., Chen, Y., Qi, J., Li, Y., Zhang, C., Peng, J., Yang, Y., Yu, W., Wang, Q., Yuan, H., Cheng, S., Jiang, L., Chong, M., Jiao, J., Wu, Y., Wen, W., Xu, L., Zhang, R., Qu, Y., He, J., Fan, X., Wang, Z., Chow, E., Pecin, I., Perica, D., Symeonides, P., Vrablik, M., Ceska, R., Soska, V., Tichy, L., Adamkova, V., Franekova, J., Cifkova, R., Kraml, P., Vonaskova, K., Cepova, J., Dusejovska, M., Pavlickova, L., Blaha, V., Rosolova, H., Nussbaumerova, B., Cibulka, R., Vaverkova, H., Cibickova, L., Krejsova, Z., Rehouskova, K., Malina, P., Budikova, M., Palanova, V., Solcova, L., Lubasova, A., Podzimkova, H., Bujdak, J., Vesely, J., Jordanova, M., Salek, T., Urbanek, R., Zemek, S., Lacko, J., Halamkova, H., Machacova, S., Mala, S., Cubova, E., Valoskova, K., Burda, L., Bendary, A., Daoud, I., Emil, S., Elbahry, A., Rafla, S., Sanad, O., Kazamel, G., Ashraf, M., Sobhy, M., El-Hadidy, A., Shafy, M. A., Kamal, S., Bendary, M., Talviste, G., Angoulvant, D., Boccara, F., Cariou, B., Carreau, V., Carrie, A., Charrieres, S., Cottin, Y., Di-Fillipo, M., Ducluzeau, P. H., Dulong, S., Durlach, V., Farnier, M., Ferrari, E., Ferrieres, D., Ferrieres, J., Gallo, A., Hankard, R., Inamo, J., Lemale, J., Moulin, P., Paillard, F., Peretti, N., Perrin, A., Pradignac, A., Rabes, J. P., Rigalleau, V., Sultan, A., Schiele, F., Tounian, P., Valero, R., Verges, B., Yelnik, C., Ziegler, O., Haack, I. A., Schmidt, N., Dressel, A., Klein, I., Christmann, J., Sonntag, A., Stumpp, C., Boger, D., Biedermann, D., Usme, M. M. N., Beil, F. U., Klose, G., Konig, C., Gouni-Berthold, I., Otte, B., Boll, G., Kirschbaum, A., Merke, J., Scholl, J., Segiet, T., Gebauer, M., Predica, F., Mayer, M., Leistikow, F., Fullgraf-Horst, S., Muller, C., Schuler, M., Wiener, J., Hein, K., Baumgartner, P., Kopf, S., Busch, R., Schomig, M., Matthias, S., Allendorf-Ostwald, N., Fink, B., Bohm, D., Jakel, A., Koschker, A. -C., Schweizer, R., Vogt, A., Parhofer, K., Konig, W., Reinhard, W., Bassler, A., Stadelmann, A., Schrader, V., Katzmann, J., Tarr, A., Steinhagen-Thiessen, E., Kassner, U., Paulsen, G., Homberger, J., Zemmrich, C., Seeger, W., Biolik, K., Deiss, D., Richter, C., Pantchechnikova, E., Dorn, E., Schatz, U., Julius, U., Spens, A., Wiesner, T., Scholl, M., Rizos, C. V., Sakkas, N., Elisaf, M., Skoumas, I., Tziomalos, K., Rallidis, L., Kotsis, V., Doumas, M., Athyros, V., Skalidis, E., Kolovou, G., Garoufi, A., Bilianou, E., Koutagiar, I., Agapakis, D., Kiouri, E., Antza, C., Katsiki, N., Zacharis, E., Attilakos, A., Sfikas, G., Koumaras, C., Anagnostis, P., Anastasiou, G., Liamis, G., Koutsogianni, A. -D., Karanyi, Z., Harangi, M., Bajnok, L., Audikovszky, M., Mark, L., Benczur, B., Reiber, I., Nagy, G., Nagy, A., Reddy, L. L., Shah, S. A. V., Ponde, C. K., Dalal, J. J., Sawhney, J. P. S., Verma, I. C., Altaey, M., Al-Jumaily, K., Rasul, D., Abdalsahib, A. F., Jabbar, A. A., Al-ageedi, M., Agar, R., Cohen, H., Ellis, A., Gavishv, D., Harats, D., Henkin, Y., Knobler, H., Leavit, L., Leitersdorf, E., Rubinstein, A., Schurr, D., Shpitzen, S., Szalat, A., Casula, M., Zampoleri, V., Gazzotti, M., Olmastroni, E., Sarzani, R., Ferri, C., Repetti, E., Sabba, C., Bossi, A. C., Borghi, C., Muntoni, S., Cipollone, F., Purrello, F., Pujia, A., Passaro, A., Marcucci, R., Pecchioli, V., Pisciotta, L., Mandraffino, G., Pellegatta, F., Mombelli, G., Branchi, A., Fiorenza, A. M., Pederiva, C., Werba, J. P., Parati, G., Carubbi, F., Iughetti, L., Iannuzzi, A., Iannuzzo, G., Calabro, P., Averna, M., Biasucci, G., Zambon, S., Roscini, A. R., Trenti, C., Arca, M., Federici, M., Del Ben, M., Bartuli, A., Giaccari, A., Pipolo, A., Citroni, N., Guardamagna, O., Bonomo, K., Benso, A., Biolo, G., Maroni, L., Lupi, A., Bonanni, L., Zenti, M. G., Matsuki, K., Hori, M., Ogura, M., Masuda, D., Kobayashi, T., Nagahama, K., Al-Jarallah, M., Radovic, M., Lunegova, O., Bektasheva, E., Khodzhiboboev, E., Erglis, A., Gilis, D., Nesterovics, G., Saripo, V., Meiere, R., Upena-RozeMicena, A., Terauda, E., Jambart, S., Khoury, P. E., Elbitar, S., Ayoub, C., Ghaleb, Y., Aliosaitiene, U., Kutkiene, S., Kasim, N. A. M., Nor, N. S. M., Ramli, A. S., Razak, S. A., Al-Khateeb, A., Kadir, S. H. S. A., Muid, S. A., Rahman, T. A., Kasim, S. S., Radzi, A. B. M., Ibrahim, K. S., Razali, S., Ismail, Z., Ghani, R. A., Hafidz, M. I. A., Chua, A. L., Rosli, M. M., Annamalai, M., Teh, L. K., Razali, R., Chua, Y. A., Rosman, A., Sanusi, A. R., Murad, N. A. A., Jamal, A. R. A., Nazli, S. A., Razman, A. Z., Rosman, N., Rahmat, R., Hamzan, N. S., Azzopardi, C., Mehta, R., Martagon, A. J., Ramirez, G. A. G., Villa, N. E. A., Vazquez, A. V., Elias-Lopez, D., Retana, G. G., Rodriguez, B., Macias, J. J. C., Zazueta, A. R., Alvarado, R. M., Portano, J. D. M., Lopez, H. A., Sauque-Reyna, L., Herrera, L. G. G., Mendia, L. E. S., Aguilar, H. G., Cooremans, E. R., Aparicio, B. P., Zubieta, V. M., Gonzalez, P. A. C., Ferreira-Hermosillo, A., Portilla, N. C., Dominguez, G. J., Garcia, A. Y. R., Cazares, H. E. A., Gonzalez, J. R., Valencia, C. V. M., Padilla, F. G., Prado, R. M., De los Rios Ibarra, M. O., Villicana, R. D. A., Rivera, K. J. A., Carrera, R. A., Alvarez, J. A., Martinez, J. C. A., de los Reyes Barrera Bustillo, M., Vargas, G. C., Chacon, R. C., Andrade, M. H. F., Ortega, A. F., Alcala, H. G., de Leon, L. E. G., Guzman, B. G., Garcia, J. J. G., Cuellar, J. C. G., Cruz, J. R. G., Garcia, A. H., Almada, J. R. H., Herrera, U. J., Sobrevilla, F. L., Rodriguez, E. M., Sibaja, C. M., Rodriguez, A. B. M., Oyervides, J. C. M., Vazquez, D. I. P., Rodriguez, E. A. R., Osorio, M. L. R., Saucedo, J. R., Tamayo, M. T., Talavera, L. A. V., Arroyo, L. E. V., Carrillo, E. A. Z., Isara, A., Obaseki, D. E., Al-Waili, K., Al-Zadjali, F., Al-Zakwani, I., Al-Kindi, M., Al-Mukhaini, S., Al-Barwani, H., Rana, A., Shah, L. S. U., Starostecka, E., Konopka, A., Lewek, J., Bartlomiejczyk, M., Gasior, M., Dyrbus, K., Jozwiak, J., Gruchala, M., Pajkowski, M., Romanowska-Kocejko, M., Zarczynska-Buchowiecka, M., Chmara, M., Wasag, B., Parczewska, A., Gilis-Malinowska, N., Borowiec-Wolna, J., Strozyk, A., Wos, M., Michalska-Grzonkowska, A., Medeiros, A. M., Alves, A. C., Silva, F., Lobarinhas, G., Palma, I., de Moura, J. P., Rico, M. T., Rato, Q., Pais, P., Correia, S., Moldovan, O., Virtuoso, M. J., Salgado, J. M., Colaco, I., Dumitrescu, A., Lengher, C., Mosteoru, S., Meshkov, A., Ershova, A., Rozkova, T., Korneva, V., Yu, K. T., Zafiraki, V., Voevoda, M., Gurevich, V., Duplyakov, D., Ragino, Y., Safarova, M., Shaposhnik, I., Alkaf, F., Khudari, A., Rwaili, N., Al-Allaf, F., Alghamdi, M., Batais, M. A., Almigbal, T. H., Kinsara, A., Alqudaimi, A. H. A., Awan, Z., Elamin, O. A., Altaradi, H., Rajkovic, N., Popovic, L., Singh, S., Stosic, L., Rasulic, I., Lalic, N. M., Lam, C., Le, T. J., Siang, E. L. T., Dissanayake, S., I-Shing, J. T., Shyong, T. E., Jin, T. C. S., Balinth, K., Buganova, I., Fabryova, L., Kadurova, M., Klabnik, A., Kozarova, M., Sirotiakova, J., Battelino, T., Kovac, J., Mlinaric, M., Sustar, U., Podkrajsek, K. T., Fras, Z., Jug, B., Cevc, M., Pilcher, G. J., Blom, D. J., Wolmarans, K. H., Brice, B. C., Muniz-Grijalvo, O., Diaz-Diaz, J. L., de Isla, L. P., Fuentes, F., Badimon, L., Martin, F., Lux, A., Chang, N. -T., Ganokroj, P., Akbulut, M., Alici, G., Bayram, F., Can, L. H., Celik, A., Ceyhan, C., Coskun, F. Y., Demir, M., Demircan, S., Dogan, V., Durakoglugil, E., Dural, I. E., Gedikli, O., Hacioglu, A., Ildizli, M., Kilic, S., Kirilmaz, B., Kutlu, M., Oguz, A., Ozdogan, O., Onrat, E., Ozer, S., Sabuncu, T., Sahin, T., Sivri, F., Sonmez, A., Temizhan, A., Topcu, S., Tuncez, A., Vural, M., Yenercag, M., Yesilbursa, D., Yigit, Z., Yildirim, A. B., Yildirir, A., Yilmaz, M. B., Atallah, B., Traina, M., Sabbour, H., Hay, D. A., Luqman, N., Elfatih, A., Abdulrasheed, A., Kwok, S., Oca, N. D., Reyes, X., Alieva, R. B., Kurbanov, R. D., Hoshimov, S. U., Nizamov, U. I., Ziyaeva, A. V., Abdullaeva, G. J., Do, D. L., Nguyen, M. N. T., Kim, N. T., Le, T. T., Le, H. A., Tokgozoglu, L., Catapano, A. L., Ray, K. K., and EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC), Borghi C
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Male ,Settore MED/09 - Medicina Interna ,Arterial disease ,Cross-sectional study ,Adult population ,Coronary Disease ,Disease ,Global Health ,Medical and Health Sciences ,Doenças Cardio e Cérebro-vasculares ,Anticholesteremic Agent ,Monoclonal ,Prevalence ,Registries ,Familial Hypercholesterolemia ,Humanized ,Stroke ,11 Medical and Health Sciences ,LS2_9 ,Studies Collaboration ,Anticholesteremic Agents ,General Medicine ,Heart Disease Risk Factor ,Middle Aged ,FHSC global registry data ,Europe ,Treatment Outcome ,Lower prevalence ,Guidance ,lipids (amino acids, peptides, and proteins) ,Female ,Proprotein Convertase 9 ,Familial hypercholesterolaemia ,Life Sciences & Biomedicine ,Human ,Adult ,medicine.medical_specialty ,Combination therapy ,FHSC global registry, heterozygous familial hypercholesterolaemia ,Cardiovascular risk factors ,Antibodies, Monoclonal, Humanized ,Insights ,Antibodies ,NO ,Hyperlipoproteinemia Type II ,Clinician ,Medicine, General & Internal ,Internal medicine ,General & Internal Medicine ,Health Sciences ,medicine ,Humans ,EAS Familial Hypercholesterolaemia Studies Collaboration (FHSC) ,Cross-Sectional Studie ,Science & Technology ,Global Perspective ,business.industry ,Cholesterol, LDL ,medicine.disease ,Cross-Sectional Studies ,Heart Disease Risk Factors ,Hydroxymethylglutaryl-CoA Reductase Inhibitor ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business - Abstract
Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.
