22 results on '"Masiukiewicz, U."'
Search Results
2. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes
- Author
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Cannon, Cp, Pratley, R, Dagogo-Jack, S, Mancuso, J, Huyck, S, Masiukiewicz, U, Charbonnel, B, Frederich, R, Gallo, S, Cosentino, F, Shih, Wj, Gantz, I, Terra, Sg, Cherney, Dzi, Mcguire, Dk, VERTIS CV Investigators, Pugliese, G, Lembo, G, Cannon, C. P., Pratley, R., Dagogo-Jack, S., Mancuso, J., Huyck, S., Masiukiewicz, U., Charbonnel, B., Frederich, R., Gallo, S., Cosentino, F., Shih, W. J., Paolisso, G, Gantz, I., Terra, S. G., Cherney, D. Z. I., and Mcguire, D. K.
- Subjects
Male ,medicine.medical_specialty ,ertugliflozin ,MEDLINE ,type 2 diabetes ,cardiovascular disease ,Type 2 diabetes ,030204 cardiovascular system & hematology ,law.invention ,Placebos ,03 medical and health sciences ,0302 clinical medicine ,Randomized controlled trial ,Double-Blind Method ,law ,Internal medicine ,Diabetes mellitus ,Humans ,Medicine ,Diabetic Nephropathies ,030212 general & internal medicine ,Sodium-Glucose Transporter 2 Inhibitors ,Placebo ,Aged ,urogenital system ,business.industry ,General Medicine ,Middle Aged ,Atherosclerosis ,medicine.disease ,Bridged Bicyclo Compounds, Heterocyclic ,Hospitalization ,Equivalence Trial ,Multicenter study ,Diabetes Mellitus, Type 2 ,Cardiovascular Diseases ,Atherosclerosi ,Diabetic Nephropathie ,Ertugliflozin ,Female ,business ,Cardiovascular outcomes ,Human - Abstract
The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established.In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo.Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck SharpDohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.).
- Published
- 2020
3. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients
- Author
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Ridker, P. M., Revkin, J., Amarenco, P., Brunell, R., Civeira, F., Flather, M., Glynn, R. J., Gregoire, J., Jukema, J. W., Karpov, Y., Kastelein, J. J. P., Koenig, W., Lorenzatti, A., Manga, P., Masiukiewicz, U., Miller, M., Mosterd, A., Murin, J., Nicolau, J. C., Nissen, S., Ponikowski, P., Santos, R. D., Schwartz, P. F., Soran, H., White, H., Wright, R. S., Vrablik, M., Yunis, C., Shear, C. L., Tardif, Conde D, J. -C., Colquhoun, D, Missault, L, Grégoire, J, Gao, R, Urina, M, Solar, M, Jensen, Hk, Grobbee, D, Savolainen, M, Schiele, Fn, Montalescot, G, Edes, I, Blake, G, Lotan, C, Maggioni, A, Savonitto, S, Lee, Cw, Leiva Pons JL, Dan, Ga, Cortada, Jb, Mellbin, L, Kahan, T, Noble, S, Hwang, Jj, Sritara, P, Tökgozoğlu, L, Tarasenko, L, Borer, Js, Black, H, Carmena, R, Furie, Kl, Mcmurray, J, Neaton, J, Zannad, F, O’Neill, B, Welty, F, Mcnamara, R, Chun, H, Abbott, Jd, Jacoby, D, Mcpherson, C, Jadbabaie, F, Pinto, D, Mccullough, L, Silverman, Ie, Sansing, Lh, Dearborn-Tomazos, J, Foody, J, Schindler, J, Piazza, G, Chakrabarti, A, Pride, Y, Gelfand, E, Baultrukonis, D, Chaudhuri, S, Frederich, R, Johnson, M, Mridha, K, Powell, C, Wang, E, Wei, C, Anderson, P, Buonanno, M, Epsley, C, Evans, B, Frolova, M, Goetsch, M, Hessinger, D, Ikehara, E, Ivanac, K, Kizko, J, Le, K, McNally-Dufort, C, Morocco, T, Nadkarni, S, Nissen, T, Nye, R, Pak, R, Pence, D, Redifer, P, Schwartz, W, Sattler, C, Schade, R, Sullivan, B, Wegner, J, Alvarez, Ca, Budassi, N, Vogel, Dr, Avaca, H, Conde, Dg, Estol, Cc, Gelersztein, E, Glenny, Ja, Hershson, Ar, Bruno, Rl, Maffei, Le, Soler, Jm, Zaidman, Cj, Carnero, Gs, Colombo, Hr, Jure, Ho, Luquez, Ha, Ramos, Hr, Resk, Jh, Rusculleda, Mm, Ulla, Mr, Caccavo, A, Farias, Ef, Wenetz, Lm, Cabella, Pr, Cuadrado, Ja, Chahin, M, Mackinnon, Ij, Zarandon, Rb, Schmidberg, J, Fernandez, Aa, Montana, O, Codutti, Or, Gorosito, Vm, Maldonado, N, Sala, J, De La Fuente RA, Casabella, Te, Di Gennaro JP, Guerrero, Ra, Alvarez, Ms, Berli, M, Botta, Ce, Montenegro, Ee, Vico, Ml, Begg, A, Lehman, R, Gilfillan, Cp, D'Emden, M, Markovic, Tp, Sullivan, D, Aroney, C, Stranks, Sn, Crimmins, Ds, Arstall, M, Van Gaal, W, Davis, T, Aylward, Pe, Amerena, J, William, M, Proietto, J, Purnell, Pw, Singh, B, Arya, Kw, Dart, Am, Thompson, P, Davis, Sm, Carroll, Pa, De Looze, F, Jayasinghe, R, Bhindi, R, Buysschaert, I, Sarens, T, van de Borne, P, Scott, Bp, Roosen, J, Cools, F, Missault, Lh, Debroye, C, Schoors, Df, Hollanders, G, Schroe, Hh, De Sutter, J, Hermans, K, Carlier, M, van Landegem, P, Verwerft, J, Mulleners, T, Delforge, Md, Soufflet, V, Elegeert, I, Descamps, Os, Janssens, S, Lemmens, Rc, Desfontaines, P, Scheen, A, Heijmans, S, Capiau, L, Vervoort, G, Carlier, Sg, Faes, D, Alzand, B, Keuleers, S, De Wolf, L, Thoeng, J, De Bruyne, L, de Santos MO, Felicio, Js, Areas, Ca, Figueiredo, El, Michalaros, Yl, Neuenschwander, Fc, Reis, G, Saad, Ja, Kormann, Ap, Nascimento, Cv, Precoma, Db, Abib, E Jr, dos Santos FR, Mello, Yg, Saraiva, Jf, Rech, Rl, Cerci, R, Fortes, Ja, Rossi, Pr, de Lima, e Silva FA, Hissa, M, Silva, Rp, de Souza WK, Guimarães Filho FV, Mangili, Oc, de Oliveira Paiva MS, Tumelero, R, Abrantes, Ja, Caramori, Pr, Dutra, Op, Leaes, Pe, Manenti, Er, Polanczyk, Ca, Bandeira, e Farias FA, de Moraes Junior JB, Russo, La, Alves AR Jr, Dracoulakis, Md, Ritt, Le, Saporito, Wf, Herdy, Ah, Maia, Ln, Sternieri, Mv, Ayoub, Jc, Bianco, Ht, da Costa FA, Eliaschewitz, Fg, Fonseca, Fa, Nakandakare, Er, Bonansea, Tc, Castro, Nm, de Barros, e Silva PG, Smith, P, Botelho, Rv, Resende, Es, Barbieri, Ds, Hernandes, Me, Bajaj, H, Beaudry, P, Berlingieri, Jc, Salter, Tj, Ajala, B, Anderson, Tj, Nanji, A, Ross, S, Pandey, S, Desrosiers, D, Gaudet, D, Moran, G, Csanadi, Ma, St-Amour, E, Cusimano, S, Halperin, Fa, Babapulle, M, Vizel, S, Petrella, J, Spence, Jd, Gupta, N, Tellier, G, Bourgeois, R, Gregóire, Jc, Wesson, T, Zadra, R, Twum-Barima, Dy, Cha, Jy, Hartleib, Mc, Bergeron, J, Chouinard, G, Mcpherson, Tp, Searles, G, Peterson, Sr, Mukherjee, A, Lepage, S, Conway, Jr, Kouz, Sm, Dion, D, Pesant, Y, Cheung, Ss, Goldenberg, Rm, Aronson, R, Gupta, Ak, O’Mahoney, M, Pliamm, L, Teitelbaum, I, Hoag, Gn, Nadra, Ij, Yared, Z, Yao, Lc, Nguyen, T, Saunders, Kk, Potthoff, S, Varleta, P, Assef, V, Godoy, Jg, Olivares, C, Roman, O, Vejar, M, Montecinos, H, Pincetti, C, Li, Y, Wang, D, Li, J, Yang, X, Du, Y, Wang, G, Yang, P, Zhang, X, Xu, P, Zhao, Y, Chen, J, Li, S, Li, W, Zhang, L, Zhu, Y, Zhang, Y, Zhou, C, Wang, Y, Liu, F, Ma, Y, Ti, Z, Zeng, X, Zhou, Y, Cui, G, Li, D, Xue, L, Jiang, J, Lian, Y, He, Y, Mendoza, Ja, Bonfanti, Ja, Dada, Fa, Urina-Triana, Ma, Rodriguez, Wr, Sanchez, Ml, Lozno, Hy, Triana, Eh, Arambula, Rm, Rico-Carrillo, Ae, Gallo, Hj, Catano, Js, Jattin, Fg, Plazas, Ja, Gomez, Je, Botero-Lopez, R, Gomez, Ni, Munoz, Cf, Pelaez, Sv, Eraso, Am, Goyes, Ar, Elbl, L, Fiserova, N, Vesely, J, Wasserburger, B, Blaha, V, Vojacek, J, Maskova, P, Hutyra, M, Vrkoc, J, Hala, T, Vodnansky, P, Bocek, P, Cifkova, R, Bufka, V, Ceska, R, Machkova, M, Zidkova, E, Lukac, M, Mikusova, T, Kellnerova, I, Kuchar, L, Ferkl, R, Cech, V, Zemek, S, Monhart, Z, Davidsen, F, Joensen, A, Lihn, As, Rasmussen, Tk, Wiggers, H, Lindgren, Lm, Schmidt, U, Galatius, S, Sillesen, H, Bronnum Schou, J, Thomsen, Kk, Urhammer, S, Jeppensen, J, Schou, M, May, O, Steffensen, R, Nielsen, Wb, Nielesen, T, Jepsen, Jm, Rai, A, Sykulski, R, Andersen, Lt, Rickers, H, Frost, L, Lomholdt, J, Egstrup, K, Wermuth, S, Klausen, L, Lassus, J, Palomaki, A, Khari, J, Tatlisumak, T, Kekki, S, Vanttinen, E, Strandberg, A, Valtonen, M, Sia, Sm, Nerg, O, Puhakka, M, Strand, J, Timonen, M, Levola, J, Arstila, L, Taurio, J, Kantola, I, Suomi, J, Humaloja, K, Askonen, K, Schiele, F, Sibon, I, Zemour, G, Goube, P, Petit, C, Chati, Z, Range, G, Rabahi, F, Rihani, R, Bergerot, C, Roubille, F, Boye, A, Probst, V, Ferrari, E, Cayla, G, Thouvenot, E, Delarche, N, Couffinhal, T, Coisne, D, Paillard, F, Elbaz, M, Decoulx, E, Angoulvant, D, Agraou, B, Caudmont, S, Berrouschot, J, Lauer, B, Schoell, I, Trenk, D, Derwahl, Km, Khariouzov, A, Proepper, F, Stawowy, P, Da Stephan, U, Stoessel, J, Voehringer, Hf, Dorsel, T, Stellbrink, C, Rinke, A, Northroff, J, Bourhaial, H, Stratmann, M, Wetzel, T, Axthelm, C, Guenzel, A, Weigmann, I, Faghih, M, Hagemann, D, Schaefer, A, Weber, D, Luedemann, J, Contzen, C, Kornmann, Mo, Winkelmann, B, Simon, J, Felix, S, Brauer, C, Laufs, U, Schmidt, E, Marten, I, Licka, M, Heisters, J, Appel, Kf, Kleinecke-Pohl, U, Klein, C, von Hodenberg EF, Maus, O, Sigal, H, Taeschner, H, Schwimmbeck, P, Lemke, B, Perings, C, Illies, G, Pfuetzner, A, Salbach, P, Hengstenberg, C, Kohler, A, Mudra, H, Behnke, T, Baar, M, Jeserich, M, Scholz, G, Naudts, I, Voller, H, Herrmann, Hj, von Engelhardt