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 (SUSTAIN OPTIMIZE).

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) versus dose-titrated IGlar (IGlar) on glycated haemoglobin (HbA), 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), and treatment with basal insulin ≤ 40 units/day were randomised 1:1 into Sema+IGlar or IGlar. The primary endpoint was change in HbA using a non-inferiority approach. Secondary endpoints assessed superiority of Sema+IGlar versus IGlar in reducing HbA, BW, daily insulin dose, and improving Diabetes Treatment Satisfaction Questionnaire change version (DTSQc) scores. RESULTS: Overall, 573 participants were randomised. Sema+IGlar achieved both non-inferiority and superiority versus IGlar in HbA reduction (estimated treatment difference [ETD]: -0.74%; 95% confidence interval [CI]: -0.90, -0.59) and superiority in BW change (ETD: -8.5 kg; CI: -9.5, -7.4), relative daily insulin dose change (ETD: -121.9%; CI: -143.1, -100.6), and DTSQc scores (ETD: 2.6; CI: 1.6, 3.5) (p < 0.0001 for all endpoints). No new safety concerns were identified. Severe hypoglycaemia was reduced (rate ratio: 0.45; CI: 0.23, 0.87; p = 0.02), while gastrointestinal events were higher for Sema+IGlar (310 vs. 32 events). CONCLUSIONS: Once-weekly subcutaneous semaglutide 2.0 mg as add-on to dose-reduced IGlar achieved superior reductions in HbA, BW, and daily insulin dose in people with T2D and overweight, while reducing their risk for severe hypoglycaemia compared to dose-titrated IGlar alone.