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- 2021
24. Effects of evolocumab therapy and low LDL‐C levels on vitamin E and steroid hormones in Chinese and global patients with type 2 diabetes
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Zuyi Yuan, Junbo Ge, Maria Laura Monsalvo, João Lindolfo C. Borges, Nan Wang, Jiyan Chen, Dirk J. Blom, and Andrew Hamer
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medicine.medical_specialty ,endocrine system ,dyslipidaemia ,medicine.drug_class ,PCSK9 inhibitor ,Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Type 2 diabetes ,Adrenocorticotropic hormone ,lcsh:Diseases of the endocrine glands. Clinical endocrinology ,Internal medicine ,medicine ,Testosterone ,hypercholesterolaemia ,lcsh:RC648-665 ,diabetes ,business.industry ,Vitamin E ,Original Articles ,medicine.disease ,Evolocumab ,Steroid hormone ,Endocrinology ,Original Article ,Gonadotropin ,business ,hormones, hormone substitutes, and hormone antagonists ,Hormone - Abstract
Aims We assessed the change from baseline in vitamin E, steroid hormones, adrenocorticotropic hormone (ACTH), and gonadotropins, overall and by lowest achieved low‐density lipoprotein‐cholesterol (LDL‐C) level, in patients with type 2 diabetes and dyslipidaemia after 12 weeks of treatment with evolocumab. Materials and Methods This was a prespecified analysis of vitamin E, cortisol, ACTH, gonadal hormones and gonadotropins in the 12‐week, placebo‐controlled BERSON trial of evolocumab in patients with type 2 diabetes and dyslipidaemia. In BERSON, 981 (451 in China) patients on daily atorvastatin 20 mg were randomized to placebo or one of two doses of evolocumab. We measured analyte levels at baseline and week 12 (vitamin E in all patients; steroid/gonadal hormones only in Chinese patients). Results In both the global and Chinese populations, absolute vitamin E levels decreased from baseline to week 12 by approximately 6 μmol/L (P, In this prespecified analysis of the BERSON study in Chinese and global patients with type 2 diabetes and dyslipidaemia, we assessed the change from baseline in vitamin E, steroid hormones, adrenocorticotropic hormone (ACTH), and gonadotropins, overall and by lowest achieved low‐density lipoprotein‐cholesterol (LDL‐C) level after 12 weeks of treatment with evolocumab. We found that evolocumab did not adversely affect vitamin E, steroid hormone or gonadotropin levels in the Chinese or global type 2 diabetic populations.
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- 2020
25. Efficacy and Safety of Alirocumab in Adults With Homozygous Familial Hypercholesterolemia: The ODYSSEY HoFH Trial
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Dirk J, Blom, Mariko, Harada-Shiba, Paolo, Rubba, Daniel, Gaudet, John J P, Kastelein, Min-Ji, Charng, Robert, Pordy, Stephen, Donahue, Shazia, Ali, Yuping, Dong, Nagwa, Khilla, Poulabi, Banerjee, Marie, Baccara-Dinet, and Robert S, Rosenson
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Adult ,Male ,Dose-Response Relationship, Drug ,Homozygote ,Cholesterol, LDL ,Middle Aged ,Antibodies, Monoclonal, Humanized ,Hyperlipoproteinemia Type II ,Treatment Outcome ,Double-Blind Method ,Risk Factors ,Humans ,Female ,Biomarkers - Abstract
Homozygous familial hypercholesterolemia (HoFH) is characterized by extremely elevated low-density lipoprotein-cholesterol (LDL-C) levels and early onset atherosclerotic cardiovascular disease despite treatment with conventional lipid-lowering treatment.This study was designed to assess LDL-C reduction with the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab in adult patients with HoFH.This randomized, double-blind, placebo-controlled, parallel-group, phase 3 study evaluated efficacy and safety of alirocumab 150 mg every 2 weeks. The primary endpoint was percent reduction from baseline in LDL-C versus placebo after 12 weeks of treatment.Patients (N = 69) were randomized 2:1 to alirocumab or placebo. At baseline, background lipid-lowering treatment included 67 patients receiving statin (59 patients on high-intensity statin); 50 patients on ezetimibe; 10 patients on lomitapide; and 10 patients undergoing apheresis. Mean baseline LDL-C was 259.6 mg/dl in the placebo group and 295.0 mg/dl in the alirocumab group. At week 12, the least squares mean difference in LDL-C percent change from baseline was -35.6% (alirocumab [-26.9%] vs. placebo [8.6%]; p 0.0001). Reductions (least squares mean difference) in other atherogenic lipids at week 12 were: apolipoprotein B, -29.8%; non-high-density lipoprotein cholesterol, -32.9%; total cholesterol, -26.5%; and lipoprotein(a), -28.4% (all p 0.0001). No serious adverse events, permanent treatment discontinuations, or deaths due to treatment-emergent adverse events were reported during the double-blind treatment period.In the largest randomized controlled interventional trial in HoFH patients to date, alirocumab resulted in significant and clinically meaningful reductions in LDL-C at week 12. Alirocumab was generally well tolerated, with a safety profile comparable to that of placebo. (Study in Participants With Homozygous Familial Hypercholesterolemia [HoFH] [ODYSSEY HoFH] NCT03156621.).
- Published
- 2020
26. Protocol for systematic review and meta-analysis: impact of statins as immune-modulatory agents on inflammatory markers in adults with chronic diseases
- Author
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Robert J. Wilkinson, Mumin Ozturk, Bongani Motaung, Emmanuel Nepolo, Sandra Mukasa, Reto Guler, Dirk J. Blom, Claudia Schacht, Friedrich Thienemann, Solima Sabeel, Karen Sliwa, Gunar Günther, Andre Pascal Kengne, University of Zurich, Wellcome Trust, and EDCTP
- Subjects
Adult ,Simvastatin ,medicine.medical_specialty ,Statin ,medicine.drug_class ,Atorvastatin ,610 Medicine & health ,2700 General Medicine ,Cochrane Library ,infectious diseases ,1117 Public Health and Health Services ,immunology ,Meta-Analysis as Topic ,Internal medicine ,medicine ,Humans ,molecular biology ,Rosuvastatin ,Immunology (Including Allergy) ,business.industry ,microbiology ,nutritional and metabolic diseases ,1103 Clinical Sciences ,General Medicine ,Systematic review ,Meta-analysis ,Chronic Disease ,Medicine ,lipids (amino acids, peptides, and proteins) ,clinical pharmacology ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,10029 Clinic and Policlinic for Internal Medicine ,business ,Pravastatin ,Systematic Reviews as Topic ,medicine.drug ,Fluvastatin ,1199 Other Medical and Health Sciences - Abstract
Introduction: Statins, also known as 3-Hydroxy-3-Methylglutaryl Co-A (HMG-CoA) reductase inhibitors, are lipid-lowering agents that are central in preventing or reducing the complications of atherosclerotic cardiovascular disease. Because statins have anti-inflammatory properties, there is considerable interest in their therapeutic potential in other chronic inflammatory conditions. We aim to identify the statin with the greatest ability to reduce systemic inflammation, independent of the underlying disease entity. Methods and analysis: We aim to conduct a comprehensive search of published and peer-reviewed randomized controlled clinical trials (RCT), with at least one intervention arm of an FDA or EMA-licensed statin and a minimum treatment duration of 12 weeks. Our objective is to investigate the effect of statins (atorvastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin) on lipid profile, particularly, cholesterol low-density lipoprotein (LDL-C) and inflammation markers such as hsCRP, CRP, TNF-α, IL-1β, IL-6, IL-8, sCD14, or sCD16 in adults, published in the last 20 years (between January 1999 and December 2019). We aim to identify the most potent statin to reduce systemic inflammation and optimal dosing. The following databases will be searched: Medline, Scopus, Web of Science, and Cochrane Library of Systematic Reviews. The risk of bias of included studies will be assessed by Cochrane Risk of Bias tool and Quality Assessment Tool for Quantitative Studies. The quality of studies will be assessed, to show uncertainty, by the Jadad score. If sufficient evidence is identified, a meta-analysis will be conducted with risk ratios or odds ratios with 95% confidence intervals (CI) in addition to mean differences. Ethics and dissemination: Ethics approval is not required as no primary data will be collected. Results will be presented at conferences and published in a peer-review journal. PROSPERO registration number: Pending Strengths and limitations of this study • This study will include randomized controlled clinical trials to determine the most effective statin on the combined reduction of lipid profile and inflammatory biomarkers. • High-quality clinical trials will be reviewed accurately to generate reliable evidence. • This study will be conducted following Preferred Reporting Items for Systematic Review and Meta-Analysis Protocol (PRISMA-P) guidelines. • Variation of statin doses among included studies will likely produce heterogeneity that will subsequently reduce the sample size of the meta-analysis.