CB, Gerke, S, Pohlmeier, L, Schaufele, T, Woehrle, J, Al-Zoebi, A, Horacek, T, Peterfai, E, Kemeny, V, Lakatos, F, Bod, E, Andrassy, P, Andreka, P, Balo, T, Davidovits, Z, Laszlo, Z, Nagy, K, Papp, A, Somogyi, A, Toldy-Schedel, E, Vertes, A, Voros, P, Paragh, G, Martyin, T, Hajdu, C, Deak, L, Farago, K, Nagy, A, Kirschner, R, Koszegi, Z, Zilahi, Z, Toth, K, Wittmann, I, Bajcsi, D, Reiber, I, Toth, L, Benczur, B, Nagy, L, Sydo, T, Lupkovics, G, Oroszlan, T, Crean, P, Mahon, Ng, Mcadam, B, Macneill, B, Katz, A, Tsalihin, D, Vazan, A, Eitan, A, Lewis, Bs, Gavish, D, Wainstein, J, Mosenzon, O, Mosseri, M, Vishlitzky, V, Atar, S, Nseir, Wb, Brenner, H, Elis, A, Fuchs, S, Shimon, I, Solodky, A, Goldhaber, A, Tanne, D, Knobler, H, Kracoff, Oh, Hussein, O, Auriel, E, Chorin, E, Sharir, T, Bitzur, R, Shechter, M, Antonicelli, R, Franceschini, E, Porcu, M, Sesti, G, Maggiolini, S, Salvioni, A, Filardi, Pp, Trimarco, B, Averna, M, Pasqualini, L, Pirro, M, Pantaleoni, M, Piovaccari, G, Arca, M, Fedele, Francesco, Roncon, L, Anselmi, M, Sganzerla, P, Morocutti, G, Bonora, E, Dimas, Al, Esperon, Ga, Morales-Villegas, E, Isunza, Jm, Beltran, Lg, Molina, Ca, Garcia, Dk, Ruiz, La, Reyna, Ls, De los Rios Ibarra MO, Soto, Jr, Gonzalez-Ortiz, M, Herrera-Marmolejo, M, Ramos, Sa, Ramos-Lopez, Ga, Stobschinski, Ca, Aguilarsalinas, Ca, Alpizar-Salazar, M, Jimenez-Sanchez, M, Sanchez Mijangos JH, Elizondo Moreno ER, Garcia Castillo, A, Garcia Hernandez PA, Gonzalez-Gonzalez, Jg, Riojas Charles CM, Valdez Lopez HG, Nuriulu Escobar PL, Lechuga Martin del Campo, A, Castro Montes BE, Mendez Bucio, A, Rodriguez-Briones, I, Torre Amione, G, Violante Ortiz, R, Luna Ceballos RI, Lopez Rosas, E, Bax, Wa, Alhakim, M, van de Wiel, A, Liem, Ss, Groutars, Rg, Herrman, Jp, Hovingh, Gk, van de Wetering ML, van Royen, N, Groenemeijer, Be, Hoedemaker, G, Schaap, J, Ronner, E, Angun, M, Mairuhu, At, Van Alem AP, Martens, Fm, Heijmeriks, Ja, van Hal JM, Schoofs, Mw, den Hartog FR, Kentgens, S, Post, Jc, Louwerenburg, Jw, van Rossum, P, Viergever, Ep, Donders, Sh, Kamphuisen, Pw, van Beek, E, Nijmeijer, R, Lenderink, T, Schreuder, T, Kuijper, Af, The, Sh, Van het Hof-Wiersma JJ, Tichelaar, P, Westerndorp, I, Breedveld, Rw, Karalis, I, Romer, Tj, Bogaard, K, Van Koningsbruggen, P, Kroon, Aa, Hoogslag, Pa, Rensing, Bj, Cramer, E, Remmen, Jj, Riksen, Np, Bokern, Mj, Cabezas, Mc, Mulder, H, Nierop, Pr, van Kempen WW, Zoet-Nugteren, Sk, van Daele ME, Swart, Hp, van der Zwaan CT, Hermans, Wr, Magro, M, van de Wal RM, Hassink, Rj, Visseren, F, Veenendaal, A, De Nooijer, C, Troquay, Rp, Imholz, Bp, van der Meer, P, Visser, Rp, van Leendert RJ, Gosselink, Ma, Baker, J, Benatar, Jr, Kerr, J, Pryke, Jr, Scott, Rs, Millar-Corte, Gd, Williams, M, Montgomery, B, Venter, Dj, Ternouth, If, Decaigney, Sc, Hart, Hh, Corin, A, Garden, Pi, Sheahan, D, Harding, Sa, Korecki, J, Supronik, J, Styczkiewicz, M, Bijata-Bronisz, R, Rusicka, T, Walczak, M, Krolikowski, Z, Ostrowski, J, Lukaszewicz, M, Przekwas-Jaruchowska, M, Zieba, B, Miekus, P, Orkwiszewska-Nalewajko, A, Piepiorka, M, Kubalski, P, Wychota, K, Blach, E, Ochala, A, Okopien, B, Wronska, D, Janion, M, Czarnecka, D, Kolodziejczyk, J, Konieczynska, M, Landa, K, Mirek-Bryniarska, E, Necki, M, Pasternak, Da, Rozpondek, P, Trebacz, J, Walczewska, J, Sidor, M, Broncel, M, Drozdz, J, Kosmider, M, Saryusz-Wolska, M, Kucharska, D, Opalinska, E, Pijanowski, Z, Wozniak, I, Banaszkiewicz, K, Klecha, A, Horodecki, M, Piskorz-Wapinska, J, Kobielusz-Gembala, I, Kim, Mh, Kim, Dk, Cho, Br, Kim, Ks, Her, Sh, Lee, Sy, Rhee, My, Kim, K, Kang, Wc, Kim, Dh, Cho, Ys, Kim, Sh, Rim, Sj, Tahk, Sj, Jeon, Hk, Yoon, J, Mociran, M, Pop, Cf, Minescu, B, Andrei, Ld, Radoi, M, Calin, A, Ciomag, Rm, Copaci, I, Fruntelata, Ag, Popescu, M, Tivadar, S, Roman, G, Avram, Ri, Mistodie, Cv, Morosanu, M, Popa, Ar, Popescu, Ml, Popoviciu, Ms, Tase, A, Busegeanu, M, Popescu, A, Szilagyi, I, Sitterli-Natea, Cn, Maximov, Dm, Munteanu, M, Negrisanu, Gd, Kuzin, A, Popov, D, Shapovalova, J, Vishneva, E, Shutemova, E, Pasechnik, E, Bogdanov, E, Khasanov, N, Barbarash, Ol, Shangina, Oa, Tarasov, N, Solonev, O, Kosmacheva, E, Chernyatina, Ma, Ginzburg, M, Blokhin, A, Bulanova, N, Drapkina, Om, Gordeev, Ig, Libov, Ia, Lomakin, N, Panchenko, E, Shogenov, Zs, Zateyshchikov, D, Klein, G, Motylev, I, Belenkiy, Di, Demin, A, Nikolaev, Ky, Oleynikov, V, Zrazhevskiy, K, Katelnitskiy, I, Khaisheva, L, Aksentiev, S, Nedoshivin, A, Popova, Vb, Agafina, As, Ballyuzek, M, Baranova, E, Burova, N, Eryshev, S, Filippov, A, Goloshchekin, Bm, Konstantinov, V, Kostenko, Va, Simanenkov, Vi, Volkova, A, Duplyakov, D, Reshetko, O, Shvarts, Y, Kuznetsov, Va, Samoylova, Yg, Tolkacheva, V, Shalaev, Sv, Khokhlov, Al, Malygin, A, Shilkina, Np, Yakusevich, Vv, Margoczy, R, Zubek, V, Dzupina, A, Dubrava, J, Dulkova, K, Fabryova, L, Gaspar, L, Kamensky, G, Kokles, M, Raslova, K, Soosova, I, Stevlik, J, Strbova, J, Sumbal, J, Uhliar, R, Micik, J, Truban, J, Fedacko, J, Pastrnakova, E, Pella, D, Fazekas, F, Ambrovicova, V, Kycina, P, Martinka, E, Nociar, J, Belicova, M, Banik, M, Kanderkova, D, Hranai, M, Duris, T, Krahulec, B, Benacka, J, Vinanska, D, Roskova, E, Skripova, D, Macek, V, Vohnout, B, Buganova, I, Engelbrecht, Jm, Pretorius, Mm, Ebrahim, Io, Bayat, J, Ganesh, S, Ranjith, N, Coetzer, Tf, Jacovides, A, Distiller, La, Hellig, Fs, Engelbrecht, Iv, Mahomed, Aa, Blignault, Sc, Burgess, Lj, Kotze, Hj, van Nieuwenhuizen, E, Musungaie, Db, Emanuel, S, van der Walt, E, Pretorius, Ce, Roos, Js, Roux, Sm, Badat, Ae, Fouche, L, Vahed, Ya, Jansen van Resburg, D, van Zyl LJ, Soto Gonzalez, A, Diaz, Jl, Segura, T, Botella Serrano, M, Botas Rodrigues, J, Molto-Jorda, Jm, Dominguez Escribano JR, Sogorb Garri, F, Blanco Coronado JL, Gaztambide Saenz MS, Brotons Cuixart, C, Bruguera Cortada, J, Garcia-Moll Marimon, X, Gonzalbez Morgaez JD, Maisterra Santos, O, Roquer Gonzalez, J, Sobrino-Martinez, J, Chueca Fernandez JE, Narejos, S, Suarez Garcia, S, Perez Martinez, P, Figueras Camos, R, Medrano Martinez, V, Bellido Guerrero, D, Martinez Deben, F, Vila Belmonte, A, Mediavilla Garcia JD, Romero Hinojosa JA, Martorell Mateu, E, Cequier Fillat AR, Pinto Sala, X, Adroer Martori, R, Bueno Diez, M, Lopez Cano, C, Worner Diz, F, Gonzalez Juanatey, C, Alvarez-Sala Walther LA, De Dios Garcia Diaz, J, Garcia Puig, J, Jodar Gimeno, E, Plaza Perez, I, Suarez-Fernandez, C, Tunon, J, Zamorano Gomez JL, Brito Sanfiel MA, Escudier Villa JM, de Mora Martin, M, Dominguez Lopez, M, Hernandez Garcia JM, Tinahones Madueno FJ, Perez Paredes, M, Aracil Villar, J, Barreda Gonzalez MJ, Ripoll Vera TV, Tofe Povedano, S, Sanchez Alvarez, J, Martinez Via, L, Robles Iniesta, A, Masana, L, Vinyoles Bargallo, E, Calvo Gomez, C, Gonzalez Juanatey JR, Cruz Fernandez JM, De La Cuesta Mayor, C, Duran Garcia, S, Jimenez Hernandez MD, Morales Portillo, C, Muniz Grijalvo, O, De Castro, R, Taverna Llaurado, E, Pons Amate JM, Terns Riera, M, Civeira Murillo, F, Linderfalk, C, Curiac, D, Saldeen-Nilehn, K, Koskinen, P, Khalili, P, Tortensson, I, Lindholm, Cj, Luts, A, Koskinen, Pt, Gottsater, A, Persson, Be, Mooe, T, Larnefeldt, H, Boman, K, Crisby, M, Rasmanis, G, Tengmark, Bo, Witt, N, Hagstrom, E, Viklund, J, Muller, C, Mach, F, Burnier, M, Nanchen, D, Wuerzner, G, Banyai, M, Moccetti, T, Miserez, Ar, Bilz, S, Weber, K, Lai, Wt, Chang, Kc, Ueng, Kc, Tsai, Wc, Chiang, Ce, Hou, C, Pei, D, Krittayaphong, R, Kiatchoosakun, S, Srimahachota, S, Boonyavarakul, A, Jintapakorn, W, Gullu, H, Onrat, E, Erkan, Af, Demirci, D, Sari, R, Ceyhan, C, Ari, H, Araz, M, Degertekin, M, Goktekin, O, Uresin, Ay, Yigit, Z, Akdeniz, B, Comlekci, A, Kayikcioglu, M, Sahin, T, Ozcan, T, Durakoglugil, E, Asamoah-Owusu, N, Reed, R, Bakhai, A, Dixon, L, Sharma, R, Avornyo, Aa, Jones, Af, Lip, G, Clark, R, Banerjee, M, Wakeling, J, Arden, C, Blagden, Md, Walukiewica, P, Marshall, A, Maxwell, Tg, Gunstone, Ae, Kadr, Hh, Patle, R, Arif, I, Jhund, Ps, Mckaig, G, Douglas, F, Mierzejewski, L, Turner, W, Sathyapalan, T, Ivan, P, Manoj, A, Rice, S, Collier, Dj, Nair, Dr, Thom, S, Fiore, G, De Belder, M, Price, D, Sobolewska, J, Martin, S, Takhar, A, Moriarty, A, Kondagunta, V, Myhill, T, Gibson, Jm, Cecil, Jt, Halcox, J, Annamalai, N, Gorog, Da, Mccormack, T, Pegge, N, Field, A, Adams, F, Klein, Jj, Busch, Rs, Bretton, Em, Jaffrani, N, Salacata, A, Assadourian, A, Gogia, Hs, Dyke, Ck, Rubenfire, M, Essandoh, Lk, Welker, Ja, Ledesma, G, Lupovitch, S, Delgado, Jp, Hendrix, El, Quyyumi, Aa, Riesenberg, Ra, Robertson, Dg, Weinstein, Dl, Weiss, R, Casaubon, L, Gammon, Rs, Brar, Hs, Bittar, Gd, Guarnieri, Tt, Ince CS Jr, Jrquraishi, Am, Saeed, S, Albert, M, Sotolongo, Rp, Bernard, Jv, Karlsbergg, Rp, Lepor, Ne, Kirby, We, Mclean, B, Miller, Ap, Ovalle, F, Townsend, Jc, Beckett, Pl, Eaves, Wb, West, Sh, Kosinski, Ej, Zarich, Sw, Mahal, Ss, Maw, K, Maynard, Km, Chen, Jc, Gelormini, J, Gottlieb, Dw, Gabra, Nw, Narayan, P, Sparks, J, Field, Jc, Willits, Vl, O’Steen, Mb, Pasquini, Ja, Sensebrenner, Jw, Yarows, Sa, Hiotis, L, Jagielo, Tj, Levinson, Dj, Diller, Pm, Kereiakes, Dj, Turner, Ta, Vincent, S, Camp, Ad, Denker, Ps, Manning, Mb, Rocco, Mb, Stamps, Hb, Strader, Jr, Uusinarkaus, Kt, Kennett, Jd, Leichter, Sb, Mcneil, Dl, Schumacher, Dr, Chang, Ar, Ellison, Hs, Updegrove, Jd, Hamroff, Gs, Kay, Js, Marar, Ie, Flores, E, Saini, S, Abdullah, S, Berk, Mr, Fordan, S, Joshi, Ph, Mccullough, Pa, Reynolds, Rd, Rosenstock, J, Sachson, Ra, Shammas, N, Fishbein, Gj, Randall, Wj, Henderson, Da, Nash, Ml, Barker, Ba, Cohen, Ss, Seidman, B, Odekirk, Ll, Grillo, Rs, Martinez, Lm, Multani, P, Alwine, Lk, Mcgarvey, Jf, Mollerus, Me, Miller, Ab, Kotek, Lw, Changlani, M, Zavaro, Sh, Munoz, F, Mehta, Pm, Helm, Rj, Farhat, Nz, Farsad, R, Raoof, Tj, Shultz, Jh, Geohas, Jg, Allaw, Ma, Dela