Efficacy and safety of once-weekly semaglutide versus daily canagliflozin as add-on to metformin in patients with type 2 diabetes (SUSTAIN 8): a double-blind, phase 3b, randomised controlled trial

Background: Existing guidelines for management of type 2 diabetes recommend a patient-centred approach to guide the choice of pharmacological agents. Although glucagon-like peptide-1 (GLP-1) receptor agonists and sodium–glucose cotransporter-2 (SGLT2) inhibitors are increasingly used as second-line agents, direct comparisons between these treatments are insufficient. In the SUSTAIN 8 trial, we compared the efficacy and safety of semaglutide (a GLP-1 receptor agonist) with canagliflozin (an SGLT2 inhibitor) in patients with type 2 diabetes. Methods: This was a double-blind, parallel-group, phase 3b, randomised controlled trial done at 111 centres in 11 countries. Eligible patients were at least 18 years old and had uncontrolled type 2 diabetes (HbA1c 7·0–10·5% [53–91 mmol/mol]) on stable daily metformin therapy. Patients were randomly assigned (1:1) by use of an interactive web response system to subcutaneous semaglutide 1·0 mg once weekly or oral canagliflozin 300 mg once daily. The primary endpoint was change from baseline in HbA1c, and the confirmatory secondary endpoint was change from baseline in bodyweight, both at week 52. The primary analysis population included all randomly assigned patients, using on-treatment data collected before initiation of rescue medication. The safety analysis was done on a population that included all patients exposed to at least one dose of trial product. The trial was powered for HbA1c and bodyweight superiority under reasonable assumptions. This trial is registered with ClinicalTrials.gov, NCT03136484. Findings: Between March 15, 2017, and Nov 16, 2018, 788 patients were randomly assigned to semaglutide 1·0 mg (394 patients) or canagliflozin 300 mg (394 patients). 739 patients completed the trial (367 in the semaglutide group and 372 in the canagliflozin group). From overall baseline mean, patients receiving semaglutide had significantly greater reductions in HbA1c and bodyweight than those receiving canagliflozin (HbA1c estimated treatment difference [ETD] −0·49 percentage points, 95% CI −0·65 to −0·33; −5·34 mmol/mol, 95% CI −7·10 to −3·57; p