Trial of Semaglutide for Diabetic Kidney Disease in Type 1 Diabetes

Inclusion Criteria:

• Adults (≥18 years) with type 1 diabetes

• Diabetes duration of ≥5 years

• Persistent urine albumin-to-creatinine ratio (UACR) ≥ 30 mg/g, on the most recenttwo measurements within the prior 3 years

• Estimated glomerular filtration rate ≥ 45 mL/min/1.73m2

• Stable doses of drugs altering blood pressure (e.g., Angiotensin-converting enzymeinhibitor) required for at least 4 weeks prior to randomization, and requested forthe duration of the trial

• Stable doses of lipid-lowering medications required for at least 4 weeks prior torandomization, and requested for the duration of the trial

• Adequate contraceptive method for females of child-bearing potential

Exclusion Criteria:

• HbA1c >9%, recent diabetic ketoacidosis, hyperosmolar hyperglycemic state or severeillness requiring hospitalization in past 30 days

• Other causes of diabetes mellitus, including type 2 diabetes and maturity-onsetdiabetes of the young (MODY)

• Chronic kidney disease unrelated to diabetes

• Personal or family history of medullary thyroid carcinoma or Multiple EndocrineNeoplasia syndrome type 2 (MEN 2) or thyroid nodule palpated by endocrinologist atscreening

• Personal history of pancreatitis

• Current/planned pregnancy or nursing

• Uncontrolled thyroid disease or hypertension (Systolic blood pressure [SBP] ≥ 160 mmHg or diastolic blood pressure [DBP] ≥ 100 mm Hg despite treatment)

• Proliferative retinopathy with treatment in the past 6 months

• Uncontrolled or potentially unstable diabetic retinopathy or maculopathy, verifiedby fundus examination with pupil dilation unless performed using a digital fundusphotography camera specified for non-dilated examination

• More than 2 severe hypoglycemic episodes (requiring glucagon and/or assistance fromanother person) in the past 6 months

• Frequent hypoglycemia during the last two weeks of the study run-in phase (timebelow range [<70 mg/dL] ≥4%)

• Pramlintide and the use of glycemia treatments not approved for type 1 diabetes bythe FDA, e.g., metformin, SGT-2 inhibitor, GLP-1 receptor agonist, closed loopinsulin delivery using unapproved algorithms

• Significant systemic conditions or treatment such as cancer or immunomodulators

• Known liver disease other than non-alcoholic fatty liver disease (NAFLD) oraspartate aminotransferase (AST) or alanine aminotransferase (ALT) >100 IU/L,history of severe gastrointestinal disease (e.g., gastroparesis) or gallstones

• Body mass index <20 kg/m2

• Inability to cooperate with or clinical contraindication for magnetic resonanceimaging including severe claustrophobia, nonremovable devices, implanted metal

• Known or suspected allergy/sensitivity to semaglutide or its excipients

• Pregnant, breast feeding, or the intention of becoming pregnant

• The receipt of any investigational drug within 3 months prior to this trial

• Previously randomized in this trial