Llana, A, Gutmann, Je, Inzerello, At, Alappat, P, George, Ar, Haddad, Tm, Lillestol, Mj, Grodman, R, Peniston, Jh, Wadud, K, Garcia, B, Hamilton, Me, Lerman, S, Perloff, De, Graff, A, Saxena, S, Alvarado, Op, Malik, A, Reddy, Rd, Kinzfogl, G, Cornett, Gm, Norwood, Pc, Gilbert, Jm, Willis, Jg, Mcgrew, F, Sharma, S, Castro, Ma, Cucher, Fh, Altafullah, Im, Khurana, S, Knutson, Tj, Kinnaman, Sj, Stuckey, T, Pudi, Kk, Mayfield, Rk, Funk, Gs, Nixon, Wa, Dor, I, Boyett, Be, Srivastava, S, Elosegui, Am, Isserman, Sm, Cheek, Hb, Promisloff, Sd, Tami, Lf, Zeig, S, fitz-Patrick, D, Dave, Kn, Ahmad, A, Arain, S, Ballantyne, Cm, Doshi, A, El Hafi SE, Feldman, J, Fragoso, Vg, Gilford, T, Hoffman, As, Pouzar, Je, Vivekananthan, K, Ansari, Sh, Strzinek, Ra, Crater, Ta, Robinson, Jg, Fulmer, Jj, Patel, Am, Pereira, Es, Stich, Ma, Sultan, S, Geskin, G, Ruoff, Ge, Gillespie, E, Bybee, Ka, Moriarty, Pm, Savin, V, Agaiby, Jm, Melucci, Mb, Jantzi, Cm, Davidson, E, Smith, Wb, Treasure, Cb, Wakefield, Ph, Deck, K, Edris, Ma, Gilmore, Rm, Seep, Mk, Andersen, Jl, Detweiler, Ro, Rosenfeld, Jc, Strobl, Dj, Steinhoff, Jp, Adams, A, Estevez, R, Molin, Cj, Kim, Cy, Dy, J, Fox, Ke, Farris, Nr, Wayne, Jd, Whitney, Rt, Randhawa, Pm, Mego, Dm, Macdolnald, L, Caputo, Rp, Rigolosi, R, Vannatta, B, Pacheco, Tr, El-Shahawy, M, Gonzalez, Ej, Guice, Mj, Cherlin, Rs, Bays, He, Shoukfeh, M, Morris, Fh, Loy, J, Vora, Sk, Staab, Pk, Frisoli, A, Kimmel, Ma, Cohen, Aj, Green, Cb, Whitlock, L, Butuk, Dj, Mccartney, Mj, Ables, Lr, Acosta, R, Alvarez, Jg, Barrera, Cm, Benitez, O, Berenguer, Ra, Breton, Cf, Chiong, R, Delgado, Mi, Dufreny, A, Fialkow, Ja, Franczek, S, Frias, Jj, Iglesias, C, Landron-Garcia, L, Llerena, Sn, Martinez, Rf, Miranda, Aa, Morytko, Ja, Rodriguez, Ij, Sotolongo, R, Suarez-Sarmiento, A, Terrelonge, Ae, Vaca, Ce, Venereo, Jm, Verdeza, C, Zeno, Ml, Chilka, S, Felten, Wr, Hartman, An, Shayani, Ss, Duprez, D, Knickelbine, T, Chambers, Jd, Cone, Cl, Broughton, R, Napoli, Mc, Seaton, Bl, Smith, Sk, Reedy, Ma, Kesani, Mk, Nicol, Pr, Stringam, So, Talano, Jv, Barnum, O, Desai, V, Montero, M, Jacks, Rk, Kostis, Jb, Owen, Jg, Makam, Sk, Grosman, I, Underberg, Ja, Masri, Be, Peters, Ss, Serje, J, Lenhard, Mj, Glover, R, Paraboschi, Cf, Lim, Eh, Connery, L, Kipgen, W, Bravo, P, Digiovanna, Mj, Tayoum, H, Gabriel, Jd, Ariani, Mk, Robinson, Mf, Clemens, Pc, Corder, Cn, Schifferdecker, B, Tahirkheli, Nk, Hurling, Rt, Rendell, Ms, Shivaswamy, V, Madu, Ij, Dahl, Cf, Ayesu, K, Kim, C, Barettella, Mb, Jamidar, Ha, Bloom, Sa, Vora, Kn, Ong, St, Aggarwala, G, Sack, G, Blaze, K, Krichmar, P, Murcia, A, Teltser, M, Villaman-Bencosme, Y, Fahdi, Ie, Williams, Dg, Lain, El, Garcia, Hl, Karim, Sn, Francyk, Dm, Gordon, Mb, Palchick, Ba, Mckenzie, Me, Gimness, Mp, Greiff, J, Ruiz-R, L, Vazquez-Tanus, Jb, Schlager, D, Connelly, T, Soroka, E, Hastings, Wl, O’Dea, Dj, Purdy, Da, Jackson, B, Arcanese, Ml, Strain, Je, Schmedtje JF Jr, Jrdavis, Mg, A, A, Prasada, S, Scott, Dl, Vukotic, G, Akhtar, N, Larsen, Dc, Rhudy, Jm, Zebrack, Js, Bailey, Sr, Grant, Dc, Mora, A, Perez, Ja, Reyes, Rg, Sutton, Jc, Brandon, Dm, First, Bp, Risser, Ja, Claudio, J, Figueroa-Cruz, Wl, Sosa-Padilla, Ma, Tan, Ae, Traboulssi, Ma, Morcos, Nc, Glaser, La, Bredlau, Ce, El Shahawy, M, Ramos, Mj, Kandath, Dd, Kaluski, E, Akright, L, Rictor, Kw, Pluto, Tm, Hermany, Pr, Bellingar, B, Clark, Gb, Herrod, Jn, Goisse, M, Hook, M, Barrington, P, Lentz, Jd, Singal, Dk, Gleason, Gp, Lipetz, Rs, Schuchard, Tn, Bonner, Jh, Forgosh, Lb, Lefebvre, Gc, Pierpoint, Be, Radin, Dm, Stoller, Sr, Segall, N, Shah, Sa, Ramstad, Ds, Nisnisan, Jm, Trippett, Jm, Benjamin, Sa, Labissiere, Jc, Nashed, An, Maaieh, M, Aslam, Aa, Mandviwala, M, Budoff, Mj, French, Wj, Vlach, Jj, Destefano, P, Bayron, Cj, Fraser, Nj, Sandberg, Jh, Fagan, Tc, Peart, Bc, Suryanarayana, Pg, Gupta, Dk, Lee, Mw, Bertolet, Bd, Hartley, Pa, Kelberman, M, Behmanesh, B, Buynak, Rj, Chochinov, Rh, Steinberg, Aa, Chandna, H, Bjasker, Kr, Perlman, Rl, Ball, Em, Pock, J, Singh, S, Baldari, D, Kaster, S, Lovell, Jp, Horowitz, Bs, Gorman, Ta, Pham, Dn, Landzberg, Js, Mootoo, Ki, Moon, E, Krawczyk, J, Alfieri, Ad, Janik, Mj, Herrington, Dm, Koilpillai, Rn, Waxler, Ar, Hoffman, Da, Sahul, Zh, Gumbiner, B, Cropp, A, Fujita, K, Garzone, P, Imai, K, Levisetti, M, Plowchalk, D, Sasson, S, Skaggs, J, Sweeney, K, Vincent, J., Curto, M, Ridker, P., Revkin, J., Amarenco, P., Brunell, R., Curto, M., Civeira, F., Flather, M., Glynn, R., Gregoire, J., Jukema, J., Karpov, Y., Kastelein, J., Koenig, W., Lorenzatti, A., Manga, P., Masiukiewicz, U., Miller, M., Mosterd, A., Murin, J., Nicolau, J., Nissen, S., Ponikowski, P., Santos, R., Schwartz, P., Soran, H., White, H., Wright, R., Vrablik, M., Yunis, C., Shear, C., Tardif, J., SPIRE Cardiovascular Outcome Investigators, Averna, M., Brigham and Women's Hospital [Boston], Université Paris Diderot - Paris 7 (UPD7), Université Sorbonne Paris Cité (USPC), RS: CARIM - R3.02 - Hypertension and target organ damage, MUMC+: MA Alg Interne Geneeskunde (9), Interne Geneeskunde, Ridker, P. M., Glynn, R. J., Jukema, J. W., Kastelein, J. J. P., Nicolau, J. C., Santos, R. D., Schwartz, P. F., Wright, R. S., Shear, C. L., Tardif, J. -C., SPIRE Cardiovascular Outcome Investigator, Perrone, Filardi, P, Vascular Medicine, ACS - Amsterdam Cardiovascular Sciences, ACS - Pulmonary hypertension & thrombosis, and ACS - Atherosclerosis & ischemic syndromes
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Male ,STATIN THERAPY ,Anticholesteremic Agents/adverse effects ,Antibodie ,Vascular damage Radboud Institute for Health Sciences [Radboudumc 16] ,Injections, Subcutaneous/adverse effects ,030204 cardiovascular system & hematology ,Bococizumab ,law.invention ,PCSK9 ,0302 clinical medicine ,Randomized controlled trial ,law ,Risk Factors ,GENETIC-VARIANTS ,Cardiovascular Disease ,Monoclonal ,Anticholesteremic Agent ,030212 general & internal medicine ,Myocardial infarction ,Treatment Failure ,Humanized ,Proprotein Convertase 9/antagonists & inhibitors ,Medicine(all) ,Antibodies ,Antibodies, Monoclonal, Humanized ,Anticholesteremic Agents ,Cardiovascular Diseases ,Cholesterol, LDL ,Double-Blind Method ,Female ,Follow-Up Studies ,Humans ,Hypercholesterolemia ,Injections, Subcutaneous ,Lipids ,Middle Aged ,Proprotein Convertase 9 ,Medicine (all) ,PCSK9 Inhibitors ,antibodies monoclonal humanized ,anticholesteremic agents ,cardiovascular diseases ,cholesterol, LDL ,double-blind method ,female ,follow-up studies ,humans ,hypercholesterolemia ,injections, subcutaneous ,lipids ,male ,middle aged ,proprotein convertase 9 ,risk factors ,treatment failure ,medicine (all) ,Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16] ,General Medicine ,Lipid ,3. Good health ,LDL/blood ,Multicenter Study ,Cholesterol ,TRIALS ,Cholesterol, LDL/blood ,Antibodies, Monoclonal, Humanized/adverse effects ,Randomized Controlled Trial ,subcutaneous ,lipids (amino acids, peptides, and proteins) ,Cardiovascular Diseases/prevention & control ,REDUCING LIPIDS ,Human ,medicine.medical_specialty ,animal structures ,Hypercholesterolemia/drug therapy ,Placebo ,Injections, Subcutaneou ,LDL ,Injections ,Follow-Up Studie ,EVENTS ,03 medical and health sciences ,Internal medicine ,medicine ,Journal Article ,Comparative Study ,METAANALYSIS ,Alirocumab ,business.industry ,Unstable angina ,Lipids/blood ,Risk Factor ,fungi ,Antibodies/blood ,ta3121 ,medicine.disease ,Surgery ,Evolocumab ,REDUCTION ,Humanized/adverse effects ,Subcutaneous/adverse effects ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
Item does not contain fulltext BACKGROUND: Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk. METHODS: In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months. RESULTS: At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P/=70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of >/=100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P
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- 2017
4. Oral Apixaban for the Treatment of Acute Venous Thromboembolism
- Author
