Glycemic and Weight Loss Effects of Semaglutide in Subjects After Spinal Cord Injury and Type 2 Diabetes - Patients with spinal cord injury (SCI) develop diabetes at an earlier age and at a much higher rate than able bodied individuals (AB). Those with SCI and T2D are at much higher risk of developing cardiovascular complications. In addition to severe insulin resistance due to muscle atrophy and enhanced adiposity after SCI, affected patients have impaired prandial insulin secretion along with autonomic nervous system dysfunction. Yet, the optimal strategies to prevent or treat diabetes and obesity and related complications after SCI remains unknown. Numerous therapeutic options based on glucagon-like peptide 1 receptor (GLP-1R) agonism (agonists and co-agonists) are approved or in the pipeline for treatment of diabetes and obesity in AB patients based on our understanding about their effectiveness and tolerability in this population. Among them, semaglutide (SGT), which is the most potent GLP-1R agonist (GLP-1RA) in glycemic improvement and weight loss, has shown to reduce cardiovascular death by ~25% in AB population. Our preliminary data demonstrate that patients with SCI are treated with GLP-1RA at a 10-times lower rate than AB population. The cause for this health disparity in diabetes management is unknown but could be partly due to the lack of insights into anti-diabetic effectiveness and safety of GLP-1RAs in this high-risk population. Our central hypothesis is that administration of semaglutide (SGT) in SCI population with T2D improves glycemic tolerance and β-cell function (Aim1) and improves insulin sensitivity along with reduced fat mass but preserved lean mass along with weight loss (Aim2). In Aim1, glucose tolerance, glucose fluxes, and β-cell function during a meal tolerance test (MTT) combined with tracer infusion before and after 24 weeks of SGT vs. placebo will be measured. In Aim 2, we will measure hepatic, muscle, and adipose tissue insulin sensitivity using a 2-step (90 min/step) euglycemic insulin (15 and 80 mU/m2/min) clamp combined with tracer infusion before and after 24 weeks of SGT vs. placebo. We will also explore potential changes in total fat/lean mass, liver fat and fibrosis. Safety and tolerability will be assessed throughout the study. This is a phase 4, single center, double-blind randomized, and placebo-controlled study. We will use approved formulary medications according to their package inserts. All studies will be conducted at the Bartter Clinical Research Unit, STVHCS (Director, Salehi, PI) or Texas Diabetes Institute, UHS (Director, DeFronzo, Co-I). The SCI subjects (N=37; 18-70 yr of age, >1-year post-SCI, BMI > 22 kg/m2) with T2D treated with metformin will be enrolled and randomized after completion of baseline studies. The established SCI cohort of patients from STVHCS (N ~450) and UTHSA (N ~ 200) are available to be enrolled in the present study. Gaining insight on the safety profile and mitigatory effect of GLP-1R activation on pathogenic factors that are involved with glucose abnormalities after SCI, can facilitate the development and utilization of GLP-1R agonists and co-agonists for treatment of diabetes and obesity in this population, improving health equity.
