SUN-075 Efficacy of Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) for Diabetes Management in Patients with Cushing’s Disease

Abstract

Management of type 2 diabetes (T2D) and obesity is challenging in patients with Cushing’s Disease (CD). While once-weekly Glucagon-Like Peptide-1 Receptor Agonists (GLP-1 RAs) are established treatments for T2D and obesity, their efficacy in the setting of CD remains unexplored. In this study, we investigated the efficacy of GLP-1 RAs for weight and diabetes management in patients with CD. We conducted a retrospective chart review of adult patients at Indiana University Healthcare System (January 2021-October 2024) with confirmed CD and T2D who received weekly GLP-1 RAs for ≥3 months. Eligible patients were identified using ICD codes for T2D, CD and GLP-1 RAs. Patients with non-pituitary Cushing's syndrome or exogenous steroid use were excluded. Primary outcomes included changes in glycated hemoglobin (HbA1c) and Body Mass Index (BMI) at 3-, 6-, and 12-month intervals. Fifteen patients (93.3% female, median age 47 years) were identified. Prescribed GLP-1 RAs included Semaglutide (60%), Dulaglutide (26.7%), and Tirzepatide (13.3%). Median baseline HbA1c and BMI were 8.2% (IQR 7.2 - 8.6%) and 37.2 kg/m² (IQR 32.4 - 44.2 kg/m2), respectively. Non-significant reductions in mean HbA1c from baseline were observed at 3, 6, and 12 months, with changes of 1.21%, 0.72%, and 1.35%, respectively (unadjusted). No reduction of BMI was observed - on the contrary, patients experienced a non-significant mean increase in BMI over the treatment period. Our findings suggest that GLP-1 RAs may retain their glucose-lowering effects in CD patients while failing to achieve weight reduction. We hypothesize that the presence of a corticotroph adenoma may interfere with central GLP-1 receptor signaling in the hypothalamus, potentially disrupting the weight-loss response while preserving peripheral glucose regulation. These findings align with our previous observations of reduced efficacy of GLP-1 RAs in patients with genetic forms of obesity1. Further research is needed to distinguish between the centrally vs peripherally-mediated effects of GLP-1 RAs. This understanding can provide insight into individualized medical therapy for obesity and/or diabetes management. 1.Klein MP, Akturk HK, Snell-Bergeon JK, Shah VN. Reduced Efficacy of Glucagon-Like Peptide-1 Receptor Agonists Therapy in People With Type 1 Diabetes and Genetic Forms of Obesity. J Diabetes Sci Technol. 2024 Apr 17:19322968241245680.