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Agnelli, G, Buller, H, Cohen, A, Gallus, A, Raskob, G, Weitz, J, Prins, M, Brandjes, D, Kolbach, D, Limburg, M, Mac Gillavry, M, Otten, Jm, Peters, R, Roos, Y, Segers, A, Slagboom, T, Bounameaux, H, Hirsh, J, Samama, Mm, Wedel, H, Curto, M, Johnson, M, Masiukiewicz, U, Pak, R, Porcari, A, Sanders, P, Sisson, M, Sullivan, B, Thompson, J, Auerbach, J, Cesario, L, Crawford, J, Gordon, M, Noble, M, Pennington, A, Reinhold, P, Simmons, M, Urwin, K, Ceresetto, J, Mcrae, S, Pabinger, I, Pereira, Ah, Spencer, F, Wang, C, Zhang, J, Gorican, K, Husted, Se, Mottier, D, Harenberg, J, Vértes, A, Pinjala, R, Zeltser, D, Prandoni, Paolo, Sandset, M, Torbicki, A, Fijalkowska, A, Alvares, Jp, Kirienko, A, Shvarts, Y, Sala, La, Jacobson, B, Gudz, I, Ortel, T, Spyropoulos, A, Beyer Westendorf, J, Sipos, G, Bredikhin, R, Della Siega, A, Klinke, W, Lawall, H, Zwettler, U, Prasol, V, Cannon, K, Vasylyuk, S, Jin, B, Prandoni, P, Desai, S, Zaichuk, A, Katelnitskiy, I, De Pellegrin, A, Santonastaso, M, Skupyy, O, Pesant, Y, Shvalb, P, Spacek, R, Visonà, A, Alvarez Sala, L, Borja, V, Noori, E, Sereg, M, Braester, A, Falvo, N, Vöhringer, H, Laperna, L, Oliven, A, Skalicka, L, Bolster, D, Haidar, A, Schellong, S, Smith, S, Sergeev, O, Pullman, J, Torp Pedersen, C, Zimlichman, R, Elias, M, Fourie, N, Pernod, G, Panchenko, E, Pendleton, R, van Nieuwenhuizen, E, Vinereanu, D, Becattini, C, Manina, G, Leduc, J, Dunaj, M, Frost, L, Gavish, D, Jakobsen, T, Lishner, M, Morales, L, Chochola, J, Gubka, O, Holaj, R, Hussein, O, Katona, A, Sergeeva, E, Bova, C, Cepeda, J, Cohen, K, Sobkowicz, B, Grzelakowski, P, Husted, S, Lupkovics, G, Dedek, V, Liu, C, Puskas, A, Ritchie, B, Ambrosio, G, Parisi, R, Heuer, H, Livneh, A, Podpera, I, Stanbro, M, Caraco, Y, Fulmer, J, Ghirarduzzi, A, Schmidt Lucke, J, Bergmann, J, Cizek, V, Leyden, M, Stein, R, Abramov, I, Chong, B, Colan, D, Jindal, R, Liu, S, Pereira, A, Porreca, E, Salem, H, Welker, J, Yusen, R, Dhar, A, Podczeck Schweighofer, A, Shtutin, O, Vital Durand, D, Balaji, V, Correa, J, Kline, J, Runyon, M, Laszlo, Z, Martelet, M, Parakh, R, Sandset, Pm, Schmidt, J, Yeo, E, Bhagavan, N, Bura Riviere, A, Ferrer, J, Lacroix, P, Lewczuk, J, Pilger, E, Sokurenko, G, Yu, H, Nikulnikov, P, Pabinger Fasching, I, Sanchez Diaz, C, Schuller, D, Suresh, K, Lobo, S, Lyons, R, Marschang, P, Palla, A, Schulman, S, Spyropoulous, A, Fraiz, J, Gerasymov, V, Lerner, R, Llamas Esperón, G, Manenti, E, Masson, J, Moreira, R, Poy, C, Rodoman, G, Bruckner, I, Gurghean, A, Carrier, M, Freire, A, Gan, E, Gibson, K, Herold, M, Hudcovic, M, Kamath, G, Koslow, A, Meneveau, N, Roos, J, Zahn, R, Balanda, J, Bratsch, H, Dolan, S, Gould, T, Hirschl, M, Hoffmann, U, Kaatz, S, Shah, V, Kadapatti, K, Kræmmer Nielsen, H, Lahav, M, Natarajan, S, Tuxen, C, Tveit, A, Alves, C, Formiga, A, Brudevold, R, Cardozo, M, Lorch, D, Marais, H, Mismetti, P, Panico, M, Pop, C, Quist Paulsen, P, Stevens, D, Tarleton, G, Yoshida, W, Cox, M, Crispin, P, Czekalski, P, Ebrahim, I, Game, M, Ghanima, W, Harrington, D, Jackson, D, Lee, A, Matoska, P, Meade, A, Camargo, Ac, Nishinari, K, Sanchez Llamas, F, Tosetto, A, Vejby Christensen, H, Basson, M, Blombery, P, Fu, G, Jha, V, Keltai, K, Le Jeunne, C, Lodigiani, C, Ma, Y, Nagy, A, Neumeister, A, Shotan, A, Wong, T, Ying, K, Anderson, S, Brenner, B, Carnovali, M, Cerana, S, Cunha, C, Diaz Castañon, J, Graham, M, Kirenko, A, Palareti, G, Rodriguez Cintron, W, Nathanson, A, Rosenthal, S, Sanders, D, Scheinberg, P, Schjesvold, F, Torp, R, van Zyl, L, Venher, I, Xia, G, Brockmyre, A, Chen, Z, Hakki, S, Hanefield, C, Mügge, A, Janczak, D, Karpovych, D, Lancaster, G, Lavigne, C, Lugassy, G, Melaniuk, M, Moran, J, Oliver, M, Schattner, A, Staroverov, I, Timi, J, Vöhringer, F, von Bilderling, P, Warr, T, White, R, Wronski, J, Wu, C, Almeida, C, Blum, A, Bono, J, Durán, M, Erzinger, F, Fu, W, Jagadesan, R, Jurecka, W, Korban, E, Nguyen, D, Raval, M, Willms, D, Zevin, S, Zhu, H, Abdullah, I, Achkar, A, Albuquerque, L, Ali, M, Bai, C, Bloomfield, D, Chen, J, Fajardo Campos, P, Garcia Bragado, F, Kobza, I, Lindhoff Last, E, Lourenço, A, Marchena Yglesias, P, Marshall, P, Siegel, M, Mikhailova, O, Oliva, M, Pottier, P, Pruszczyk, P, Sauer, M, Baloira, A, Cromer, M, D'Angelo, A, Faucher, J, Gutowski, P, Hong, S, Lissauer, M, Lopes, A, Lopes, R, Maholtz, M, Mesquita, E, Miekus, P, Mohan, B, Ng, H, Peterson, M, Piovella, F, Siragusa, S, Srinivas, R, Tiberio, G, Van Bellen, B, Arutyunov, G, Assi, N, Baker, R, Blanc, F, Curnow, J, Fu, C, Gonzalez Porras, J, Guijarro Merino, R, Gunasingam, S, Gupta, P, Laule, M, Liu, Z, Luber, J, Serifilippi, G, Paulson, R, Shevela, A, Simonneau, G, Siu, D, Sosa Liprandi, M, Takács, J, Tay, J, Vora, K, Witkiewicz, W, Zhao, L, Aquilanti, S, Dabbagh, O, Dellas, C, Denaro, C, Doshi, A, Flippo, G, Giumelli, C, Gomez Cerezo, J, Han, D, Harris, L, Hofmann L., Jr, Kamerkar, D, Kaminski, L, Kazimir, M, Kloczko, J, Ko, Y, Koura, F, Lavender, R, Maly, J, Margolis, B, Mos, L, Sanchez Escalante, L, Solvang, A, Soroka, V, Szopinski, P, Thawani, H, Vickars, L, Yip, G, Zangroniz, P., Internal and Cardiovascular Medicine - Stroke Unit (PERUGIA - ICM-SU), Università degli Studi di Perugia (UNIPG), Department of Vascular Medicine (DVM - AMC), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), King's College Hospital (KCH), Department of Haematology (ADELAIDE - Dep Haemato), Flinders Medical Centre-Flinders University, Health Sciences Center (OKLAHOMA - HSC), University of Oklahoma (OU), Thrombosis and Atherosclerosis Research Institute (TARI), McMaster University [Hamilton, Ontario], Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), Université de Brest (UBO)-Université de Brest (UBO), ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, APH - Amsterdam Public Health, Cardiology, ANS - Amsterdam Neuroscience, Neurology, and Other departments
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Male ,MESH: Factor Xa ,[SDV]Life Sciences [q-bio] ,Administration, Oral ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,THERAPY ,MESH: Venous Thromboembolism ,chemistry.chemical_compound ,0302 clinical medicine ,Edoxaban ,MESH: Double-Blind Method ,030212 general & internal medicine ,MESH: Warfarin ,MESH: Treatment Outcome ,MESH: Aged ,RISK ,MESH: Middle Aged ,General Medicine ,MESH: Follow-Up Studies ,Venous Thromboembolism ,Middle Aged ,3. Good health ,Pulmonary embolism ,Treatment Outcome ,MESH: Administration, Oral ,Acute Disease ,MESH: Acute Disease ,Apixaban ,Female ,MESH: Hemorrhage ,medicine.drug ,Andexanet alfa ,Adult ,medicine.medical_specialty ,MESH: Enoxaparin ,Pyridones ,PULMONARY-EMBOLISM ,Hemorrhage ,MESH: Anticoagulants ,03 medical and health sciences ,Double-Blind Method ,BINOMIAL TRIALS ,Internal medicine ,MESH: Pyridones ,medicine ,Humans ,Enoxaparin ,MESH: Kaplan-Meier Estimate ,RIVAROXABAN ,Aged ,Rivaroxaban ,MESH: Humans ,business.industry ,Warfarin ,Anticoagulants ,MESH: Adult ,medicine.disease ,Confidence interval ,MESH: Male ,Surgery ,chemistry ,Relative risk ,Pyrazoles ,business ,MESH: Female ,MESH: Pyrazoles ,Factor Xa Inhibitors ,Follow-Up Studies - Abstract
International audience; BACKGROUND: Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism. METHODS: In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding. RESULTS: The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P
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- 2013
5. Apixaban for extended treatment of venous thromboembolism
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Agnelli, G, Buller, H, Cohen, A, Gallus, A, Raskob, G, Weitz, J, Prins, M, Brandjes, D, Kolbach, D, Limburg, M, Mac Gillavry, M, Otten, Jm, Peters, R, Roos, Y, Segers, A, Slagboom, T, Bounameaux, H, Hirsh, J, Samama, Mm, Wedel, H, Curto, M, Johnson, M, Masiukiewicz, U, Pak, R, Porcari, A, Sanders, P, Sisson, M, Sullivan, B, Thompson, J, Auerbach, J, Cesario, L, Gamero, M, Gordon, M, Griffiths, A, Noble, M, Ott, J, Pennington, A, Peffer, A, Reinhold, P, Simmons, M, Urwin, K, Ceresetto, J, Mcrae, S, Pabinger, I, Pereira, Ah, Spencer, F, Gorican, K, Husted, Se, Mottier, D, Harenberg, J, Pinjala, R, Zeltser, D, Imberti, D, Sandset, M, Torbicki, A, Fijalkowska, A, Albino, Jp, Kirienko, A, Shvarts, Y, Monreal, M, Jacobson, B, Dolan, G, Gudz, I, Ortel, T, Spyropoulos, A, Skupyy, O, Beryer Westendorf, J, De Pellegrin, A, Prasol, V, Schellong, S, Falvo, N, Abramov, I, Cizek, V, Husted, S, Desai, S, Barillari, G, Sergeev, O, Chetter, I, Inbal, A, Mccollum, C, Shvalb, P, Torp Pedersen, C, Vasylyuk, S, Kraemmer Nielsen, H, Pernod, G, Schmidt, J, Bova, C, Gerasymov, V, Pabinger Fasching, I, Skalicka, L, Zaichuk, A, Achkar, A, Bremmelgaard, A, Chochola, J, Gould, T, Khalafallah, A, Jakobsen, T, Rose, P, Zhukov, B, Dedek, V, Mirete Ferrer, J, Pesant, Y, Repin, A, Salem, H, Solis Morales, L, Spacek, R, Cannon, K, Grzelakowski, P, Jindal, R, Pereira, A, Zidkova, E, Ambrosio, G, Cardozo, M, Dunaj, M, Gavish, D, Ghanima, W, Leduc, Jj, Mismetti, P, Panico, M, Porreca, E, Riera, A, Bareford, D, Chong, B, Dvoryashina, I, Gómez Cerezo, J, Kobza, I, Nielsen, T, Pendleton, R, Pullman, J, Schiffman, G, Stanbro, M, Zwettler, U, Aquilanti, S, Bratsch, H, Cohen, K, Elias, D, Gan, E, Holaj, R, Klinke, W, Liu, Hs, Sandset, Pm, van Nieuwenhuizen, E, Álvarez Sala LA, Basson, M, Braester, A, Bura Riviere, A, Calvo Vargas, C, Correa, J, Elias, M, Frost, L, Landolfi, R, Marschang, P, Moreira, R, Natarajan, S, Pottier, P, Tosetto, A, Tuxen, C, Vöhringer, Hf, Alexander, A, Barbarash, O, Fajardo Campos, P, Graham, M, Gubka, O, Hudcovic, M, Hussein, O, Jackson, D, Katelnitskiy, I, Lawall, H, Palareti, G, Poggio, R, Roos, J, Simonneau, G, Smith, Sw, Szopinski, P, Zimlichman, R, Bridgers, D, Colan, D, Czekalski, P, De Jong, D, Fortinez, Jt, Garcia Bragado, F, Harrington, D, Izbicki, G, Kadr, H, Koslow, A, Loftus, I, Marais, H, Neumeister, A, Oliven, A, Palla, A, Pop, C, Prandoni, Paolo, Puskas, A, Sanchez