Alleviating carbohydrate counting in adults with type 1 diabetes with weekly Semaglutide injections added to an automated insulin delivery with Lyumjev - Project summary/Abstract One of the main challenges in maintaining tight glucose control in individuals with type 1 diabetes (T1D) occurs at mealtimes. Current intensive insulin therapy in T1D involves prandial insulin boluses dependent on the carbohydrate content of the ingested meal. However, accurate carbohydrate counting is a challenging and burdensome task for many individuals with T1D. In this proposal, we aim to simplify mealtime diabetes management with a combination of glucose- lowering drugs and our automated insulin delivery (AID) system using Lyumjev. Glucagon-Like-Peptide-1 is a hormone released by gut endocrine cells in response to glucose consumption. Exogenous GLP-1 receptor agonists (GLP-1 RAs) have been developed to decrease fasting and postprandial blood glucose by (i) increasing insulin secretion, (ii) decreasing glucagon secretion, (iii) slowing gastric emptying, and (iv) reducing appetite by stimulating satiety brain centers. Randomized controlled trials in type 2 diabetes have shown that GLP-1 RAs improve glucose control without increasing hypoglycemia, and recent data in type 1 diabetes have also shown promising results. Lyumjev is a novel ultra-rapid insulin lispro formulation with a faster onset of insulin action compared to the conventional insulin lispro – Humalog. Delivering Lyumjev at mealtimes significantly lowers postprandial glucose levels and reduces post-meal incremental area under the curve compared to Humalog. We aim to conduct a 2 × 2 factorial, randomized, placebo-controlled, double-blind, crossover trial to assess if the addition of Semaglutide to an AID system with Lyumjev can alleviate the burden of carbohydrate counting, without degrading daytime glucose control in 26 adults with T1D. The study will consist of 4 interventions, each 4-weeks in length, testing Semaglutide-plus-lyumjev with (i) a system that requires carb counting (AID-count) and (ii) a system that requires meal announcement only (AID-announce), as well as placebo-plus-lyumjev with (iii) AID-count and (iv) AID-announce. The order of the of the drug sequence (Semaglutide vs placebo) will be randomized 1:1. Within each drug sequence, the order of the AID configuration will also be randomized 1:1. At the start of each drug sequence, 12-week dose titration period will be initiated. A 2-week washout period will be applied between the drug sequences. The primary outcome is the daytime (6:00-24:00) percentage of time spent in the target glucose range (TIR), defined as 70-180mg/dL, over 4 weeks between sema-plus-lyumjev-AID-announce and placebo-plus- lyumjev-AID-count (control arm). We hypothesize that sema-plus-lyumjev-AID-announce will achieve non-inferior daytime TIR compared to the control arm. Page 1 of 1