Efficacy and Safety of Once‐Weekly Semaglutide 2.0 mg as an Add‐On to Dose‐Reduced Insulin Glargine versus Dose‐Titrated Insulin Glargine in People With Type 2 Diabetes and Overweight ( <scp>SUSTAIN OPTIMIZE</scp> )

ABSTRACT Aims Type 2 diabetes (T2D) management with basal insulin can lead to hypoglycaemia and weight gain. SUSTAIN OPTIMIZE compared once‐weekly semaglutide 2.0 mg as add‐on to dose‐reduced insulin glargine (Sema+IGlar reduced ) versus dose‐titrated IGlar (IGlar titrated ) on glycated haemoglobin (HbA 1c ), body weight (BW), daily insulin dose, and participant satisfaction. Materials and Methods SUSTAIN OPTIMIZE was a 40‐week, phase 3b, open‐label, randomised study. Adults with T2D, overweight (body mass index ≥ 25 kg/m 2 ), and treatment with basal insulin ≤ 40 units/day were randomised 1:1 into Sema+IGlar reduced or IGlar titrated . The primary endpoint was change in HbA 1c using a non‐inferiority approach. Secondary endpoints assessed superiority of Sema+IGlar reduced versus IGlar titrated in reducing HbA 1c , BW, daily insulin dose, and improving Diabetes Treatment Satisfaction Questionnaire change version (DTSQc) scores. Results Overall, 573 participants were randomised. Sema+IGlar reduced achieved both non‐inferiority and superiority versus IGlar titrated in HbA 1c reduction (estimated treatment difference [ETD]: −0.74%; 95% confidence interval [CI 95 ]: −0.90, −0.59) and superiority in BW change (ETD: −8.5 kg; CI 95 : −9.5, −7.4), relative daily insulin dose change (ETD: −121.9%; CI 95 : −143.1, −100.6), and DTSQc scores (ETD: 2.6; CI 95 : 1.6, 3.5) ( p &lt; 0.0001 for all endpoints). No new safety concerns were identified. Severe hypoglycaemia was reduced (rate ratio: 0.45; CI 95 : 0.23, 0.87; p = 0.02), while gastrointestinal events were higher for Sema+IGlar reduced (310 vs. 32 events). Conclusions Once‐weekly subcutaneous semaglutide 2.0 mg as add‐on to dose‐reduced IGlar achieved superior reductions in HbA 1c , BW, and daily insulin dose in people with T2D and overweight, while reducing their risk for severe hypoglycaemia compared to dose‐titrated IGlar alone.