Llamas, F, Shotan, A, Singh, P, Tveit, A, Baker, R, Borja, V, Brenner, B, Brown, H, Cha, Tj, Cohen, Y, D'Angelo, A, Dhar, A, Friis, E, Hueur, H, Jiménez Rodríguez Madridejos, R, Karl, J, Karrasch, J, Lishner, M, Manenti, E, Meneveau, N, Nguyen, D, Sanchez Escalante, L, Santoscoy Ibarra, J, Sokurenko, G, Staroverov, I, Stein, R, Abdullah, I, Alcocer Gamba, M, Balanda, J, Bruckner, I, Calabuig Alborch, J, Caraco, Y, Comerota, A, Cromer, M, de Araujo Filho, J, De los Rios Ibarra, M, Diaz Castañon, J, Doshi, A, Ebrahim, I, Fessel, Wj, Fletcher, E, Fourie, N, Fu, C, Gutowski, P, Haddad, G, Hoffman, U, Jardula, M, Kvasnicka, T, Lewczuk, J, Leyden, M, Livneh, A, Lodigiani, C, Lovell, C, Miekus, P, Paloma, Mj, Parakh, R, Raval, M, Schmidt Lucke, J, Shtutin, O, Soroka, V, Stevens, D, Sulik, P, Tay, Jc, Vejby Christensen, H, Vinereanu, D, Baghestanian, M, Bono, J, Cerana, S, Freire, A, Gibson, K, Giumelli, C, Iastrebner, C, Karpenko, A, Kelly, A, Lacroix, P, Lafata, J, Lobo, S, Macik, Bg, Marchena Yglesias, P, Nishinari, K, Podczeck Schweighofer, A, Raby, K, Sirpal, S, Solymoss, S, van Zyl, L, Vargas Núñez JA, von Bilderling, P, Warr, T, Wronski, J, Wurster, M, Albino, Ja, Albuquerque, L, Averill, F, Baek, Sh, Bello, F, Bergoeing, M, Blanc, Fx, Bloomberg, R, Bolster, D, Brockmyre, A, Calimano, C, Checketts, D, Cieplinski, W, Chervu, A, Collado, F, Denaro, C, Gaciong, Z, Game, M, Iskander, A, Kaatz, S, Kim, Di, Koura, F, Laguna, F, Lanas Zanetti, F, Lindhoff Last, E, Melaniuk, M, Meade, A, Murphy, T, Ng, Hj, Páramo Fernández JA, Patil, C, Piovella, F, Prisco, D, Pruszczyk, P, Reimers, G, Rivera, E, Rodriguez Cintron, W, Rosenthal, S, Salbach, P, Salvador, D, Schuller, D, Siragusa, S, Staniszewski, R, Torp, R, Vora, K, Yip, G, Alfieri, A, Belaji, V, Bhagavan, N, Carnovali, M, Cobos Segarra, J, Di Todaro, F, Dowell, A, Corder, C, Crispin, P, Cuadrado, J, Flippo, G, Fraiz, J, Guillaumon, A, Gvora, T, Hakki, S, Harris, L, Ison, R, Htun, Pt, Jasani, R, Kates, M, Kaminski, L, Kamerkar, D, Kroger, K, Laperna, L, Leiva, J, Luber, J, Mccann, A, Mckenzie, W, Menna Barreto, S, Moran, J, Nikulnikov, P, Paliwal, Y, Patel, M, Pilger, E, Renwick, W, Shevela, A, Starosiliz, D, Stringam, S, To, R, Updegrove, J, Van Bellen, B, Waintrub, M, White, J, Yeo, E, Zangroniz, P, Zeltser, D., ACS - Amsterdam Cardiovascular Sciences, Vascular Medicine, APH - Amsterdam Public Health, Cardiology, ANS - Amsterdam Neuroscience, Neurology, Department of Vascular Medicine (DVM - AMC), Academic Medical Center - Academisch Medisch Centrum [Amsterdam] (AMC), University of Amsterdam [Amsterdam] (UvA)-University of Amsterdam [Amsterdam] (UvA), Thrombosis and Atherosclerosis Research Institute (TARI), McMaster University [Hamilton, Ontario], Centre d'Investigation Clinique (CIC - Brest), Université de Brest (UBO)-Institut National de la Santé et de la Recherche Médicale (INSERM), Groupe d'Etude de la Thrombose de Bretagne Occidentale (GETBO), Université de Brest (UBO)-Institut Brestois Santé Agro Matière (IBSAM), and Université de Brest (UBO)-Université de Brest (UBO)
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Male ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Placebo group ,DISEASE ,law.invention ,0302 clinical medicine ,Randomized controlled trial ,law ,Recurrence ,Fibrinolytic agents ,030212 general & internal medicine ,IDRAPARINUX ,Administration of drugs ,Follow up studies ,food and beverages ,General Medicine ,Venous Thromboembolism ,Middle Aged ,3. Good health ,Intention to Treat Analysis ,Treatment Outcome ,Treatment dose ,Anesthesia ,Creatinine ,Factor Xa ,Fibrinolítics ,Apixaban ,Female ,Administració de medicaments ,Major bleeding ,medicine.drug ,ARTERIAL CARDIOVASCULAR EVENTS ,INTENSITY WARFARIN THERAPY ,PULMONARY-EMBOLISM ,LONG-TERM ,PREVENTION ,Adult ,Pyridones ,Hemorrhage ,03 medical and health sciences ,Double-Blind Method ,Fibrinolytic Agents ,Thromboembolism ,medicine ,Humans ,Tromboembolisme ,Aged ,Intention-to-treat analysis ,business.industry ,fungi ,Pyrazoles ,business ,Venous thromboembolism ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Factor Xa Inhibitors ,Follow-Up Studies - Abstract
International audience; Background Apixaban, an oral factor Xa inhibitor that can be administered in a simple, fixed-dose regimen, may be an option for the extended treatment of venous thromboembolism. Methods In this randomized, double-blind study, we compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in patients with venous thromboembolism who had completed 6 to 12 months of anticoagulation therapy and for whom there was clinical equipoise regarding the continuation or cessation of anticoagulation therapy. The study drugs were administered for 12 months. Results A total of 2486 patients underwent randomization, of whom 2482 were included in the intention-to-treat analyses. Symptomatic recurrent venous thromboembolism or death from venous thromboembolism occurred in 73 of the 829 patients (8.8%) who were receiving placebo, as compared with 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban (a difference of 7.2 percentage points; 95% confidence interval [CI], 5.0 to 9.3) and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (a difference of 7.0 percentage points; 95% CI, 4.9 to 9.1) (P
- Published
- 2012
6. The role of parathyroid hormone in the pathogenesis, prevention and treatment of postmenopausal osteoporosis
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Masiukiewicz, U. S., primary and Insogna, K. L., additional
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- 1998
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7. Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes.
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Cannon, C. P., Pratley, R., Dagogo-Jack, S., Mancuso, J., Huyck, S., Masiukiewicz, U., Charbonnel, B., Frederich, R., Gallo, S., Cosentino, F., Shih, W. J., Gantz, I., Terra, S. G., Cherney, D. Z. I., McGuire, D. K., Cannon, Christopher P, Pratley, Richard, Dagogo-Jack, Samuel, Mancuso, James, and Huyck, Susan
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ATHEROSCLEROSIS complications , *RESEARCH , *CLINICAL trials , *RESEARCH methodology , *CARDIOVASCULAR diseases , *EVALUATION research , *MEDICAL cooperation , *ATHEROSCLEROSIS , *TYPE 2 diabetes , *PLACEBOS , *COMPARATIVE studies , *HOSPITAL care , *BLIND experiment , *DIABETIC nephropathies , *DISEASE complications ,CARDIOVASCULAR disease related mortality - Abstract
Background: The cardiovascular effects of ertugliflozin, an inhibitor of sodium-glucose cotransporter 2, have not been established.Methods: In a multicenter, double-blind trial, we randomly assigned patients with type 2 diabetes and atherosclerotic cardiovascular disease to receive 5 mg or 15 mg of ertugliflozin or placebo once daily. With the data from the two ertugliflozin dose groups pooled for analysis, the primary objective was to show the noninferiority of ertugliflozin to placebo with respect to the primary outcome, major adverse cardiovascular events (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke). The noninferiority margin was 1.3 (upper boundary of a 95.6% confidence interval for the hazard ratio [ertugliflozin vs. placebo] for major adverse cardiovascular events). The first key secondary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure.Results: A total of 8246 patients underwent randomization and were followed for a mean of 3.5 years. Among 8238 patients who received at least one dose of ertugliflozin or placebo, a major adverse cardiovascular event occurred in 653 of 5493 patients (11.9%) in the ertugliflozin group and in 327 of 2745 patients (11.9%) in the placebo group (hazard ratio, 0.97; 95.6% confidence interval [CI], 0.85 to 1.11; P<0.001 for noninferiority). Death from cardiovascular causes or hospitalization for heart failure occurred in 444 of 5499 patients (8.1%) in the ertugliflozin group and in 250 of 2747 patients (9.1%) in the placebo group (hazard ratio, 0.88; 95.8% CI, 0.75 to 1.03; P = 0.11 for superiority). The hazard ratio for death from cardiovascular causes was 0.92 (95.8% CI, 0.77 to 1.11), and the hazard ratio for death from renal causes, renal replacement therapy, or doubling of the serum creatinine level was 0.81 (95.8% CI, 0.63 to 1.04). Amputations were performed in 54 patients (2.0%) who received the 5-mg dose of ertugliflozin and in 57 patients (2.1%) who received the 15-mg dose, as compared with 45 patients (1.6%) who received placebo.Conclusions: Among patients with type 2 diabetes and atherosclerotic cardiovascular disease, ertugliflozin was noninferior to placebo with respect to major adverse cardiovascular events. (Funded by Merck Sharp & Dohme and Pfizer; VERTIS CV ClinicalTrials.gov number, NCT01986881.). [ABSTRACT FROM AUTHOR]- Published
- 2020
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8. Ertugliflozin Delays Insulin Initiation and Reduces Insulin Dose Requirements in Patients With Type 2 Diabetes: Analyses From VERTIS CV.
