Hepatotoxicity of Alogliptin
| العنوان: | Hepatotoxicity of Alogliptin |
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| المؤلفون: | Elizabeth Barbehenn, Sammy Almashat, Sidney Wolfe, Michael Carome |
| المصدر: | Clinical Pharmacokinetics. 53:1055-1056 |
| بيانات النشر: | Springer Science and Business Media LLC, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Pharmacology, Dipeptidyl-Peptidase IV Inhibitors, medicine.medical_specialty, business.industry, Liver Diseases, Incretin, Context (language use), medicine.disease, Placebo, Fulminant hepatic failure, Pharmacotherapy, Diabetes Mellitus, Type 2, Internal medicine, Diabetes mellitus, Statistical significance, Receptors, Glucagon, Humans, Medicine, Pharmacology (medical), business, Alogliptin |
| الوصف: | In a recent article, Scheen [1] reviews the hepatic safety of incretin-based medications. The author concluded that ‘‘no hepatotoxicity has been reported in the development programme of alogliptin,’’ citing a review article from 2010, the year of alogliptin’s first approval (in Japan) [2]. However, the Food and Drug Administration (FDA) [3] and European Medicines Agency (EMA) [4] subsequently conducted detailed analyses of phase 2 and 3 pre-approval trials and post-marketing surveillance data from Japan and concluded that alogliptin’s potential hepatotoxicity warranted inclusion of warning language in the drug’s label [5, 6]. The post-marketing reports of alogliptin-associated hepatotoxicity from Japan were of particular concern to the FDA and prompted extensive consultations with agency hepatologists. The lead FDA hepatologist assigned to the review determined that a causal link to alogliptin was ‘‘possible/probable’’ in one case, ‘‘probable’’ in two cases, and ‘‘probable to highly likely’’ in two other cases [7]. One of the cases deemed ‘‘probabl[y] to highly likely’’ caused by alogliptin resulted in fulminant hepatic failure and death. This led the FDA’s hepatologists to recommend strict monitoring of hepatic enzymes before and during use of alogliptin [3]. In addition, in reporting on results of the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial of alogliptin, the author concludes, based on the numbers of subjects with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) elevations more than three times the upper limit of normal (ULN) in Table 3, that ‘‘no signal of hepatotoxicity was detected in the alogliptin group’’ vs. placebo. However, the figures in the placebo and alogliptin groups have been reversed. The correct values, as published in the supplement to the EXAMINE trial results in the New England Journal of Medicine, were as follows: [8] ALT [3 9 ULN: Alogliptin 64 (2.4 %); Placebo 46 (1.7 %); p = 0.10. AST [3 9 ULN: Alogliptin 48 (1.8 %); Placebo 43 (1.6 %); p = 0.67. Thus, more subjects on alogliptin experienced a substantial increase in ALT levels (a more specific marker of drug-induced liver injury than AST [9]) than those in the placebo group. In addition, the unusually low ULN of 25 U/L used for ALT may have masked even more striking imbalances in ALT elevations at higher thresholds [10, 11]. While the numerical imbalance did not reach statistical significance, a p value of 0.10 in the context of a trial not specifically powered to detect a significant difference in this safety outcome raises concerns over a potential signal for hepatotoxicity. Taken together, we feel that the author’s conclusions about alogliptin’s hepatic safety do not accurately reflect the current state of evidence on alogliptin toxicity. |
| تدمد: | 1179-1926 0312-5963 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::212bbf667cc3cf35bf8416876d76bb65 https://doi.org/10.1007/s40262-014-0199-1 |
| حقوق: | CLOSED |
| رقم الأكسشن: | edsair.doi.dedup.....212bbf667cc3cf35bf8416876d76bb65 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 11791926 03125963 |
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