Abstract
Semaglutide, a GLP-1 receptor agonist, improves metabolic health and reduces liver fat in people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease (MASLD). This post hoc analysis of the 24-week SLIM LIVER single-arm trial (ACTG A5371, No. NCT04216589, registered 02nd Jan 2020) in 41 PWH with MASLD receiving semaglutide (1.0 mg weekly) aimed to evaluate its effect on epigenetic aging and determine whether changes in epigenetic clocks associate with clinical responsiveness. Over 24 weeks, we observed DunedinPACE median change +0.018 (IQR –0.023 to +0.053), PCDNAmTL –0.006 kb (IQR –0.073 to +0.054), and PCGrimAge +0.54 years (IQR –0.33 to +1.26). Participants with decreased DunedinPACE (41.5%) showed greater liver fat reduction (p = 0.024) and trend towards improved gait speed (p = 0.081). Increased PCDNAmTL was associated with better gait speed (p = 0.012). These data suggest early signals of semaglutide responsiveness and relationships to epigenetic age biomarkers. Epigenetic biomarkers may enhance precision in GLP-1RA therapy and enable noninvasive monitoring of biological aging. Trial Registration: ClinicalTrials.gov ID: NCT04216589, registered 02nd Jan 2020.
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Data availability
Due to ethical restrictions, study data are available upon request from sdac.data@sdac.harvard.edu with the written agreement of the Advancing Clinical Therapeutics Globally. The epigenetic data from this study was submitted to the NCBI Gene Expression Omnibus (GEO) http://www.ncbi.nlm.nih.gov/geo/.
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Acknowledgements
The study investigators thank the study participants, site staff, and study-associated personnel for their ongoing participation in the trial. In addition, we thank the following: the ACTG for clinical site support; ACTG Clinical Trials Specialists (Christina Vernon, Katharine Bergstrom) for protocol development and implementation support; the data management center, Frontier Science Foundation, for data support; the Center for Biostatistics in AIDS Research for statistical support; and the Community Advisory Board for input for the community. This manuscript is the result of funding in whole or in part by the National Institutes of Health and is subject to the NIH Public Access Policy. This work was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under [UM1 AI068634, UM1 AI068636, UM1 AI106701] with additional funding provided by McGovern School of Medicine at UTHealth. Additional support was provided by National Institute of Allergy and Infectious Diseases [K24 AI120834 to TTB], San Diego Center for AIDS Research (P30 AI036214), the National Institute on Aging under [K24 AG082527 to KME], and the James B. Pendleton Charitable Trust.
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Conceptualization (M.J.C., A.L., K.M.E.); data curation, formal analysis, visualization, and methodology (A.J.C., A.P.P., D.W.K., A.K.); funding acquisition (J.E.L., K.M.E.); investigation (all authors); project administration (M.J.C., J.E.L., K.M.E.); writing—original draft (M.J.C., A.P.P.); writing—review and editing (all authors). M.J.C. had full access to and verified all the data in the study. All authors had final responsibility for the decision to submit for publication.
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M.J.C. serves as a scientific advisor for TruDiagnostic. A.P.S.P. declares no disclosures. K.M.E. has received research funding from the NIH/NIA in support of the present manuscript; outside of the current work, she has received research funding from Gilead Sciences and has consulted for Gilead Sciences, Merck, and ViiV Pharmaceuticals, all paid to her institution. T.T.B. has served as a consultant to Merck, ViiV Healthcare, EMD Serono, and Janssen. P.F.B.-Z. is the Division of AIDS medical officer for the study; however, his views are personal and do not represent the NIH/NIAID’s views.
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Corley, M.J., Pang, A.P.S., Kitch, D.W. et al. Pilot study of epigenetic aging and treatment response to semaglutide in the SLIM LIVER study. npj Aging (2026). https://doi.org/10.1038/s41514-026-00383-9
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DOI: https://doi.org/10.1038/s41514-026-00383-9