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Dagogo-Jack S, Frederich R, Liu J, Cannon CP, Shi H, Cherney DZI, Cosentino F, Masiukiewicz U, Gantz I, and Pratley RE
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- Humans, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Double-Blind Method, Hypoglycemic Agents adverse effects, Insulin adverse effects, Diabetes Mellitus, Type 2 complications, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 chemically induced, Hypoglycemia chemically induced, Hypoglycemia epidemiology, Hypoglycemia drug therapy, Metformin therapeutic use, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Abstract
Context: VERTIS CV evaluated the cardiovascular safety of ertugliflozin in patients with type 2 diabetes and atherosclerotic cardiovascular disease (ASCVD)., Objective: The aim of these analyses was to assess the insulin requirements of VERTIS CV patients over the trial duration., Methods: Patients received ertugliflozin 5 mg, 15 mg, or placebo once daily; mean follow-up was 3.5 years. Time to insulin initiation in patients who were insulin naïve at baseline, change in insulin dose in patients receiving baseline insulin, and hypoglycemia incidence in both patient groups were assessed., Results: In VERTIS CV, mean duration of type 2 diabetes was 13.0 years; glycated hemoglobin was 8.2%. Among 4348 (53%) insulin-naïve patients, the likelihood of insulin initiation was significantly reduced with ertugliflozin vs placebo (ertugliflozin 5 mg: hazard ratio [HR] 0.70, 95% CI 0.58-0.84; ertugliflozin 15 mg: HR 0.64, 95% CI 0.53-0.78). Time to insulin initiation was delayed with ertugliflozin; the estimated delay in reaching a 10% cumulative incidence of new insulin initiations vs placebo was 399 days with ertugliflozin 5 mg and 669 days with ertugliflozin 15 mg. Among 3898 (47%) patients receiving baseline insulin, the likelihood of requiring a ≥20% increase in insulin dose was significantly reduced with ertugliflozin vs placebo (ertugliflozin 5 mg: HR 0.62, 95% CI 0.52-0.75; ertugliflozin 15 mg: HR 0.51, 95% CI 0.41-0.62). The incidence of hypoglycemia events was not increased with ertugliflozin treatment., Conclusion: In VERTIS CV patients, ertugliflozin reduced the likelihood of insulin initiation, delayed the time to insulin initiation by up to ∼1.8 years, and reduced insulin dose requirements vs placebo, without increasing hypoglycemia events., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society.)
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- 2023
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9. Ertugliflozin and incident obstructive sleep apnea: an analysis from the VERTIS CV trial.
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Wojeck BS, Inzucchi SE, Neeland IJ, Mancuso JP, Frederich R, Masiukiewicz U, Cater NB, McGuire DK, Cannon CP, and Yaggi HK
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- Humans, Male, Middle Aged, Female, Bridged Bicyclo Compounds, Heterocyclic adverse effects, Diabetes Mellitus, Type 2 drug therapy, Diabetes Mellitus, Type 2 epidemiology, Sodium-Glucose Transporter 2 Inhibitors therapeutic use, Sodium-Glucose Transporter 2 Inhibitors adverse effects, Cardiovascular Diseases epidemiology, Sleep Apnea, Obstructive drug therapy, Sleep Apnea, Obstructive epidemiology, Sleep Apnea, Obstructive chemically induced
- Abstract
Purpose: The sodium-glucose transporter 2 inhibitor (SGLT2i) empagliflozin may reduce the incidence of obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) and cardiovascular (CV) disease. This analysis of VERTIS CV, the CV outcome trial for the SGLT2i ertugliflozin conducted in a similar group of patients, explored the effects of ertugliflozin on reported incident OSA., Methods: In VERTIS CV, patients ≥ 40 years with T2D and atherosclerotic CV disease (ASCVD) were randomized to ertugliflozin 5 or 15 mg or placebo. The primary endpoint was the composite of major adverse CV events. This exploratory analysis evaluated the impact of ertugliflozin (5 and 15 mg pooled) on incident OSA. Patients with prevalent OSA were excluded. Incident OSA events were based on investigator-reported events using the MedDRA SMQ term "sleep apnea syndrome." A multivariable Cox proportional hazards regression model was constructed to assess the association between ertugliflozin and incident OSA., Results: Of 8246 patients enrolled, 7697 (93.3%) were without baseline OSA (placebo, n = 2561; ertugliflozin, n = 5136; mean age 64.4 years; BMI 31.7 kg/m
2 ; HbA1c, 8.2%; 69.2% male; 88.3% White). The OSA incidence rate was 1.44 per 1000 person-years versus 2.61 per 1000 person-years among patients treated with ertugliflozin versus placebo, respectively, corresponding to a 48% relative risk reduction (HR 0.52; 95% CI 0.28-0.96; P = 0.04)., Conclusions: In VERTIS CV, ertugliflozin reduced by nearly half the incidence of OSA in patients with T2D and ASCVD. These data contribute to the literature that SGLT2is may have a significant beneficial impact on OSA., Clinicaltrials: gov identifier: NCT01986881., (© 2022. Pfizer Inc. and The Author(s).)- Published
- 2023
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10. Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis.
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McGuire DK, Shih WJ, Cosentino F, Charbonnel B, Cherney DZI, Dagogo-Jack S, Pratley R, Greenberg M, Wang S, Huyck S, Gantz I, Terra SG, Masiukiewicz U, and Cannon CP
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- Cardiovascular Diseases mortality, Diabetes Mellitus, Type 2 metabolism, Disease Progression, Humans, Proportional Hazards Models, Renal Insufficiency, Chronic metabolism, Diabetes Mellitus, Type 2 drug therapy, Heart Failure physiopathology, Hospitalization statistics & numerical data, Renal Insufficiency, Chronic physiopathology, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Abstract
Importance: Sodium-glucose cotransporter 2 (SGLT2) inhibitors favorably affect cardiovascular (CV) and kidney outcomes; however, the consistency of outcomes across the class remains uncertain., Objective: To perform meta-analyses that assess the CV and kidney outcomes of all 4 available SGLT2 inhibitors in patients with type 2 diabetes., Data Sources: A systematic literature search was conducted in PubMed from January 1, 2015, to January 31, 2020., Study Selection: One hundred forty-five records were initially identified; 137 were excluded because of study design or topic of interest. As a result, a total of 6 randomized, placebo-controlled CV and kidney outcomes trials of SGLT2 inhibitors in patients with type 2 diabetes were identified, with contributory data from 9 publications. All analyses were conducted on the total patient population of these trials., Data Extraction and Synthesis: Standardized data search and abstraction were performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) Statement. Data were analyzed using a fixed-effect model., Main Outcomes and Measures: Outcomes included time to the first event of (1) the composite of major adverse CV events of myocardial infarction, stroke, or CV death, and each component, (2) the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death) and each component, and (3) kidney composite outcomes. For outcomes in the overall trial populations and in selected subgroups, hazard ratios (HRs) and 95% CIs were pooled and meta-analyzed across trials., Results: Data from 6 trials comprised 46 969 unique patients with type 2 diabetes, including 31 116 (66.2%) with atherosclerotic CV disease. The mean (SD) age of all trial participants was 63.7 (7.9) years; 30 939 (65.9%) were men, and 36 849 (78.5%) were White. The median number of participants per trial was 8246 (range, 4401-17 160). Overall, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events (HR, 0.90; 95% CI, 0.85-0.95; Q statistic, P = .27), HHF/CV death (HR, 0.78; 95% CI, 0.73-0.84; Q statistic, P = .09), and kidney outcomes (HR, 0.62; 95% CI, 0.56-0.70; Q statistic, P = .09), with no significant heterogeneity of associations with outcome. Associated risk reduction for HHF was consistent across the trials (HR, 0.68; 95% CI, 0.61-0.76; I2 = 0.0%), whereas significant heterogeneity of associations with outcome was observed for CV death (HR, 0.85; 95% CI, 0.78-0.93; Q statistic, P = .02; I2 = 64.3%). The presence or absence of atherosclerotic CV disease did not modify the association with outcomes for major adverse CV events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 0.94; 95% CI, 0.83-1.07, respectively; P = .63 for interaction), with similar absence of associations with outcome modification by prevalent atherosclerotic CV disease for HHF/CV death (P = .62 for interaction), HHF (P = .26 for interaction), or kidney outcomes (P = .73 for interaction)., Conclusions and Relevance: In this meta-analysis, SGLT2 inhibitors were associated with a reduced risk of major adverse CV events; in addition, results suggest significant heterogeneity in associations with CV death. The largest benefit across the class was for an associated reduction in risk for HHF and kidney outcomes, with benefits for HHF risk being the most consistent observation across the trials.
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- 2021
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11. Efficacy of Ertugliflozin on Heart Failure-Related Events in Patients With Type 2 Diabetes Mellitus and Established Atherosclerotic Cardiovascular Disease: Results of the VERTIS CV Trial.
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Cosentino F, Cannon CP, Cherney DZI, Masiukiewicz U, Pratley R, Dagogo-Jack S, Frederich R, Charbonnel B, Mancuso J, Shih WJ, Terra SG, Cater NB, Gantz I, and McGuire DK
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- Aged, Atherosclerosis diagnosis, Atherosclerosis mortality, Cardiovascular Diseases diagnosis, Cardiovascular Diseases drug therapy, Cardiovascular Diseases mortality, Diabetes Mellitus, Type 2 diagnosis, Diabetes Mellitus, Type 2 mortality, Double-Blind Method, Female, Heart Failure diagnosis, Heart Failure mortality, Humans, Male, Middle Aged, Atherosclerosis drug therapy, Bridged Bicyclo Compounds, Heterocyclic therapeutic use, Diabetes Mellitus, Type 2 drug therapy, Heart Failure drug therapy, Sodium-Glucose Transporter 2 Inhibitors therapeutic use
- Abstract
Background: In patients with type 2 diabetes mellitus, sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure (HHF). We assessed the effect of ertugliflozin on HHF and related outcomes., Methods: VERTIS CV (Evaluation of Ertugliflozin Efficacy and Safety Cardiovascular Outcomes Trial), a double-blind, placebo-controlled trial, randomly assigned patients with type 2 diabetes mellitus and atherosclerotic cardiovascular (CV) disease to once-daily ertugliflozin 5 mg, 15 mg, or placebo. Prespecified secondary analyses compared ertugliflozin (pooled doses) versus placebo on time to first event of HHF and composite of HHF/CV death, overall and stratified by prespecified characteristics. Cox proportional hazards modeling was used with the Fine and Gray method to account for competing mortality risk, and Andersen-Gill modeling to analyze total (first+recurrent) HHF and total HHF/CV death events., Results: A total of 8246 patients were randomly assigned to ertugliflozin (n=5499) or placebo (n=2747); n=1958 (23.7%) had a history of heart failure (HF) and n=5006 (60.7%) had pretrial ejection fraction (EF) available, including n=959 with EF ≤45%. Ertugliflozin did not significantly reduce first HHF/CV death (hazard ratio [HR], 0.88 [95% CI, 0.75-1.03]). Overall, ertugliflozin reduced risk for first HHF (HR, 0.70 [95% CI, 0.54-0.90]; P =0.006). Previous HF did not modify this effect (HF: HR, 0.63 [95% CI, 0.44-0.90]; no HF: HR, 0.79 [95% CI, 0.54-1.15]; P interaction=0.40). In patients with HF, the risk reduction for first HHF was similar for those with reduced EF ≤45% versus preserved EF >45% or unknown. However, in the overall population, the risk reduction tended to be greater for those with EF ≤45% (HR, 0.48 [95% CI, 0.30-0.76]) versus EF >45% (HR, 0.86 [95% CI, 0.58-1.29]). Effect on risk for first HHF was consistent across most subgroups, but greater benefit of ertugliflozin was observed in 3 populations: baseline estimated glomerular filtration rate <60 mL·min
-1 ·1.73 m-2 , albuminuria, and diuretic use (each P interaction <0.05). Ertugliflozin reduced total events of HHF (rate ratio, 0.70 [95% CI, 0.56-0.87]) and total HHF/CV death (rate ratio, 0.83 [95% CI, 0.72-0.96])., Conclusions: In patients with type 2 diabetes mellitus, ertugliflozin reduced the risk for first and total HHF and total HHF/CV death, adding further support for the use of sodium-glucose cotransporter 2 inhibitors in primary and secondary prevention of HHF. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01986881.- Published
- 2020
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12. Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV).
