Arlington, VA—Once-weekly SC semaglutide was significantly more effective than once-daily subcutaneous liraglutide in promoting weight loss in adults with overweight or obesity—but without diabetes, according to a new study.

The report in the Journal of the American Medical Association said that participants also had counseling for diet and physical activity in the 68-week trial.

Researchers from industry and academia sought to determine the effect of once-weekly subcutaneous semaglutide 2.4 mg versus once-daily SC liraglutide 3.0 mg on weight loss in 338 participants. They determined that, mean body weight change from baseline to 68 weeks was –15.8% with semaglutide versus –6.4% with liraglutide, which they deemed a statistically significant difference.

This is the first phase III trial to compare semaglutide and liraglutide, both glucagon-like peptide-1 analogues available for weight management.

The randomized, open-label trial was conducted at 19 sites in the United States from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11). Participants were adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities; none had a diabetes diagnosis.

For the study, participants were randomized (3:1:3:1) to receive once-weekly SC semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily SC liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. The study gave an option for participants unable to tolerate 2.4 mg of semaglutide to receive 1.7 mg and for participants unable to tolerate 3.0 mg of liraglutide to discontinue treatment and could restart the 4-week titration. Placebo groups involving 85 participants were pooled.

Defined as the primary endpoint was percentage change in body weight, while confirmatory secondary endpoints were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide versus liraglutide at Week 68.

The randomized participants had a mean age of 49 years and were mostly, 78.4%, women with mean body weight of 104.5 [23.8] kg and mean body mass index of 37.5. The trial was completed by 94.4%, and 80.2% completed treatment.

Results indicate that the mean weight change from baseline was –15.8% with semaglutide versus –6.4% with liraglutide (difference, –9.4 percentage points [95% CI, –12.0 to –6.8]; P <.001); weight change with pooled placebo was –1.9%.

"Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P <.001)," researchers write.

Treatment was discontinued for any reason by 13.5% of participants taking semaglutide and 27.6% taking liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide, the authors note.

Background information in the article advises that semaglutide and liraglutide are modified, long-acting analogs of native GLP-1. Through addition of an albumin-binding C16 fatty acid side chain, liraglutide's half-life is 13 to 15 hours. Semaglutide's half-life is 165 hours, resulting from an amino acid replacement (preventing dipeptidyl peptidase 4 degradation) and a C18 fatty diacid addition.

Researchers also pointed to significantly greater improvements in several cardiometabolic risk factors.

The study notes that semaglutide and liraglutide induce weight loss by lowering energy intake. "However, the reduction in caloric intake vs placebo appears to be larger with semaglutide (35%) than liraglutide (approximately 16%)," the authors advise. "Semaglutide has also been associated with reductions in food cravings, which is less evident with liraglutide, suggesting different mechanisms of energy intake regulation. Further research is needed to investigate whether structural differences affect these mechanisms, for example, by allowing semaglutide to target a wider range of neuronal GLP-1 receptors than liraglutide."

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