Another Weight-Loss Trial Win for Weekly GLP-1 Drug

When paired with lifestyle management, once-weekly semaglutide (Ozempic) yielded significant weight loss for overweight adults with type 2 diabetes, the manufacturer-sponsored Semaglutide Treatment Effect in People with Obesity (STEP) 2 study found.

In the superiority phase III trial of over 1,200 adults with a body mass index (BMI) of at least 27, those on 2.4 mg of weekly subcutaneous semaglutide lost an average of 9.6% of baseline body weight after 68 weeks of treatment versus 3.4% for those on placebo and lifestyle intervention alone (treatment difference -6.2 percentage points, 95% CI -7.3 to -5.2, P<0.0001), reported Ildiko Lingvay, MD, of the University of Texas Southwestern Medical Center in Dallas, and colleagues.

The study, published online in The Lancet, also included a third treatment group of patients who received 1.0 mg of once-weekly semaglutide -- a dose already approved for type 2 diabetes (as is a 0.5 mg dose). After 68 weeks of treatment, this group had an average reduction of 7% of baseline body weight.

By week 68, patients on 2.4 mg of weekly semaglutide had a nearly five-fold higher chance of achieving at least a 5% body weight reduction versus placebo (OR 4.88, 95% CI 3.58-6.64, P<0.0001).

In total, about 69% of those on 2.4 mg semaglutide were able to cut at least 5% of their baseline body weight -- meeting the trial's other coprimary endpoint -- compared with only 29% of those on lifestyle intervention alone. About 57% of those on the 1 mg dose achieved at least a 5% weight reduction.

Beyond weight loss benefits, those on 2.4 mg of semaglutide also saw significant improvements in waist circumference, systolic blood pressure, lipid profile, inflammatory markers, and physical functioning, the researchers reported.

In addition, not surprising, significant improvements were also seen in blood glucose, with 68% of those on the higher dose able to achieve an HbA1c of 6.5% or lower, while 79% were able to achieve a number below 7%.

These findings build upon the recently reported STEP 1 trial that tested semaglutide in a population of adults with obesity (BMI of 30+) but without type 2 diabetes.

In that similar 68-week trial, adults on 2.4 mg of weekly semaglutide lost an average 14.9% of baseline body weight versus only 2.4% for those on placebo and lifestyle intervention alone (treatment difference -12.4%, 95% CI -13.4 to -11.5, P<0.001).

"This is the first trial to show that in adults with overweight or obesity and type 2 diabetes, once a week subcutaneous semaglutide 2.4 mg produces clinically meaningful reductions in body weight," Lingvay's group wrote. "The magnitude of weight loss achieved with semaglutide 2.4 mg in STEP 2 was greater than that seen with liraglutide and other approved anti-obesity medications in similar patient populations."

Liraglutide (Saxenda) was approved in December 2014 at a 3-mg/day dose 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 an accompanying commentary, Roberto Latini, MD, and Lidia Staszewsky, MD, both of the Mario Negri Institute of Pharmacological Research IRCCS in Milan, Italy, pointed out that two major advantages of semaglutide are its once-a-week dosing -- rather than once daily with liraglutide -- and the stronger effect on weight loss.

The STEP 2 trial included 1,210 adults from 149 outpatient clinics across North America, Europe, South America, the Middle East, South Africa, and Asia. For inclusion, all participants had to have a BMI of at least 27 and an HbA1c of 7-10% with a type 2 diabetes diagnosis at least 180 days prior to screening.

However, patients on insulin were excluded, which Latini and Staszewsky called, "an issue to be considered in future studies, given the widespread use of insulin."

Participants were randomized in a 1:1:1 fashion -- 404 received 2.4 mg semaglutide, 403 on 1 mg semaglutide, and 403 on placebo.

Treatment was started on a 0.25-mg per week dose and was titrated in a fixed-dose regimen every 4 weeks until the target dose was achieved. All participants also underwent lifestyle intervention, which involved 150 minutes per week of physical exercise plus a 500-kcal deficit per day.

Adverse events in the STEP clinical program were generally in line with what has already been seen with other GLP-1 receptor agonists, with gastrointestinal side effects being the most common.

In total, about 64% of those on the higher semaglutide dose experienced gastrointestinal adverse events including nausea, vomiting, diarrhea, and constipation -- most of which were mild to moderate. About a third of patients on 1 mg semaglutide had gastrointestinal side effects.

In December 2020, Novo Nordisk filed for U.S. marketing approval for 2.4 mg semaglutide for chronic weight management for adults with obesity or overweight plus at least one weight-related comorbidity, based on the STEP program.

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