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Cannon CP, McGuire DK, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Charbonnel B, Shih WJ, Gallo S, Masiukiewicz U, Golm G, Cosentino F, Lauring B, and Terra SG
- Subjects
- Adult, Aged, Cardiovascular Diseases etiology, Cardiovascular Diseases prevention & control, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 complications, Dose-Response Relationship, Drug, Double-Blind Method, Europe epidemiology, Female, Follow-Up Studies, Glycated Hemoglobin metabolism, Humans, Incidence, Male, Middle Aged, Prospective Studies, Sodium-Glucose Transporter 2 Inhibitors administration & dosage, Survival Rate trends, Treatment Outcome, United States epidemiology, Blood Glucose metabolism, Bridged Bicyclo Compounds, Heterocyclic administration & dosage, Cardiovascular Diseases epidemiology, Diabetes Mellitus, Type 2 drug therapy
- Abstract
Background: Ertugliflozin is an inhibitor of sodium-glucose co-transporter-2 (SGLT2), approved in the United States and European Union to improve glycemic control in adults with type 2 diabetes mellitus (T2DM). The VERTIS cardiovascular (CV) outcomes trial (NCT01986881) has a primary objective to demonstrate non-inferiority of ertugliflozin versus placebo on major adverse CV events: time to the first event of CV death, nonfatal myocardial infarction, or nonfatal stroke. Secondary objectives are to demonstrate superiority of ertugliflozin versus placebo on time to: 1) the composite outcome of CV death or hospitalization for heart failure (HF); 2) CV death; and 3) the composite outcome of renal death, dialysis/transplant, or doubling of serum creatinine from baseline., Methods: Patients ≥40 years old with T2DM (HbA1c 7.0-10.5%) and established atherosclerotic cardiovascular disease (ASCVD) of the coronary, cerebral, and/or peripheral arterial systems, were randomized 1:1:1 to once daily double-blind placebo, ertugliflozin 5 mg or 15 mg added to existing therapy., Results: 8246 patients were randomized and 8238 received at least 1 dose of investigational product. Mean age was 64.4 years, 11.0% were ≥75 years old, and mean diabetes duration was 12.9 years with screening HbA1c of 8.3%. At entry, coronary artery disease, cerebrovascular disease, and peripheral arterial disease were present in 76.3%, 23.1%, and 18.8% of patients, respectively. HF was present in 23.1%, and Stage 3 kidney disease in 21.6% of patients., Conclusion: The results from the VERTIS-CV trial will define the CV and renal safety and efficacy of ertugliflozin in patients with T2DM and ASCVD., (Copyright © 2018. Published by Elsevier Inc.)
- Published
- 2018
- Full Text
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13. Cardiovascular Efficacy and Safety of Bococizumab in High-Risk Patients.
- Author
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Ridker PM, Revkin J, Amarenco P, Brunell R, Curto M, Civeira F, Flather M, Glynn RJ, Gregoire J, Jukema JW, Karpov Y, Kastelein JJP, Koenig W, Lorenzatti A, Manga P, Masiukiewicz U, Miller M, Mosterd A, Murin J, Nicolau JC, Nissen S, Ponikowski P, Santos RD, Schwartz PF, Soran H, White H, Wright RS, Vrablik M, Yunis C, Shear CL, and Tardif JC
- Subjects
- Antibodies blood, Antibodies, Monoclonal, Humanized adverse effects, Antibodies, Monoclonal, Humanized immunology, Anticholesteremic Agents adverse effects, Anticholesteremic Agents immunology, Double-Blind Method, Female, Follow-Up Studies, Humans, Injections, Subcutaneous adverse effects, Lipids blood, Male, Middle Aged, Proprotein Convertase 9 immunology, Risk Factors, Treatment Failure, Antibodies, Monoclonal, Humanized therapeutic use, Anticholesteremic Agents therapeutic use, Cardiovascular Diseases prevention & control, Cholesterol, LDL blood, Hypercholesterolemia drug therapy, PCSK9 Inhibitors
- Abstract
Background: Bococizumab is a humanized monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and reduces levels of low-density lipoprotein (LDL) cholesterol. We sought to evaluate the efficacy of bococizumab in patients at high cardiovascular risk., Methods: In two parallel, multinational trials with different entry criteria for LDL cholesterol levels, we randomly assigned the 27,438 patients in the combined trials to receive bococizumab (at a dose of 150 mg) subcutaneously every 2 weeks or placebo. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death; 93% of the patients were receiving statin therapy at baseline. The trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies, as seen in data from other studies in the program. The median follow-up was 10 months., Results: At 14 weeks, patients in the combined trials had a mean change from baseline in LDL cholesterol levels of -56.0% in the bococizumab group and +2.9% in the placebo group, for a between-group difference of -59.0 percentage points (P<0.001) and a median reduction from baseline of 64.2% (P<0.001). In the lower-risk, shorter-duration trial (in which the patients had a baseline LDL cholesterol level of ≥70 mg per deciliter [1.8 mmol per liter] and the median follow-up was 7 months), major cardiovascular events occurred in 173 patients each in the bococizumab group and the placebo group (hazard ratio, 0.99; 95% confidence interval [CI], 0.80 to 1.22; P=0.94). In the higher-risk, longer-duration trial (in which the patients had a baseline LDL cholesterol level of ≥100 mg per deciliter [2.6 mmol per liter] and the median follow-up was 12 months), major cardiovascular events occurred in 179 and 224 patients, respectively (hazard ratio, 0.79; 95% CI, 0.65 to 0.97; P=0.02). The hazard ratio for the primary end point in the combined trials was 0.88 (95% CI, 0.76 to 1.02; P=0.08). Injection-site reactions were more common in the bococizumab group than in the placebo group (10.4% vs. 1.3%, P<0.001)., Conclusions: In two randomized trials comparing the PCSK9 inhibitor bococizumab with placebo, bococizumab had no benefit with respect to major adverse cardiovascular events in the trial involving lower-risk patients but did have a significant benefit in the trial involving higher-risk patients. (Funded by Pfizer; SPIRE-1 and SPIRE-2 ClinicalTrials.gov numbers, NCT01975376 and NCT01975389 .).
- Published
- 2017
- Full Text
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14. Oral apixaban for the treatment of acute venous thromboembolism.
- Author
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Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, and Weitz JI
- Subjects
- Acute Disease, Administration, Oral, Adult, Aged, Anticoagulants adverse effects, Anticoagulants therapeutic use, Double-Blind Method, Enoxaparin adverse effects, Enoxaparin therapeutic use, Female, Follow-Up Studies, Hemorrhage chemically induced, Hemorrhage mortality, Humans, Kaplan-Meier Estimate, Male, Middle Aged, Pyrazoles adverse effects, Pyridones adverse effects, Treatment Outcome, Warfarin adverse effects, Warfarin therapeutic use, Anticoagulants administration & dosage, Factor Xa Inhibitors, Pyrazoles administration & dosage, Pyridones administration & dosage, Venous Thromboembolism drug therapy
- Abstract
Background: Apixaban, an oral factor Xa inhibitor administered in fixed doses, may simplify the treatment of venous thromboembolism., Methods: In this randomized, double-blind study, we compared apixaban (at a dose of 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months) with conventional therapy (subcutaneous enoxaparin, followed by warfarin) in 5395 patients with acute venous thromboembolism. The primary efficacy outcome was recurrent symptomatic venous thromboembolism or death related to venous thromboembolism. The principal safety outcomes were major bleeding alone and major bleeding plus clinically relevant nonmajor bleeding., Results: The primary efficacy outcome occurred in 59 of 2609 patients (2.3%) in the apixaban group, as compared with 71 of 2635 (2.7%) in the conventional-therapy group (relative risk, 0.84; 95% confidence interval [CI], 0.60 to 1.18; difference in risk [apixaban minus conventional therapy], -0.4 percentage points; 95% CI, -1.3 to 0.4). Apixaban was noninferior to conventional therapy (P<0.001) for predefined upper limits of the 95% confidence intervals for both relative risk (<1.80) and difference in risk (<3.5 percentage points). Major bleeding occurred in 0.6% of patients who received apixaban and in 1.8% of those who received conventional therapy (relative risk, 0.31; 95% CI, 0.17 to 0.55; P<0.001 for superiority). The composite outcome of major bleeding and clinically relevant nonmajor bleeding occurred in 4.3% of the patients in the apixaban group, as compared with 9.7% of those in the conventional-therapy group (relative risk, 0.44; 95% CI, 0.36 to 0.55; P<0.001). Rates of other adverse events were similar in the two groups., Conclusions: A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201).
- Published
- 2013
- Full Text
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15. Role of the interleukin-6/interleukin-6 soluble receptor cytokine system in mediating increased skeletal sensitivity to parathyroid hormone in perimenopausal women.
- Author
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Insogna K, Mitnick M, Pascarella J, Nakchbandi I, Grey A, and Masiukiewicz U
- Subjects
- Adult, Animals, Bone Resorption metabolism, Bone and Bones drug effects, Collagen urine, Collagen Type I, Disease Models, Animal, Estrogens deficiency, Estrogens physiology, Female, Follow-Up Studies, Humans, Hyperparathyroidism complications, Hyperparathyroidism metabolism, Interleukin-6 blood, Menopause metabolism, Mice, Middle Aged, Osteoporosis, Postmenopausal complications, Osteoporosis, Postmenopausal metabolism, Parathyroid Hormone blood, Parathyroid Hormone pharmacology, Peptides urine, Postmenopause metabolism, Predictive Value of Tests, Premenopause metabolism, Receptors, Interleukin-6 drug effects, Reference Values, Retrospective Studies, Bone and Bones metabolism, Cytokines metabolism, Interleukin-6 physiology, Parathyroid Hormone physiology, Receptors, Interleukin-6 physiology
- Abstract
We have observed a strong correlation between circulating levels of both interleukin-6 (IL-6) and interleukin-6 soluble receptor (IL-6sR) and rates of bone turnover in patients with primary hyperparathyroidism. Furthermore, we have found that serum levels of IL-6sR predict rates of bone loss in postmenopausal women with this disease. Estrogen modulates parathyroid hormone (PTH)-induced increases in serum IL-6/IL-6sR, such that, in the estrogen-deficient state, there is an exaggerated release of these cytokines. We therefore propose that the perimenopausal period represents a time when skeletal sensitivity to the resorbing actions of PTH increases because of augmented release of IL-6 and IL-6sR. To test this hypothesis, we retrospectively examined data from 91 women with primary hyperparathyroidism who were seen over the last 5 years at our institution. Women were categorized, based on their age, as premenopausal (n = 20, 41 +/- 2 years), perimenopausal (n = 17, 54 +/- 1 years), or postmenopausal (n = 54, 64 +/- 1 years). Despite having similar mean values for PTH, perimenopausal women had a mean serum IL-6 value that was significantly higher than that in the premenopausal group (13 +/- 2 vs. 8 +/- 2 pg/ml; p = 0.03). This difference in cytokine profile was mirrored by higher mean values for urine N telopeptides of type I collagen (NTX) in the perimenopausal group compared with premenopausal women (114 +/- 9 vs. 80 +/- 11 nM bone collagen equivalents (BCE)/mM creatinine, p = 0.01). Of the three groups of patients, values for IL-6 and urine NTX were highest in the postmenopausal group. We conclude that the perimenopausal period may be a time of increased risk for the skeletal complications of hyperparathyroidism. This is because of increased skeletal sensitivity to the resorbing actions of PTH, mediated in part, by the IL-6/IL-6sR cytokine system.
- Published
- 2002
16. IL-6 negatively regulates IL-11 production in vitro and in vivo.
- Author
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Nakchbandi IA, Mitnick MA, Masiukiewicz US, Sun BH, and Insogna KL
- Subjects
- Animals, Cell Line, Female, Humans, Hyperparathyroidism blood, In Vitro Techniques, Interleukin-11 biosynthesis, Interleukin-11 blood, Interleukin-6 antagonists & inhibitors, Interleukin-6 blood, Interleukin-6 genetics, Mice, Mice, Inbred Strains, Mice, Knockout genetics, Osteoblasts metabolism, Parathyroid Hormone pharmacology, Parathyroidectomy, RNA, Messenger metabolism, Rats, Rats, Sprague-Dawley, Interleukin-11 antagonists & inhibitors, Interleukin-6 physiology
- Abstract
IL-6 and IL-11 are two cytokines that increase osteoclast formation and augment bone resorption. PTH stimulates the production of both cytokines by human osteoblast-like cells. Circulating levels of IL-6 are elevated in patients with states of PTH excess and correlate strongly to markers of bone resorption. In contrast, serum levels of IL-11 were significantly reduced in patients with primary hyperparathyroidism compared with values in euparathyroid controls. Further, after successful parathyroid adenomectomy, circulating levels of IL-6 fell, whereas IL-11 levels increased. Five-day infusions of human PTH-(1--84) in rodents resulted in a significant decline in mean circulating levels of IL-11, whereas IL-6 levels significantly increased. Pretreatment of cells and mice with neutralizing serum to IL-6 enhanced PTH-induced IL-11 production compared with the effect of pretreatment with nonimmune sera. These data indicate that IL-6 negatively regulates IL-11 production in vivo and in vitro. Analysis of steady state mRNA levels in SaOS-2 cells indicated that this effect is posttranscriptional. As both IL-6 and IL-11 stimulate osteoclast formation, down-regulation of IL-11 by IL-6 may help modulate the resorptive response to PTH.
