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Start Over Author "Kastelein, John J.P." Database Digital Access to Scholarship at Harvard (DASH)
4 results on '"Kastelein, John J.P."'

1. Effect of alirocumab dose increase on LDL lowering and lipid goal attainment in patients with dyslipidemia

Author

Kastelein, John J.P., Kereiakes, Dean J., Cannon, Christopher P., Bays, Harold E., Minini, Pascal, Lee, L. Veronica, Maroni, Jaman, and Farnier, Michel

Subjects
alirocumab, coronary heart disease, dosing, dyslipidemia, LDL cholesterol, proprotein convertase subtilisin kexin type 9
Abstract

Objectives: The objective of this study is to report the dose response in ODYSSEY phase 3 clinical trials of proprotein convertase subtilisin kexin type 9 inhibition with alirocumab in patients not at prespecified lipid goals who received a per-protocol dose increase from 75 every 2 weeks (Q2W) to 150 mg Q2W. Methods: Patients (n=2181) receiving statins were enrolled in six phase 3 randomized, double-blind, double-dummy trials (24–104 weeks): alirocumab versus placebo or ezetimibe 10 mg/day. The 75 mg subcutaneous Q2W dose was increased to 150 mg at week 12 if week 8 LDL cholesterol (LDL-C) was greater than or equal to 70 mg/dl (>100 mg/dl in OPTIONS studies for patients without previous coronary heart disease, but with other risk factors). LDL-C percentage reductions from baseline (on-treatment data, n=1291) were compared at week 12 versus week 24. Results: Most patients (n=951; 73.7%) with 75 mg Q2W dose plus background statin achieved LDL-C less than 70 or less than 100 mg/dl at week 8. In 340 (26.3%) patients, alirocumab dose was increased to 150 mg Q2W at week 12, and 60.9% of these patients achieved LDL-C goals at week 24, with an additional 14.2% reduction in LDL-C from week 12 to week 24. Adverse event rates were comparable in patients with versus without a dose increase (72.4 vs. 71.8% in placebo-controlled trials; 67.0 vs. 67.6% in ezetimibe-controlled trials). Conclusion: Most patients achieved LDL-C goals with alirocumab 75 mg Q2W plus statins. Of those (26.3%) receiving a dose increase, 60.9% achieved LDL-C goals at week 24 with an additional 14.2% reduction in LDL-C.

Published
2017
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2. Safety and Tolerability of CSL112, a Reconstituted, Infusible, Plasma-Derived Apolipoprotein A-I, After Acute Myocardial Infarction: The AEGIS-I Trial (ApoA-I Event Reducing in Ischemic Syndromes I)

Author

Michael Gibson, C., Korjian, Serge, Tricoci, Pierluigi, Daaboul, Yazan, Yee, Megan, Jain, Purva, Alexander, John H., Steg, P. Gabriel, Lincoff, A. Michael, Kastelein, John J.P., Mehran, Roxana, D’Andrea, Denise M., Deckelbaum, Lawrence I., Merkely, Bela, Zarebinski, Maciej, Ophuis, Ton Oude, and Harrington, Robert A.

Subjects
alipoprotein A-I, myocardial infarction
Abstract

Background: Human or recombinant apolipoprotein A-I (apoA-I) has been shown to increase high-density lipoprotein–mediated cholesterol efflux capacity and to regress atherosclerotic disease in animal and clinical studies. CSL112 is an infusible, plasma-derived apoA-I that has been studied in normal subjects or those with stable coronary artery disease. This study aimed to characterize the safety, tolerability, pharmacokinetics, and pharmacodynamics of CSL112 in patients with a recent acute myocardial infarction. Methods: The AEGIS-I trial (Apo-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b trial. Patients with myocardial infarction were stratified by renal function and randomized 1:1:1 to CSL112 (2 g apoA-I per dose) and high-dose CSL112 (6 g apoA-I per dose), or placebo for 4 consecutive weekly infusions. Coprimary safety end points were occurrence of either a hepatic safety event (an increase in alanine transaminase >3 times the upper limit of normal or an increase in total bilirubin >2 times the upper limit of normal) or a renal safety event (an increase in serum creatinine >1.5 times the baseline value or a new requirement for renal replacement therapy). Results: A total of 1258 patients were randomized, and 91.2% received all 4 infusions. The difference in incidence rates for an increase in alanine transaminase or total bilirubin between both CSL112 arms and placebo was within the protocol-defined noninferiority margin of 4%. Similarly, the difference in incidence rates for an increase in serum creatinine or a new requirement for renal replacement therapy was within the protocol-defined noninferiority margin of 5%. CSL112 was associated with increases in apoA-I and ex vivo cholesterol efflux similar to that achieved in patients with stable coronary artery disease. In regard to the secondary efficacy end point, the risk for the composite of major adverse cardiovascular events among the groups was similar. Conclusions: Among patients with acute myocardial infarction, 4 weekly infusions of CSL112 are feasible, well tolerated, and not associated with any significant alterations in liver or kidney function or other safety concern. The ability of CSL112 to acutely enhance cholesterol efflux was confirmed. The potential benefit of CSL112 to reduce major adverse cardiovascular events needs to be assessed in an adequately powered phase 3 trial. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT02108262.