- Published
- 2020
27. Heterozygous familial hypercholesterolaemia in specialist centres in South Africa, Australia and Brazil: Importance of early detection and lifestyle advice
- Author
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Cinthia E. Jannes, Alexandre C. Pereira, Jing Pang, Kausik K. Ray, Dirk J. Blom, Brigitte C. Brice, Raul D. Santos, Pamela R.S. Silva, A. David Marais, Amanda J. Hooper, and Gerald F. Watts
- Subjects
Adult ,Genetic Markers ,Male ,Heterozygote ,Early detection ,Comorbidity ,Coronary Artery Disease ,030204 cardiovascular system & hematology ,Risk Assessment ,Hyperlipoproteinemia Type II ,South Africa ,03 medical and health sciences ,Sex Factors ,0302 clinical medicine ,Predictive Value of Tests ,Risk Factors ,Diabetes mellitus ,Humans ,Medicine ,Genetic Predisposition to Disease ,In patient ,Healthy Lifestyle ,030212 general & internal medicine ,Myocardial infarction ,business.industry ,Atherosclerotic cardiovascular disease ,Smoking ,Age Factors ,Genetic variants ,Cholesterol, LDL ,Western Australia ,Middle Aged ,Prognosis ,medicine.disease ,Early Diagnosis ,Phenotype ,Lifestyle advice ,Mutation ,Disease risk ,Female ,Smoking Cessation ,Cardiology and Cardiovascular Medicine ,business ,Risk Reduction Behavior ,Biomarkers ,Brazil ,BRASILEIROS ,Demography - Abstract
Familial hypercholesterolaemia (FH) is the commonest monogenic disorder that accelerates atherosclerotic cardiovascular disease. We compared and contrasted the characteristics of patients from three specialist centres in the southern hemisphere.Adult index-cases with molecularly diagnosed heterozygous FH attending specialist lipid centres in Cape Town, Perth and São Paulo were studied. Myocardial infarction, revascularisation, hypertension, diabetes, smoking and lipid-lowering treatment were recorded at the time of diagnosis and compared across the three centres.The spectrum of genetic variants causative of FH was significantly different in patients attending the centres in South Africa compared with Australia and Brazil. Hypertension and diabetes were more prevalent in Brazilian and Australian patients, than in South African patients, but the frequency of smoking was significantly greater in South Africa than the other two centres (p0.01). Age, male sex and smoking were significant independent predictors of coronary artery disease (CAD) in all three countries (p0.05).Patients with FH in three specialist centres in the southern hemisphere exhibit a high prevalence of non-cholesterol cardiovascular disease risk factors. Older age, male sex and smoking were more common among subjects with CAD. In all three countries, there should be vigorous programmes for the control of risk factors beyond good control of hypercholesterolaemia among patients with FH. Promotion of a healthy lifestyle, especially anti-smoking advice, is of paramount importance.
- Published
- 2018
28. Lomitapide and Mipomersen—Inhibiting Microsomal Triglyceride Transfer Protein (MTP) and apoB100 Synthesis
- Author
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Frederick J. Raal, Dirk J. Blom, A. David Marais, and Raul D. Santos
- Subjects
Cardiovascular event ,Apolipoprotein B ,Mipomersen ,Oligonucleotides ,030204 cardiovascular system & hematology ,Pharmacology ,Microsomal triglyceride transfer protein ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,Subcutaneous injection ,chemistry.chemical_compound ,0302 clinical medicine ,Microsomes ,Humans ,Medicine ,In patient ,030212 general & internal medicine ,Liver injury ,biology ,business.industry ,Anticholesteremic Agents ,medicine.disease ,Lomitapide ,chemistry ,Cardiovascular Diseases ,Apolipoprotein B-100 ,biology.protein ,Benzimidazoles ,Carrier Proteins ,Cardiology and Cardiovascular Medicine ,business - Abstract
The goal of this review is to evaluate the role of inhibiting the synthesis of lipoproteins when there is no or little residual LDL-receptor function as in patients with homozygous familial hypercholesterolaemia. Lomitapide is administered orally once a day while mipomersen is given by subcutaneous injection once a week. Lomitapide inhibits microsomal triglyceride transfer protein while mipomersen is an antisense oligonucleotide directed against apoB100. The pivotal registration trials for lomitapide and mipomersen were published in 2013 and 2010, respectively. More recently published data from extension trials and cohort studies provides additional information on long-term safety and efficacy. The mean LDL cholesterol reduction was 50% with lomitapide in its single-arm open-label registration trial. Mipomersen reduced LDL cholesterol by approximately 25% in its double-blind, placebo-controlled registration study. Both lomitapide and mipomersen therapy are associated with variable increases in hepatic fat content. The long-term safety of increased hepatic fat content in patients receiving these therapies is uncertain and requires further study. Both drugs may cause elevated transaminase in some patients, but no cases of severe liver injury have been reported. Lomitapide may also cause gastrointestinal discomfort and diarrhoea, especially if patients consume high-fat meals and patients are advised to follow a low-fat diet supplemented with essential fatty acids and fat-soluble vitamins. Mipomersen may cause injection-site and influenza-like reactions. The effect of lomitapide and mipomersen on cardiovascular outcomes has not been studied, but circumstantial evidence suggests that the LDL cholesterol lowering achieved with these two agents may reduce cardiovascular event rates.
- Published
- 2019
29. Target achievement and cardiovascular event rates with Lomitapide in homozygous Familial Hypercholesterolaemia
- Author
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Helen Phillips, Dirk J. Blom, Miranda Ager, Marina Cuchel, Division of Lipidology, and Faculty of Health Sciences
- Subjects
Cardiovascular event ,Male ,Target ,medicine.medical_specialty ,Major adverse cardiovascular event ,Mipomersen ,Oligonucleotides ,Phases of clinical research ,lcsh:Medicine ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Low-density lipoprotein cholesterol ,030212 general & internal medicine ,Coronary Artery Bypass ,Genetics (clinical) ,Number needed to treat ,business.industry ,Research ,Homozygote ,lcsh:R ,Antibodies, Monoclonal ,General Medicine ,Cholesterol, LDL ,Lomitapide ,Evolocumab ,chemistry ,Cohort ,(3–10): Homozygous familial hypercholesterolemia ,Benzimidazoles ,Female ,business ,Mace - Abstract
Background Homozygous familial hypercholesterolaemia (HoFH) is characterized by a markedly increased risk of premature cardiovascular (CV) events and cardiac death. Lomitapide reduces low-density lipoprotein cholesterol (LDL-C) levels; however, the probable impact on LDL-C goals and CV events is unknown. Methods We used data collected in the first 26 weeks of the lomitapide pivotal phase 3 study (NCT00730236) to evaluate achievement of European Atherosclerosis Society (EAS) LDL-C targets. We used publicly available data reporting major adverse CV events (MACE) rates from other cohorts of HoFH patients to compare event rates for an equivalent number of patient years of exposure (98) in the lomitapide extension trial (NCT00943306). Results Twenty-nine patients were included in the phase 3 study. During the first 26 weeks, 15 (51%) and eight (28%) reached LDL-C targets of 100 mg/dL and 70 mg/dL, respectively, at least once. Fourteen (74%) and 11 (58%) of the 19 patients who remained in the extension study after week 126 reached LDL-C targets of 100 mg/dL and 70 mg/dL at least once during the entire study period. Only two MACE were reported in the lomitapide trials (one cardiac death and one coronary artery bypass graft (CABG)) – equivalent to 1.7 events per 1000 patient months of treatment. MACE rates were 21.7, 9.5 and 1.8 per 1000 patient-months respectively in cohorts of HoFH patients pre- and post-mipomersen, and receiving evolocumab. On treatment LDL-C levels were 166, 331 and 286 mg/dL for lomitapide, mipomersen and evolocumab, respectively. Conclusions Approximately three quarters and half of patients who took lomitapide for at least 2 years reached LDL-C goals of 100 mg/dL and 70 mg/dL, respectively. There were fewer major CV events per 1000 patient months of treatment in patients taking lomitapide, mipomersen or evolocumab than reported in the mipomersen cohort prior to starting mipomersen. These results support the hypothesis that novel lipid-lowering therapies may reduce CV events in HoFH patients by lowering LDL-C further. Trial registration NCT00730236 (registered 8 Aug 2008) and NCT00943306 (registered 22 July 2009).
- Published
- 2018
30. Efficacy and Safety of Alirocumab Versus Ezetimibe Over 2 Years (from ODYSSEY COMBO II)
- Author
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Dirk J. Blom, Helen M. Colhoun, Christopher P. Cannon, James M. McKenney, Umesh Chaudhari, Guillaume Lecorps, Robert Pordy, Mahfouz El Shahawy, and Bertrand Cariou
- Subjects
Male ,Time Factors ,Clinical Trial, Phase III ,Coronary Disease ,030204 cardiovascular system & hematology ,law.invention ,chemistry.chemical_compound ,0302 clinical medicine ,Randomized controlled trial ,law ,030212 general & internal medicine ,Lipoprotein cholesterol ,Anticholesteremic Agents ,Antibodies, Monoclonal ,Middle Aged ,Multicenter Study ,Treatment Outcome ,Randomized Controlled Trial ,Cardiology ,Female ,Cardiology and Cardiovascular Medicine ,medicine.drug ,medicine.medical_specialty ,Statin ,Post hoc ,medicine.drug_class ,Injections, Subcutaneous ,Clinical Decision-Making ,Hypercholesterolemia ,Urology ,Antibodies, Monoclonal, Humanized ,Medication Adherence ,03 medical and health sciences ,Double-Blind Method ,Ezetimibe ,Internal medicine ,Journal Article ,medicine ,Humans ,Alirocumab ,Dose-Response Relationship, Drug ,business.industry ,Cholesterol ,Cholesterol, LDL ,Clinical trial ,chemistry ,business ,Follow-Up Studies - Abstract
The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab has been shown to substantially reduce low-density lipoprotein cholesterol (LDL-C). Demonstrating whether efficacy and safety are maintained over a long duration of exposure is vital for clinical decision-making. The COMBO II trial compared the efficacy and safety of alirocumab versus ezetimibe over 2 years. A prespecified first analysis was reported at 52 weeks. Here we report the final end-of-study data (on-treatment) and evaluate post hoc the safety profile with longer versus shorter duration of alirocumab exposure. Patients (n = 720) on maximally tolerated statin dose were treated with alirocumab (75/150 mg every 2 weeks) or ezetimibe (10 mg/day). Overall mean adherence for both treatment groups during the first and second year was >97%. At 2 years, LDL-C was reduced by 49% (alirocumab) versus 17% (ezetimibe; p
- Published
- 2017
31. Long-Term Efficacy and Safety of the Microsomal Triglyceride Transfer Protein Inhibitor Lomitapide in Patients With Homozygous Familial Hypercholesterolemia
- Author
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Dominique Larrey, Daniel J. Rader, Pamela Foulds, Claudia Stefanutti, Emma A. Meagher, LeAnne T. Bloedon, Daniel Gaudet, Dirk J. Blom, Maurizio Averna, Cesare R. Sirtori, Giovanni Battista Vigna, Robert A. Hegele, Marina Cuchel, Hendrik Du Toit Theron, Prediman K. Shah, Blom, D., Averna, M., Meagher, E., Toit Theron, H., Sirtori, C., Hegele, R., Shah, P., Gaudet, D., Stefanutti, C., Vigna, G., Larrey, D., Bloedon, L., Foulds, P., Rader, D., and Cuchel, M.
