Alleviating Carbohydrate Counting for Patients with Type-1 Diabetes Using a Closed Loop System with Weekly Subcutaneous Semaglutide

The main questions this study aims to answer are:

• Can weekly injections of semaglutide at the maximum tolerated dose in individuals with T1D on closed-loop therapy with SMA and rapid-acting insulin result in a non-inferior time spent in target range (3.9-10 mmol/L) compared to weekly placebo injections on closed-loop system with full carbohydrate counting.
• Can weekly injections of semaglutide at the maximum tolerated dose, in combination with ultra-rapid actin insulin (Lyumjev);

• Eliminate carbohydrate counting and any meal announcement (i.e fully closed-loop) in people with T1D on closed-loop therapy without degrading glucose control.
• Be more effective in substituting carbohydrate counting with SMA in people with T1D on closed-loop therapy compared with traditional rapid-acting insulin.

Participants will be asked to undergo two subsequent blinded drug interventions; one with semaglutide and the other with placebo. Both interventions include 4 meal strategies each with a 3-week duration; full carbohydrate counting with rapid-acting insulin, SMA with rapid-acting insulin, SMA with Lyumjev and fully closed-loop system with Lyumjev.

Inclusion criteria

• At least 18 years of age
• A clinical diagnosis of T1D for at least one year, as per their treating diabetes physician in agreement with the primary investigator's clinical judgment (confirmatory C-peptide and antibodies will not be required)
• Minimum 3-month use of a commercial advanced automated insulin delivery system. 4.4. Agreement to use an effective method of birth control for individuals with child-bearing potential. Child-bearing potential refers to participants of the female sex post-menarche who have not reached menopause and who do not have a medical condition causing sterility (e.g., hysterectomy). Post-menopausal state refers to the absence of menses for 12 months without any alternative cause.

Exclusion criteria

• Use of GLP1-RAs within the last 4 weeks.
• Use of any anti-hyperglycemic agent other than insulin within the last 2 weeks.
• Planned or ongoing pregnancy
• Breastfeeding
• Severe hypoglycemic episode within the last 3 months, defined as an event where glucose was < 4 mmol/L resulting in seizure, loss of consciousness, or need to present to the emergency department
• Severe diabetic ketoacidosis (DKA) within the last 6 months ("severe" referring to need to present to medical attention and requirement of intravenous insulin)
• Prior history of acute pancreatitis, chronic pancreatitis, or gallbladder disease
• Personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2
• Severe impairment of renal function with eGFR <30 mL/min/1.73 m2 (using CKD-EPI formula), measured within the last 12 months
• Clinically significant diabetic retinopathy or gastroparesis, as per the clinical judgment of the investigator
• Bariatric surgery within the last 6 months.
• A serious medical or psychiatric illness that is likely to interfere with study participation as per the judgment of the investigator (e.g. cirrhosis, active cancer, decompensated schizophrenia).
• Body mass index ≤ 21 kg/m2
• Inability or unwillingness to comply to safe diabetes management in the view of the study group (e.g. inappropriate treatment of hypoglycemia or lack thereof)
• Concern for safety of the participant, as per the clinical judgment of the primary investigator