Published
2016
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3. Discovery and Refinement of Loci Associated with Lipid Levels

Author

Willer, Cristen J., Schmidt, Ellen M., Sengupta, Sebanti, Peloso, Gina M., Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L., Mora, Samia, Beckmann, Jacques S., Bragg-Gresham, Jennifer L., Chang, Hsing-Yi, Demirkan, Ayşe, Den Hertog, Heleen M., Do, Ron, Donnelly, Louise A., Ehret, Georg B., Esko, Tõnu, Feitosa, Mary F., Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Fraser, Ross M., Freitag, Daniel F., Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U., Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E., Li, Xiaohui, Luan, Jian’an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K.E., Mangino, Massimo, Mihailov, Evelin, Montasser, May E., Müller-Nurasyid, Martina, Nolte, Ilja M., O’Connell, Jeffrey R., Palmer, Cameron D., Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Service, Susan K., Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J., Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M., Thorleifsson, Gudmar, Van den Herik, Evita G., Voight, Benjamin F., Volcik, Kelly A., Waite, Lindsay L., Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Been, Latonya F., Bolton, Jennifer L., Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S., Cesana, Giancarlo, Dimitriou, Maria, Doney, Alex S.F., Döring, Angela, Elliott, Paul, Epstein, Stephen E., Ingi Eyjolfsson, Gudmundur, Gigante, Bruna, Goodarzi, Mark O., Grallert, Harald, Gravito, Martha L., Groves, Christopher J., Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A., Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R., Kaleebu, Pontiano, Kastelein, John J.P., Khaw, Kay-Tee, Kim, Eric, Klopp, Norman, Komulainen, Pirjo, Kumari, Meena, Langenberg, Claudia, Lehtimäki, Terho, Lin, Shih-Yi, Lindström, Jaana, Loos, Ruth J.F., Mach, François, McArdle, Wendy L, Meisinger, Christa, Mitchell, Braxton D., Müller, Gabrielle, Nagaraja, Ramaiah, Narisu, Narisu, Nieminen, Tuomo V.M., Nsubuga, Rebecca N., Olafsson, Isleifur, Ong, Ken K., Palotie, Aarno, Papamarkou, Theodore, Pomilla, Cristina, Pouta, Anneli, Rader, Daniel J., Reilly, Muredach P., Ridker, Paul M., Rivadeneira, Fernando, Rudan, Igor, Ruokonen, Aimo, Samani, Nilesh, Scharnagl, Hubert, Seeley, Janet, Silander, Kaisa, Stančáková, Alena, Stirrups, Kathleen, Swift, Amy J., Tiret, Laurence, Uitterlinden, Andre G., van Pelt, L. Joost, Vedantam, Sailaja, Wainwright, Nicholas, Wijmenga, Cisca, Wild, Sarah H., Willemsen, Gonneke, Wilsgaard, Tom, Wilson, James F., Young, Elizabeth H., Zhao, Jing Hua, Adair, Linda S., Arveiler, Dominique, Assimes, Themistocles L., Bandinelli, Stefania, Bennett, Franklyn, Bochud, Murielle, Boehm, Bernhard O., Boomsma, Dorret I., Borecki, Ingrid B., Bornstein, Stefan R., Bovet, Pascal, Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C., Chen, Yii-Der Ida, Collins, Francis S., Cooper, Richard S., Danesh, John, Dedoussis, George, de Faire, Ulf, Feranil, Alan B., Ferrières, Jean, Ferrucci, Luigi, Freimer, Nelson B., Gieger, Christian, Groop, Leif C., Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B., Hingorani, Aroon, Hirschhorn, Joel N., Hofman, Albert, Hovingh, G. Kees, Hsiung, Chao Agnes, Humphries, Steve E., Hunt, Steven C., Hveem, Kristian, Iribarren, Carlos, Järvelin, Marjo-Riitta, Jula, Antti, Kähönen, Mika, Kaprio, Jaakko, Kesäniemi, Antero, Kivimaki, Mika, Kooner, Jaspal S., Koudstaal, Peter J., Krauss, Ronald M., Kuh, Diana, Kuusisto, Johanna, Kyvik, Kirsten O., Laakso, Markku, Lakka, Timo A., Lind, Lars, Lindgren, Cecilia M., Martin, Nicholas G., März, Winfried, McCarthy, Mark I., McKenzie, Colin A., Meneton, Pierre, Metspalu, Andres, Moilanen, Leena, Morris, Andrew D., Munroe, Patricia B., Njølstad, Inger, Pedersen, Nancy L., Power, Chris, Pramstaller, Peter P., Price, Jackie F., Psaty, Bruce M., Quertermous, Thomas, Rauramaa, Rainer, Saleheen, Danish, Salomaa, Veikko, Sanghera, Dharambir K., Saramies, Jouko, Schwarz, Peter E.H., Sheu, Wayne H-H, Shuldiner, Alan R., Siegbahn, Agneta, Spector, Tim D., Stefansson, Kari, Strachan, David P., Tayo, Bamidele O., Tremoli, Elena, Tuomilehto, Jaakko, Uusitupa, Matti, van Duijn, Cornelia M., Vollenweider, Peter, Wallentin, Lars, Wareham, Nicholas J., Whitfield, John B., Wolffenbuttel, Bruce H.R., Ordovas, Jose M., Boerwinkle, Eric, Palmer, Colin N.A., Thorsteinsdottir, Unnur, Chasman, Daniel I., Rotter, Jerome I., Franks, Paul W., Ripatti, Samuli, Cupples, L. Adrienne, Sandhu, Manjinder S., Rich, Stephen S., Boehnke, Michael, Deloukas, Panos, Kathiresan, Sekar, Mohlke, Karen L., Ingelsson, Erik, and Abecasis, Gonçalo R.

