Efficacy of REducing cardiometabolic risk with SEmaglutide in Type 1 diabetes

INTERVENTION: Subcutaneous injection semaglutide, self‐administered according to the following dose titration schedule: 0.25mg weekly for 4 weeks, 0.5mg weekly for 4 weeks, then 1mg weekly (or maximum tolerated dose). Total duration post initiation of treatment 26 weeks (18 weeks at 1mg or maximum tolerated dose). CONDITION: Cardiovascular ‐ Coronary heart disease Metabolic and Endocrine ‐ Diabetes type 1 diabetes; ; type 1 diabetes PRIMARY OUTCOME: Change in arterial stiffness[Carotid femoral pulse wave velocity using applanation tonometry of carotid artery and thigh cuff baseline, 13 weeks and 26 weeks post initiation of treatment (primary endpoint), 12 weeks post cessation of treatment] SECONDARY OUTCOME: Change in % time above range[Percentage of time that glucose is greater than 10.0 mmol/L, as measured by continuous glucose monitor Baseline and 26 weeks post initiation of treatment] Change in % time below range[Percentage of time that glucose is less than 3.9 mmol/L, as measured by continuous glucose monitor Baseline and 26 weeks post initiation of treatment] Change in % time in range[Percentage of time that glucose is between 3.9‐10.0 mmol/L, as measured by continuous glucose monitor Baseline and 26 weeks post initiation of treatment] Change in % time in tighter range[Percentage of time that glucose is between 3.9‐7.8 mmol/L, as measured by continuous glucose monitor Baseline and 26 weeks post initiation of treatment] Change in adiponectin[serum assay Baseline and 26 weeks post initiation of treatment] Change in arterial stiffness[Augmentation inde Xmeasured by radial artery applanation tonometry Baseline and 26 weeks post initiation of treatment] Change in basal insulin dose[Review of insulin diary or insulin pump output Baseline and 26 weeks post initiation of treatment] Change in blood pressure[Digital sphygmomanometer Baseline and 26 weeks post initiation of treatment] Change in bolus insulin dose[Review of insulin diary or insulin pump output Baseline and 26 weeks post initiation of treatment] Change in C peptide[serum assay Baseline and 26 weeks post initiation of treatment] Change in energy expenditure[Indirect calorimetry Baseline and 26 weeks post initiation of treatment] Change in fasting free fatty acid profile[serum assay Baseline and 26 weeks post initiation of treatment] Change in fasting lipid profile [serum assay Baseline and 26 weeks post initiation of treatment] Change in fat free mass[dual x‐ray absorptiometry (DXA) Baseline and 26 weeks post initiation of treatment] Change in glucagon[serum assay Baseline and 26 weeks post initiation of treatment] Change in glycaemic variability[Continuous glucose monitoring Baseline and 26 weeks post initiation of treatment] Change in growth differentiation factor 15 (GDF‐15)[serum assay Baseline and 26 weeks post initiation of treatment] Change in HbA1c[serum assay Baseline and 26 weeks post initiation of treatment] Change in heart rate[Digital sphygmomanometer Baseline and 26 weeks post initiation of treatment] Change in hepatic steatosis[controlled attenuation parameter measured using transient elastography (Fibroscan) Baseline and 26 weeks post initiation of treatment] Change in high sensitivity C‐reactive protein (hsCRP)[serum assay Baseline and 26 weeks post initiation of treatment] Change in insulin sensitivity[glucose infusion rate during hyperinsulinaemic‐euglycaemic clamp Baseline and 26 weeks post initiation of treatment] Change in time below 3.0 mmol/L[Percentage of time that glucose is less than 3.0 mmol/L, as measured by continuous glucose monitor Baseline and 26 weeks post initiation of treatment] Change in total daily insulin dose[Review of insulin diary or insulin pump output Baseline and 26 weeks post initiation of treatment] Change in total fat mass[dual x‐ray absorptiometry (DXA) Baseline and 26 weeks post initiation of treatment] Change in vascular inflammation[soluble intercellular adhesion molecule‐1 (sICAM‐1), soluble E‐selectin (sE‐selectin), interleukin 6 (IL‐6) via serum assay Baseline and 26 weeks post initiation of treatment] Change in visceral adipose tissue[dual x‐ray absorptiometry (DXA) Baseline and 26 weeks post initiation of treatment] Change in waist circumference[tape measure (cm) Baseline and 26 weeks post initiation of treatment] Change in waist:hip ratio[tape measure (cm) Baseline and 26 weeks post initiation of treatment] Change in weight[Digital scales (kg) Baseline and 26 weeks post initiation of treatment] Mean 24‐hour glucose[Measured by continuous glucose monitor Baseline and 26 weeks post initiation of treatment] Mean daytime glucose[Measured by continuous glucose monitor (6.00am to midnight) Baseline and 26 weeks post initiation of treatment] Mean overnight glucose[Measured by continuous glucose monitor (midnight to 6.00am) Baseline and 26 weeks post initiation of treatment] INCLUSION CRITERIA: Main study: 1. type 1 diabetes of greater than or equal to 2 years duration 2. body mass inde Xgreater than or equal to 25 kg/m2 3. HbA1c greater than or equal to 7.0% 4. at least one cardiovascular risk factor: ‐ history of microalbuminuria [urinary albumin:creatinine ratio greater than 2.5 mg/mmol for males, greater than 3.5 mg/mmol for females] ‐ hypertension [Blood pressure (BP) greater than 140/90mmHg] or anti‐hypertensive treatment ‐ hyperlipidemia [Total Cholesterol(TC):High Density Lipoprotein (HDL) ratio greater than 6] or lipid lowering therapy ‐ current smoking Sub‐study (Pancreatic hormones and carotid femoral pulse wave velocity only in people without diabetes to provide comparative data for baseline measures in type 1 diabetes group): 1. body mass inde Xgreater than or equal to 25 kg/m2