The impact of novel antidiabetic medications among people with HIV

Abstract

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 inhibitors (SGLT2is) have proven metabolic and kidney benefits in the general population, but evidence among people with HIV (PWH), a population with high comorbidity burden, is limited. This thesis evaluated their safety and effectiveness in PWH, focusing on bodyweight, glycemic control, kidney function, and depressive symptoms. Methods: Four observational studies were conducted using data from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a multicenter cohort of PWH in care across the US (2013–2024). Study 1 assessed one-year changes in bodyweight and hemoglobin A1c (HbA1c) following semaglutide initiation. Study 2 used a new-user, active-comparator design to compare weight outcomes across four antidiabetic classes: GLP-1RAs, SGLT2is, dipeptidyl peptidase-4 inhibitors, and sulfonylureas. Study 3 applied propensity score matching to compare SGLT2is versus other antidiabetic classes on acute estimated glomerular filtration rate (eGFR) decline (≥10% and ≥30% at 6 months) and longer-term eGFR trajectories. Study 4 used a pre-post design to evaluate changes in depressive symptoms (Patient Health Questionnaire-9; PHQ-9) after semaglutide initiation. Continuous outcomes were analyzed using linear mixed models, and time-to-event outcomes using Cox proportional hazards models. Results: In Study 1, semaglutide initiation was associated with a mean weight reduction of 6.47 kg (95% CI: -7.71, -5.23) and an HbA1c reduction of 1.07% (95% CI -1.64, -0.50). In Study 2, GLP-1RAs were associated with the greatest weight loss (4.44%; 95% CI -5.51, -3.36), particularly among individuals without diabetes, with obesity, and those receiving semaglutide. SGLT2is were associated with modest weight loss, while other classes showed minimal changes. In Study 3 (295 matched pairs), SGLT2i use was associated with higher rates of acute eGFR decline (≥10%: aHR 1.79 [95% CI 1.40–2.28]; ≥30%: aHR 1.69 [95% CI 1.05–2.73]), although the mean decline was small (-2.6 mL/min/1.73 m²) and appeared transient over time. In Study 4, semaglutide was not associated with worsening depressive symptoms (mean PHQ-9 change: -0.1; 95% CI: -0.7, 0.5). Conclusion: Among PWH, GLP-1RAs, particularly semaglutide, were associated with clinically meaningful weight and HbA1c reductions without evidence of worsening depressive symptoms, while SGLT2is were associated with modest weight loss and generally favorable kidney outcomes.