Two-Year Biomarker Trends and Kidney/Mortality Outcomes After Semaglutide Versus Phentermine–Topiramate and Naltrexone–Bupropion in People With Obesity and Without Diabetes

Background: – Laboratory changes after antiobesity drugs in routine care are not well-described. Study Question: – In adults with obesity and no diabetes, how do 2-year laboratory trends and major clinical outcomes compare after starting semaglutide versus naltrexone-bupropion or phentermine-topiramate? Study Design: – Retrospective cohort study in the TriNetX US Collaborative Network (2021–2025). New users were propensity-score matched 1:1 and followed for up to 24 months in an intention-to-treat framework. A prespecified 3-month landmark analysis and a global network replication were performed. Measures and Outcomes: – Lipids, HbA1c, ALT, AST, lipase, creatinine, and estimated glomerular filtration rate were assessed at baseline and at 6, 12, and 24 months. Outcomes were all-cause mortality, major adverse kidney events (MAKEs), major adverse liver outcomes, and acute pancreatitis. Cox models estimated hazard ratios (HRs); 24-month absolute risk differences (ARDs) were derived from Kaplan–Meier estimates. Results: – Matching yielded 11, 484 semaglutide–naltrexone–bupropion pairs and 16, 316 semaglutide–phentermine–topiramate pairs. Compared with each comparator, semaglutide users had lower total cholesterol and LDL-C across follow-up; triglycerides were lower versus naltrexone–bupropion. HDL-C was higher with phentermine–topiramate at 12–24 months. HbA1c was lower with semaglutide versus naltrexone–bupropion at 12 and 24 months and slightly higher versus phentermine–topiramate. Between-group differences in creatinine and estimated glomerular filtration rate were limited. Semaglutide use was associated with lower hazards of mortality (vs. naltrexone–bupropion: HR 0.51; ARD −0.4%; vs. phentermine–topiramate: HR 0.62; ARD −0.2%) and MAKE (vs. naltrexone–bupropion: HR 0.47; ARD −0.5%; vs. phentermine–topiramate: HR 0.48; ARD −0.4%). Major adverse liver outcome and pancreatitis estimates were near the null, and landmark results were similar. Conclusions: – Over 2 years in routine care, semaglutide use was associated with lower atherogenic lipid levels and lower hazards of death and MAKEs than naltrexone–bupropion or phentermine–topiramate, while kidney laboratory differences were limited.