Background
The glucagon-like peptide-1 receptor agonist semaglutide (SEMA) reduces weight and inflammation in the general population. We previously reported reductions in weight (mean -7.8 kg, 95% confidence interval, [CI, -9.5, -6.1]), insulin resistance (IR), serum triglycerides and liver fat in people with HIV (PWH) receiving SEMA in ACTG A5371, the SLIM LIVER study. Here we report additional metabolic, fat imaging and inflammatory marker endpoints, including follow-up after SEMA discontinuation.
Methods
ACTG A5371 enrolled PWH >/=18 years old on suppressive antiretroviral therapy (ART) with metabolic dysfunction-associated steatotic liver disease. All received low-dose, subcutaneous (sc) SEMA 1mg weekly for 24 weeks (W) followed by 24 W off SEMA. Biomarker/immune profiles and magnetic resonance imaging (MRI) were available at W 0 and 24, and other measures at W 0, 24 and 48. Mean (95% CI) changes were estimated using linear regression and risk estimates by a log link GEE model (a=0.05)
Results
PWH (n=49) had: median age 52 years, BMI 35 kg/m2, 39% Hispanic ethnicity, 33% Black/African American race, 43% cis/trans female and 82% INSTI-based ART. 24 W of SEMA was associated with a 25% reduction in metabolic syndrome risk and reduced visceral (-13%) and abdominal sc (-12%) fat by MRI (all p<0.05). A trend towards improvement in the frequency of elevated alanine aminotransferase (ALT, a steatohepatitis surrogate) occurred in women (women: 68% to 42%, p=0.06; men: 43% to 41%). Significant changes in adiponectin (↑), leptin (↓) and CRP (↓) were observed, with no change in IL-6 or monocyte/T cell profiles (data not shown).
After 24 W off SEMA (Fig.), absolute weight regain was +2.9 kg (1.5, 4.3), with women, White non-Hispanics and PWH <40 years of age regaining more. Among those who lost and regained weight (n=31), 75% of lost weight was regained. Weight regain was accompanied by significant increases in waist circumference (2.0 cm [0.9, 3.1]) and fasting glucose (5.1 mg/dL [0.9, 9.3]) without significant short-term changes in blood pressure, total or LDL cholesterol, triglycerides or metabolic syndrome. Elevated ALT frequency increased (women: 42% to 59%; men: 41% to 54%).
Conclusions
Short-term, low-dose SEMA was associated with cardiometabolic benefit in PWH. Rapid weight regain and some loss of cardiometabolic benefit occurred off SEMA, similar to the general population. Further study of higher-dose SEMA and strategies to maintain benefits of SEMA following initial therapy are needed in PWH.