Semaglutide improves markers of cardiovascular risk in people with HIV.

OBJECTIVE: Semaglutide improves cardiovascular disease (CVD) risk in people who are diabetic, overweight or obese through incompletely understood mechanisms. To address this, we explored novel lipidomic and lipo-/glyco-protein profiling with semaglutide therapy. DESIGN: Secondary analysis of SLIM LIVER (ACTG A5371), an open-label, phase 2b, single-arm trial of 1 mg semaglutide weekly in adult people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease. METHODS: Participants (n = 36) experiencing clinical response (>5 lb weight loss) to semaglutide were included. Lipidomic and lipo-/glyco-protein profiling was performed from stored serum. RESULTS: Median age was 52 years and BMI 34 kg/m 2 ; 39% were Hispanic, 28% Black, 45% female and 22% had stable statin use. Lipidomics : Semaglutide reduced triglycerides, diglycerides and sphingomyelins and increased some bile acids and phosphatidylcholines. Lipoproteins : CVD-linked species decreased; LDL particle size increased and large HDL particle number decreased. Glycoproteins : Most participants had elevated baseline GlycA and GlycB, CVD-associated markers of systemic inflammation. 56% with elevated Glyc A improved and 32% normalized; 41% with elevated Glyc B improved and 42% normalized. Lipo-/glycol-protein concentrations generally did not correlate with baseline weight, liver fat or insulin resistance or their magnitude of change. CONCLUSIONS: In this first human report of lipidomic and lipo-/glyco-protein profiling during semaglutide therapy in any population, lipidomic changes suggest reductions in toxic lipid species and improved hepatic insulin sensitivity. Significant reductions in CVD-risk associated lipo-/glyco-protein species were observed that did not correlate with magnitude of changes in weight, liver fat or insulin resistance, suggesting an independent mechanism.