- Subjects
Adult ,Male ,medicine.medical_specialty ,Settore MED/09 - Medicina Interna ,Apolipoprotein B ,Socio-culturale ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Gastroenterology ,Microsomal triglyceride transfer protein ,LDL ,Time ,Sudden cardiac death ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,lomitapide ,biology ,business.industry ,Cholesterol ,Anticholesteremic Agents ,Cholesterol, LDL ,Benzimidazoles ,Carrier Proteins ,Female ,medicine.disease ,Lomitapide ,Endocrinology ,chemistry ,biology.protein ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,business ,Lipoprotein - Abstract
Homozygous familial hypercholesterolemia is a genetic disorder characterized by low-density lipoprotein (LDL)-receptor dysfunction, markedly elevated levels of LDL-cholesterol (LDL-C) and premature atherosclerosis. Patients are often poorly responsive to conventional lipid-lowering therapies that upregulate LDL-receptor expression.1 Lomitapide inhibits microsomal triglyceride transfer protein, which lipidates nascent apolipoprotein (apo)B-containing lipoproteins. In a pivotal 78-week open-label trial, lomitapide, titrated to the maximal tolerable dose, decreased LDL-C by 50% at the end of the efficacy phase (week 26) in patients with homozygous familial hypercholesterolemia.2 The principal adverse events included gastrointestinal disturbances, hepatic enzyme elevations, and increased liver fat. Here we provide additional long-term efficacy and safety data, including an exploratory analysis of the potential metabolic consequences of hepatic fat accumulation from an extension trial (NCT00943306). Patients continued on lomitapide at the maximally tolerated dose until transition to commercial or compassionate lomitapide. Lipid-lowering therapies, including apheresis, could be modified at the investigator’s discretion if LDL-C was
- Published
- 2017
32. Survival in homozygous familial hypercholesterolaemia is determined by the on-treatment level of serum cholesterol
- Author
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Mary Seed, Gilbert R. Thompson, Dirk J. Blom, Gillian J. Pilcher, A. David Marais, and Frederick J. Raal
- Subjects
Male ,Cardiac & Cardiovascular Systems ,Atorvastatin ,PLASMA-EXCHANGE ,Kaplan-Meier Estimate ,ATORVASTATIN ,030204 cardiovascular system & hematology ,PLACEBO-CONTROLLED TRIAL ,DOUBLE-BLIND ,chemistry.chemical_compound ,0302 clinical medicine ,Risk Factors ,030212 general & internal medicine ,Anticholesteremic Agents ,Homozygote ,Confounding ,Hazard ratio ,Cholesterol ,Treatment Outcome ,Quartile ,Female ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,Life Sciences & Biomedicine ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,INHIBITION ,LIPID-LOWERING THERAPY ,1102 Cardiovascular Medicine And Haematology ,PANEL ,Hyperlipoproteinemia Type II ,Young Adult ,03 medical and health sciences ,Ezetimibe ,Internal medicine ,MANAGEMENT ,medicine ,Humans ,CORONARY-HEART-DISEASE ,Retrospective Studies ,Science & Technology ,business.industry ,Statins ,ATHEROSCLEROSIS SOCIETY ,Evolocumab ,Survival Analysis ,Cardiovascular System & Hematology ,chemistry ,Cardiovascular System & Cardiology ,Apheresis ,business ,Mace - Abstract
Aims Homozygous familial hypercholesterolaemia (FH) is a rare inherited disorder characterized by extreme hypercholesterolaemia from birth, accelerated atherosclerosis, and premature death. Many forms of lipid-lowering therapies have been used in the past, but definitive evidence of benefit has been lacking. We therefore undertook a retrospective survey of lipid levels and clinical outcomes of FH homozygotes treated with a combination of lipid-lowering measures between 1990 and 2014 in South Africa and the UK. Methods and results We divided 133 previously statin-naive homozygotes into quartiles according to their on-treatment levels of serum cholesterol and compared the occurrence of any death, cardiovascular death, and major adverse cardiovascular events (MACE) between the quartiles during 25 years of follow-up, using Cox and competing risks regression analysis. Patients in Quartile 4, with an on-treatment serum cholesterol >15.1 mmol/L, had a hazard ratio of 11.5 for any death compared with those in Quartile 1, with an on-treatment cholesterol of
- Published
- 2017
33. Autoantibodies against GPIHBP1 as a Cause of Hypertriglyceridemia
- Author
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Sybil Charrière, Tetsuo Machida, Mikael Larsson, Philippe Moulin, Clive R. Pullinger, Weerapan Khovidhunkit, Xuchen Hu, Dirk J. Blom, Christopher M. Allan, Ira J. Goldberg, Norma P. Sandoval, Karen Reue, Robert Dufour, Katsuyuki Nakajima, Michael Ploug, Masumi Ai, Peter Tontonoz, Maureen McMahon, Stephen G. Young, Abhimanyu Garg, Anne P. Beigneux, Kazuya Miyashita, MacRae F. Linton, Masami Murakami, Loren G. Fong, School Medicine, Department Medicine, University of California [Los Angeles] (UCLA), University of California-University of California, Graduate School Medicine, Department Clinical Laboratory Medicine, Gunma University, Finsen Laboratory, Copenhagen Biocenter, Department Medicine, Universität Salzburg, Graduate School Medicine and and Dental Science, Insured Medical Care Management, Tokyo Medical and Dental University, Center Medicine, Department Medicine, Vanderbilt University [Nashville], Center Medicine, Department Pharmacology, Faculty Medicine, Department Medicine, Chulalongkorn University [Bangkok], Thai Red Cross Society, Institut Recherche Clinique Montreal, Clinique Préventive Cardiovasculaire, University of Montreal, Medicine Center Dallas, Department Medicine, University of Texas Southwestern Medical Center (UTSW), School Medicine, Department Rheumatologie, Cardiovascular Research Institute (UCSF), Cardiovascular Research Institute, School Medicine, Department Human Genetic, University of Utah, School Medicine, Department Pathology and Laboratory Medicine, School Medicine Department Medicine, Division Endocrinology Diabetology and Metabolic, New York University [New York] (NYU), NYU System (NYU)-NYU System (NYU), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Heart, Lung, and Blood Institute, Leducq Foundation, and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL)
- Subjects
Male ,0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Plasma protein binding ,030204 cardiovascular system & hematology ,Medical and Health Sciences ,0302 clinical medicine ,hydrolyse ,Receptors ,2.1 Biological and endogenous factors ,Aetiology ,Lipoprotein ,Immunoassay ,Lipoprotein lipase ,medicine.diagnostic_test ,GPIHBP1 ,General Medicine ,Middle Aged ,3. Good health ,Protein Transport ,Biochemistry ,lipoprotéine lipase ,endothelial cell ,Female ,Hyperlipoproteinemia Type I ,lipids (amino acids, peptides, and proteins) ,Protein Binding ,Biotechnology ,Adult ,medicine.medical_specialty ,medicine.drug_class ,Lipolysis ,hypertriglyceridemia ,lipoprotein lipase ,autoanticorps ,Monoclonal antibody ,03 medical and health sciences ,Western blot ,General & Internal Medicine ,Internal medicine ,medicine ,Humans ,triglyceride ,Receptors, Lipoprotein ,Autoantibodies ,business.industry ,Hypertriglyceridemia ,Autoantibody ,medicine.disease ,saccharification ,Lipoprotein Lipase ,030104 developmental biology ,Endocrinology ,hypertriglyceridemie ,business ,cellule endotheliale ,autoantibody - Abstract
BackgroundA protein that is expressed on capillary endothelial cells, called GPIHBP1 (glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1), binds lipoprotein lipase and shuttles it to its site of action in the capillary lumen. A deficiency in GPIHBP1 prevents lipoprotein lipase from reaching the capillary lumen. Patients with GPIHBP1 deficiency have low plasma levels of lipoprotein lipase, impaired intravascular hydrolysis of triglycerides, and severe hypertriglyceridemia (chylomicronemia). During the characterization of a monoclonal antibody-based immunoassay for GPIHBP1, we encountered two plasma samples (both from patients with chylomicronemia) that contained an interfering substance that made it impossible to measure GPIHBP1. That finding raised the possibility that those samples might contain GPIHBP1 autoantibodies.MethodsUsing a combination of immunoassays, Western blot analyses, and immunocytochemical studies, we tested the two plasma samples (as well as samples from other patients with chylomicronemia) for the presence of GPIHBP1 autoantibodies. We also tested the ability of GPIHBP1 autoantibodies to block the binding of lipoprotein lipase to GPIHBP1.ResultsWe identified GPIHBP1 autoantibodies in six patients with chylomicronemia and found that these autoantibodies blocked the binding of lipoprotein lipase to GPIHBP1. As in patients with GPIHBP1 deficiency, those with GPIHBP1 autoantibodies had low plasma levels of lipoprotein lipase. Three of the six patients had systemic lupus erythematosus. One of these patients who had GPIHBP1 autoantibodies delivered a baby with plasma containing maternal GPIHBP1 autoantibodies; the infant had severe but transient chylomicronemia. Two of the patients with chylomicronemia and GPIHBP1 autoantibodies had a response to treatment with immunosuppressive agents.ConclusionsIn six patients with chylomicronemia, GPIHBP1 autoantibodies blocked the ability of GPIHBP1 to bind and transport lipoprotein lipase, thereby interfering with lipoprotein lipase-mediated processing of triglyceride-rich lipoproteins and causing severe hypertriglyceridemia. (Funded by the National Heart, Lung, and Blood Institute and the Leducq Foundation.).
