Semaglutide: Four STEPs ahead in obesity care

With four STEP* studies published on the profound impact that semaglutide 2.4 mg confers on weight loss, these indicate GLP-1 signalling as a powerful and effective target for obesity therapy and thus, usher in a new era for obesity care, said a leading expert during the ADA 2021 session.  

“Obesity needs to be recognized as a disease in its own right, as well as a risk factor for numerous other diseases, [and] equitable access to obesity treatment needs to be broadened,” said Dr Lee M Kaplan of Massachusetts General Hospital in Boston, Massachusetts, US, who talked about the implications of the STEP trials and was not affiliated with the studies.

Once-weekly semaglutide 2.4 mg was just recently approved for weight management by the US FDA in June 2021. It was indicated as an “adjunct to diet and exercise in adults with obesity or who are overweight with at least one weight-related comorbidity”.

“It provides a new clinical opportunity for the control of obesity and its medical complications … [and] where clinically important risks — including from cardiovascular disease may be reduced,” said Kaplan.

“Phenomenal” weight loss

The excitement around semaglutide 2.4 mg in obesity care stems from its efficacy in inducing weight loss by magnitudes that have been thought unachievable with conventional noninvasive treatment.

Prior to the STEP studies, semaglutide 2.4 mg has been shown to induce weight loss that was double the extent achieved with liraglutide 3 mg in an early phase study — corresponding to approximately 10–15 percent weight loss at 68 weeks, according to Kaplan. 

Four pivotal, phase III trials under the STEP programme had been published subsequently, which involved a total of more than 4,700 patients, said STEP 1 co-author Professor Robert Kushner of Northwestern University Feinberg School of Medicine in Chicago, Illinois, US, who gave an overview of the trials.

STEP 1 investigated weight reduction, while STEP 3 added a component of intensive behavioural therapy (IBT) with low-calorie diet (LCD) and STEP 4 looked at sustained weight loss after the initial run-in period, Kushner summarized. STEP 2, on the other hand, involved specifically patients with type 2 diabetes.

In STEP 1, semaglutide 2.4 mg led to a mean weight loss of 14 percent compared with 2.4 percent reduction in the placebo group. [N Engl J Med 2021;384:989-1002]

“One-third of individuals in the trial achieved at least a 20 percent weight loss or more,” said Kushner, who called the finding “really phenomenal which we have not seen in any weight loss trial before”.

“Weight did not plateau until about 68 weeks; this is the first time we have ever seen that type of long-term weight loss in obesity trials,” he continued.

Speaking on STEP 3, Kushner said the results suggest that “semaglutide with monthly brief lifestyle counselling alone is sufficient to produce a mean weight loss of 15 percent.” [JAMA 2021;325:1403-1413]

“Addition of LCD and IBT appears to accelerate initial weight loss but does not provide additive weight loss at week 68,” he pointed out, noting that the final weight loss achieved was similar regardless of LCD and IBT.

Variability among patients

“Like other anti-obesity therapies, however, there’s large patient-to-patient variability in its effects,” said Kaplan.

“Success or failure in one patient doesn’t predict response in another, and we should always remember that as we treat different patients with these medications,” he advised.

Semaglutide induced profound weight loss in many patients: with a third of patients experiencing >20 percent weight loss, and 10 percent had >30 percent weight loss — similar to the efficacy of bariatric surgery. [N Engl J Med 2021;384:989-1002]

On the other hand, there were also some patients who failed to respond to treatment, Kaplan noted. Almost 10 percent of patients without diabetes and more than 30 percent of those with diabetes will experience <5 percent weight loss.

“We shouldn’t be dissuaded [from treating other patients] by the fact that some patients will not lose much weight with this medication,” he said.

 

 

*STEP: Semaglutide Treatment Effect in People with obesity