Semaglutide Added to Basal Insulin in Type 2 Diabetes (SUSTAIN 5): A Randomized, Controlled Trial

Helena W Rodbard, Ildiko Lingvay, John Reed, Raymond de la Rosa, Ludger Rose, Danny Sugimoto, Eiichi Araki, Pei-Ling Chu, Nelun Wijayasinghe, Paul Norwood

Combination therapy with insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) is increasingly important for treating type 2 diabetes (T2D). This trial assesses the efficacy and safety of semaglutide, a GLP-1RA, as an add-on to basal insulin. To demonstrate the superiority of semaglutide versus placebo on glycaemic control as add-on to basal insulin in patients with T2D. Phase 3a, double blind, placebo-controlled, 30-week trial. 90 sites in five countries. 397 patients with uncontrolled T2D receiving stable therapy with basal insulin ± metformin. Subcutaneous semaglutide 0.5 or 1.0 mg once weekly, or volume-matched placebo. Primary endpoint was change in glycated haemoglobin (HbA1c) from baseline to Week 30. Confirmatory secondary endpoint was change in body weight from baseline to Week 30. At Week 30, mean HbA1c reductions (mean baseline value 8.4% [67.9 mmol/mol]) with semaglutide 0.5 and 1.0 mg were 1.4% (15.8 mmol/mol) and 1.8% (20.2 mmol/mol), versus 0.1% (1.0 mmol/mol) with placebo (estimated treatment difference [ETD] [95% confidence interval (CI)] versus placebo -1.35 (14.8 mmol/mol), [-1.61; -1.10] and -1.75% (19.2 mmol/mol), [-2.01; -1.50]; both p<0.0001). Severe or blood glucose-confirmed hypoglycaemic episodes were reported in 11 patients (17 events) and 14 (25 events) patients with semaglutide 0.5 mg and 1.0 mg, respectively, versus 7 patients (13 events) with placebo (estimated rate ratios versus placebo [95% CI], 2.08 [0.67; 6.51] and 2.41 [0.84; 6.96] for 0.5 and 1.0 mg; both p=nonsignificant). Mean body weight decreased with semaglutide 0.5 and 1.0 mg, versus placebo from baseline to end-of-treatment: 3.7, 6.4 and 1.4 kg (ETD [95% CI], -2.31 [-3.33; -1.29], and -5.06 [-6.08; -4.04] kg; both p<0.0001). Premature treatment discontinuation due to adverse events were higher for semaglutide 0.5 and 1.0 mg versus placebo (4.5, 6.1 and 0.8%), mainly due to gastrointestinal disorders. Semaglutide, added to basal insulin, significantly reduced HbA1c and body weight in patients with uncontrolled T2D versus placebo.