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In conjunction with lifestyle management, once-weekly semaglutide helped people with obesity lose a significant amount of weight, the found.

In a double-blind trial of 1,961 adults with a body mass index (BMI) of 30 or higher, adults on 2.4 mg of weekly semaglutide lost an average 14.9% of baseline body weight after 68 weeks of treatment versus only 2.4% for a group on placebo and lifestyle intervention alone (treatment difference -12.4%, 95% CI -13.4 to -11.5, P<0.001), reported Robert Kushner, MD, of Northwestern University Feinberg School of Medicine in Chicago, and colleagues.

A total of 86.4% of adults on semaglutide were able to cut at least 5% of their baseline body weight during the trial compared with only 31.5% of those adhering to lifestyle intervention alone, the researchers wrote in the study online in the .

Beyond that, almost 70% of those on semaglutide plus lifestyle intervention achieved a 10% or more weight loss, and more than half were able to lose 15% of their baseline body weight.

In total, adults on semaglutide treatment lost an average 33.7 lb (15.3 kg) by week 68, while those in the placebo/lifestyle intervention group saw only a modest 5.7 lb (2.6 kg) weight loss (estimated treatment difference -30 lb [-12.7 kg], 95% CI -13.7 to -11.7).

Within only the first 4 weeks of treatment initiation, those on semaglutide had more than a 2% reduction in body weight, and continued to lose weight throughout the 68-week trial.

In addition to weight loss, semaglutide also improved cardiovascular risk factors including greater reductions in waist circumference, BMI, systolic and diastolic blood pressures, HbA1c, fasting plasma glucose, C-reactive protein, and fasting lipid levels, as well as physical functioning scores and quality of life.

"I was surprised and gratified to see the unprecedented results from the medication," Kushner told 番茄社区. "The fact that 50% of participants were able to lose at least 15% of initial body weight and one-third lost at least 20% body weight is a game changer."

"Semaglutide is by far the most effective drug intervention we have seen for weight management," he continued. "We know that a lot of the health concerns we see in people who struggle with their weight, such as type 2 diabetes, hypertension, GERD [gastroesophageal reflux disease], and arthritis of the weight-bearing joints, are improved by losing at least 10% of their body weight. In this study, nearly 70% of participants were able to achieve this 10% weight loss threshold by taking semaglutide."

As for the next steps, Kushner said it's all about putting this into practice: "We now need to explore how to encourage and educate healthcare providers to provide obesity care in the primary care setting."

The STEP 1 trial included 1,961 adults with a BMI of 30 or greater, or those with a BMI of 27 or greater with at least one weight-related comorbidity, randomized in a 2:1 fashion. All participants were free of diabetes at baseline -- although 40% had prediabetes -- and about 75% of the cohort were female and white.

Those who received semaglutide were started on a dose of 0.25 mg once weekly for the initial 4 weeks, which was subsequently titrated up every 4 weeks until the maintenance dose of 2.4 mg was achieved by week 16.

Both study groups received individual diet-related counseling sessions every 4 weeks aimed at encouraging a 500-kcal deficit per day paired with a goal of 150 minutes of physical activity per week.

Adverse events were similar to what has already been demonstrated with semaglutide, with gastrointestinal side effects being the most common, the team said.

Overall, about 74% of those on semaglutide reported at least one gastrointestinal side effect -- mostly nausea, diarrhea, vomiting, or constipation -- versus 48% of those on placebo. About 4.5% of those on semaglutide ended up discontinuing treatment due to gastrointestinal events vs 0.8% of those on placebo.

In December 2017, the GLP-1 receptor agonist was first approved in a 0.5 mg and 1 mg injectable dosing 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. And in September 2019, an oral form of semaglutide was approved in 7 and 14 mg tablets, sold under the trade name Rybelsus, likewise indicated for type 2 diabetes.

Novo Nordisk's other GLP-1 receptor agonist agent, liraglutide -- sold under the trade name Victoza (1.2 or 1.8 mg/day) for type 2 diabetes in 2010 -- was also approved under the name Saxenda (3 mg/day) for chronic weight management in adults with a BMI of 30 or over, or with a BMI of 27 or more and at least one weight-related medical condition in 2014.

Despite the positive results, the authors of an , NEJM editors Julie Ingelfinger, MD, and Clifford Rosen, MD, called the gastrointestinal side effects concerning and noted that oral semaglutide has been associated with pancreatitis and with thyroid C-cell tumors in rodents.

"In the real world, it seems unlikely that once-weekly subcutaneous administration would be a palatable or cost-effective solution in the long run," Ingelfinger and Rosen wrote; instead, daily oral semaglutide might be a more "appealing" option to patients. They suggested that future head-to-head trials compare oral GLP-1 agonists with SGLT-2 antagonists, and also compare these pharmacologic therapies with bariatric surgery to assess long-term outcomes.

Kushner noted that the 5-year trial is currently underway, and that additional trials will explore other important questions related to semaglutide in patients with obesity.

Based on the results of the phase III STEP program, Novo Nordisk 2.4 mg semaglutide for chronic weight management.

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