Long-term Semaglutide Leads to Continued Weight Loss Versus Placebo

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Patients who continued taking semaglutide (Rybelsus/Novo Nordisk) after an initial 20-week therapy period saw continued weight loss, leading to the hope that a new pharmacologic approach to weight loss could be on the horizon.

Continuation of semaglutide (Rybelsus/Novo Nordisk) after 20 weeks of initial therapy leads to significant continued weight loss, according to a new study, but stopping the therapy causes patients to regain much of the weight they initially lost.

Semaglutide, sold under the brand name Rybelsus, is approved to help boost glycemic control in patients with type 2 diabetes, leading to weight loss. A glucagon-like peptide 1 (GLP-1) receptor agonist, the therapy has been associated with weight loss, which is believed to be due to appetite control. In type 2 diabetes, it is generally prescribed at a dose of 1.0 mg per week or less.

Corresponding author Domenica Rubino, MD, of the Washington Center for Weight Management and Research, in Virginia, and colleagues, noted that a higher Rybelsus dose of 2.4 mg per week is currently being investigated for the treatment of overweight and obese patients. The higher dose is based on a phase 2 trial, in which daily 0.4 mg doses led to greater weight loss than current approved therapies.

In the new report, Rubino and colleagues sought to find out what would happen when patients were treated with a more convenient weekly dose of the drug for 20 weeks and then either kept on the therapy or switched to placebo. Patients in the trial were given escalating doses over 16 weeks and then were left at the maintenance dose for either another 48 weeks (in the continued therapy group) or 4 weeks followed by a switch to placebo.

The investigators recruited 902 participants, all of whom were at least 18 years old and reported unsuccessful efforts to lose weight by dieting. The patients each had a body mass index (BMI) of at least 30 or a BMI of at least 27 with at least 1 weight-related comorbidity, such as hypertension or obstructive sleep apnea).

Of those recruited, 803 participants completed the 20 weeks of therapy and had a mean weight loss of 10.6%. The patients were randomized at a 2:1 ratio, with 535 patients continuing with another 48 weeks of semaglutide therapy, and the remaining 268 given placebo. Both groups were also treated with lifestyle interventions.

In the continued therapy group, patients saw continued weight loss, with a mean body weight change between week 20 and week 68 of -7.9%. However, those who were switched to placebo saw an average weight gain of 6.9%. Other measures showed similar results: waist circumference, systolic blood pressure, and 36-Item Short Form Survey physical functioning scores all improved for patients who received continued therapy versus placebo.

“The sustained effects of semaglutide on body weight and cardiometabolic risk factors, as well as participants’ physical and mental functioning, indicate the potential positive effects on such obesity-related complications,” Rubino and colleagues wrote.

About half of the patients in the semaglutide group (49.1%) reported gastrointestinal events, compared with 26.1% in the placebo group, but both groups had similar rates of discontinuation due to adverse events 2.4% for the semaglutide group and 2.2% in the placebo group.

The investigators noted that weight loss was broad across the study participants. Four in 10 patients in the semaglutide continuation group lost an additional 10% of body weight on top of what they lost in the initial 20 weeks. And nearly two-thirds of patients (64%) lost at least 15% of their body weight over the course of the trial. They said these results compare favorably to many currently available pharmacotherapies.

“Given the modest efficacy of currently approved pharmacotherapies, semaglutide may offer the potential to bridge the gap between behavioral and pharmacological options and bariatric surgery, which is currently considered the most effective and reliable intervention for weight management,” the authors said.

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