- Published
- 2017
34. Impact of Target‐Mediated Elimination on the Dose and Regimen of Evolocumab, a Human Monoclonal Antibody Against Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9)
- Author
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Dirk J. Blom, Sameer Doshi, Anita Grover, Scott M. Wasserman, John P. Gibbs, Mita Kuchimanchi, Michael G. Dodds, Ransi Somaratne, Megan A. Gibbs, and Maurice Emery
- Subjects
Male ,0301 basic medicine ,Hypercholesterolemia ,Biological Availability ,Pharmacology ,Antibodies, Monoclonal, Humanized ,Models, Biological ,030226 pharmacology & pharmacy ,PCSK9 ,03 medical and health sciences ,0302 clinical medicine ,Pharmacokinetics ,Humans ,Pharmacology (medical) ,Dosing ,LDL‐C ,Chemistry ,PCSK9 Inhibitors ,Antibodies, Monoclonal ,Cholesterol, LDL ,Middle Aged ,Proprotein convertase ,target‐mediated drug disposition ,Evolocumab ,Regimen ,030104 developmental biology ,monoclonal antibody ,Pharmacodynamics ,Kexin ,pharmacokinetic/pharmacodynamic ,Female - Abstract
Understanding the pharmacokinetic (PK) and pharmacodynamic (PD) relationship of a therapeutic monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9) exhibiting target‐mediated drug disposition (TMDD) is critical for selecting optimal dosing regimens. We describe the PK/PD relationship of evolocumab using a mathematical model that captures evolocumab binding and removal of unbound PCSK9 as well as reduction in circulating low‐density lipoprotein cholesterol (LDL‐C). Data were pooled from 2 clinical studies: a single‐dose escalation study in healthy subjects (7‐420 mg SC; n = 44) and a multiple‐dose escalation study in statin‐treated hypercholesterolemic patients (14 mg weekly to 420 mg monthly [QM] SC; n = 57). A TMDD model described the time course of unbound evolocumab concentrations and removal of unbound PCSK9. The estimated linear clearance and volume of evolocumab were 0.256 L/day and 2.66 L, respectively, consistent with other monoclonal antibodies. The time course of LDL‐C reduction was described by an indirect response model with the elimination rate of LDL‐C being modulated by unbound PCSK9. The concentration of unbound PCSK9 associated with half‐maximal inhibition (IC50) of LDL‐C elimination was 1.46 nM. Based on simulations, 140 mg every 2 weeks (Q2W) and 420 mg QM were predicted to achieve a similar time‐averaged effect of 69% reduction in LDL‐C in patients on statin therapy, suggesting that an approximate 3‐fold dose increase is required for a 2‐fold extension in the dosing interval. Evolocumab dosing regimens of 140 mg Q2W or 420 mg QM were predicted to result in comparable reductions in LDL‐C over a monthly period, consistent with results from recently completed phase 3 studies.
- Published
- 2016
35. The challenge of multiple cardiovascular risk factor control outside Western Europe: Findings from the International ChoLesterol management Practice Study
- Author
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Florence Mercier, Nicolas Danchin, Dirk J. Blom, Veronique Daclin, Álvaro J. Ruiz, and Raul D. Santos
- Subjects
Male ,dyslipidaemia ,hypertension ,Epidemiology ,Hypercholesterolemia ,Cardiovascular risk factors ,Control (management) ,030204 cardiovascular system & hematology ,03 medical and health sciences ,CVD Risk Factors ,0302 clinical medicine ,Risk Factors ,Environmental health ,Medicine ,Humans ,030212 general & internal medicine ,Cholesterol management ,business.industry ,Anticholesteremic Agents ,Incidence ,Risk factor (computing) ,Middle Aged ,Cardiovascular disease ,medicine.disease ,Obesity ,Full Research Papers ,Europe ,Cholesterol ,Cross-Sectional Studies ,Heart Disease Risk Factors ,Multinational corporation ,Cardiovascular Diseases ,Western europe ,diabetes mellitus ,observational study ,Observational study ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business - Abstract
BackgroundComprehensive control of multiple cardiovascular risk factors reduces cardiovascular risk but is difficult to achieve.DesignA multinational, cross-sectional, observational study.MethodsThe International ChoLesterol management Practice Study (ICLPS) investigated achievement of European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guideline low-density lipoprotein cholesterol (LDL-C) targets in patients receiving lipid-modifying therapy in countries outside Western Europe. We examined the rate of, and association between, control of multiple risk factors in ICLPS participants with dyslipidaemia, diabetes and hypertension (N = 2377).ResultsMean (standard deviation) age of patients was 61.4 (10.4) years; 51.3% were male. Type 2 diabetes was the most common form of diabetes (prevalence, 96.9%). The prevalence of metabolic syndrome was 67.8%, obesity 40.4%, atherosclerotic disease 39.6% and coronary artery disease 33.5%. All patients were at high (38.2%) or very high (61.8%) cardiovascular risk according to ESC/EAS guidelines. Body mass index (BMI) was 2in 20.3% of patients, 62.8% had never smoked and 25.2% were former smokers. Overall, 12.2% achieved simultaneous control of LDL-C, diabetes and blood pressure. Risk factor control was similar across all participating countries. The proportion of patients achieving individual guideline-specified treatment targets was 43.9% for LDL-C, 55.5% for blood pressure and 39.3% for diabetes. Multiple correspondence analysis indicated that control of LDL-C, control of blood pressure, control of diabetes, BMI and smoking were associated.ConclusionComprehensive control of multiple cardiovascular risk factors in high-risk patients is suboptimal worldwide. Failure to control one risk factor is associated with poor control of other risk factors.
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- 2019
36. Long-Term Evolocumab in Patients With Familial Hypercholesterolemia
- Author
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Evan A. Stein, Handrean Soran, Gerald F. Watts, Dirk J. Blom, Frederick J. Raal, Sarah Bray, G. Kees Hovingh, J. Antonio G. López, Christopher E. Kurtz, Raul D. Santos, Andrew Hamer, Experimental Vascular Medicine, Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
safety ,Adult ,Male ,Pediatrics ,medicine.medical_specialty ,PCSK9 inhibitor ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,medicine ,Clinical endpoint ,Humans ,In patient ,030212 general & internal medicine ,Adverse effect ,LDL-C ,Aged ,familial hypercholesterolemia ,lipid-lowering therapy ,business.industry ,Incidence (epidemiology) ,Anticholesteremic Agents ,Treatment options ,Cholesterol, LDL ,Middle Aged ,medicine.disease ,Evolocumab ,Apheresis ,evolocumab ,lipids (amino acids, peptides, and proteins) ,Female ,Cardiology and Cardiovascular Medicine ,business - Abstract
Background: Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals. Objectives: The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH). Methods: In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids. Results: In total, 300 patients (106 with HoFH, including 14
- Published
- 2019
37. Reduced Lipoprotein(a) Associated With the Apolipoprotein E2 Genotype Confers Cardiovascular Protection in Familial Hypercholesterolemia
- Author
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Dirk J. Blom, Mikaël Croyal, Ilya Khantalin, Stéphane Ramin-Mangata, Kévin Chemello, Valentin Blanchard, Brice Nativel, A. David Marais, Gilles Lambert, Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'Etude sur l'Inflammation Chronique et l'Obésité (GEICO), Université de La Réunion (UR), Bureau d'Économie Théorique et Appliquée (BETA), Institut National de la Recherche Agronomique (INRA)-Université de Strasbourg (UNISTRA)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Lambert, Gilles, and University of Cape Town
- Subjects
0301 basic medicine ,Apolipoprotein E ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Médecine humaine et pathologie ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,03 medical and health sciences ,0302 clinical medicine ,LETTER ,Internal medicine ,medicine ,Food and Nutrition ,Receptor ,biology ,nutritional and metabolic diseases ,Lipoprotein(a) ,medicine.disease ,LRP1 ,030104 developmental biology ,Endocrinology ,LDL receptor ,Alimentation et Nutrition ,biology.protein ,Human health and pathology ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,Apolipoprotein E2 ,Lipoprotein - Abstract
International audience; There are 3 isoforms of apolipoprotein E (apo E) in humans (ε2, ε3, and ε4). They differ by single amino acid substitutions that variably affect their affinity for the low-density lipoprotein receptor (LDLR) and for the LDLR-related protein (LRP1), with ε2 having the weakest binding to these receptors (1). The plasma levels of lipoprotein(a) [Lp(a)], a highly atherogenic LDL-like lipoprotein species, are influenced by the polymorphism of apo E, with ε2/ε2 and ε4/ε4 carriers presenting with the lowest and highest Lp(a) plasma concentrations, respectively (1).
