Low-dose semaglutide spurs MASLD regression in people with HIV

Treatment with low-dose semaglutide helps reduce the severity of metabolic dysfunction-associated steatotic liver disease (MASLD) in people with HIV, according to data from the single-arm phase IIb ACTG A5371 trial.

Clinically significant reductions in intrahepatic triglyceride (IHTG) content were observed over 24 weeks of treatment, reported Prof Jordan Lake of the University of Texas at Houston, Houston, Texas, US.

The absolute reduction in IHTG was 4.2 percent (95 percent confidence interval [CI], –5.4 to –3.1; p<0.001), which translated to a relative reduction of 31.3 percent (95 percent CI, –39.0 to –23.6; p<0.001). [CROI 2024, abstract 159]

More than half (58 percent) of the participants achieved at least a 30-percent relative reduction in IHTG, with 29 percent having complete MASLD resolution (absolute IHTG <5 percent).

While the trial was not powered for subgroup analyses, Lake noted substantially greater IHTG reductions in female participants, Hispanic and non-Hispanic White participants, and those who were >60 years of age.

Semaglutide was well tolerated, she said, adding that there were only two grade 3 adverse events (AEs) possibly related to treatment (nausea and serotonin syndrome) and no grade 4 AEs.

Weight loss

Other than the decline in liver fat, semaglutide also induced weight loss, as expected, Lake said.

The participants lost a mean of 7.8 kg (95 percent CI, –9.5 to –6.1; p<0.001) or 17 lbs over 28 weeks of treatment, with greater weight loss seen among female participants, Hispanic and non-Hispanic White participants, and those who were at least 40 years of age. Furthermore, waist circumference decreased by –6.7 cm (95 percent CI, –8.5 to –4.8; p<0.001).

According to Lake, weight loss strongly correlated with IHTG improvements (p<0.0001), and the semaglutide nonresponder rate was comparable to that of the general population of about 28 percent.

Of note, participants who lost >2.27 kg (5 lbs) on semaglutide had even greater mean absolute and relative IHTG reductions (–5.1 percent and –39.0 percent, respectively).

Lipids and glucose homeostasis

Further analyses showed significant changes in circulating lipids and glucose homeostasis at week 24.

Fasting glucose decreased by 9.9 mg/dL (95 percent CI, –14.7 to –5.1; p<0.001), HOMA-IR by 1.5 (95 percent CI, –2.3 to –0.8; p<0.001), and HbA1c by 0.3 percent (95 percent CI, –0.3 to –0.2; p<0.001). High-density lipoprotein cholesterol levels increased by 2.0 mg/dL (95 percent CI, –0.02 to 4.1; p=0.053), whereas triglycerides dropped by 26.8 mg/dL (95 percent CI, –46.0 to –7.5; p=0.007).

Lake noted that larger glucose reductions were seen among female participants, Black participants, and those who were at least 40 years of age. On the other hand, triglyceride reductions were pronounced among male participants, Hispanic participants, and those who were <40 years of age.

Next steps

ACTG A5371 included 49 adult participants (median age 52 years, 43 percent cis or trans women, 39 percent Hispanic) on suppressive antiretroviral therapy who had central adiposity, insulin resistance or prediabetes, and steatotic liver disease (defined as ≥5 percent IHTG on magnetic resonance imaging-proton density fat fraction). All participants received semaglutide subcutaneously for 24 weeks, titrated to 1 mg weekly by week 4.

“There are many further analyses coming to assess immunologic and inflammatory pathway changes with semaglutide therapy in people with HIV, including those that may be unique to this population,” Lake said.

While such analyses are expected to provide additional insights, the researcher acknowledged a few important questions that need to be addressed, including the effects of semaglutide on lean mass loss, as well as the durability of benefit and strategies to maintain benefit after induction.