Weekly semaglutide lowered HbA1c and weight in first phase 3 trial

The first phase 3 trial results for injectable semaglutide showed that a once-weekly shot lowered blood sugar and body weight in adults with type 2 diabetes who were not taking other diabetes medicines, according to a randomized, double-blind, placebo-controlled study called SUSTAIN 1 ^[1].

The trial enrolled 388 people at 72 sites in Canada, Italy, Japan, Mexico, Russia, South Africa, the United Kingdom and the United States ^[1]. Participants were 18 or older, had been managing their diabetes with diet and exercise alone for at least 30 days before screening, and had a baseline HbA1c between 7.0% and 10.0% ^[1]. They were assigned in a 2:2:1:1 ratio to semaglutide 0.5 mg, semaglutide 1.0 mg, or a matching placebo, injected under the skin once a week for 30 weeks using prefilled pens; participants gave themselves the injections ^[1]. Enrollment ran from February 3, 2014, to August 21, 2014, and 387 of the 388 people assigned to a group received at least one dose ^[1].

Mean HbA1c at the start was 8.05% ^[1]. At week 30, it had fallen by 1.45 percentage points (95% CI -1.65 to -1.26) with the 0.5 mg dose and by 1.55 points (95% CI -1.74 to -1.36) with the 1.0 mg dose, while the placebo group fell 0.02 points, a change the study called non-significant ^[1]. The estimated difference from placebo was 1.43 points for the lower dose and 1.53 points for the higher dose, both with p<0.0001 ^[1].

Mean starting body weight was 91.93 kg ^[1]. At week 30, weight had dropped by an average of 3.73 kg (95% CI -4.54 to -2.91) with 0.5 mg and 4.53 kg (95% CI -5.34 to -3.72) with 1.0 mg, compared with 0.98 kg in the placebo group, which the study also called non-significant ^[1].

No deaths were reported in any group, and most side effects were mild or moderate ^[1]. Nausea was the most common complaint, reported by 26 people (20%) on 0.5 mg, 31 (24%) on 1.0 mg and 10 (8%) on placebo; diarrhea was reported by 16 (13%), 14 (11%) and three (2%) ^[1]. Seventeen people (13%) on 0.5 mg, 16 (12%) on 1.0 mg and 14 (11%) on placebo stopped treatment, with gastrointestinal side effects such as nausea the main reason ^[1]. Novo Nordisk, the drug's manufacturer, funded the study, which was registered as NCT02054897 ^[1]. The authors concluded that semaglutide significantly improved HbA1c and body weight compared with placebo and showed a safety profile similar to currently available GLP-1 receptor agonists ^[1]. A commentary published alongside the trial called semaglutide "a promising new glucagon-like peptide-1 receptor agonist" ^[1].

Why it matters for patients

These results describe a narrow group: adults whose type 2 diabetes was not controlled by diet and exercise and who were taking no other diabetes medication ^[1]. The trial does not show how semaglutide performs in people already taking metformin, insulin or other drugs, because those patients were not studied here ^[1].

The treatment tested was a self-administered weekly injection, which the trial ran for 30 weeks; effects beyond that period were not reported ^[1]. The comparison to existing GLP-1 drugs was the authors' assessment rather than a head-to-head test, since the trial compared semaglutide only with placebo ^[1].

Gastrointestinal side effects were common and were the leading reason participants quit, and rates of nausea and diarrhea were roughly two to three times higher on semaglutide than on placebo ^[1]. The average weight changes are averages, so individual results varied, and the trial did not measure effects on heart attacks, strokes or kidney disease ^[1]. Sustained weight loss and long-term safety data are not available from this 30-week study.

What happens next

At the time of publication in January 2017, semaglutide was still in phase 3 development for type 2 diabetes ^[1]. The report does not say when the manufacturer planned to seek regulatory review or how long regulators might take to decide ^[1].