Targeting inflammation in sickle cell disease: Association of GLP-1 agonist use with improved survival and reduced sickle cell crisis and cardiopulmonary complications

Abstract Sickle cell disease (SCD) is a hereditary hemoglobinopathy characterized by chronic hemolysis, vaso-occlusion, and a systemic inflammatory state, leading to recurrent pain crises, end-organ damage, and reduced life expectancy. Vascular dysfunction, oxidative stress, and heightened thrombo-inflammatory activity are central to SCD pathophysiology. Glucagon-like peptide-1 agonists (GLP-1a), originally developed for glycemic control, have demonstrated anti-inflammatory, endothelial-protective, and cardiometabolic benefits through modulation of the NF-κβ, ERK/AMPK, and JAK/STAT signaling pathways, attenuation of oxidative stress, macrophage polarization, and reduction of platelet aggregation. Furthermore, activation of GLP1R in monocytes, macrophages, and neutrophils has been shown to suppress NF-κβ signaling, limit NLRP3 inflammasome priming, and mitigate oxidative stress. Given the overlapping mechanisms of vascular injury and inflammation in SCD, GLP-1a may offer a novel adjunctive therapeutic strategy. However, their clinical impact on patients with SCD remains largely unexplored. This study investigates the effects of GLP-1a use on SCD patients using a large global real-world cohort of SCD patients. We conducted a retrospective, propensity score-matched (PSM) cohort study using the TriNetX Analytics Network database. Our analysis included SCD patients with (n=5,638) and without (n=232,459) GLP-1a therapy between 2005 and 2022. PSM (1:1) was applied using a greedy nearest-neighbor method with a caliper of 0.1 pooled standard deviations, adjusting for demographics, SCD-directed therapy, comorbidities, laboratory parameters, and cardiovascular medications. Primary outcomes were all-cause mortality, sickle cell crisis, ischemic stroke/TIA, and venous thromboembolism (VTE). Secondary outcomes included hospitalizations, ICU admissions, thrombocytopenia, acute kidney injury (AKI), heart failure (HF), pulmonary fibrosis (PF), pulmonary hypertension (PH), and Myocardial Infarction (MI). Outcomes were compared using odds ratios (ORs) with 95% confidence intervals (CIs) over a 3-year follow-up period. After PSM, 4,807 matched pairs (mean age 48.7±14.1 years for GLP-1a users and mean age 51.6 ±18.1 years for non-users, 73% females in both groups) were analyzed. The mean duration of GLP-1a therapy among users was 136.0 ± 179.2 days. GLP-1a therapy was associated with significantly lower odds of all-cause mortality (OR 0.337, 95% CI 0.272, 0.417, p<0.001), sickle cell crisis (OR 0.792, 95% CI 0.643, 0.974, p=0.027), ischemic stroke/TIA (OR 0.691, 95% CI 0.600, 0.795, p<0.001), and VTE (OR 0.659, 95% CI 0.574, 0.756, p<0.001). Additionally, GLP users demonstrated reduced odds of all-cause hospitalizations (OR 0.556, 95% CI 0.511, 0.605, p<0.001), ICU admissions (OR 0.554, 95% CI 0.482, 0.637, p<0.001), thrombocytopenia (OR: 0.570, 95% CI: 0.475, 0.684,p <0.001), AKI (OR: 0.636, 95% CI: 0.570, 0.710,p <0.001), HF (OR 0.652, 95% CI 0.584, 0.728, p<0.001), PF (OR 0.528, 95% CI 0.348, 0.802, p=0.002), PH (OR 0.616, 95% CI 0.520, 0.728, p<0.001), and MI (OR 0.496, 95% CI 0.408, 0.604, p<0.001). In this large, real-world, propensity-matched cohort study, GLP-1a therapy in SCD patients was associated with significantly lower risks of all-cause mortality, ischemic stroke/TIA, VTE, sickle cell crisis, and multiple cardiopulmonary complications, including HF, PH, PF, and MI. GLP-1a use was also linked to reduced health care utilization, including all-cause hospitalizations and ICU admissions. While the observational nature and limited clinical granularity of the dataset preclude causal inference, these findings support a compelling rationale for prospective randomized controlled trials to evaluate GLP-1a as a disease-modifying adjunct in SCD management.