SUSTAIN 7 publishes: semaglutide beats dulaglutide head to head

A head-to-head trial comparing two once-weekly GLP-1 drugs was published on Feb. 1, 2018, in The Lancet Diabetes & Endocrinology ^[1]. In SUSTAIN 7, semaglutide beat dulaglutide on both blood sugar control and weight loss at low and high doses in adults with type 2 diabetes ^[2].

The trial enrolled 1,201 patients at 194 hospitals, clinics and private practices across 16 countries between Jan. 6, 2016, and June 22, 2016 ^[2]. Participants were 18 or older, had type 2 diabetes with an A1C of 7.0% to 10.5% (53.0 to 91.0 mmol/mol), and were taking metformin alone ^[2]. They were randomly assigned in equal groups to weekly injections of semaglutide 0.5 mg (301 patients), dulaglutide 0.75 mg (299), semaglutide 1.0 mg (300), or dulaglutide 1.5 mg (299) ^[2]. The study was open-label, meaning patients and doctors knew which drug was given ^[2]. Novo Nordisk, which makes semaglutide, funded the trial ^[2].

What the numbers showed

At week 40, the higher doses produced the headline comparison: A1C fell 1.8 percentage points with semaglutide 1.0 mg versus 1.4 percentage points with dulaglutide 1.5 mg, an estimated treatment difference of -0.41 percentage points (95% CI -0.57 to -0.25; p<0.0001) ^[2]. At the lower doses, A1C fell 1.5 points with semaglutide 0.5 mg versus 1.1 points with dulaglutide 0.75 mg (difference -0.40 points; 95% CI -0.55 to -0.25; p<0.0001) ^[2].

Weight results favored semaglutide by a wider relative margin. Body weight dropped 6.5 kg (about 14 pounds) with semaglutide 1.0 mg compared with 3.0 kg with dulaglutide 1.5 mg, a difference of -3.55 kg (95% CI -4.32 to -2.78; p<0.0001) ^[2]. At the lower doses, the drops were 4.6 kg versus 2.3 kg, a difference of -2.26 kg (95% CI -3.02 to -1.51; p<0.0001) ^[2]. The trial was designed to test whether semaglutide was non-inferior on A1C, using a 0.4% margin, and superior on weight ^[2].

Side effects looked broadly similar between the drugs. Gastrointestinal problems were the most common adverse events, reported by 129 of 301 patients (43%) on semaglutide 0.5 mg, 133 of 300 (44%) on semaglutide 1.0 mg, 100 of 299 (33%) on dulaglutide 0.75 mg, and 143 of 299 (48%) on dulaglutide 1.5 mg ^[2]. Stomach and bowel problems were also the leading reason people stopped either drug ^[2]. Overall, 72 patients (6%) withdrew from the trial, and there were six deaths — one in each semaglutide group and two in each dulaglutide group ^[2]. The authors concluded that semaglutide was superior to dulaglutide at both dose levels for glucose control and weight, "with a similar safety profile" ^[2].

Why it matters for patients

Until SUSTAIN 7, most GLP-1 trials compared a drug against placebo or against older diabetes medicines, which made it hard to judge one weekly injection against another. This trial put two weekly GLP-1 drugs side by side in the same patients, on the same background metformin, for the same 40 weeks ^[2].

The practical takeaway is that the two drugs are not interchangeable in terms of average effect. A difference of roughly 0.4 percentage points in A1C and about 3.5 kg in weight at the higher doses is the kind of gap that can determine whether someone reaches a treatment target ^[2]. The published interpretation says the larger effects let "a significantly greater number of patients" hit clinically meaningful glucose and weight goals ^[2].

Several things the trial does not answer are worth flagging. It ran 40 weeks, so longer-term durability is not addressed here ^[2]. It was open-label, not blinded, which can influence reported outcomes ^[2]. It enrolled people with type 2 diabetes on metformin, not people without diabetes seeking weight loss ^[2]. And it was not designed to compare heart attacks, strokes or other cardiovascular outcomes. Costs, insurance coverage and US availability are not covered in the published trial report.

The journal ran an accompanying commentary titled "Once-weekly GLP-1R agonists: moving the goal posts," published in the April 2018 issue ^[2] — a sign that the field saw these results as raising the bar for what a weekly GLP-1 injection is expected to deliver.