Glucagon-like peptide receptor (GLP-1R) agonists are an established treatment option for type 2 diabetes. In addition to their blood glucose lowering effect (with a low risk of hypoglycaemia) they also promote weight loss. With the approval of liraglutide 3.0 mg/wk last year, a GLP-1R agonist is now also available for the treatment of obesity.
SUSTAIN 7 was an open-label, parallel-group, phase 3b trial at 194 sites in 16 countries investigating GLP-1R agonists semaglutide and dulaglutide [1]. Participants were 18 years and older and had type 2 diabetes with an HbA1c of 7.0-10.5% on metformin therapy (n=1201). Patients were assigned to either semaglutide 0.5 mg, dulaglutide 0.75 mg, semaglutide 1.0 mg or dulaglutide 1.5 mg. The study medication was injected once weekly for 40 weeks. Primary endpoint was change from baseline in HbA1c; the confirmatory secondary endpoint was change in bodyweight, both after 40 weeks of treatment.
Semaglutide was superior to dulaglutide in reducing HbA1c at both dose levels. HbA1c was reduced by 1.5% (SE 0.06) with semaglutide 0.5 mg versus 1.1 % (0.05) with dulaglutide 0.75 mg (estimated treatment difference –0·40 % [95% CI –0·55 to –0·25]; p<0·0001) and by 1.8 (0.06) % with semaglutide 1.0 mg versus 1.4 (0.06) with dulaglutide 1.5 mg (estimated treatment difference –0.41 % [–0.57 to –0.25]; p<0.0001). Accordingly, a significant greater amount of patients on semaglutide treatment achieved their recommended HbA1c target levels.
Most remarkably, semaglutide was also twice as effective in lowering mean body weight as dulaglutide. Mean bodyweight was reduced by 4.6 kg (SE 0.28) with semaglutide 0.5 mg compared with 2.3 kg (0.27) with dulaglutide 0.75 mg (estimated treatment difference –2.26 kg [–3.02 to –1.51]; p<0.0001) and by 6.5 kg (0.28) with semaglutide 1.0 mg compared with 3.0 kg (0.27) with dulaglutide 1.5 mg (estimated treatment difference –3.55 kg [–4.32 to –2.78]; p<0.0001). In line with this, twice as many semaglutide-treated patients achieved clinically relevant weight loss of more than 5% as did the dulaglutide-treated patients. Given that this was not actually a trial designed to maximise weight loss, these changes in body weight are certainly quite impressive.
The overall safety profile of semaglutide and dulaglutide was similar. Adverse events occurred in 68% of the semaglutide 0.5 mg group, 62% of the dulaglutide 0.75 mg group, 69% of the semaglutide 1.0 mg group and 74% of the dulaglutide 1.5 mg group. Gastrointestinal disorders were the most frequent adverse events reported.
These findings establish semaglutide as the first-in-class once weekly GLP-1R agonist.