- Published
- 2001
- Full Text
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17. Parathyroid hormone induces hepatic production of bioactive interleukin-6 and its soluble receptor.
- Author
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Mitnick MA, Grey A, Masiukiewicz U, Bartkiewicz M, Rios-Velez L, Friedman S, Xu L, Horowitz MC, and Insogna K
- Subjects
- Animals, Cell Division, Cells, Cultured, Endothelium, Vascular drug effects, Endothelium, Vascular metabolism, Hepatocytes chemistry, Hepatocytes drug effects, Hepatocytes metabolism, Humans, Interleukin-6 genetics, Interleukin-6 pharmacology, Kupffer Cells drug effects, Kupffer Cells metabolism, Male, Peptide Fragments pharmacology, RNA, Messenger analysis, Rats, Rats, Sprague-Dawley, Interleukin-6 biosynthesis, Liver drug effects, Liver metabolism, Parathyroid Hormone pharmacology, Receptors, Interleukin-6 biosynthesis
- Abstract
Interleukin-6 (IL-6) is an important mediator of parathyroid hormone (PTH)-induced bone resorption. Serum levels of IL-6 and its soluble receptor (IL-6sR) are regulated in part by PTH. The PTH/PTH-related protein type 1 receptor is highly expressed in the liver, and in the current study we investigated whether the liver produces IL-6 or IL-6sR in response to PTH. Perfusion of the isolated rat liver with PTH-(1-84) stimulated rapid, dose-dependent production of bioactive IL-6 and the IL-6sR. These effects were observed at near physiological concentrations of the hormone such that 1 pM PTH induced hepatic IL-6 production at a rate of approximately 0.6 ng/min. In vitro, hepatocytes, hepatic endothelial cells, and Kupffer cells, but not hepatic stellate cells, were each found to produce both IL-6 and IL-6sR in response to higher (10 nM) concentrations of PTH. Our data suggest that hepatic-derived IL-6 and IL-6sR contribute to the increase in circulating levels of these cytokines induced by PTH in vivo and raise the possibility that PTH-induced, liver-derived IL-6 may exert endocrine effects on tissues such as bone.
- Published
- 2001
- Full Text
- View/download PDF
18. Estrogen modulates parathyroid hormone-induced interleukin-6 production in vivo and in vitro.
- Author
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Masiukiewicz US, Mitnick M, Grey AB, and Insogna KL
- Subjects
- Biomarkers, Bone Resorption metabolism, Estradiol administration & dosage, Humans, Interleukin-6 blood, Osteoblasts metabolism, Ovariectomy, Tumor Cells, Cultured, Estradiol pharmacology, Interleukin-6 biosynthesis, Parathyroid Hormone pharmacology
- Abstract
Interleukin (IL)-6 promotes osteoclastogenesis and is thought to play a role in the bone loss that follows estrogen withdrawal. In vitro studies have demonstrated that IL-6 is produced in response to PTH by cells in the osteoblast lineage and that PTH-induced bone resorption is inhibited by a neutralizing antibody to the IL-6 receptor. In addition, we have recently reported that IL-6 plays a role in PTH-induced bone resorption in humans with chronic PTH excess and in experimental animals during the short-term infusion of PTH. In the current study, we examined whether estrogen withdrawal augments PTH-induced IL-6 production. When cultured in the absence of estrogen, human osteosarcoma cells (Saos-2) treated with PTH demonstrated significantly greater release of IL-6 than cells grown under estrogen-replete conditions, 30-fold vs. 15-fold (P = 0.005). A similar effect but of lesser magnitude was seen with primary human osteoblasts. In vivo, PTH induced IL-6 production was also increased in the estrogen-deficient state (ovx) such that at the end of a 5-day PTH infusion, the mean circulating level of IL-6 was significantly higher in ovx vs. sham/ovx mice (60.1 vs. 16.9 pg/ml; P < 0.0001). The greater increase in circulating levels of IL-6 in PTH-treated ovx mice was paralleled by a greater rise in bone resorption markers with the mean level of urine collagen cross-links in the PTH-treated ovx group being more than 2.5-fold higher than in the PTH-treated sham/ovx animals (236 vs. 88.5 microg/mmol creatinine, P < 0.0001). Mean serum collagen cross-link values were 17.4 microg/liter in PTH-treated ovx vs. 7.4 microg/liter in PTH-treated sham/ovx animals (P < 0.0001). Treatment of animals with estrogen prevented the exaggerated response to PTH infusion such that the increase in both circulating levels of IL-6 and bone turnover markers in estrogen-treated animals were similar to those observed in sham/ovx animals and significantly lower than those in PTH-treated ovx animals. These findings may help to explain the increased skeletal sensitivity to the resorbing effects of PTH seen in the estrogen-deficient state.
- Published
- 2000
- Full Text
- View/download PDF
19. A role for interleukin-6 in parathyroid hormone-induced bone resorption in vivo.
- Author
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Grey A, Mitnick MA, Masiukiewicz U, Sun BH, Rudikoff S, Jilka RL, Manolagas SC, and Insogna K
- Subjects
- Animals, Antibodies, Monoclonal immunology, Antibodies, Monoclonal pharmacology, Female, Humans, Interleukin-6 genetics, Interleukin-6 immunology, Mice, Mice, Knockout genetics, Ovariectomy, Parathyroid Hormone pharmacology, Rats, Rats, Inbred Strains, Rats, Sprague-Dawley, Reference Values, Bone Resorption etiology, Interleukin-6 physiology, Parathyroid Hormone physiology
- Abstract
Parathyroid hormone (PTH) exerts its regulatory effects on calcium homeostasis in part by stimulating the release of calcium from the skeleton. PTH stimulates bone resorption indirectly, by inducing the production by stromal/osteoblastic cells of paracrine agents which recruit and activate the bone-resorbing cell, the osteoclast. The identity of the stromal cell/osteoblast-derived paracrine factor(s) responsible for mediating the effects of PTH on osteoclasts is uncertain. Recently, it has been demonstrated that the cytokine interleukin-6 (IL-6), which potently induces osteoclastogenesis, is produced by osteoblastic cells in response to PTH. Further, we have reported that circulating levels of IL-6 are elevated in patients with primary hyperparathyroidism, and correlate with biochemical markers of bone resorption. Thus, IL-6 may play a permissive role in PTH-induced bone resorption. In the current studies, we demonstrate that low-dose PTH infusion in rodents increased serum levels of IL-6, coincident with a rise in biochemical markers of bone resorption. In mice, both acute neutralization and chronic deficiency of IL-6 were associated with markedly lower levels of biochemical markers of bone resorption in response to PTH infusion than were observed in animals with normal IL-6 production. Acute neutralization of IL-6 did not affect PTH-induced changes in markers of bone formation. These findings demonstrate that PTH regulates systemic levels of IL-6 in experimental animals, that IL-6 is an important mediator of the bone-resorbing actions of PTH in vivo and suggest that IL-6 plays a role in coupling PTH-induced bone resorption and formation.
- Published
- 1999
- Full Text
- View/download PDF
20. Papillary thyroid carcinoma metastatic to the pituitary gland.
- Author
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Masiukiewicz US, Nakchbandi IA, Stewart AF, and Inzucchi SE
- Subjects
- Carcinoma, Papillary pathology, Carcinoma, Papillary therapy, Female, Humans, Hypopituitarism etiology, Iodine Radioisotopes therapeutic use, Magnetic Resonance Imaging, Male, Middle Aged, Pituitary Neoplasms complications, Recombinant Proteins therapeutic use, Thyroid Neoplasms therapy, Thyrotropin biosynthesis, Thyrotropin therapeutic use, Thyroxine administration & dosage, Carcinoma, Papillary secondary, Pituitary Neoplasms secondary, Thyroid Neoplasms pathology
- Abstract
Many malignancies may present with metastases to the pituitary gland. The association of thyroid carcinoma with pituitary metastases is, however, very rare. This report describes two patients in whom metastases from a papillary thyroid carcinoma to the pituitary gland resulted in panhypopituitarism with blunted endogenous thyrotropin (TSH) production following withdrawal of levothyroxine. Both required the use of recombinant human TSH prior to radioiodine therapy. Symptoms of hypopituitarism may be difficult to distinguish clinically from those of hypothyroidism in the setting of levothyroxine withdrawal. Clinicians should be aware of the clinical and biochemical manifestations of this rare association.
- Published
- 1999
- Full Text
- View/download PDF
21. Hyperthyroidism in pregnancy: diagnosis and treatment.
- Author
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Masiukiewicz US and Burrow GN
- Subjects
- Adrenergic beta-Antagonists therapeutic use, Antithyroid Agents therapeutic use, Female, Graves Disease complications, Graves Disease diagnosis, Graves Disease therapy, Humans, Iodine Radioisotopes therapeutic use, Pregnancy, Pregnancy Outcome, Propylthiouracil therapeutic use, Thyroidectomy, Thyrotoxicosis etiology, Hyperthyroidism diagnosis, Hyperthyroidism therapy, Pregnancy Complications diagnosis, Pregnancy Complications therapy
- Abstract
Hyperthyroidism due to autoimmune Graves' disease is the leading cause of thyrotoxicosis in pregnant women. The peak incidence of the disease is in the second through the fourth decade of life, which encompasses the reproductive years for women. Although menstrual irregularity is frequent in women with mild to moderate hyperthyroidism, convincing evidence that fertility is impaired is lacking. In general, 2 of every 1000 pregnancies have been reported to be complicated by hyperthyroidism. Hyperthyroidism associated with pregnancy may pose a challenging diagnostic and therapeutic dilemma. The current review focuses on the discussion of symptomatology and diagnosis of the disease, on therapeutic options available to women presenting with hyperthyroidism during gestation, and on the controversy surrounding maternal and fetal outcome in pregnancies complicated by thyrotoxicosis.
- Published
- 1999
- Full Text
- View/download PDF
22. The role of parathyroid hormone in the pathogenesis, prevention and treatment of postmenopausal osteoporosis.
- Author
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Masiukiewicz US and Insogna KL
- Subjects
- Aged, Aging physiology, Female, Humans, Middle Aged, Osteoporosis, Postmenopausal drug therapy, Osteoporosis, Postmenopausal etiology, Osteoporosis, Postmenopausal prevention & control, Parathyroid Hormone administration & dosage, Parathyroid Hormone physiology
- Abstract
Parathyroid hormone (PTH) is the principal regulator of bone remodeling in the adult skeleton. The acute in vivo effect of PTH is to increase bone resorption, although sustained increases in its circulating levels accelerate both formation and resorption. These divergent effects have focused attention on PTH as a factor contributing to bone loss in some postmenopausal women, as well as interest in its role as therapy for the disease. Sustained increases in PTH are classically seen in primary hyperparathyroidism. While still controversial, increasing evidence suggests that primary hyperparathyroidism is associated with increased rates of bone loss, particularly from cortical sites in the skeleton. It is clear that the remodeling space is increased in primary hyperparathyroidism, and that surgical correction of the disease leads to substantial increases in bone mass in patients with osteoporosis. Recently, secondary hyperparathyroidism has emerged as an important contributor to increased rates of bone turnover and bone loss in postmenopausal women. The etiology of secondary hyperparathyroidism in postmenopausal women is complex, and is probably related to alterations in vitamin D metabolism and tissue responsiveness to 1,25(OH)2vitamin D. PTH has emerged at the forefront of anabolic therapies for the treatment of postmenopausal osteoporosis. When given as a single agent, intermittent daily subcutaneous administration of PTH induces consistent gains in trabecular bone mass with more varying effects on the cortical envelope. However, recent therapeutic trials employing a second agent, most notably estrogen, give hope that this approach may provide the first truly efficacious anabolic therapy for this devastating disease.
- Published
- 1998
- Full Text
- View/download PDF
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