- Published
- 2019
38. Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome
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Louis O'Dea, Sotirios Tsimikas, Qingqing Yang, Erik S.G. Stroes, Daniel Gaudet, Fernando Civeira, Handrean Soran, Dirk J. Blom, Linda C. Hemphill, Steven D. Freedman, Jean Bergeron, Joseph L. Witztum, Steven Hughes, Richard S. Geary, Eric Bruckert, Andres Digenio, Veronica J. Alexander, Marcello Arca, Karren R Williams, University of California [San Diego] (UC San Diego), University of California, Université de Montréal (UdeM), Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Université Laval [Québec] (ULaval), Manchester University NHS Foundation Trust (MFT), University of Zaragoza - Universidad de Zaragoza [Zaragoza], Massachusetts General Hospital [Boston], University of Cape Town, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Vascular Medicine, and ACS - Atherosclerosis & ischemic syndromes
- Subjects
Adult ,Male ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Injections, Subcutaneous/adverse effects ,030204 cardiovascular system & hematology ,Triglycerides blood ,Hyperlipoproteinemia Type I/blood ,familial chylomicronemia, volanesorsen, triglycerides, therapy, apoCIII ,familial chylomicronemia ,Injections ,Oligonucleotides/administration & dosage ,Young Adult ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,apoCIII ,Internal medicine ,Humans ,Medicine ,volanesorsen ,030212 general & internal medicine ,triglycerides ,Aged ,RNA, Messenger/antagonists & inhibitors ,therapy ,Analysis of Variance ,Triglyceride ,Platelet Count ,Thrombocytopenia/chemically induced ,business.industry ,Genetic disorder ,General Medicine ,Middle Aged ,Familial Chylomicronemia ,medicine.disease ,3. Good health ,Triglycerides/blood ,Endocrinology ,Multicenter study ,chemistry ,RNA ,Female ,Subcutaneous/adverse effects ,Apolipoprotein C-III/antagonists & inhibitors ,business ,Lipoprotein lipase activity ,Messenger/antagonists & inhibitors - Abstract
Background Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels. Methods We conducted a phase 3, double-blind, randomized 52-week trial to evaluate the safety and effectiveness of volanesorsen in 66 patients with familial chylomicronemia syndrome. Patients were randomly assigned, in a 1:1 ratio, to receive volanesorsen or placebo. The primary end point was the percentage change in fasting triglyceride levels from baseline to 3 months. Results Patients receiving volanesorsen had a decrease in mean plasma apolipoprotein C-III levels from baseline of 25.7 mg per deciliter, corresponding to an 84% decrease at 3 months, whereas patients receiving placebo had an increase in mean plasma apolipoprotein C-III levels from baseline of 1.9 mg per deciliter, corresponding to a 6.1% increase (P
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- 2019
39. Proprotein Convertase Subtilisin Kexin Type 9 Inhibition for Autosomal Recessive Hypercholesterolemia—Brief Report
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Frederick J. Raal, Geesje Dallinga-Thie, Livia Pisciotta, Maurizio Averna, Jorge Peter, Maxime Passard, Dirk J. Blom, Barbara Sjouke, Kees Hovingh, Alexis Guedon, Maria Laura Cossu, Aurélie Thedrez, Milco Ciccarese, Raul D. Santos, Mickael Croyal, Angelo B. Cefalù, Simon Prampart-Fauvet, Gilles Lambert, Paolo Pintus, Physiologie des Adaptations Nutritionnelles [UMR_A1280] (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), Department of Vascular Medicine, Emma Children’s Hospital Academic Medical Centre, Lipidology Division of Internal Medicine, University of Cape Town, Dipartimiento di Nefrologia Dialisi e Trapianto, SS Annunziata Hospital, School of Medicine, University of Patras [Greece], University of Genoa (UNIGE), Lipid Clinic Heart Institute (InCor), University of São Paulo, Sao Paolo Medica School Hospital, Faculty of Health Sciences, Aarhus University [Aarhus], Dipartimento di Medicina Interna, Brotzu Hospital, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Université de La Réunion (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de La Réunion (UR), Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), Investigator Initiated Study Concept Research Grant from Sanofi-Regeneron, Agence Nationale de la Recherche (Programme blanc BCNCT), Thedrez, A., Sjouke, B., Passard, M., Prampart-Fauvet, S., Guédon, A., Croyal, M., Dallinga-Thie, G., Peter, J., Blom, D., Ciccarese, M., Cefalù, A., Pisciotta, L., Santos, R., Averna, M., Raal, F., Pintus, P., Cossu, M., Hovingh, K., Lambert, G., Physiologie des Adaptations Nutritionnelles (PhAN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Vascular Medicine, and Experimental Vascular Medicine
- Subjects
Male ,0301 basic medicine ,Settore MED/09 - Medicina Interna ,[SDV]Life Sciences [q-bio] ,receptors ,alirocumab ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,proprotein convertase subtilisin kexin type 9 ,0302 clinical medicine ,therapeutics ,Lymphocytes ,Cells, Cultured ,hypercholesterolemia ,Anticholesteremic Agents ,PCSK9 Inhibitors ,Antibodies, Monoclonal ,Middle Aged ,3. Good health ,Phenotype ,Autosomal Recessive Hypercholesterolemia ,Kexin ,Drug Therapy, Combination ,Female ,lipids (amino acids, peptides, and proteins) ,Lovastatin ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Adult ,medicine.medical_specialty ,Serine Proteinase Inhibitors ,Adolescent ,Biology ,Antibodies, Monoclonal, Humanized ,LDL ,Young Adult ,03 medical and health sciences ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Adaptor Proteins, Signal Transducing ,Alirocumab ,PCSK9 ,receptors, LDL ,Cholesterol, LDL ,medicine.disease ,Proprotein convertase ,therapeutic ,030104 developmental biology ,Endocrinology ,Case-Control Studies ,Mutation ,LDL receptor ,Hydroxymethylglutaryl-CoA Reductase Inhibitors - Abstract
Objective— Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors lower low-density lipoprotein (LDL) cholesterol in the vast majority of patients with autosomal dominant familial hypercholesterolemia. Will PCSK9 inhibition with monoclonal antibodies, in particular alirocumab, be of therapeutic value for patients with autosomal recessive hypercholesterolemia (ARH)? Approach and Results— Primary lymphocytes were obtained from 28 genetically characterized ARH patients and 11 controls. ARH lymphocytes treated with mevastatin were incubated with increasing doses of recombinant PCSK9 with or without saturating concentrations of alirocumab. Cell surface LDL receptor expression measured by flow cytometry and confocal microscopy was higher in ARH than in control lymphocytes. PCSK9 significantly reduced LDL receptor expression in ARH lymphocytes albeit to a lower extent than in control lymphocytes (25% versus 76%, respectively), an effect reversed by alirocumab. Fluorescent LDL cellular uptake, also measured by flow cytometry, was reduced in ARH lymphocytes compared with control lymphocytes. PCSK9 significantly lowered LDL cellular uptake in ARH lymphocytes, on average by 18%, compared with a 46% reduction observed in control lymphocytes, an effect also reversed by alirocumab. Overall, the effects of recombinant PCSK9, and hence of alirocumab, on LDL receptor expression and function were significantly less pronounced in ARH than in control cells. Conclusions— PCSK9 inhibition with alirocumab on top of statin treatment has the potential to lower LDL cholesterol in some autosomal recessive hypercholesterolemia patients.
- Published
- 2016
40. LONG-TERM SAFETY AND EFFICACY OF LOMITAPIDE IN PATIENTS WITH HOMOZYGOUS FAMILIAL HYPERCHOLESTEROLEMIA: FIVE-YEAR DATA FROM THE LOMITAPIDE OBSERVATIONAL WORLDWIDE EVALUATION REGISTRY (LOWER)
- Author
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James A. Underberg, Helen Phillips, Lukas Makris, Dirk J. Blom, Christopher P. Cannon, and Dominique Larrey
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Time Factors ,Endocrinology, Diabetes and Metabolism ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Microsomal triglyceride transfer protein ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Pregnancy ,Internal medicine ,Internal Medicine ,Humans ,Medicine ,In patient ,030212 general & internal medicine ,Registries ,Nutrition and Dietetics ,biology ,business.industry ,Incidence (epidemiology) ,Middle Aged ,medicine.disease ,Lomitapide ,Alanine transaminase ,Tolerability ,chemistry ,biology.protein ,Benzimidazoles ,Female ,Observational study ,Long term safety ,Cardiology and Cardiovascular Medicine ,business - Abstract
Lomitapide is a lipid-lowering agent indicated as adjunct therapy for homozygous familial hypercholesterolemia (HoFH) in adults.The Lomitapide Observational Worldwide Evaluation Registry is an international, observational registry assessing long-term safety, tolerability, and effectiveness of lomitapide.This analysis examines 5-year data from the registry up to February 28, 2019.At lomitapide initiation, enrolled patients (N = 187) were a mean ± SD age of 52.2 ± 15.3 years with a mean ± SD low-density lipoprotein cholesterol (LDL-C) measurement of 232.0 ± 94.9 mg/dL. Exposure duration was up to 5.9 years (median, 1.98 years), and median dose was 10 mg (range, 5 mg QOD to 40 mg QD). After treatment, there was a mean 33% reduction in LDL-C (45% in patients remaining on lomitapide), 65.4% achieved LDL-C100 mg/dL, and 41.1% achieved LDL-C70 mg/dL. At year 4, the absolute mean change from baseline in LDL-C was -70.6 ± 76.21 mg/dL. Adverse events (AEs) occurred in 75.7% of patients, treatment-related AEs in 54.6%, and serious AEs in 22.2%; 23.2% of patients discontinued because of an AE. Events of special interest included gastrointestinal (13.5%), hepatic (15.1%), major adverse cardiovascular events (10.8%, resulting in 5 deaths), tumors (2.2%), and 4 pregnancies in 3 of 32 women of childbearing potential.The efficacy and safety of lomitapide are consistent with phase III trial data despite using a much lower median dose of 10 mg vs 40 mg in phase III. No new safety signals were identified. The incidence of AEs, serious AEs, and aminotransferase alanine transaminase elevations was lower than that seen in the phase III trial, potentially related to the lower median dose.
- Published
- 2020
41. Heterozygous familial hypercholesterolaemia in specialist centres in South Africa, Australia and Brazil: Importance of early detection and lifestyle advice
- Author
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Jing Pang, A.D. Marais, Dirk J. Blom, Brigitte C. Brice, Pamela R. Silva, Cinthia E. Jannes, Alexandre C. Pereira, Amanda J. Hooper, Kausik K. Ray, Raul D. Santos, and Gerald F. Watts
- Subjects
Cardiovascular System & Hematology ,Internal Medicine ,1103 Clinical Sciences ,General Medicine ,Cardiology and Cardiovascular Medicine ,1102 Cardiovascular Medicine And Haematology - Abstract
Background and aims: Familial hypercholesterolaemia (FH) is the commonest monogenic disorder that accelerates atherosclerotic cardiovascular disease. We compared and contrasted the characteristics of patients from three specialist centres in the southern hemisphere. Methods: Adult index-cases with molecularly diagnosed heterozygous FH attending specialist lipid centres in Cape Town, Perth and São Paulo were studied. Myocardial infarction, revascularisation, hypertension, diabetes, smoking and lipid-lowering treatment were recorded at the time of diagnosis and compared across the three centres. Results: The spectrum of genetic variants causative of FH was significantly different in patients attending the centres in South Africa compared with Australia and Brazil. Hypertension and diabetes were more prevalent in Brazilian and Australian patients, than in South African patients, but the frequency of smoking was significantly greater in South Africa than the other two centres (p
- Published
- 2018
42. Therapeutic Management of Dyslipidemia Patients at Very High Cardiovascular Risk (CARDIO TRACK): Protocol for the Observational Registry Study
- Author
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Rashem Mothilal, Poobalan Naidoo, and Dirk J. Blom
- Subjects
medicine.medical_specialty ,Statin ,medicine.drug_class ,Registry study ,maximally tolerated statin ,030204 cardiovascular system & hematology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Ezetimibe ,Internal medicine ,Protocol ,Medicine ,030212 general & internal medicine ,Risk factor ,novel lipid lowering therapy ,Protocol (science) ,business.industry ,Cholesterol ,dyslipidemia ,very high cardiovascular risk ,General Medicine ,medicine.disease ,chemistry ,Observational study ,business ,Dyslipidemia ,medicine.drug - Abstract
Background: Dyslipidemia is a major modifiable risk factor for atherosclerotic cardiovascular disease. Current South African guidelines recommend titrating lipid-lowering therapy (LLT) to low-density lipoprotein cholesterol (LDL-C) targets stratified by cardiovascular risk. The LDL-C goal for very high-risk patients is
- Published
- 2018
43. Apolipoprotein E2 (APOE2) is associated with reduced lipoprotein (a) [Lp(a)] in patients with familial hypercholesterolemia (FH)
- Author
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Dirk J. Blom, Mikaël Croyal, Valentin Blanchard, A. David Marais, Gilles Lambert, Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM), University of Cape Town, and European Atherosclerosis Society. SWE.
