Maintenance Semaglutide Keeps Shedding the Pounds

Sticking with weekly semaglutide injections resulted in continued weight loss for adults with overweight and obesity, according to the Semaglutide Treatment Effect in People with Obesity (STEP) 4 study.

In this 68-week, randomized double-blind trial among adults with obesity but free of diabetes, mean weight loss for those on 2.4 mg semaglutide totalled 17.8 kg (39.2 lb), with 7.1 kg (15.6 lb) of that loss coming after participants had already been on the drug for 20 weeks, reported Domenica Rubino, MD, of the Washington Center for Weight Management and Research in Arlington, Virginia, and colleagues.

Similar patterns were seen for other endpoints, according to the study's presentation at the Endocrine Society's virtual ENDO 2021 meeting and simultaneously publication in JAMA.

The trial included 803 participants who all completed a 20-week run-in phase, in which they received the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide -- starting with 16 initial weeks of dose escalation until they reached 4 weeks on the full maintenance dose of 2.4 mg per week -- in conjunction with lifestyle intervention aimed around a 500-calorie-deficit diet and target of 150 minutes per week of physical activity.

All participants were 18 or older with at least one prior unsuccessful attempt to lose weight through diet. Participants had a body mass index (BMI) of 30 or higher, or a BMI of ≥27 plus at least one weight-related comorbidity including hypertension, dyslipidemia, obstructive sleep apnea, or cardiovascular disease. None of the participants had type 2 diabetes at baseline.

During these initial 20 weeks, the total cohort experienced an average loss of 10.6% of baseline body weight.

Following this, 535 participants -- who already achieved their target maintenance dose of 2.4 mg weekly -- were randomized to continue on their 2.4-mg-per-week dose of semaglutide for an additional 48 weeks. They were compared with 268 participants who were switched to placebo.

Throughout the remaining 48 weeks of the trial, those who continued on semaglutide continued to shed the pounds, losing an additional average of 7.9% of body weight. On the other hand, those who were switched to placebo saw the weight loss benefits reverse, gaining back an average of 6.9% of body weight (difference -14.8%, 95% CI -16.0 to -13.5%, P<0.001).

Those who continued on treatment also saw a slew of other benefits, including a significant drop in waist circumference (-9.7 cm, 95% CI -10.9 to -8.5 cm), systolic blood pressure (-3.9 mm Hg, 95% CI -5.8 to -2.0 mm Hg), and Short Form 36 Version 2 Health Survey, Acute Version (SF-36) physical functioning score (2.5 points, 95% CI 1.6-3.3).

As to be expected with a GLP-1 receptor agonist, about half of patients who continued on semaglutide experienced gastrointestinal adverse events versus about 26% of those on placebo. Most adverse events were mild to moderate, the most common of which included diarrhea, nausea, and constipation.

This is the fourth and final installment in the phase III STEP clinical program, building upon three previous trials. The first trial -- STEP 1, published in the New England Journal of Medicine this February -- found that patients with a BMI of 30 or higher without diabetes saw an average 14.9% loss of baseline body weight after 68 weeks of treatment.

As for the STEP 2 trial, semaglutide was also proven effective in overweight adults with type 2 diabetes, yielding an average 9.6% loss of baseline body weight after 68 weeks. And the third installment in this clinical program found that semaglutide plus intensive behavioral therapy helped adults with overweight or obesity lose an average of 16% of body weight.

Based on this clinical program, Novo Nordisk filed for FDA approval of the 2.4-mg weekly dose of semaglutide, seeking an indication for chronic weight management in December 2020.

Semaglutide is already available in a 0.5-mg and 1-mg injectable dose sold under the trade name Ozempic, which is indicated for type 2 diabetes and risk reduction of major cardiovascular events, including heart attack, stroke, and death, in adults with type 2 diabetes with known heart disease, which was first approved in December 2017. And in September 2019, an oral form of semaglutide was approved in 7-mg and 14-mg tablets, sold under the trade name Rybelsus, likewise indicated for type 2 diabetes.

Novo Nordisk also holds approval for liraglutide, another GLP-1 receptor agonist, sold under the trade name Victoza (1.2 or 1.8 mg/day) indicated for type 2 diabetes. Following this initial approval in 2010, liraglutide was later approved under the name Saxenda (3 mg/day) in 2014 for chronic weight management in adults with a BMI of 30 or higher, or a BMI of 27 or higher and at least one weight-related medical condition.

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