Semaglutide once weekly as add-on to SGLT-2 inhibitor therapy in type 2 diabetes (SUSTAIN 9): a randomised, placebo-controlled trial.
Level 2 - randomized trial
Individual randomized controlled trial
PubMed 30833170 · doi:10.1016/S2213-8587(19)30066-X
What was done
The SUSTAIN 9 double-blind, parallel-group, phase 3 trial evaluated the efficacy and safety of adding subcutaneous semaglutide to SGLT-2 inhibitor therapy. Adults with type 2 diabetes and HbA1c 7.0–10.0% (53–86 mmol/mol) despite at least 90 days on an SGLT-2 inhibitor across 61 centres in six countries were randomized 1:1 to once-weekly semaglutide 1.0 mg (after dose escalation of 4 weeks at 0.25 mg and 4 weeks at 0.5 mg) or volume-matched placebo for 30 weeks. Background antidiabetic medications were continued (71.5% on metformin, 12.9% on sulphonylurea). The primary outcome was change in HbA1c from baseline at week 30 in the full analysis set before rescue medication; the confirmatory secondary outcome was bodyweight change.
What was found
302 patients were randomized (full analysis set) and 301 received at least one dose. Semaglutide led to significantly greater reductions compared to placebo in HbA1c (estimated treatment difference -1.42% [95% CI -1.61 to -1.24]; -15.55 mmol/mol [-17.54 to -13.56], p<0.0001) and bodyweight (-3.81 kg [-4.70 to -2.93], p<0.0001). Adverse events occurred in 104 of 150 (69.3%) patients on semaglutide versus 91 of 151 (60.3%) on placebo, with gastrointestinal events most common (37.3% vs 13.2%). Serious adverse events occurred in 7 (4.7%) on semaglutide and 6 (4.0%) on placebo. Early discontinuation due to adverse events occurred in 13 semaglutide patients and 3 placebo patients. Severe or blood glucose-confirmed hypoglycaemia occurred in 4 semaglutide patients (2.7%). There were no deaths.
Why it matters
Combining once-weekly semaglutide with SGLT-2 inhibitor therapy produces substantial additional glycaemic and weight-loss benefits with a safety profile consistent with GLP-1 receptor agonists.
Limits
The trial had a relatively short duration (30 weeks), limiting assessment of long-term durability and clinical outcomes. The sample size was modest (n=302), and patients with baseline HbA1c outside 7.0–10.0% were excluded.
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