- Subjects
0303 health sciences ,medicine.medical_specialty ,biology ,business.industry ,[SDV]Life Sciences [q-bio] ,Lipoprotein(a) ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,medicine.disease ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Internal medicine ,medicine ,biology.protein ,In patient ,Cardiology and Cardiovascular Medicine ,Apolipoprotein E2 ,business ,ComputingMilieux_MISCELLANEOUS ,030304 developmental biology - Abstract
International audience
- Published
- 2018
44. LDL-cholesterol target achievement in patients with heterozygous familial hypercholesterolemia at Groote Schuur Hospital: Minority at target despite large reductions in LDL-C
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Dirk J. Blom, Karen H. Wolmarans, Roeland Huijgen, Jennifer K. Barron, Brigitte C. Brice, Xander M. van Delden, A. David Marais, VU University medical center, and Internal medicine
- Subjects
Male ,Pediatrics ,Heredity ,Time Factors ,Familial hypercholesterolemia ,Disease ,030204 cardiovascular system & hematology ,South Africa ,0302 clinical medicine ,Risk Factors ,Prevalence ,Medicine ,030212 general & internal medicine ,education.field_of_study ,Anticholesteremic Agents ,PCSK9 Inhibitors ,Middle Aged ,Pedigree ,Phenotype ,Treatment Outcome ,Cardiovascular Diseases ,Population study ,lipids (amino acids, peptides, and proteins) ,Drug Therapy, Combination ,Female ,Proprotein Convertase 9 ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Cardiovascular event ,Adult ,medicine.medical_specialty ,Heterozygote ,Serine Proteinase Inhibitors ,Population ,Down-Regulation ,Risk Assessment ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,Ezetimibe ,Humans ,In patient ,Genetic Predisposition to Disease ,education ,Retrospective Studies ,Ldl cholesterol ,business.industry ,Cholesterol, LDL ,medicine.disease ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,business ,Biomarkers - Abstract
Background and aims: Familial hypercholesterolemia (FH) is characterized by markedly increased LDL-cholesterol (LDL-C) and premature cardiovascular disease (CVD). LDL-C lowering is the cornerstone of therapy. The aim of our study was to evaluate LDL-C target achievement and explore reasons for not reaching target in FH patients attending a public-sector lipid clinic at Groote Schuur Hospital in Cape Town, South Africa. Methods: We reviewed clinical records of patients with genetically confirmed heterozygous FH (heFH) retrospectively. For patients seen after 2013, when new guidelines were published, we determined reasons for use of submaximal therapy. Results: Our study population consisted of 776 adult heFH patients. A substantial proportion (41%) of those younger than 50 years of age had already experienced a cardiovascular event. The mean (±SD) untreated and best achieved LDL-C values during follow up were 8.1 ± 2.1 and 4.0 ± 1.5 mmol/l, respectively. Despite a mean LDL-C reduction of 50%, only 140 (25%) achieved an LDL-C ≤ 3.0 mmol/l. Of the 164 participants with follow up after 2013, 42 did not reach LDL-C < 3.0 mmol/l and did not use maximal therapy (26%). The commonest reasons for not using maximum therapy were statin side-effects (n = 15, 36%) and acceptance by the patient (n = 9, 22%) or the physician (n = 8, 19%) of the control achieved. Conclusions: The heFH population in Cape Town is characterized by high baseline LDL-C, a high prevalence of CVD at presentation and low rates of achieving an LDL-C target of 3.0 mmol/l.
- Published
- 2018
45. Statins and other lipid-lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: A retrospective review of 39 pregnancies
- Author
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Theunis C. Botha, Dirk J. Blom, Karen H. Wolmarans, Gillian J. Pilcher, and Frederick J. Raal
- Subjects
Adult ,Pediatrics ,medicine.medical_specialty ,Down-Regulation ,030204 cardiovascular system & hematology ,Risk Assessment ,Lipid-lowering therapy ,Drug Administration Schedule ,Hyperlipoproteinemia Type II ,03 medical and health sciences ,chemistry.chemical_compound ,South Africa ,Young Adult ,0302 clinical medicine ,Pregnancy ,Risk Factors ,medicine ,Humans ,Genetic Predisposition to Disease ,030212 general & internal medicine ,Retrospective Studies ,Retrospective review ,Fetus ,business.industry ,Cholesterol ,Homozygote ,Pregnancy Outcome ,Cholesterol, LDL ,medicine.disease ,Pregnancy Complications ,Breast Feeding ,Phenotype ,Treatment Outcome ,chemistry ,Cohort ,Life expectancy ,Blood Component Removal ,Female ,Patient Safety ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Cardiology and Cardiovascular Medicine ,business ,Lipoprotein apheresis ,Biomarkers - Abstract
Background and aims Pregnancy in HoFH females is associated with further elevation of already markedly elevated low density lipoprotein cholesterol (LDL-C) levels, particularly if lipid-lowering therapy is discontinued, placing the mother and fetus at increased cardiovascular risk. Lipoprotein apheresis is the current recommended treatment for pregnant HoFH patients. However, this is costly, time consuming, and is not available in many countries. Alternative treatment strategies to control hypercholesterolaemia during pregnancy in HoFH patients are necessary. Methods This study was a retrospective review of 39 pregnancies from a cohort of 20 genotypically confirmed female HoFH patients. Results No maternal cardiac complications or deaths occurred during the pregnancies or during the first year postpartum. Twenty five pregnancies were exposed to lipid-lowering therapy, of which 18 were exposed to statin therapy, just prior to or during the pregnancy. Thirty three (84%) pregnancies carried to term, 3 (8%) premature deliveries and 3 (8%) miscarriages were observed. Complications associated with pregnancy in these HoFH patients, did not differ from those reported during pregnancies of otherwise healthy woman. Conclusions HoFH is a severe disease impacting significantly on life expectancy. However, for many females with HoFH, despite the high cardiovascular risk, pregnancy is not uncommon. In resource poor settings and when LA is not available, lipid lowering therapy, particularly statin therapy during pregnancy, appears to be safe for both mother and fetus and is an acceptable alternative for LDL-C reduction in these high risk patients.
- Published
- 2018
46. Characterizing familial chylomicronemia syndrome: Baseline data of the APPROACH study
- Author
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Linda C. Hemphill, Raul D. Santos, Dirk J. Blom, Seth J. Baum, Andres Digenio, Ewa Karwatowska-Prokopczuk, Joseph L. Witztum, Ovidio Muñiz-Grijalvo, Louis O'Dea, Karren R Williams, and Veronica J. Alexander
- Subjects
0301 basic medicine ,Adult ,Male ,Chylomicronemia ,medicine.medical_specialty ,Endocrinology, Diabetes and Metabolism ,Natural history ,Oligonucleotides ,Hyperlipoproteinemia ,030204 cardiovascular system & hematology ,Cohort Studies ,03 medical and health sciences ,Lipoprotein lipase deficiency ,Young Adult ,0302 clinical medicine ,Internal medicine ,Internal Medicine ,medicine ,Humans ,Young adult ,Hypertriglyceridemia ,Nutrition and Dietetics ,business.industry ,Extremely restrictive low-fat diet ,Metabolic disorder ,Middle Aged ,medicine.disease ,Acute pancreatitis ,030104 developmental biology ,Treatment Outcome ,Population study ,Pancreatitis ,lipids (amino acids, peptides, and proteins) ,Female ,Hyperlipoproteinemia Type I ,Familial Chylomicronemia Syndrome ,DIETA COM RESTRIÇÃO DE GORDURAS ,Cardiology and Cardiovascular Medicine ,business ,Body mass index - Abstract
Background Familial chylomicronemia syndrome (FCS) is a rare metabolic disorder caused by mutations in lipoprotein lipase (LPL) or genes required for LPL functionality and is characterized by hyperchylomicronemia that results in recurrent episodes of acute pancreatitis. Owing to the rarity of FCS, there are few case series describing the phenotypic variability in FCS patients in detail. Objective To provide baseline characteristics in the largest study population to date of patients with FCS. Methods We analyzed baseline demographic and clinical characteristics of adult FCS patients in the phase 3 APPROACH study of volanesorsen sodium (antisense inhibitor of apolipoprotein C-III). Results Sixty-six patients were included in the analysis. Mean (SD) age was 46 (13) years; and mean body mass index was 24.9 (5.7) kg/m2. We identified causal mutations in 79% (52) of patients, with LPL mutations accounting for 62% (41) of cases. Median age at diagnosis was 24 years, 54% were females, and 81% were Caucasian. All patients followed a low-fat diet, 43% received fibrates, 27% fish oils, and 21% statins. Median fasting triglyceride levels (P25, P75) were 1985 (1179, 3047 mg/dL). Overall, 76% of patients reported ≥1 lifetime episode of acute pancreatitis; 23 patients reported a total of 53 pancreatitis events in the 5 years before enrollment. Conclusions Our data emphasize the severe hypertriglyceridemia characteristic of FCS patients despite restrictive low-fat diets and frequent use of existing hypolipemic therapies. Acute pancreatitis and recurrent acute pancreatitis are frequent complications of FCS. Diagnosis at an older age suggests likely underdiagnosis and underappreciation of this rare disorder.