Abstract

Low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and total cholesterol are heritable, modifiable, risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,578 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5×10−8, including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian, and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipids are often associated with cardiovascular and metabolic traits including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio, and body mass index. Our results illustrate the value of genetic data from individuals of diverse ancestries and provide insights into biological mechanisms regulating blood lipids to guide future genetic, biological, and therapeutic research.

Published
2013
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4. Common variants associated with plasma triglycerides and risk for coronary artery disease

Author

Do, Ron, Willer, Cristen J., Schmidt, Ellen M., Sengupta, Sebanti, Gao, Chi, Peloso, Gina M., Gustafsson, Stefan, Kanoni, Stavroula, Ganna, Andrea, Chen, Jin, Buchkovich, Martin L., Mora, Samia, Beckmann, Jacques S., Bragg-Gresham, Jennifer L., Chang, Hsing-Yi, Demirkan, Ayşe, Den Hertog, Heleen M., Donnelly, Louise A., Ehret, Georg B., Esko, Tõnu, Feitosa, Mary F., Ferreira, Teresa, Fischer, Krista, Fontanillas, Pierre, Fraser, Ross M., Freitag, Daniel F., Gurdasani, Deepti, Heikkilä, Kauko, Hyppönen, Elina, Isaacs, Aaron, Jackson, Anne U., Johansson, Åsa, Johnson, Toby, Kaakinen, Marika, Kettunen, Johannes, Kleber, Marcus E., Li, Xiaohui, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Magnusson, Patrik K.E., Mangino, Massimo, Mihailov, Evelin, Montasser, May E., Müller-Nurasyid, Martina, Nolte, Ilja M., O'Connell, Jeffrey R., Palmer, Cameron D., Perola, Markus, Petersen, Ann-Kristin, Sanna, Serena, Saxena, Richa, Service, Susan K., Shah, Sonia, Shungin, Dmitry, Sidore, Carlo, Song, Ci, Strawbridge, Rona J., Surakka, Ida, Tanaka, Toshiko, Teslovich, Tanya M., Thorleifsson, Gudmar, Van den Herik, Evita G., Voight, Benjamin F., Volcik, Kelly A., Waite, Lindsay L., Wong, Andrew, Wu, Ying, Zhang, Weihua, Absher, Devin, Asiki, Gershim, Barroso, Inês, Been, Latonya F., Bolton, Jennifer L., Bonnycastle, Lori L, Brambilla, Paolo, Burnett, Mary S., Cesana, Giancarlo, Dimitriou, Maria, Doney, Alex S.F., Döring, Angela, Elliott, Paul, Epstein, Stephen E., Eyjolfsson, Gudmundur Ingi, Gigante, Bruna, Goodarzi, Mark O., Grallert, Harald, Gravito, Martha L., Groves, Christopher J., Hallmans, Göran, Hartikainen, Anna-Liisa, Hayward, Caroline, Hernandez, Dena, Hicks, Andrew A., Holm, Hilma, Hung, Yi-Jen, Illig, Thomas, Jones, Michelle R., Kaleebu, Pontiano, Kastelein, John J.P., Khaw, Kay-Tee, Kim, Eric, Klopp, Norman, Komulainen, Pirjo, Kumari, Meena, Langenberg, Claudia, Lehtimäki, Terho, Lin, Shih-Yi, Lindström, Jaana, Loos, Ruth J.F., Mach, François, McArdle, Wendy L, Meisinger, Christa, Mitchell, Braxton D., Müller, Gabrielle, Nagaraja, Ramaiah, Narisu, Narisu, Nieminen, Tuomo V.M., Nsubuga, Rebecca N., Olafsson, Isleifur, Ong, Ken K., Palotie, Aarno, Papamarkou, Theodore, Pomilla, Cristina, Pouta, Anneli, Rader, Daniel J., Reilly, Muredach P., Ridker, Paul