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Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.

Publication ,  Journal Article
Nunez, DJ; Alexander, M; Yerges-Armstrong, L; Singh, G; Byttebier, G; Fabbrini, E; Waterworth, D; Meininger, G; Galwey, N; Wallentin, L ...
Published in: Am J Physiol Gastrointest Liver Physiol
March 1, 2019

Liver enzyme concentrations are measured as safety end points in clinical trials to detect drug-related hepatotoxicity, but little is known about the epidemiology of these biomarkers in subjects without hepatic dysfunction who are enrolled in drug trials. We studied alanine and aspartate aminotransferase (ALT and AST) in subjects randomized to placebo who completed assessments over 36 mo in a cardiovascular outcome trial [the Stabilisation of Atherosclerotic Plaque by Initiation of Darapladib Therapy ("STABILITY") trial; n = 4,264; mean age: 64.2 yr] or over 12 mo in three trials that enrolled only subjects with type 2 diabetes (T2D) [the DIA trials; n = 308; mean age: 62.4 yr] to investigate time-dependent relationships and the factors that might affect ALT and AST, including body mass index (BMI), T2D, and renal function. Multivariate linear mixed models examined time-dependent relationships between liver enzyme concentrations as response variables and BMI, baseline T2D status, hemoglobin A1c levels, and renal function, as explanatory variables. At baseline, ALT was higher in individuals who were men, <65 yr old, and obese and who had glomerular filtration rate (GFR) >60 ml·min-1·1.73 m-2. ALT was not significantly associated with T2D at baseline, although it was positively associated with HbA1c. GFR had a greater impact on ALT than T2D. ALT concentrations decreased over time in subjects who lost weight but remained stable in individuals with increasing BMI. Weight change did not alter AST concentrations. We provide new insights on the influence of time, GFR, and HbA1c on ALT and AST concentrations and confirm the effect of sex, age, T2D, BMI, and BMI change in subjects receiving placebo in clinical trials. NEW & NOTEWORTHY Clinical trials provide high-quality data on liver enzyme concentrations from subjects randomized to placebo that can be used to investigate the epidemiology of these biomarkers. The adjusted models show the influence of sex, age, time, renal function, type 2 diabetes, HbA1c, and body mass index on alanine aminotransferase and aspartate aminotransferase concentrations and their relative importance. These factors need to be considered when assessing potential signals of hepatotoxicity in trials of new drugs and in clinical trials investigating subjects with nonalcoholic fatty liver disease.

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Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

March 1, 2019

Volume

316

Issue

3

Start / End Page

G372 / G386

Location

United States

Related Subject Headings

  • Obesity
  • Non-alcoholic Fatty Liver Disease
  • Middle Aged
  • Male
  • Liver
  • Humans
  • Glycated Hemoglobin
  • Gastroenterology & Hepatology
  • Female
  • Diabetes Mellitus, Type 2
 

Citation

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Chicago
ICMJE
MLA
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Nunez, D. J., Alexander, M., Yerges-Armstrong, L., Singh, G., Byttebier, G., Fabbrini, E., … Ferrannini, E. (2019). Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials. Am J Physiol Gastrointest Liver Physiol, 316(3), G372–G386. https://doi.org/10.1152/ajpgi.00051.2018
Nunez, Derek J., Myriam Alexander, Laura Yerges-Armstrong, Gurparkash Singh, Geert Byttebier, Elisa Fabbrini, Dawn Waterworth, et al. “Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.Am J Physiol Gastrointest Liver Physiol 316, no. 3 (March 1, 2019): G372–86. https://doi.org/10.1152/ajpgi.00051.2018.
Nunez DJ, Alexander M, Yerges-Armstrong L, Singh G, Byttebier G, Fabbrini E, et al. Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials. Am J Physiol Gastrointest Liver Physiol. 2019 Mar 1;316(3):G372–86.
Nunez, Derek J., et al. “Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials.Am J Physiol Gastrointest Liver Physiol, vol. 316, no. 3, Mar. 2019, pp. G372–86. Pubmed, doi:10.1152/ajpgi.00051.2018.
Nunez DJ, Alexander M, Yerges-Armstrong L, Singh G, Byttebier G, Fabbrini E, Waterworth D, Meininger G, Galwey N, Wallentin L, White HD, Vannieuwenhuyse B, Alazawi W, Kendrick S, Sattar N, Ferrannini E. Factors influencing longitudinal changes of circulating liver enzyme concentrations in subjects randomized to placebo in four clinical trials. Am J Physiol Gastrointest Liver Physiol. 2019 Mar 1;316(3):G372–G386.

Published In

Am J Physiol Gastrointest Liver Physiol

DOI

EISSN

1522-1547

Publication Date

March 1, 2019

Volume

316

Issue

3

Start / End Page

G372 / G386

Location

United States

Related Subject Headings

  • Obesity
  • Non-alcoholic Fatty Liver Disease
  • Middle Aged
  • Male
  • Liver
  • Humans
  • Glycated Hemoglobin
  • Gastroenterology & Hepatology
  • Female
  • Diabetes Mellitus, Type 2