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 lipoprotein/glycoprotein 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 lipoprotein/glycoprotein 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. Lipoprotein/glycoprotein concentrations generally did not correlate with baseline weight, liver fat, or insulin resistance or their magnitude of change. CONCLUSION: In this first human report of lipidomic and lipoprotein/glycoprotein 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 lipoprotein/glycoprotein species were observed that did not correlate with magnitude of changes in weight, liver fat. or insulin resistance, suggesting an independent mechanism.