- Published
- 2018
47. Homozygous Familial Hypercholesterolemia Patients With Identical Mutations Variably Express the LDLR (Low-Density Lipoprotein Receptor): Implications for the Efficacy of Evolocumab
- Author
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Steeve Bourane, Stéphane Ramin-Mangata, Valentin Blanchard, Dirk J. Blom, Kévin Chemello, Frederick J. Raal, Aurélie Thedrez, Mikaël Croyal, Matthieu Pichelin, L. Tang, Bertrand Cariou, Michel Farnier, Brice Nativel, Gilles Lambert, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department Medicine, Universität Salzburg, Diabète athérothrombose et thérapies Réunion Océan Indien (DéTROI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de La Réunion (UR), Nutrition périnatale [Nantes] (Centres de Recherche en Nutrition Humaine - CRNH), Centre de Recherche en Nutrition Humaine - Ouest, INRA: UMR1280 Physiologie des adaptations (UMR1280), Institut National de la Recherche Agronomique (INRA), Shanghai Academy of Agricultural Sciences, Point médical (Dijon), Amgen, Allocation de Recherche Chaire Mixte (Inserm-Universite), Agence Nationale de la Recherche [ANR-16-RHUS-0007 CHOPIN], Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
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0301 basic medicine ,Male ,Apolipoprotein B ,[SDV]Life Sciences [q-bio] ,Familial hypercholesterolemia ,030204 cardiovascular system & hematology ,Compound heterozygosity ,0302 clinical medicine ,Lymphocytes ,Cells, Cultured ,biology ,Anticholesteremic Agents ,PCSK9 Inhibitors ,Antibodies, Monoclonal ,Middle Aged ,3. Good health ,homozygote ,Phenotype ,Treatment Outcome ,Apolipoprotein B-100 ,Drug Therapy, Combination ,Female ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,medicine.drug ,Adult ,medicine.medical_specialty ,Serine Proteinase Inhibitors ,Adolescent ,Antibodies, Monoclonal, Humanized ,Hyperlipoproteinemia Type II ,lipids ,03 medical and health sciences ,Young Adult ,Mevastatin ,Internal medicine ,medicine ,Humans ,Genetic Predisposition to Disease ,Lovastatin ,business.industry ,PCSK9 ,Cholesterol, LDL ,medicine.disease ,Ezetimibe ,heterozygote ,Evolocumab ,030104 developmental biology ,Endocrinology ,Receptors, LDL ,LDL receptor ,biology.protein ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,mutation ,business ,metabolism ,Lipoprotein - Abstract
Objective— Evolocumab, a PCSK9 (proprotein convertase subtilisin kexin type 9)–neutralizing antibody, lowers low-density lipoprotein cholesterol (LDL-C) in homozygous familial hypercholesterolemic (HoFH) patients with reduced LDLR (low-density lipoprotein receptor) function. However, their individual responses are highly variable, even among carriers of identical LDLR genetic defects. We aimed to elucidate why HoFH patients variably respond to PCSK9 inhibition. Approach and Results— Lymphocytes were isolated from 22 HoFH patients enrolled in the TAUSSIG trial (Trial Assessing Long Term Use of PCSK9 Inhibition in Subjects With Genetic LDL Disorders). Ten patients were true homozygotes (FH1/FH1) and 5 identical compound heterozygotes (FH1/FH2). Lymphocytes were plated with or without mevastatin, recombinant PCSK9 (rPCSK9), or a PCSK9-neutralizing antibody. Cell surface LDLR expression was analyzed by flow cytometry. All HoFH lymphocytes had reduced cell surface LDLR expression compared with non-FH lymphocytes, for each treatment modality. Lymphocytes from FH1/FH2 patients (LDLR defective/negative) displayed the lowest LDLR expression levels followed by lymphocytes from FH1/FH1 patients (defective/defective). Mevastatin increased, whereas rPCSK9 reduced LDLR expression. The PCSK9-neutralizing antibody restored LDLR expression. Lymphocytes displaying higher LDLR expression levels were those isolated from patients presenting with lowest levels of LDL-C and apolipoprotein B, before and after 24 weeks of evolocumab treatment. These negative correlations remained significant in FH1/FH1 patients and appeared more pronounced when patients with apolipoprotein E3/E3 genotypes were analyzed separately. Significant positive correlations were found between the levels of LDLR expression and the percentage reduction in LDL-C on evolocumab treatment. Conclusions— Residual LDLR expression in HoFH is a major determinant of LDL-C levels and seems to drive their individual response to evolocumab.
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- 2018
48. PCSK9 Modulates the Secretion But Not the Cellular Uptake of Lipoprotein(a) Ex Vivo: An Effect Blunted by Alirocumab
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Elise F, Villard, Aurélie, Thedrez, Jorg, Blankenstein, Mikaël, Croyal, Thi-Thu-Trang, Tran, Bruno, Poirier, Jean-Christophe, Le Bail, Stéphane, Illiano, Estelle, Nobécourt, Michel, Krempf, Dirk J, Blom, A David, Marais, Philip, Janiak, Anthony J, Muslin, Etienne, Guillot, and Gilles, Lambert
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PCSK9 ,primary human hepatocytes ,familial hypercholesterolemia ,lipoprotein(a) ,LDL receptor ,Article - Abstract
SUMMARY To elucidate how the proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor alirocumab modulates lipoprotein(a) [Lp(a)] plasma levels, the authors performed a series of Lp(a) uptake studies in primary human hepatocytes and dermal fibroblasts and measured Lp(a) secretion from human hepatocytes. They found that Lp(a) cellular uptake occurred in a low-density lipoprotein receptor–independent manner. Neither PCSK9 nor alirocumab altered Lp(a) internalization. By contrast, the secretion of apolipoprotein (a) from human hepatocytes was sharply increased by PCSK9, an effect that was reversed by alirocumab. They propose that PCSK9 does not significantly modulate Lp(a) catabolism, but rather enhances the secretion of Lp(a) from liver cells., VISUAL ABSTRACT
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- 2018
49. Achievement of low-density lipoprotein cholesterol goals in 18 countries outside Western Europe: The International ChoLesterol management Practice Study (ICLPS)
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Carlos A Aguilar Salinas, Khalid Al-Rasadi, Dirk J. Blom, Yuri Karpov, Olena Mitchenko, Wael Almahmeed, Upendra Kaul, Carlos Alberto Cuneo, Raul D. Santos, Meral Kayıkçıoğlu, Abdelkrim Berrah, Joseph Azuri, Álvaro J. Ruiz, Florence Mercier, Nicolas Danchin, and Ege Üniversitesi
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Adult ,Male ,medicine.medical_specialty ,Time Factors ,Epidemiology ,Down-Regulation ,Low density lipoprotein cholesterol ,Comorbidity ,030204 cardiovascular system & hematology ,statins ,lipids ,03 medical and health sciences ,chemistry.chemical_compound ,Sex Factors ,LIPOPROTEÍNAS LDL ,0302 clinical medicine ,Risk Factors ,Diabetes mellitus ,Internal medicine ,medicine ,Humans ,In patient ,030212 general & internal medicine ,guidelines ,Practice Patterns, Physicians' ,Aged ,Dyslipidemias ,Cholesterol management ,Cholesterol ,business.industry ,Anticholesteremic Agents ,Smoking ,Cholesterol, LDL ,Middle Aged ,medicine.disease ,Cross-Sectional Studies ,Treatment Outcome ,chemistry ,Cardiovascular Diseases ,Western europe ,Practice Guidelines as Topic ,LDL Cholesterol Lipoproteins ,Female ,observational study ,Guideline Adherence ,Cardiology and Cardiovascular Medicine ,business ,Biomarkers - Abstract
WOS: 000438569100017, PubMed ID: 29771156, Background Little is known about the achievement of low density lipoprotein cholesterol (LDL-C) targets in patients at cardiovascular risk receiving stable lipid-lowering therapy (LLT) in countries outside Western Europe. Methods This cross-sectional observational study was conducted in 452 centres (August 2015-August 2016) in 18 countries in Eastern Europe, Asia, Africa, the Middle East and Latin America. Patients (n=9049) treated for 3 months with any LLT and in whom an LDL-C measurement on stable LLT was available within the previous 12 months were included. Results The meanSD age was 60.2 +/- 11.7 years, 55.0% of patients were men and the mean +/- SD LDL-C value on LLT was 2.6 +/- 1.3mmol/L (101.0 +/- 49.2mg/dL). At enrolment, 97.9% of patients were receiving a statin (25.3% on high intensity treatment). Only 32.1% of the very high risk patients versus 51.9% of the high risk and 55.7% of the moderate risk patients achieved their LDL-C goals. On multivariable analysis, factors independently associated with not achieving LDL-C goals were no (versus lower dose) statin therapy, a higher (versus lower) dose of statin, statin intolerance, overweight and obesity, female sex, neurocognitive disorders, level of cardiovascular risk, LDL-C value unknown at diagnosis, high blood pressure and current smoking. Diabetes was associated with a lower risk of not achieving LDL-C goals. Conclusions These observational data suggest that the achievement of LDL-C goals is suboptimal in selected countries outside Western Europe. Efforts are needed to improve the management of patients using combination therapy and/or more intensive LLTs., SanofiSanofi-Aventis, The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: sponsored by Sanofi.
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- 2018
50. Effect of evolocumab on lipoprotein particles
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Mary Elliott, Ransi Somaratne, Maria Laura Monsalvo, Dirk J. Blom, Naveed Sattar, Michael T. Davis, Seth S. Martin, David Preiss, Peter P. Toth, and Steven R. Jones
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Male ,medicine.medical_specialty ,Hyperlipidemias ,030204 cardiovascular system & hematology ,Antibodies, Monoclonal, Humanized ,Placebo ,Lipoprotein particle ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Double-Blind Method ,Internal medicine ,Hyperlipidemia ,medicine ,Humans ,030212 general & internal medicine ,Cholesterol ,business.industry ,Anticholesteremic Agents ,PCSK9 ,Cholesterol, HDL ,Antibodies, Monoclonal ,Cholesterol, LDL ,Middle Aged ,medicine.disease ,Confidence interval ,Evolocumab ,Treatment Outcome ,Endocrinology ,chemistry ,Female ,lipids (amino acids, peptides, and proteins) ,Cardiology and Cardiovascular Medicine ,business ,Lipoprotein - Abstract
The level of low-density lipoprotein cholesterol (LDL-C) reflects the cholesterol carried mainly by low-density lipoprotein particles (LDL-P). LDL-C, however, does not always correlate with LDL-P because of the variable amounts of cholesterol per particle. Consideration of LDL-P concentrations in addition to LDL-C may help guide therapeutic decisions in a select number of patients. Evolocumab is a fully human monoclonal antibody directed against proprotein convertase subtilisin-kexin type 9 that lowers both LDL-C and cardiovascular events. To evaluate the effect of evolocumab on serum levels and size of lipoprotein particles, we conducted a post hoc subanalysis of 619 patients from the Durable Effect of PCSK9 Antibody Compared with Placebo Study or DESCARTES trial, a 52-week, randomized, double-blind, placebo-controlled, global study of patients with hyperlipidemia. At baseline, mean LDL-P concentration was 1077 nmol/L for the placebo group and 1100 nmol/L for the evolocumab group. In patients receiving evolocumab, week 52 total LDL-P concentration decreased to 610 nmol/L, a treatment difference of 50% versus placebo. Evolocumab also reduced concentrations of medium very low-density lipoprotein particles (VLDL-P), small VLDL-P, and intermediate-density lipoprotein particle: median (Q1, Q3) changes were -15.2% (-48, 48), -29% (-54, 18), and -36% (-70, 22), respectively. Mean (95% confidence interval) % changes in total LDL particle size in the evolocumab group was -1.7 (-2.0, -1.4); % changes in HDL and VLDL particle sizes were 1.1 (0.7, 1.5) and 8.7 (7.0, 10.5), respectively. Changes in total LDL, HDL, and VLDL particle sizes (vs placebo) were all significant (p
- Published
- 2017
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