Nature Medicine: Published on November, 2022

Obesity is a chronic, relapsing disease with a substantial morbidity, mortality, and healthcare burden. Drug interventions for the treatment of obesity provide a potential valuable adjunct to lifestyle interventions, which often achieve only limited weight loss that is difficult to maintain.

Semaglutide, a glucagon-like peptide-1 analog, is an antidiabetic medication that is approved for chronic weight management in adults with obesity or overweight with at least one weight-related condition based on results from the Semaglutide Treatment Effect in People with Obesity (STEP) clinical trial program.

Previous studies in the STEP trial program have been limited to treatment periods of up to just over a year at 68 weeks.

The present study, the 2-year STEP 5 trial, was a phase IIIb trial that was conducted to evaluate the long-term effect of once-weekly subcutaneous administration of 2.4-mg semaglutide, compared with placebo, as an adjunct to lifestyle interventions on body weight and cardiometabolic risk factors in adults with obesity (BMI ≥ 30 kg/m²) or with overweight (BMI ≥ 27 kg/m²) and at least one weight-related comorbidity, without diabetes. 

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This placebo-controlled randomized trial investigated the efficacy and safety of once-weekly subcutaneous semaglutide administration as long-term treatment in adults with obesity or in those who are overweight with at least one weight-related comorbidity (excluding diabetes).

The investigators found that once-weekly injections of 2.4-mg semaglutide led to an initial reduction in weight that plateaued after approximately week 60 and was maintained until the end of the study at week 104 (2 years), with a 15.2% mean weight loss from baseline with semaglutide compared with a 2.6% weight loss with placebo.

With respect to cardiometabolic risk factors, semaglutide treatment improved a range of parameters, including waist circumference, blood pressure, HbA1c levels, and lipid levels, as well as reducing fasting insulin and glucose, which may represent an increase in insulin sensitivity. Safety and tolerability were consistent with adverse events seen with this drug class, with no new safety signals.

At 104 weeks, treatment with semaglutide was associated achieving weight loss ≥5% from baseline compared with placebo. Weight loss of ≥5%, a threshold widely used to indicate a clinically meaningful response to therapy, was achieved by >75% of participants in the semaglutide group at week 104.

Moreover, 61.8% of participants on semaglutide lost ≥10% of baseline weight, and over a third of participants had achieved at least 20% weight loss at week 104 in the semaglutide group. 

However, mild to moderate gastrointestinal adverse events were more frequent with semaglutide.

Thus, study findings indicate that the substantial weight losses reported during 68 weeks’ treatment with Subcutaneous Semaglutide 2.4 mg in prior STEP trials can be maintained with continued semaglutide treatment up to at least 104 weeks. 

This study suggests that semaglutide is a safe and effective treatment for patients who are overweight and obese, promoting sustained weight loss over a 2-year period.

In conclusion, treatment with once-weekly subcutaneous semaglutide in conjunction with behavioral intervention in adults with overweight (with at least one weight-related comorbidity) or obesity (without diabetes) was associated with clinically impactful and sustained weight loss of 15.2% at week 104, along with improvements in weight-related cardiometabolic risk factors.