113 – Epigenetic Age Predictors of Semaglutide-Related Liver Fat Changes in People With HIV

Background

In a recent pilot study (ACTG A5371, SLIM LIVER: NCT04216589), 24 weeks of low-dose semaglutide (1 mg sc weekly) reduced metabolic dysfunction-associated steatotic liver disease (MASLD) in people with HIV (PWH), with 58% having improved MRI-proton-derived fat fraction-quantified intrahepatic triglycerides (IHTG). Although trends suggested greater IHTG improvements in women and older participants, the role of biological age indicators was not assessed. We investigated whether epigenetic indicators incorporating physical fitness were associated with IHTG changes on semaglutide.

Methods

The SLIM LIVER study enrolled PWH ≥18 years on suppressive ART with central adiposity and MASLD. All participants received semaglutide for 24 weeks and PBMCs were available at weeks 0 and 24. Genome-wide DNA methylation profiles were analyzed in 41 participants with available PBMCs and used to calculate DNAm-based aging biomarkers, DNAmFitAge, that provides an estimate of biological age using DNAm-based estimates of three physical fitness measurements: maximal oxygen uptake (DNAmVO₂max), maximal gripping force (DNAmGripmax), and gait speed (DNAmGaitspeed). R code was used calculate DNAm fitness biomarkers available at GitHub repository at https://github.com/ kristenmcgreevy/DNAmFitAge. Linear regression models evaluated relationships between relative percent (%) change in IHTG (PCHG) and DNAm indicators, controlling for sex at birth and age.

Results

At entry, the mean age of participants (n=41) was 49 years (39% female), CD4⁺ T cell count was 776 cells/mm³ and absolute IHTG was 12.7%. Relative IHTG decrease was -29% (95% CI: -37, -20).  The mean epigenetic age estimate at entry for DNAmFitAge was 59.2 years (mean epigenetic age acceleration of 10.2 years).  A less accelerated DNAmFitAge at entry was associated with greater IHTG improvements (β=-1.6, p=0.10 when controlling for sex and chronological age. Weaker DNAmGripmax was also associated with greater improvements in IHTG over 24 weeks (β=4.68, p=0.009) when controlling for sex and chronological age. 

Conclusions

Epigenetic age indicators incorporating physical fitness, specifically worse DNAmGripmax and younger DNAmFitAge were associated with greater improvements in IHTG following 24 weeks of low-dose semaglutide treatment in PWH, suggesting a potential role for epigenetic biomarkers in predicting treatment responses.

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