M., Rivadeneira, Fernando, Rudan, Igor, Ruokonen, Aimo, Samani, Nilesh, Scharnagl, Hubert, Seeley, Janet, Silander, Kaisa, Stančáková, Alena, Stirrups, Kathleen, Swift, Amy J., Tiret, Laurence, Uitterlinden, Andre G., van Pelt, L. Joost, Vedantam, Sailaja, Wainwright, Nicholas, Wijmenga, Cisca, Wild, Sarah H., Willemsen, Gonneke, Wilsgaard, Tom, Wilson, James F., Young, Elizabeth H., Zhao, Jing Hua, Adair, Linda S., Arveiler, Dominique, Assimes, Themistocles L., Bandinelli, Stefania, Bennett, Franklyn, Bochud, Murielle, Boehm, Bernhard O., Boomsma, Dorret I., Borecki, Ingrid B., Bornstein, Stefan R., Bovet, Pascal, Burnier, Michel, Campbell, Harry, Chakravarti, Aravinda, Chambers, John C., Chen, Yii-Der Ida, Collins, Francis S., Cooper, Richard S., Danesh, John, Dedoussis, George, de Faire, Ulf, Feranil, Alan B., Ferrières, Jean, Ferrucci, Luigi, Freimer, Nelson B., Gieger, Christian, Groop, Leif C., Gudnason, Vilmundur, Gyllensten, Ulf, Hamsten, Anders, Harris, Tamara B., Hingorani, Aroon, Hirschhorn, Joel N., Hofman, Albert, Hovingh, G. Kees, Hsiung, Chao Agnes, Humphries, Steve E., Hunt, Steven C., Hveem, Kristian, Iribarren, Carlos, Järvelin, Marjo-Riitta, Jula, Antti, Kähönen, Mika, Kaprio, Jaakko, Kesäniemi, Antero, Kivimaki, Mika, Kooner, Jaspal S., Koudstaal, Peter J., Krauss, Ronald M., Kuh, Diana, Kuusisto, Johanna, Kyvik, Kirsten O., Laakso, Markku, Lakka, Timo A., Lind, Lars, Lindgren, Cecilia M., Martin, Nicholas G., März, Winfried, McCarthy, Mark I., McKenzie, Colin A., Meneton, Pierre, Metspalu, Andres, Moilanen, Leena, Morris, Andrew D., Munroe, Patricia B., Njølstad, Inger, Pedersen, Nancy L., Power, Chris, Pramstaller, Peter P., Price, Jackie F., Psaty, Bruce M., Quertermous, Thomas, Rauramaa, Rainer, Saleheen, Danish, Salomaa, Veikko, Sanghera, Dharambir K., Saramies, Jouko, Schwarz, Peter E.H., Sheu, Wayne H-H, Shuldiner, Alan R., Siegbahn, Agneta, Spector, Tim D., Stefansson, Kari, Strachan, David P., Tayo, Bamidele O., Tremoli, Elena, Tuomilehto, Jaakko, Uusitupa, Matti, van Duijn, Cornelia M., Vollenweider, Peter, Wallentin, Lars, Wareham, Nicholas J., Whitfield, John B., Wolffenbuttel, Bruce H.R., Altshuler, David, Ordovas, Jose M., Boerwinkle, Eric, Palmer, Colin N.A., Thorsteinsdottir, Unnur, Chasman, Daniel I., Rotter, Jerome I., Franks, Paul W., Ripatti, Samuli, Cupples, L. Adrienne, Sandhu, Manjinder S., Rich, Stephen S., Boehnke, Michael, Deloukas, Panos, Mohlke, Karen L., Ingelsson, Erik, Abecasis, Goncalo R., Daly, Mark J., Neale, Benjamin M., and Kathiresan, Sekar

Abstract

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiologic studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P<5×10−8 for each) to examine the role of triglycerides on risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglycerides, and show that the direction and magnitude of both are factors in determining CAD risk. Second, we consider loci with only a strong magnitude of association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol, a polymorphism's strength of effect on triglycerides is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Published
2013
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