Trial finds weekly semaglutide outperforms daily liraglutide on weight loss

A head-to-head trial published Jan. 11, 2022, in JAMA found that weekly semaglutide 2.4 mg produced more weight loss than daily liraglutide 3.0 mg over 68 weeks in adults with overweight or obesity who did not have diabetes ^[1][2].

The study, called STEP 8, was a phase 3b randomized clinical trial run at 19 US sites. It enrolled 338 adults between Sept. 11 and Nov. 26, 2019, and ended follow-up on May 11, 2021 ^[2][3]. Participants had a body mass index of 30 or higher, or 27 or higher with at least one weight-related condition, and none had diabetes. Their average age was 49, 78.4% were women, and their average starting weight was 104.5 kg, with an average BMI of 37.5 ^[2].

Participants were assigned in a 3:1:3:1 ratio to weekly semaglutide, matching placebo, daily liraglutide or matching placebo, each added to counseling on diet and physical activity. The two placebo groups were combined for analysis, for a total of 85 people ^[2].

Mean body weight change from baseline to week 68 was −15.8% with semaglutide versus −6.4% with liraglutide, a difference of 9.4 percentage points (95% CI, −12.0 to −6.8; P < .001). The pooled placebo group lost a mean of 1.9% ^[2].

More participants on semaglutide reached each weight-loss threshold. Of those on semaglutide, 70.9% lost at least 10% of body weight, versus 25.6% on liraglutide; 55.6% versus 12.0% lost at least 15%; and 38.5% versus 6.0% lost at least 20%. All of those differences were statistically significant ^[2].

Gastrointestinal side effects were reported by nearly the same share of people in both groups: 84.1% on semaglutide and 82.7% on liraglutide. Discontinuation was not equal, however. Of the semaglutide group, 13.5% stopped treatment for any reason, compared with 27.6% of the liraglutide group ^[2]. Overall, 319 of the 338 participants (94.4%) completed the trial and 271 (80.2%) completed treatment ^[2].

The comparison between the two active drugs was open-label, meaning participants and investigators knew which of the two they were receiving, while the comparisons against placebo were double-blinded ^[2]. The trial was funded by Novo Nordisk, which makes semaglutide, and representatives of the company were involved in the design and conduct of the study, the analysis and interpretation of data, and preparation of the manuscript ^[3].

Why it matters for patients

Both drugs are glucagon-like peptide-1 analogs available for weight management, but the trial shows they do not produce the same results, and the dosing schedules differ: semaglutide was given once a week and liraglutide once a day ^[2].

These results apply to adults with overweight or obesity who do not have diabetes. People with diabetes were excluded from the trial, so the numbers here have not been shown to carry over to them ^[2].

The discontinuation figures are a second practical difference separate from weight loss. Even though the two groups reported gastrointestinal side effects at similar rates, more than twice as many people on liraglutide stopped treatment ^[2]. The report does not break down what share of those stops were for side effects versus other reasons.

The trial compared only semaglutide and liraglutide. It does not include a comparison with other weight-management medications ^[2].

What happens next

The trial is complete and registered as NCT04074161 ^[2]. Its protocol and statistical analysis plan are published as supplements to the JAMA article ^[1]. Results beyond the 68-week treatment period for this head-to-head comparison have not been reported, and long-term outcomes such as heart health in this specific comparison have not been disclosed.