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1.
N Engl J Med ; 384(17): 1589-1600, 2021 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-33913637

RESUMO

BACKGROUND: Vadadustat is an oral hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitor, a class of drugs that stabilize HIF and stimulate erythropoietin and red-cell production. METHODS: In two phase 3, randomized, open-label, active-controlled, noninferiority trials, we compared vadadustat with the erythropoiesis-stimulating agent (ESA) darbepoetin alfa in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) not previously treated with an ESA who had a hemoglobin concentration of less than 10 g per deciliter and in patients with ESA-treated NDD-CKD and a hemoglobin concentration of 8 to 11 g per deciliter (in the United States) or 9 to 12 g per deciliter (in other countries). The primary safety end point, assessed in a time-to-event analysis, was the first major adverse cardiovascular event (MACE; a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke), pooled across the two trials. Secondary safety end points included expanded MACE (MACE plus hospitalization for either heart failure or a thromboembolic event). The primary and key secondary efficacy end points in each trial were the mean change in hemoglobin concentration from baseline during two evaluation periods: weeks 24 through 36 and weeks 40 through 52. RESULTS: A total of 1751 patients with ESA-untreated NDD-CKD and 1725 with ESA-treated NDD-CKD underwent randomization in the two trials. In the pooled analysis, in which 1739 patients received vadadustat and 1732 received darbepoetin alfa, the hazard ratio for MACE was 1.17 (95% confidence interval [CI], 1.01 to 1.36), which did not meet the prespecified noninferiority margin of 1.25. The mean between-group differences in the change in the hemoglobin concentration at weeks 24 through 36 were 0.05 g per deciliter (95% CI, -0.04 to 0.15) in the trial involving ESA-untreated patients and -0.01 g per deciliter (95% CI, -0.09 to 0.07) in the trial involving ESA-treated patients, which met the prespecified noninferiority margin of -0.75 g per deciliter. CONCLUSIONS: Vadadustat, as compared with darbepoetin alfa, met the prespecified noninferiority criterion for hematologic efficacy but not the prespecified noninferiority criterion for cardiovascular safety in patients with NDD-CKD. (Funded by Akebia Therapeutics and Otsuka Pharmaceutical; PRO2TECT ClinicalTrials.gov numbers, NCT02648347 and NCT02680574.).


Assuntos
Anemia/tratamento farmacológico , Darbepoetina alfa/uso terapêutico , Glicina/análogos & derivados , Hematínicos/uso terapêutico , Ácidos Picolínicos/uso terapêutico , Inibidores de Prolil-Hidrolase/uso terapêutico , Insuficiência Renal Crônica/complicações , Administração Oral , Idoso , Anemia/sangue , Anemia/etiologia , Doenças Cardiovasculares/induzido quimicamente , Darbepoetina alfa/efeitos adversos , Feminino , Glicina/efeitos adversos , Glicina/uso terapêutico , Hematínicos/efeitos adversos , Hemoglobinas/análise , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Ácidos Picolínicos/efeitos adversos , Inibidores de Prolil-Hidrolase/efeitos adversos , Insuficiência Renal Crônica/mortalidade
2.
Hum Mol Genet ; 17(18): 2894-9, 2008 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-18596051

RESUMO

Recent genome-wide association (GWA) studies have identified new genetic determinants of complex quantitative traits, including plasma triglyceride (TG). We hypothesized that common variants associated with mild TG variation identified in GWA studies would also be associated with severe hypertriglyceridemia (HTG). We studied 132 patients of European ancestry with severe HTG (fasting plasma TG > 10 mmol/l), who had no mutations found by resequencing of candidate genes, and 351 matched normolipidemic controls. We determined genotypes for: GALNT2 rs4846914, TBL2/MLXIPL rs17145738, TRIB1 rs17321515, ANGPTL3 rs12130333, GCKR rs780094, APOA5 rs3135506 (S19W), APOA5 rs662799 (-1131T > C), APOE (isoforms) and LPL rs328 (S447X). We found that: (i) genotypes, including those of APOA5 S19W, APOA5 -1131T > C, APOE, GCKR, TRIB1 and TBL2/MLXIPL, were significantly associated with severe HTG; (ii) odds ratios for these genetic variables were significant in both univariate and multivariate regression analyses, irrespective of the presence or absence of diabetes or obesity; (iii) a significant fraction-about one-quarter-of the explained variation in disease status was associated with these genotypes. Therefore, common SNPs (single nucleotide polymorphisms) that are associated with mild TG variation in GWA studies of normolipidemic subjects are also associated with severe HTG. Our findings are consistent with the emerging model of a complex genetic trait. At the extremes of a quantitative trait, such as severe HTG, are found the cumulative contributions of both multiple rare alleles with large genetic effects and common alleles with small effects.


Assuntos
Predisposição Genética para Doença , Hipertrigliceridemia/genética , Herança Multifatorial , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Apolipoproteínas/genética , Estudos de Casos e Controles , Feminino , Proteínas de Ligação ao GTP/genética , Genótipo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Masculino , Pessoa de Meia-Idade , Análise Multivariada , N-Acetilgalactosaminiltransferases/genética , Proteínas Serina-Treonina Quinases/genética , Triglicerídeos/sangue , População Branca/genética , Polipeptídeo N-Acetilgalactosaminiltransferase
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